Cen o Singula de in es igación en Química Biológica y
Ma e iales Molecula es
Rh(III)-ca alyzed annula ions based on C-H
ac i a ion. Sus ainable syn hesis o ca bo-
and he e ocycles.
Memo ia que, pa a op a al g ado de Doc o en Química po la
Uni e sidad de San iago de Compos ela, p esen a
And és Seoane Fe nández
San iago de Compos ela, ab il 2016
D. JOSÉ LUIS MASCAREÑAS CID, CATEDRÁTICO DEL DEPARTAMENTO DE QUÍMICA
ORGÁNICA DE LA UNIVERSIDAD DE SANTIAGO DE COMPOSTELA Y D. MOISÉS
GULÍAS COSTA, PROFESOR AYUDANTE DOCTOR DEL DEPARTAMENTO DE
QUÍMICA ORGÁNICA DE LA UNIVERSIDAD DE SANTIAGO DE COMPOSTELA,
Fdo.: José Luis Masca eñas Cid Fdo.: Moisés Gulías Cos a
CERTIFICAN: Que la memo ia adjun a, i ulada Rh(III)-
ca alyzed annula ions based on C-H ac i a ion. Sus ainable
syn hesis o ca bo- and he e ocycles, que pa a op a al
g ado de Doc o en química p esen a Don And és Seoane
Fe nández, ha sido ealizada bajo nues a di ección en los
labo a o ios del Cen o Singula de In es igación en
Química Biológica y Ma e iales Molecula es (CIQUS) de la
Uni e sidad de San iago de Compos ela.
Conside ando que cons i uye abajo de esis, au o izamos
su p esen ación en la Uni e sidad de San iago de
Compos ela.
Y pa a que así cons e, se expide el p esen e ce i icado en
San iago de Compos ela, a 28 de ab il de 2016.
-We’ll Ne e Su i e.
- Nonsense. You’ e only saying ha because no
one e e has.
William Goldman, The P incess B ide.
Aknowledgemen s.
En p ime luga me gus a ía ag adece a mis di ec o es de esis, José Luis y el Moisés
po habe con iado en mí dándome la opo unidad de dedica casi 5 años a un p oyec o
apasionan e den o de un g upo inc eíble. Es a esis ha llegado a buen pue o g acias a su
apoyo y enseñanzas, que han pe mi ido que el mindundi que en ó, salga con más
conocimien o, con ianza y ca iño po la química. Espe o habe hecho jus icia a la con ianza
deposi ada que deposi a on en mí.
También me gus a ía ag adece a mi amilia el apoyo que me han dado. A mi mad e
po acili a me la decisión sob e el camino que a segui ; a mi he mano, que, pese a se más
jo en, es un g an ejemplo y que, además me ayudó eno memen e a eje ci a el ce eb o
mien as encon aba nue as mane as de me e me con él y a mi pad e que, ya desde
pequeño, aguan aba mis incansables p egun as alen ando mi cu iosidad y encendiendo en
mí la chispa de la ciencia.
Ag adezco ambién a Susana que ap o echó esa chispa y la a i ó g acias a unas
clases que siemp e me ma a illa on y ambién a Ma , que me que consiguió que la química
se con i iese en mi p ime a opción y sin la cual no es a ía esc ibiendo es o. Y, po supues o,
al g upo del P o . Rica do Alonso con el que me inicié en el mundo in es igación.
Tampoco puedo deja a ás a mis compañe os del g upo que consiguie on que el
desa ollo de es a esis, que a muchos les pa ece un camino in e minable y lleno de
obs áculos, se con i ie a en una expe iencia excepcional que epe i ía sin duda . P ime o, a
los que me ecibie on el p ime año haciéndome sen i como en casa: A Helio, que es aba
iéndose siemp e de ondo; a Luci y su in ini a paciencia; Isaac, bueno, una coma más; a
La a, po las ases lapida ias y a C is, po se de las pocas que ecue da lo ímido que puedo
llega a se . Ma eo, muchas g acias po pode me hace me sen i o gulloso de la locu a.
Además quie o ag adece Ma ía Rey, que además de alige a nos abajo me mos ó cómo
dis u a a pesa de cada segundo de la ida sea un in ie no y que las pe sonas no males
ambién leen cómics. No me puedo ol ida de Fe nando, Paloma, Ma isel, Se gio, Ma a que
ue on de g an ayuda du an e, al menos, g an pa e de es os años. Noe, muchísimas g acias,
no sólo po los p oyec os compa idos si no po se un ejemplo y po lo mucho que me
enseñas e, no sólo en sob e química si no sob e cómo se puede sob e i i en es e mundo con
una son isa en la ca a. En segundo luga , a los que llega on de ás: Ronald, siemp e
dispues o a apo a un da o sob e lo que sea; Noelia 2, con la que he compa ido p oyec o en
la mayo pa e de és a esis y po lo que me sien o eno memen e ag adecido. Muchas g acias
ambién a I án, po que el labo a o io sin él hab ía sido eno memen e abu ido; Da id, que
ue mi p ime pupilo y con el que ap endí mucho; Jaime, que desg aciadamen e pa a los
demás, en iende el humo de una o ma muy pa ecida a la mía. Ag adece ambién a Felipe,
un g an Compañe o y a Cagiao, que siemp e iene iempo pa a apun a se a un plan. No me
puedo ol ida (aunque casi lo haya hecho) de Ceza y Xabi con los que compa í el úl imo
p oyec o de la esis. Aunque po al a de espacio no les puedo dedica las palab as que se
me ecen, ambién me gus a ía ag adece a Jéssica, Na alia, Suso, So aya, Ma ía Tomás,
Rebeca, Paolo, Miguel, Tasneem, Jose, Jo ge, Sand a y demás compañe os de edi icio.
Es a esis ambién hab ía sido imposible sin la es imable ayuda de Ramón y Men xa y
el es o de écnicos de la USC que han hecho una pa e c ucial del abajo p esen ado aquí.
Me aleg o ambién de pode habe comple ado es a e apa de mi ida man eniendo
elación con algunos compañe os a los que conocí allá po p ime o de ca e a. I ia… casi 10
años desde que empezamos y siemp e un apoyo con el que con a y a Ti o y Ma ía,
descub imien o a dío pe o eno memen e ele an e en los años de doc o ado.
Me gus a ía ag adece ambién a la Fundación Ba ié po da me la opo unidad de
ealiza una es ancia p edoc o al en el g upo del P o . Rueping. I would also like o
acknowledge P o . Rueping o gi ing me he chance o doing a esea ch s ay in his g oup
and o Ele, Lau a, Thomas, Pa icia, Aleksand a, Quen in, An hony and Roman o ea ing
mi so well and making me miss Aachen.
A pesa de odo el apoyo ecibido en el g upo, es a esis hab ía sido más di ícil sin
odos aquellos que me pe mi ie on desconec a al sali del labo a o io. Fundamen almen e el
g upo Mon o o/Ex San Agus inos: Vi i, Ada, Po , Wences, Colo, Judoka, Ilda a, Ja i, Soso,
Ka y Ma ía que con i ie on la mayo ía de los ma es y muchos o os días en una
expe iencia digna de se i ida y llena de zo cilla. A Colo le ag adezco nue amen e po
aguan a me como compañe o de piso du an e la mayo pa e de és os años y po las e e nas
di agaciones sob e el mundo en gene al y la ciencia en pa icula .
También ag adezco a odas las pe sonas que no he podido nomb a , ya sea po al a
de espacio o po un ol ido impe donable. Espe o que pe donéis la omisión. Y po úl imo a
odo aquel que lea algo de es a memo ia, aunque sea un pá a o, g acias po hace que odo
el abajo que hay de ás no caiga en el ol ido.
A mi amilia y amigos.
Abb e ia ions and ac onyms.
i
TFA T i luo oace ic acid
TFAc T i luo oace yl
THF Te ahyd o u an
TMEDA N,N,N’,N’-
e ame hyle hylenediamine
TMS T ime hylsilyl
TS T ansi ion s a e
Ts 4-Me hylbenzenesul onyl
.
CHAPTER I: In oduc ion.
In oduc ion.
3
1- O ganic Syn hesis: Applica ions and challenges.
1.1 In oduc ion.
De ined as “The b anch o science conce ned wi h he subs ances o which ma e is
composed, he in es iga ion o hei p ope ies and eac ions, and he use o such eac ions o
o m new subs ances”,1 Chemis y is, a guably, one o he disciplines ha ha e con ibu ed
he mos o he well-being o mankind. Since he disco e y o he i e un il age o plas ics,
humans ha e modi ied molecules a hei wish o hei own bene i . By doing so, he a o
c ea ing and b eaking chemical bonds has e ol ed, allowing us o ad ance as socie y o
become wha we cu en ly a e. This is he eason why he s udy o chemis y is o i al
impo ance o pa e he oad owa ds a be e wo ld.
Among he many b anches o chemis y, O ganic Syn hesis has gained i s p i ileged place
by i s own me i s. I s ques s a ed on he beginning o he XIX cen u y, when chemis s
ound ou ha he e was no need o any “ i al o ce” in o de o c ea e na u ally occu ing
molecules. The success o O ganic Syn hesis as main a ea o chemis y a ises om he ac
ha , s a ing om a ela i ely small a ie y o “b icks” ( undamen ally C, H, O, N, P, S and
halogens) allows he ob en ion o a i ually in ini e numbe o s uc u es wi h a ying
p ope ies. By using his ool we a e able; no only o mimic na u e, bu o c ea e ou own
molecules ha , di e ging om ou en i onmen , possess uses in medicine, biology,
cosme ics, ood indus y and much mo e. In ac , om he momen we wake up o when we
go o sleep, almos e e y objec we lay ou eyes on has been c ea ed o modi ied by using
O ganic Chemis y o make ou exis ence easie .
One o he basic needs o he mode n socie y and, speci ically, chemical indus y is he
a ailabili y o ela i ely big amoun s o di e se na u al o syn he ic molecules wi h
di e gen p ope ies, which can be s udied and used o sol e p oblems encoun e ed in ou
daily li es. To be able o ob ain such quan i ies, i is manda o y o disco e me hods o he
syn hesis and isola ion o hese p oduc s. Mo eo e , o ganic compounds p esen high
di e si y and s uc u al complexi y, which leads o he necessi y o highly selec i e
ans o ma ions ha can inco po a e di e en mo i s in he p esence o a ious unc ional
g oups. Du ing he pas cen u ies, syn he ic chemis s ha e disco e ed and de eloped new
me hods ha ha e been used o syn hesize ex emely complex molecules.2
1 "Chemis y, n." OED Online. Ox o d Uni e si y P ess, Decembe 2015.
2 (a) Nicoulaou, K. C.; So ensen, E. J. Classics in o al syn hesis: Ta ge s, s a egies, me hods Ed. Wiley-
VCH, 1996. (b) Nicoulaou, K. C.; So ensen, E. J. Classics in o al syn hesis II: Mo e a ge s, s a egies,
me hods Ed. Wiley-VCH, 2003. (c) Nicoulaou, K. C.; Chen, J. S. Classics in o al syn hesis III: Fu he
a ge s, s a egies, me hods Ed. Wiley-VCH, 2011.
In oduc ion.
4
Fig 1. Example o classic o al syn heses and hei numbe o s eps and o al yield.
Despi e hese achie emen s a e ce ainly imp essing, hey a e somehow s ained because,
un il no so long ago, chemis s only pu chased he syn hesis o a complex molecule wi hou
s opping oo much o e alua e he de ails o i s ob en ion. Nowadays his ision has changed
owa ds he ques o sho and e icien syn hesis.3
1.2. Requi emen s o mode n O ganic Chemis y.
As i has been men ioned be o e, O ganic Syn hesis has mo ed om he pu chase o he
syn hesis o a gi en molecule o ocus on he ou e needed o achie ing ha goal. This new
ision has gi en ise o se e al new concep s:4 A om economy, which is he e iciency o a
chemical ans o ma ion in e ms o he maximizing he inco po a ion o he a oms p esen
in he eac an s in o he inal p oduc ;5 edox economy meaning he use as ew edox s eps as
possible in he syn he ic conques o a a ge compound;6 s ep economy, ha e e s o he
minimiza ion o ans o ma ions pe o med in an syn hesis;7 po economy meaning he use he
minimum amoun o wo kups and pu i ica ion s eps as possible8 and g een chemis y which
3 Gaich, T.; Ba an, P. S. J. O g. Chem. 2010, 75, 4657.
4 Newhouse, T.; Ba an, P. S.; Ho mann, R. W. Chem. Soc. Re . 2009, 38, 3010.
5(a)T os , B. M. Science 1991, 254, 1471. (b) T os , B. M. Angew. Chem. In . Ed. 1995, 34, 259. (c) Wende ,
P. A. Te ahed on 2013, 69, 7529.
6 Bu ns, N. Z.; Ba an, P. S.; Ho mann, R. W. Angew. Chemie - In . Ed. 2009, 48, 2854.
7(a)Wende , P. A.; C oa ,M. P.; Wi ulski, B. Te ahed on 2006, 62,7505. (b)Wende , P. A.; Ve ma, V. A.;
Pax on, T. J.; Pillow, T. H. Acc. Chem. Res. 2008, 41, 40. (c) Wende , P. A.; Mille , B. L. Na u e 2009,
460,197.
8 Hayashi, Y. Chem. Sci. 2016, 7, 866.
In oduc ion.
5
includes, bu is no limi ed o, minimiza ion o was e and he use o oxic o haza dous
chemicals9.
2– O ganome allic Chemis y: The hamme in he eac ion de elopmen
oolbox.
One way o lowe ing he amoun o s eps needed o a o al syn hesis is he use o new
eac ions leading o di e en disconnec ions. In o de o ul ill his goal, i is needed o ind
no el eac i i ies ha do no su e he limi a ions associa ed o ca bon-based O ganic
Chemis y. This is why, om he la e XIX cen u y, chemis s ha e been wo king wi h me als
o expand he amoun o ans o ma ions a ailable. Du ing he dawn o he so-called
o ganome allic chemis y, he scien i ic communi y paid much o hei a en ion in o main
g oup me als such as Li, Mg o B10. Howe e , om he hal o he XX cen u y, he
de elopmen o eac ions ca alyzed wi h me als such as Pd, Ni, Rh o Ru among o he has
gi en ise o a e y p oduc i e e a o ansi ion me al-ca alyzed chemis y, widening he
scope o ans o ma ions a ailable o he Syn he ic Chemis . The main ad an ages o
employing hese eagen s s em om hei ich coo dina ion chemis y and he possibili y o
changing hei oxida ion s a es, which esul in mechanis ic pa hways wi h lowe ac i a ion
ene gies. 11
While o ganome allic s oichiome ic eac ions ha e been used om he e y beginning o
his chemis y, i was soon ealized ha ansla ing i in o syn he ically use ul con ex s
would equi e de eloping ca aly ic ans o ma ions.12 In his way, wi h small amoun s o
o ganome allic p ecu so i is possible o ans o m la ge amoun s o eac an s.
2.2. T ansi ion me al-ca alyzed cycloaddi ions.
One o he ields in which ansi ion me al ca alysis has p o en pa icula ly use ul is in he
cycloaddi ion chemis y. Acco ding o he IUPAC gold book, cycloaddi ions a e eac ions in
which wo o mo e unsa u a ed molecules (o pa s o he same molecule) a e combined wi h
he o ma ion o a cyclic adduc in which he e is a ne educ ion o he bond mul iplici y.13
The mos ep esen a i e example o his kind o ans o ma ions is he Diels-Alde , a (4+2)
eac ion be ween a diene and a dienophile ha gene a es cyclohexenes wi h a hund ed
pe cen a om economy.14
9 Anas as P.T.; Wa ne , J.C. G een chemis y: Theo y and p ac ice, Ed. Ox o d uni e si y p ess, 1998.
10 As uc, D. O ganome allic chemis y and ca alysis, Sp inge -Ve lag, 2007.
11 (a) Hegedus, L.S. T ansi ion me als in he syn hesis o complex o ganic molecules, Ed. Uni e si y Science
o books, 1994. (b) C ab ee, R.H. The o ganome allic chemis y o ansi ion me als, Ed. Wiley, 2001.
12 Saba ie , P. Ca alysis in o ganic chemis y, D. Van Nos and Company, 1922.
13 McNaugh , A. D.; Wilkinson, A. IUPAC. compendium o chemical e minology 2nd Ed. (The “gold” book),
Ox o d, 1997. XML on-line co ec ed e sion: h p://goldbook.iupac.o g (2006-) c ea ed by Nic, M.;
Ji a , J.; Kosa a, B. upda es compiled by Jenkins, A.
14 Diels, O.; Alde , K. Jus us Liebigs Ann. Chem. 1928, 460, 98.
In oduc ion.
6
Scheme 1. Model o he Diels-Alde eac ion.
These cycloaddi ions, wo k unde he limi a ions o Woodwa d and Ho mann ules, which
esul on he need o speci ic subs i u ion so he on ie o bi als could o e lap keeping
o bi al symme y du ing he p ocess.15 These s uc u al equi emen s limi he scope o hese
eac ions o speci ic subs a es ha a e app op ia ely ma ched om he elec onic poin o
iew. One way o imp o ing he scope o cycloaddi ions consis s on he use o ligh o Lewis
acids as p omo e s, al hough, hey only wo k wi h subs a es wi h s a egically loca ed
subs i uen s.16 T ansi ion me als can be used o ci cum en hese limi a ions since hey
ope a e ia di e en mechanisms, esul ing in eac ions ha could no be ob ained by any
o he means17 such as in his example by he g oup o Paul Wende , whe e hey pe o m a
Nickel- ca alyzed (4+4) cycloaddi ion, o he wise o bidden unde he mal condi ions.18
Scheme 2. Paul Wende ’s Nickel-ca alyzed (4+4) cycloaddi ion.
The use o ansi ion me al complexes as p omo e s in his chemis y allows, no only o
pe o m classically o bidden ans o ma ions, bu also o do i unde milde condi ions and,
in some cases, achie ing highly enan ioselec i e ans o ma ions such as demons a ed in
ou esea ch g oup wi h allenamides and gold ca alysis.19
Scheme 3. Enan ioselec i e gold (I) ca alyzed (4+2) cycloaddi ion.
15 (a) Woodwa d, R.; Ho mann, R. J. Am. Chem. Soc. 1965, 87, 395. (b) Woodwa d, R.; Ho mann, R. J.
Am. Chem. Soc. 1965, 87, 2046. (c) Woodwa d, R.; Ho mann, R. J. Am. Chem. Soc. 1965, 87, 2511.
16 Ca u he s, W. Cycloaddi ion eac ions in o ganic syn hesis, Pe gamon p ess, 1990. Kobayashi, S.;
Jø gensen, K. A. Cycloaddi ion eac ions in o ganic syn hesis, Ed. Wiley-VCH, 2001.
17 Lau ens, M.; Klu e, W.; Tam, W. Chem. Re . 1996, 96, 49.
18 Wende , P. A.; Ihle, N. C. J. Am.. Chem. Soc. 1986, 8, 4678.
19 F ancos, J.; G ande-Ca mona, F.; Faus ino, H.; Iglesias-Sigüenza, J.; Díez, E.; Alonso, I.; Fe nández,
R.; Lassale a, J. M.; López, F.; Masca eñas, J. L. J. Am. Chem. Soc. 2012, 134, 14322.
In oduc ion.
7
Ano he ad an age o he use o ansi ion me als as ca alys s, is ha i is also possible o
pe o m mul icomponen annula ions in a single s ep, as can be seen in a ecen example
om ou esea ch g oup.20
Scheme 4. Rh (I)-ca alyzed (3+2+2) cycloaddi ion.
Mos o hese ansi ion me al ca alyzed cycloaddi ions in ol e he gene a ion o
me allacycles esul ing om he oxida ion o he me al cen e and a subsequen educ i e
elimina ion o egene a e he ac i e ca alys as can be seen in his o he example om ou
esea ch g oup.21
Scheme 5. (2+2) cycloaddi ion occu ing ia me allacycle.
This ype o me al-ca alyzed annula ions a e ex emely a ac i e and ha e led o many
impo an disco e ies in he las decades. Howe e , since hese eac ions ely on he
ans o ma ion o pi in o sigma bonds, hey equi e he p esence o unc ionalized,
unsa u a ed p ecu so s and he e o e, in many cases, he p epa a ion o he p ecu so s
in ol e a ela i ely la ge numbe o s eps.
2.3. C oss coupling eac ions.
While me al-ca alyzed cycloaddi ions like hose shown abo e a e ex emely impo an
eac ions, ansi ion me al ca alysis has been also ex ensi ely used o many o he
ans o ma ions, p ominen ly c oss coupling eac ions. The Mizo oki-Heck eac ion is one
elegan example o his app oach22 which led Richa d F. Heck o be awa ded wi h he Nobel
P ize in Chemis y in he yea 2010.23
20 A aya, M.; Gulías, M.; Fe nández, I.; Bha ga a, G.; Cas edo, L.; Masca eñas, J. L.; López, F. Chem.
Eu . J. 2014, 20, 10255.
21 Gulías, M.; Collado, A.; T illo, B.; López, F.; Oña e, E.; Es e uelas, M. A.; Masca eñas, J. L. J. Am.
Chem. Soc. 2011, 133, 7660.
22 (a) Mizo oki, T.; Mo i, K.; Ozaki, A. Bull. Chem. Soc. Jpn. 1971, 44, 581 (b) Heck, R. F.; Nolley, J. P. J.
O g. Chem. 1972, 37, 2320.
23 h p://www.nobelp ize.o g/nobel_p izes/chemis y/lau ea es/2010/
In oduc ion.
8
Scheme 6. The Heck eac ion.
One o he ad an ages o he use o ansi ion me als is he possibili y o une hei eac i i y
by adding di e en ligands o imp o e he p ope ies o he me allic cen e.11a Fo ins ance,
Heck demons a ed ha he ange o eac i e alkenes o his eac ion could be expanded by
adding phosphines o he eac ion media.24
Scheme 7. Use o phosphines as ligands o imp o e he Heck eac ion.
F om he second hal o he XX cen u y, c oss coupling eac ions ha e been gaining ele ance
o he cons uc ion o molecules, being nowadays widely used in indus y.25 Indeed, he
well-known couplings de eloped by Suzuki and Negishi, which we e also awa ded wi h he
Nobel P ize in chemis y in 2010, can be conside ed among he mos ele an me al-
ca alyzed eac ions disco e ed so a .
Scheme 8. Me al-ca alyzed c oss coupling eac ion.
The mechanism o hese eac ions o en s a s wi h an oxida i e addi ion o he me al o he
C-X bond (being X a halogen o pseudohalogen) ollowed by he ansme alla ion wi h
ano he me al-con aining species (such as a bo a e in he case o he Suzuki coupling o
zinca e in he case o a Negishi coupling). A inal educ i e elimina ion joins he wo
hyd oca bons and egene a es he ca alys .26
24 Dieck, H. A.; Heck, R. F. J. Am. Chem. Soc. 1974, 96, 1133.
25 (a) Magano, J.; Dune z, J. R. Chem. Re . 2011, 111, 2177. (b) Busacca, C. A.; Fand ick, D. R.; Song, J. J.;
Senanayake, C. H. T ansi ion me al ca alysis in he pha maceu ical indus y Ed. John Wiley and sons, 2012.
26 (a) De Mejie e, A.; Diede ich, F. Me al-ca alyzed c oss coupling eac ions Ed. Wiley-VCH, 2004.
In oduc ion.
9
Scheme 9. Classic mechanis ic explana ion o Pd ca alyzed c oss-couplings.
A e he ini ial disco e y o such p ocesses, he scien i ic communi y demons a ed ha he
coupling eac ions could be ca ied ou using o he o ganome allic compounds (such as
magnesium in he Kumada coupling,27 in in he S ille coupling28 o silicon in he Hiyama
coupling29) and ema kably educing he ca alys loadings; he e o e, u ning hem in o a
ool which has been used in uncoun able syn he ic applica ions.30 In addi ion o he abo e
eac ions, he Sonogashi a coupling p o ides an excellen way o a aching alkynes o
di e en subs a es. Fo ins ance, Thomas and co-wo ke s a Abbo demons a ed he u ili y
o his ans o ma ion in he kilog am-scale syn hesis o 1, an in e media e o Fenleu on a 5-
lipoxigenase inhibi o .31
Scheme 10. Kilog am syn hesis o Fenleu on in e media e 1.
While he abo e eac ions we e designed o he cons uc ion o ca bon-ca bon bonds, i is
also possible o make ca bon-ni ogen bonds using he well-known Buchwald-Ha wig
amina ion,32 o in oduce o he he e oa oms such as sul u o oxygen33 s a ing om
27 (a) Co iu, R. J. P.; Masse, J. P. J. Chem. Soc. Chem. Commun. 1972, No. 3, 144a. (b) Tamao, K.;
Sumi ani, K.; Kumada, M. J. Am. Chem. Soc. 1972, 94, 4374.
28 Mils ein, D.; S ille, J. K. J. Am. Chem. Soc. 1978, 100, 3636.
29 Ha anaka, Y.; Hiyama, T. J. O g. Chem. 1988, 53, 918.
30 Nicolaou, K. C.; Bulge , P. G.; Sa lah, D. Angew. Chemie. In . Ed. 2005, 44, 4442.
31 Thomas, A. V.; Pa el, H. H.; Rei , L. A.; Chembu ka , S. R.; Sawick, D. P.; Shela , B.; Balme , M. K.;
Pa el, R. R. O g. P ocessRes.De . 1997, 1, 294.
32 Yang, B. H.; Buchwald, S. L. J. O ganome . Chem. 1999, 576, 125.
In oduc ion.
16
Fig 2. Di e si y o di ec ing g oups.
While in mos cases he di ec ing g oups ha e been used o unc ionalizing a yl C-H bonds
in o ho posi ions, he e ha e been also elegan app oaches ha allow me a52 o e en pa a53
unc ionaliza ions.
3.3 Mechanisms o C-H ac i a ion.54
C-H unc ionaliza ion eac ions may ope a e unde di e en ac i a ion modes ha a e
s ongly dependan on he choice o he me al ca alys and he di e en addi i es employed.
The di e en eac ion pa hways can be summa ized in o he ollowing ca ego ies:
3.3.1 Oxida i e addi ion.
Oxida i e addi ion eac ions usually occu wi h low- alen , elec on- ich ansi ion me als
and hey a e acili a ed when hey a e coo dina i ely unsa u a ed. In his mechanism, he
me al “inse s” in o he C-H bond, aising i s oxida ion s a e by wo uni s.37d
Scheme 23. Mechanism o an oxida i e addi ion in o a C-H bond.
This mechanism o ac i a ion is he one p oposed in his wo k by Ha wig whe e hey
achie e he me a-selec i e bo yla ion o anilines.55
52 Phipps, R. J.; Gaun , M. J. Science, 2009, 323, 1953.
53 Bag, S.; Pa a, T.; Modak, A.; Deb, A.; Mai y, S.; Du a, U.; Dey, A.; Kanche la, R.; Maji, A.; Haz a, A.;
Be a, M.; Mai i, D. J. Am. Chem. Soc. 2015, 137, 11888.
54 Fo e iews on he di e en modes o C-H ac i a ion see: (a) Labinge , J. a; Be caw, J. E. Na u e 2002,
417, 507. (b) Lapoin e, D.; Fagnou, K. Chem. Le . 2010, 39, 1118. (c) Balcells, D.; Clo , E.; Eisens ein, O.
Chem. Re . 2010, 110, 749. (d) Edi o , G.; Mcg ady, J.; Bou adla, Y.; Da ies, D. L.; Macg ego , S. A.;
Poblado -bahamonde, A. I.; Balcells, D.; Moles, P.; Blakemo e, J. D.; Raynaud, C.; B ud ig, G. W.;
C ab ee, R. H.; Eisens ein, O.; T ans, D. Dal . T ans. 2009, 5820.
37d Be gman, R. G. Na u e 2007, 446, 391.
55 La sen, M. A.; Ha wig, J. F. J. Am. Chem. Soc. 2014, 136, 4287.
In oduc ion.
17
Scheme 24. Example o C-H ac i a ion ia oxida i e addi ion.
In his eac ion an ini ial dissocia ion o cyclooc adiene ligand om he I (I) complex
unsa u a es he me al cen e, which allows he oxida i e addi ion in o he C-H bond o
gene a e an I (III) in e media e. This species e ol es upon educ i e elimina ion leading o
he bo yla ed picoline and he educed ca alys , which unde goes ansme alla ion o een e
he cycle.
3.3.2 Sigma bond me a hesis.
A di e en way o achie ing me alla ion o C-H bonds, mainly p omo ed by ea ly ansi ion
me als wi h d0 con igu a ion like scandium, lan hanides o ac inides and, in some cases,
o he me als such as Ru,56 elies on a conce ed exchange o a me al-ligand sigma bond wi h
one ca bon-hyd ogen bond o an incoming subs a e in a o mal [2σ + 2σ] ansi ion s a e
s uc u e.57
Scheme 25. Mechanism o he σ bond me a hesis.
The g oup o Hou epo ed a a e ea h-based C-H addi ion o py idines o ole ins ha
p oceeded ia sigma bond me a hesis. The mechanism s a s wi h an ini ial C-H ac i a ion
ollowed mig a o y inse ion gene a ing a me allacyclic in e media e II which eac s wi h
ano he molecule o py idine by a second me a hesis ha egene a es he ca alys and
deli e s he p o on o he C-M bond.58
56 Ha wig, J. F.; Bhanda i, S.; Rablen, P. R. J. Am. Chem. Soc. 1994, 116, 1839.
57 Wa e man, R. O ganome allics 2013, 32, 7249.
55a Labinge , J. a; Be caw, J. E. Na u e 2002, 417, 507.
58 Guan, B. T.; Hou, Z. J. Am. Chem. Soc. 2011, 133, 18086.
In oduc ion.
18
Scheme 26. Example o C-H ac i a ion ia σ bond me a hesis.
3.3.3 Elec ophilic subs i u ion.
When he me al is in a highe oxida ion s a e and he subs a e is ela i ely elec on- ich,
ano he me alla ion mode can ake place. In his case, he nucleophilic hyd oca bon a acks
he me al gene a ing a delocalized ca ionic species (Wheland in e media e, in he case o an
a oma ic sys em) ha now loses he acidic p o on gene a ing he me alla ed in e media e.55a
Scheme 27. Mechanism o he elec ophilic me alla ion.
This mechanism is in oked in he a yla ion o naph halene pe o med by he g oup o
Melanie San o d.59 The obse a ion o a KIE alue o 1.0 ± 0.1 was in e p e ed in e ms o he
clea age o he ca bon-hyd ogen bond no being in ol ed in he u no e -limi ing s ep. This
esul is consis en wi h an elec ophilic pallada ion ollowed by a as clea age o he acidic
C-H bond om he Wheland in e media e.
59 Hickman, A. J.; San o d, M. S. ACS Ca al. 2011, 1, 170.
In oduc ion.
19
Scheme 28. Pd-ca alyzed a yla ion o naph halene.
3.3.4 Conce ed me alla ion-dep o ona ion (CMD).
Closely ela ed o he elec ophilic subs i u ion mechanism is he CMD p ocess. Bo h
mechanisms ha e been o en mis aken and, in ac , CMD was p oposed in o de o jus i y
some expe imen al da a ha elec ophilic subs i u ion could no ully explain. In he la e ,
he me al cen e weakens he C-H bond while a base, gene ally coo dina ed o he me al,
abs ac s he p o on in a conce ed mani old. 55b,60
Scheme 29. Mechanism o he CMD.
Recen ly, he g oup o La osa, desc ibed his mode o ac i a ion in his Ru (II)- ca alyzed
a yla ion o luo oa enes wi h a yl halides. In hei publica ion hey also s udy his pa hway
by DFT calcula ions, which helped hem o p opose a mechanism. Thei hypo hesis s a s
wi h he in si u o ma ion o he ca ionic species I which unde goes he CMD in o he
luo oa ene leading o complex II. This in e media e a yl u henium species unde goes a
55b Lapoin e, D.; Fagnou, K. Chem. Le . 2010, 39, 1118
60 Acke mann, L. Chem. Re . 2011, 111, 1315.
In oduc ion.
20
o mal oxida i e addi ion/ educ i e elimina ion s ep wi h he a yl halide and complex III,
which, a e halide abs ac ion egene a es I closing he cycle.61
Scheme 30. Ru-ca alyzed a yla ion o luo oa enes.
3.4. Rhodium (III)-ca alyzed C-H unc ionaliza ions.
In compa ison o he widely used nickel, pla inum and palladium ca alys s; Rhodium
p esen s exci ing di e gen p ope ies o ca aly ic p ocesses in ol ing C-H ac i a ions.62 In
pa icula , Rhodium has he abili y o swi ch easily be ween oxida ion s a es such as Rh (III)
and Rh (IV) o e en Rh (V) which opens a window o new eac i i ies. I also allows
di e en coo dina ion geome ies, p o iding e sa ili y in e ms o ligand a iabili y.63 A
pionee ing example on he use o Rh (III) o ac i a e C-H bonds was demons a ed by Mai lis
in 1987, p esumably ope a ing ia σ bond me a hesis,64 and, la e by Da ies employing a
pen ame hylcyclopen adienyl Rhodium dime .65
61 Simone i, M.; Pe y, G. J. P.; Cambei o, X. C.; Juliá, F.; A okiana ha , J. N.; La osa, I. J. Am. Chem.
Soc. 2016, 138, 3596.
62 E ans, A. Mode n Rhodium-ca alyzed o ganic eac ions, Ed. Wiley-VCH, 2005.
63 Housec o , C. E.; Sha pe, A. G. Ino ganic chemis y 2º Ed. Ed. Pea son P en ice Hall, 2006.
64 Kisenyi, J.M.; Sunley, G. J.; Cabeza, J. A.; Smi h, A. J.; Adams, H.; Sal , N. J.; Mai lis, P. M. J. Chem.
Soc., Dal on T ans., 1987, 2459.
65 Da ies, D. L.; Al-Duaij, O.; Fawce , J.; Gia diello, M.; Hil on, S. T.; Russell, D. R. Dal . T ans. 2003, 2,
4132.
In oduc ion.
21
Scheme 31. Fi s example o C-H ac i a ion by [Cp*RhCl2]2.
Following he pionee ing wo k o Miu a, which demons a ed ha a Cp*Rh complex could
be an e icien ca alys o C-H unc ionaliza ion,66 many o he examples ha e been epo ed
in he li e a u e.67 Fo ins ance, he g oup o Glo ius de eloped an ole ina ion o
ace ilanilides using s y enes and a sil e sal o ac i a e he Rhodium (III) ca alys by
abs ac ing a chlo ine a om om he ac i e ca aly ic complex.68
Scheme 32. Rh (III)-ca alyzed C-H ole ina ion.
The mos widely employed p eca alys in his chemis y is [Cp*RhCl2]2 which dissocia es in
p esence o ex e nal ligands o addi i es o o m he ac i e monome s ha pe o m he C-H
ac i a ion s ep. The p esence o he Cp* ligand appea s o be c ucial o he eac i i y which
can be explained in e ms o he s abiliza ion o he high oxida ion s a es o he hodium.69
A e he me alla ion o he o ganic subs a e, he complex adop s a cha ac e is ic piano s ool
con igu a ion as shown in Figu e 3 whe e phenylpy idine is ac i a ed and one o he
chlo ine a oms has been eplaced by iodine o acili a e c ys alliza ion.70
66 Ueu a, K.; Sa oh, T.; Miu a, M. O g. Le . 2007, 9, 1407.
67 (a) Sa oh, T.; Miu a, M. Chem. Eu . J. 2010, 16, 11212. (b) Song, G.; Wang, F.; Li, X. Chem. Soc. Re .
2012, 41, 3651.
68 Pa u eau, F. W.; Glo ius, F. J. Am. Chem. Soc. 2010, 132, 9982.
69 Mai lis, P. M. Acc. Chem. Res. 1978, 11, 301.
70 Luo, C. Z.; Gandeepan, P.; Jayakuma , J.; Pa hasa a hy, K.; Chang, Y. W.; Cheng, C. H. Chem. Eu . J.
2013, 19, 14181.
In oduc ion.
22
Fig 3. C ys al s uc u e o he Cp*Rh(ppy)I complex.
The mode o C-H bond ac i a ion by Cp*Rh (III) complexes, pa icula ly o a enes, has been
mainly desc ibed as conce ed me alla ion-dep o ona ion.71
4–Annula ions based on C-H ac i a ion, an in e es ing ma ch.
4.2. Gene al o e iew.
As i has been explained be o e, one o he mos p ominen ways o pe o ming success ul C-
H unc ionaliza ions consis s on he employmen o di ec ing g oups.40 Howe e , despi e he
conside able ad an ages o using such g oups o achie ing selec i i y, he e is s ill one
majo d awback, which is ha , in mos o he cases, he di ec ing g oup is only used as
coo dina ing mo i and i is no needed in he inal s uc u e. This means ha addi ional
s eps a e needed o he inclusion o such moie y in he backbone and o i s subsequen
elimina ion a e he eac ion. The use o ansien di ec ing g oups a oids he ex a s eps
needed o hei elimina ion72 bu hey s ill gene a e was e and p esen low a om economy.
Howe e , gi en he ac ha some di ec ing g oups can o m me allacyciclic species a e he
C-H ac i a ion, i is possible o en ision he use o such in e media es o simila
ans o ma ions han hose a ising om al eady o med me allacycles, as he cycloaddi ions
seen be o e. In his way, a leas some a oms o he di ec ing g oup will become pa o he
inal cycle and he e o e, i is no was ed. In addi ion, his app oach p o ides a e y
appealing way o making eac i e me allacycles ha does no equi e he p esence o
unsa u a ions in he pa en subs a e. These eac ions would imply an impo an inc ease in
he molecula complexi y and could become a e y in e es ing and a om economical
al e na i e o build cyclic molecules.
This me hodology would also open a doo o a s aigh o wa d access o a wide ange o
he e ocycles, which a e e y common skele ons p esen in coun less na u ally occu ing
40 Chen, Z.; Wang, B.; Zhang, J.; Yu, W.; Liu, Z.; Zhang, Y. O g. Chem. F on . 2015, 2, 1107.
71 Li, L.; B ennessel, W. W.; Jones, W. D. O ganome allics 2009, 28, 3492.
72 Wang, X.-C.; Gong, W.; Fang, L.-Z.; Zhu, R.-Y.; Li, S.; Engle, K. M.; Yu, J.-Q. Na u e 2015, 519, 334.
In oduc ion.
23
and/o biologically ac i e p oduc s73, as well as molecules ele an o ma e ials science such
as OLEDS.74
While one could be emp ed o include his app oach o cyclic skele ons among he ca ego y
o o mal cycloaddi ions, he name oxida i e annula ion migh be mo e sui able, owing o
he oxida ion s a e o he inal p oduc in compa ison wi h he s a ing ma e ials and he
IUPAC gold book de ini ion o annula ion: “A ans o ma ion in ol ing usion o a new ing
o a molecule ia wo new bonds”.13
Scheme 33. Oxida i e annula ions in con as wi h cycloaddi ion and di ec ed C-H unc ionaliza ion.
4.2. Gene al mechanis ic aspec s o oxida i e annula ions.
The mos common mechanism o hese ans o ma ions in ol es he o ma ion o he
me allacyclic species which, a e mig a o y inse ion in o an unsa u a ed pa ne gene a es a
new me allacycle ha , upon educ i e elimina ion leads o he inal molecule. The me al
complex (usually om Pd, Rh, Ru o I ) no mally needs an addi ional eoxida ion s ep in
o de o comple e he ca aly ic cycle.
13 McNaugh , A. D.; Wilkinson, A. IUPAC. compendium o chemical e minology 2nd Ed. (The “gold” book),
Ox o d, 1997. XML on-line co ec ed e sion: h p://goldbook.iupac.o g (2006-) c ea ed by Nic, M.;
Ji a , J.; Kosa a, B. upda es compiled by Jenkins, A.
73 (a) Majumda , K. C.; Cha opadyay, S. K. He e ocycles in na u al p oduc syn hesis Ed. Wiley-VCH,
2011. (b) Lambe h, C.; Dinges, J. Bioac i e he e ocyclic compound classes: Pha maceu icals Ed. Wiley-VCH,
2012.
74 Chen, D.; Su, S.-J.; Cao, Y. J. Ma e . Chem. C 2014, 2, 9565.
In oduc ion.
24
Scheme 34. Gene al mechanism o oxida i e annula ions.
The e is also he possibili y ha he di ec ing g oup is no included in he inal cycle i wo
consecu i e C-H ac i a ions occu howe e in his la e case, he u ili y o he di ec ing
g oup would be jus as auxilia y.
4.3. Some examples o oxida i e annula ions.
Oxida i e annula ions can be so ed acco ding o di e en c i e ia. He ein we ha e chosen a
classi ica ion based on he numbe o a oms p o ided by he unsa u a ed eac ion pa ne .
We ha e selec ed only a ew ep esen a i e examples among he as numbe o eac ions
ha ha e been desc ibed in ecen yea s.75
4.3.1 (n+1) oxida i e annula ions.
In hese eac ions, he coupling pa ne ac s as a one-ca bon su oga e. The mos common
eagen o his pu pose is ca bon monoxide. An example o he use o his gas is sown in
scheme 35.76
Scheme 35. (3+1) Oxida i e annula ions o alipha ic amines wi h CO.
A key elemen o he success o his eac ion is he use o highly hinde ed amines unable o
o m inac i e palladium diamine species. In he same communica ion he au ho s desc ibe
he isola ion o a ime ic palladium complex o med p io o he ca bonyla ion, a e he C-
H ac i a ion.
I is also possible o use o he molecules o ac as one-a om dono s such as diazo compounds,
since hey can gene a e ca benes by he loss o a ni ogen molecule such as can be seen in he
75 Gulías, M.; Masca eñas, J. L. Angew. Chem. In . Ed. 2016, in P ess.
76 McNally, A.; Ha emaye , B.; Collins, B. S. L.; Gaun , M. J. Na u e 2014, 510, 129.
In oduc ion.
25
ollowing example in ol ing a Rh (III)-ca alyzed eac ion be ween imidamides and
diazocompounds o he syn hesis o indoles.77
Scheme 36. Oxida i e annula ions o imidamides o diazocompounds.
In his case, he las s ep o he eac ion in ol es a mig a o y inse ion ins ead o he mo e
s anda d educ i e elimina ion so he eac ion can be ca ied ou in he absence o ex e nal
oxidan s.
Scheme 37. (4+1) Oxida i e annula ions o imidamides wi h diazocompounds.
4.3.2 (n+2) oxida i e annula ions.
In hese ans o ma ions, he eac ion pa ne s a e usually compounds ea u ing double o
iple ca bon-ca bon bonds. F equen ly, hese ans o ma ions p esen a highe ca aly ic
u no e when using hodium (III) ins ead o palladium, p obably due o he easie inse ion
o alkynes.68a The seminal wo k o Miu a in oxida i e annula ions o benzoic67 acids opened
he doo o hese eac ions usually pe o med wi h he s anda d Rh (III) complexes al hough
i has been la e shown ha i is possible o use o he ansi ion me als such as Ru78 o Co.79
77 Qi, Z.; Yu, S.; Li, X. O g. Le . 2016, 18, 700.
68a Sa oh, T.; Miu a, M. Chem. Eu . J. 2010, 16, 11212.
67 Ueu a, K.; Sa oh, T.; Miu a, M. O g. Le . 2007, 9, 1407.
78 (a) Acke mann, L.; Wang, L.; Lygin, A. V. Chem. Sci. 2012, 3, 177. (b) Depon i, M.; Kozhushko , S. I.;
Yu i , D. S.; Acke mann, L. O g. Biomol. Chem. 2013, 142.
Chap e II.
33
1– C-H unc ionaliza ion o benzamides.
1.1 C-H unc ionaliza ion o benzamides.
Benzamides, owing o he p esence o an amide di ec ing g oup, a e able o pa icipa e in a
wide ange o C-H unc ionaliza ion eac ions. In ac , a g ea a ie y o ans o ma ions has
been desc ibed using di e en me al complexes o in oduce di e se unc ional g oups.40
Fo ins ance, Sukbok Chang and co-wo ke s de eloped an i idium-ca alyzed o ho-amina ion
o benzamides. In hei communica ion, hey epo he o ma ion o a 5-membe ed
me allacycle coo dina ed o he azide which would o m a ni ene in e media e ha , upon
educ i e elimina ion, gene a es he amida ed p oduc .85
Scheme 45. I (III)-ca alyzed C-H amida ion o benzamides.
Also, he g oup o P o . Jin-Quan Yu has demons a ed he impo ance o an app op ia e
choice o he di ec ing g oup by using an elec onically uned pen a luo ophenyl benzamide
o ca y ou se e al Palladium ca alyzed eac ions.86 One example o his di ec ing g oup is
he palladium-ca alyzed bo yla ion o a enes.87
40 Chen, Z.; Wang, B.; Zhang, J.; Yu, W.; Liu, Z.; Zhang, Y. O g. Chem. F on . 2015, 2, 1107.
85 Ryu, J.; Kwak, J.; Shin, K.; Lee, D.; Chang, S. J. Am. Chem. Soc. 2013, 135, 12861.
86 (a) Wasa, M.; Engle, K. M.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 3680. (b) Yoo, E. J.; Ma, S.; Mei, T.;
Chan, K. S. L.; Yu, J. J. Am. Chem. Soc. 2011, 133, 7652. (c) He, J.; Shigena i, T.; Yu, J.-Q. Angew. Chemie
In . Ed. 2015, 54, 6545.
87 Dai, H.-X.; Yu, J.-Q. J. Am. Chem. Soc. 2012, 134, 134.
Chap e II.
34
Scheme 46. C-H bo yla ion o pen a luo ophenyl benzamides.
Fo hese eac ions hey epo he use o he e y elec on poo pen a luo ophenyl
benzamide as c i ical o he success o he eac ions. P obably due o he delocaliza ion o
he nega i e cha ge which makes i beha e mo e as an L ligand while s ill keeping i s
coo dina ing abili ies.88
Rhodium ca alysis has been p edominan ly used wi h his mo i . An elegan example
epo ed by Glo ius and cowo ke s desc ibe he Rhodium-ca alyzed c oss dehyd ogena i e
coupling o benzamides and simple a enes wi h hexab omobenzene as addi i e.89 Al hough
c ucial o he success o he eac ion, he ole o he addi i e is s ill unclea . Howe e , i was
sugges ed ha i ac s as an oxidan . This is due o he ac ha pen a luo obenzene was
isola ed om he eac ion mix u e, p obably a ising om an oxida i e addi ion o he
educed Rh (I) ca alys o he A -B bond ollowed by p o odeme alla ion. I is also supposed
o be somehow a o ing he undi ec ed C-H ac i a ion o he simple a ene.
Scheme 47. Rh (III)-ca alyzed C-H c oss dehyd ogena i e coupling o benzamides wi h a enes.
Amide-di ec ed C-H unc ionaliza ions can be also applied o inylic subs a es. Fo
ins ance, he g oup o Glo ius was also able o ca y ou a simila a yla ion o he abo e one,
bu using ac ylamides ins ead o benzamides.90
Scheme 48. Rh (III)-ca alyzed C-H c oss dehyd ogena i e coupling o ac ylamides wi h a enes.
88 Chan, K. S. L.; Wasa, M.; Wang, X.; Yu, J. Q. Angew. Chemie. In . Ed. 2011, 50, 9081.
89 Wencel-Delo d, J.; Nimphius, C.; Wang, H.; Glo ius, F. Angew. Chemie - In . Ed. 2012, 51, 13001.
90 Wencel-Delo d, J.; Nimphius, C.; Pa u eau, F. W.; Glo ius, F. Chem. Asian J. 2012, 7, 1208.
Chap e II.
35
1.2 Oxida i e annula ion o benzamides.
The i s epo o he use o benzamides in Rh(III) ca alyzed C-H unc ionaliza ions was, in
ac an oxida i e annula ion. I was epo ed by he g oup o Fagnou as an ex ension o hei
wo k on he syn hesis o indoles.91 Inspi ed by Yu’s wo k,92 hey used benzhyd oxamic acid
de i a i es and, in e es ingly, hey ound ou ha he N-O bond was clea ed a e he
eac ion, p esumably by oxida i e addi ion o he educed Rh (I) in o he N-O bond ollowed
by ligand exchange. This side eac ion allowed hem o ge id o he coppe oxidan needed
o eco e he ca alys .
Scheme 49. Rh (III)-ca alyzed oxida i e annula ion o benzhyd oxamic acid de i a i es.
They u he de eloped hei wo k by es ablishing calcula ions on he mechanism, uning he
in e nal oxidan and signi ican ly expanding he scope including e minal alkynes and
ole ins as coupling pa ne s.93
Scheme 50. Rh (III)-ca alyzed oxida i e annula ion o pi aloyl subs i u ed benzhyd oxamic acids.
The inclusion o an in e nal oxidan has been widely used since his wo k, no only clea ing
he N-O bond as in his case, bu also swi ching he connec ion o elease he R-NH94 o using
N-N bonds.95
91 Guimond, N.; Goulia as, C.; Fagnou, K. J. Am. Chem. Soc. 2010, 132, 6908.
92 Wasa, M.; Yu, J.-Q. J. Am. Chem. Soc. 2008, 130, 14058.
93 Guimond, N.; Go elsky, S. I.; Fagnou, K. J. Am. Chem. Soc. 2011, 133, 6449.
94 Zhang, Z.; Jiang, H.; Huang, Y. ACS Ca al. 2015, 6999.
95 Liu, B.; Song, C.; Sun, C.; Zhou, S.; Zhu, J. J. Am. Chem. Soc. 2013, 135, 16625.
Chap e II.
36
Sho ly a e , he g oup o Miu a96 and he g oup o Hys e and Ro is published an ex ension
o his wo k whe e hey managed o ca y ou he eac ion wi hou he need o he N-O
bond.97
Scheme 51. Ro is’ Rh (III)-ca alyzed oxida i e annula ion o benzamides wi h alkynes.
A e ex ensi e mechanis ic s udies, hey es ablished a mechanis ic hypo hesis. Thei
p oposal in ol es he o ma ion o he ac i e ca aly ic species98 by ligand exchange o he
chlo ides wi h he ace a es and a subsequen N-H clea age leading o in e media e I. A CMD
s ep would deli e he me allacycle II ha can unde go mig a o y inse ion in o he alkyne
ollowed by educ i e elimina ion yielding he isoquinoline. The educed ca alys is hen
eoxidized by he coppe ace a e.
Scheme 52. (4+2) oxida i e annula ions o benzamides wi h alkynes.
Inspi ed on Fagnou’s wo k on he annula ion o benzamides and alkenes, he g oup o
C ame sough o an enan ioselec i e e sion o such coupling. Since he Cp* is essen ial o
96 Mochida, S.; Umeda, N.; Hi ano, K.; Sa oh, T.; Miu a, M. Chem. Le . 2010, 39, 744.
97 Hys e , T. K.; Ro is, T. J. Am. Chem. Soc. 2010, 132, 10565.
98 The ligand exchange be ween chlo ines and ace a es is de ec ed by UV/Vis in: Li, L.; B ennessel, W.
W.; Jones, W. D. O ganome allics 2009, 28, 3492.
Chap e II.
37
he eac i i y and he o he h ee posi ions ha e o be a ailable o di e en mechanis ic
s eps, he e is no possibili y o adding any chi al ligand o ob ain enan ioselec i i y. To sol e
his p oblem hey in oduced he use o chi al cyclopen adienes ha shield one ace o he
benzamide a o ing one o ien a ion o he alkene.99
Scheme 53. Rh (III)-ca alyzed enan ioselec i e oxida i e annula ion o benzhyd oxamic de i a i es.
A he same ime, he g oups o Ro is and Wa d published an al e na i e e sion o
achie ing enan ioselec i e annula ions by enginee ing an a i icial me allozyme based on
bio in-s ep a idin in e ac ions leading o yields up o 95% and enan iome ic excesses up o
86%.100
Scheme 54. S ep a idin/Rh (III)-ca alyzed enan ioselec i e oxida i e annula ion o benzhyd oxamic acid
de i a i es.
Ac ylamides also unde go oxida i e annula ions unde ansi ion-me al ca alysis. Fo
ins ance, Acke mann and co-wo ke s desc ibed an oxida i e annula ion o ac ylamides o
he syn hesis o 2-py idones using a u henium complex.101
Scheme 55. Rh (III)-ca alyzed oxida i e annula ion o benzamides wi h alkynes.
99 Ye, B.; C ame , N. Science. 2012, 338, 504.
100 Hys e , T. K.; Wa d, T. R.; Ro is, T. Science. 2012, 338, 501.
101 Acke mann, L.; Lygin, A. V; Ho mann, N. O g. Le . 2011, 13, 3278.
Chap e II.
38
These annula ions o benzamides and ac ylamides we e u he s udied by he g oups o
Fagnou, Miu a and Ro is as well as o he s. becoming a powe ul and obus
ans o ma ion.102
102 Fo mo e epo s on he oxida i e annula ion o benzamides see: (a) Ya Du, T. K. H.; Ro is, T. Chem.
Commun. 2011, 47, 12074. (b) Cui, S.; Zhang, Y.; Wu, Q. Chem. Sci., 2013, 4, 3421. (c) Cui, S.; Zhang, Y.;
Wu, Q. Chem. Sci., 2013, 4, 3912. (d) Hys e , T. K.; Ruhl, K. E.; Ro is, T. J. Am. Chem. Soc. 2013, 135,
5364. (e) Huckins, J. R.; Be co , E. A.; Thiel, O. R.; Hwang, T.; Bio, M. M. J. Am. Chem. Soc. 2013, 135,
14492. ( ) Shi, Z.; G ohmann, C.; Glo ius, F. Angew. Chemie. In . Ed. 2013, 52, 5393. (g) Yu, D.;
Azambuja, F. De; Glo ius, F. Angew. Chemie. In . Ed. 2014, 53, 2754. (h) Yu, D.-G.; de Azambuja, F.;
Gensch, T.; Daniliuc, C. G.; Glo ius, F. Angew. Chemie In . Ed. 2014, 53, 1. (i) Peng, X.; Wang, W.; Jiang,
C.; Sun, D.; Xu, Z.; Tung, C.-H. O g. Le . 2014, 16, 5354.
Chap e II.
39
2– Objec i es
When we s a ed ou wo k in his esea ch a ea, he epo s in he oxida i e annula ions o
benzamides we e sca ce and limi ed o he ini ial epo s o Ro is, Miu a and Fagnou.
The e o e we conside ed ha he e we e many aspec s in his chemis y ha would dese e
u he a en ion.
Among o he s, we conside ed he possibili y o achie ing in amolecula annula ions, gi en
ha his would p o ide a nice way o ob ain ela i ely complex polycycles om e y simple
s a ing ma e ials in an a om economical manne . Following hese hough s we conside ed
he de elopmen o a ully in amolecula oxida i e annula ion leading o icyclic
isoquinolines.
Scheme 56. Gene al objec i e.
This ype o icyclic co es is p esen in a wide ange o biologically ele an p oduc s, such
as he ones shown in he igu e and he e o e, a p ac ical access o hese s uc u es was
conside ed wo hy.
Fig 4. Na u al p oduc s p esen ing a icyclic isoquinoline co e.
Al hough, his adap a ion om in e o in amolecula eac ions migh seem ob ious, a mo e
ca e ul analysis on he basis o he p oposed mechanism e ealed ha i could be no so
i ial. Acco ding o he hypo he ical mechanism, consis ing o a mig a o y inse ion o he
alkyne in o he C-Rh bond o he esul ing species om he C-H ac i a ion, his s ep would
gene a e a b idged bicyclic in e media e such as I, ha seems o be qui e s ained and, hence,
Chap e II.
40
migh no be o med. Al e na i ely, he eac ion could ake place by mig a o y inse ion in o
he Rh-H bond, which would p oduce a much mo e com o able species II.103
Scheme 57. Possible in e media es a e he mig a o y inse ion.
On hese bases he e we e a numbe o in e es ing challenges o be pu sued:
S udy he e ec o he in amolecula i y, including changes on he eac i i y and
egioselec i i y.
Easily access o biologically ele an icyclic isoquinolines
S udy he mechanis ic pa hway h ough expe imen al and compu a ional
calcula ions.
103 These wo possibili es a e desc ibed in: Li, B.; Feng, H.; Xu, S.; Wang, B. Chem. Eu . J. 2011, 17,
12573.
Chap e II.
41
3– Resul s and discussion.
3.1 Op imiza ion o he eac ion condi ions.
To s udy he iabili y o he eac ion we syn hesized he model subs a e 10. The p epa a ion
o his alkyne- e he ed benzamide was achie ed by an ini ial Boc p o ec ion o benzamide
ollowed by a Mi sunobu ype eac ion wi h pen ynol and dep o ec ion. This sequence led o
he e minal alkyne- e he ed benzamide 9. A inal Sonogashi a coupling wi h iodobenzene
p o ided 10 in a 17% o e all yield wi hou majo op imiza ion.
Scheme 58. Syn hesis o model subs a e 10.
Wi h he model subs a e in hand we sc eened se e al eac ion condi ions, a ying he
sol en and he ca aly ic sys em. The esul s o hese expe imen s a e summa ized in Table 1.
Chap e II.
48
we syn hesized he benzamide 10-D5 as desc ibed in scheme 58. We hen un he eac ions in
sepa a e essels unde he op imized condi ions aking aliquo s e e y 5 minu es which we e
quenched by dilu ing wi h dichlo ome hane and il e ed h ough a lo isil pad. NMR
analysis o he amoun o isoquinoline p esen a each aliquo allowed calcula ing a KIE
alue o 2.5. This is consis en wi h a mode a e in luence o he C-H clea age in he eac ion
a e, which is in ag eemen wi h he ene ge ic p o ile esul ing om he compu a ional
s udies.
Scheme 66. S udy o he KIE
3.3 Fu he s udies on he in amolecula oxida i e annula ion o anilides.
A his poin o he esea ch, we we e cu ious abou he possibili y o ex ending he
in amolecula i y in oxida i e annula ions o o he p ecu so s like anilides, as his would
lead o in e es ing polycyclic indoles. As commen ed in he in oduc ion, Fagnou and co-
wo ke s had p e iously de eloped a b illian me hod o he ob en ion o indoles by a
hodium-ca alyzed in amolecula oxida i e annula ion be ween ace amides and alkynes
(scheme 40). 81 Howe e , in amolecula e sions had no been s udied and, hence, we
decided o make he p ecu so s 38 (scheme 68) o check hei eac i i y.
y = 5E-05x - 0,0161
y = 5E-05x - 0,0116
y = 2E-05x - 0,0067
y = 2E-05x - 0,005
0
0,01
0,02
0,03
0,04
0,05
0,06
0 500 1000 1500 2000 2500 3000
Ammoun o p oduc (mmol)
Time (s)
Measu emen o he KIE
10- un1
10- un2
10-D5- un1
10-D5- un2
81 (a) S ua , D. R.; Be and-Lape le, M.; Bu gess, K. M. N.; Fagnou, K. J. Am. Chem. Soc. 2008, 130,
16474. (b) S ua , D. R.; Alsabeh, P.; Kuhn, M.; Fagnou, K. J. Am. Chem. Soc. 2010, 132, 18326.
Chap e II.
49
Scheme 67. Syn hesis o indoles by oxida i e annula ion.
The syn hesis o he alkyne e he ed anilide 18a was done by he condensa ion o aniline
wi h 5-pen ynoic acid ollowed by a Sonogashi a coupling o yield he in e nal alkyne.
Scheme 68. Syn hesis o anilide 18a.
T ea men o he anilide 18a unde he same condi ions desc ibed by Fagnou o he
in e molecula cases ailed on yielding e en aces o he icyclic indole, ei he wi h o
wi hou he sil e sal and he a complex mix u e o s a ing ma e ial was eco e ed
espec i ely. Al hough a he beginning we we e a li le su p ised by his esul , a close look
in o he hypo he ical in e media e esul ing om he C-H ac i a ion (III), allows in e ing
ha i would no be easy o he alkyne o come close o he C-Rh bond and, he eby,
unde go he equi ed mig a o y inse ion s ep. So species III is likely a dea h in e media e
unable o u he e ol e which hampe s he ca aly ic cycle.
Scheme 69. Failed in amolecula e sion o he annula ion o anilide 28a.
We also syn hesized and es ed he naph haleneace amide 18b, which was easily assembled
by an analogous p ocedu e as s a ed be o e. Rema kably, in his case we did obse e
eac i i y bu , ins ead o o ming he indole esul ing om a (3+2) annula ion, we obse ed
he (4+2) adduc 19 in he absence o he chlo ine sca enge while wi h he addi ion o he
sil e sal , decomposi ion o he s a ing ma e ial was obse ed. The o ma ion o e acycle
Chap e II.
50
19 can a ionalized assuming ha he 5-membe ed hodacycle IV esul ing om he
ac i a ion o he C8-H bond, can e ol e o he p oduc by N-me alla ion and educ i e
elimina ion.
Scheme 70. In amolecula (4+2) oxida i e annula ion o naph haleneace amide 18b.
In e es ingly, a compe i ion expe imen be ween naph haleneace amide 18b and an ex e nal
alkyne in p esence o a sli e sal , led o he p e e en ial o ma ion o he indole 20 in a 25%
yield. This esul con i ms he iabili y o ac i a ing he C-H bond a he posi ion 8 o he
naph halene, mos p obably in a e e sible manne .
Scheme 71. Compe i ion be ween in e - and in amolecula annula ions o naph haleneace amide 18b.
O e all, he abo e esul s con i m ha a di ec ansla ion o in amolecula oxida i e
annula ions o in amolecula se ings is no ob ious and di e en ac o s can signi ican ly
a ec he eac ion ou come.
3.4 Pa ially in amolecula oxida i e annula ion o benzhyd oxamic de i a i es.
Du ing ou in es iga ions, and jus be o e we submi ed ou wo k o publica ion, he g oup
o Pa k desc ibed an in e es ing s a egy o con ol he egioselec i i y o he annula ion.
Thei idea was based on connec ing he alkyne e he o he benzamide using a clea able N-
O bond. Al hough he eac ion mechanism could be conside ed in amolecula , he equi ed
clea age o he N-O bond o egene a e he ca alys leads o p oduc s simila o hose
ob ained in in e molecula annula ions.111
111 Xu, X.; Liu, Y.; Pa k, C. Angew. Chem. In . Ed. 2012, 51, 9372.
Chap e II.
51
Scheme 72. Rh (III)-ca alyzed semi-in amolecula oxida i e annula ion o benzhyd oxamic acid de i a i es.
Chap e II.
53
4– Conclusions.
In conclusion we ha e de eloped a ully in amolecula e sion o he oxida i e annula ion
o benzamides and alkynes and demons a ed ha i p esen s a wide scope o make a g ea
a ie y o icycles and ha , his chemis y can be ex ended o mo e challenging ac ylamides.
Scheme 73. Oxida i e annula ion o ac yl and benzamides.
Ou mechanis ic s udies p o ide e idences poin ing ha he mig a o y inse ion in o he Rh-
N bond is mo e a o able han he inse ion in o he Rh-C bond, mos p obably because o
geome ic easons. Simila in e molecula p ocesses p e e o p oceed h ough
ca bome alla ion ins ead o aminome alla ions.
Scheme 74. Rh-C s. Rh-N inse ion.
We ha e also demons a ed how, in he case o anilides, e he ing he wo eac i e moie ies
can shu down he eac i i y, while in naph haleneace amides ha ha e o he a ailable C-H
bonds o be ac i a ed, he in amolecula annula ion is possible, in his case leading o
p oduc s which a ise om o mal (4+2) annula ions.112
Scheme 75. Oxida i e annula ion o naph haleneace amides.
112 This wo k was done in collabo a ion wi h D . Noelia Quiñones and published in: Quiñones, N.;
Seoane, A.; Ga cía-Fandiño, R.; Masca eñas, J. L.; Gulías, M. Chem. Sci. 2013, 4, 2874.
CHAPTER III: Assembly o benzoxepines and couma ins by
oxida i e annula ions o
o-
inylphenols.
Chap e III.
57
1– In oduc ion.
1.1 Rele ance o he phenolic co e: Benzoxepines and couma ins.
The phenolic skele on is widely sp ead in a huge a ie y o na u al p oduc s and de i a i es,
ei he in i s ee o m o p o ec ed as cyclic o acyclic e he s o es e s. Many phenol-
con aining p oduc s show highly ele an biological p ope ies113 and he e o e, he
de elopmen o syn he ic access o hese de i a i es is a e y appealing goal.114
Scheme 76. Na u ally occu ing phenols.
Among all he p oduc s wi h phenolic amewo ks, benzoxepines and couma ins s and ou
o hei in e es ing p ope ies. The o me , ha e p o en o ha e an iplasmodial,
an imycobac e ium and an icance ac i i ies as well as o he o he s.115 On he o he hand,
couma ins a e a e sa ile sca old o o ganic syn hesis and p esen a wide ange o
in e es ing p ope ies, which esul in hei use in e y di e en ields wi h a ying pu pose
such as luo escence p obes o an icance and an icoagulan d ugs.116 These p ope ies make
benzoxepines and couma ins qui e in e es ing syn he ic a ge s. 117
113 Gomes, C. A.; Gi ão Da C uz, T. G.; And ade, J. L.; Milhazes, N.; Bo ges, F.; Ma ques, M. P. M. J.
Med. Chem. 2003, 46, 5395.
114 (a) Tyman, J. H. P Syn he ic and na u al phenols. Ed. Else ie , 1996. (b) Rappapo , Z.The chemis y o
phenols. Ed. Wiley In e science, 2003.
115(a) Sp ogøe, K.; Manniche, S.; La sen, O.; Ch is ophe sen, C. Te ahed on 2005, 61, 8718. (b) Na i a,
K.; Nakamu a, K.; Abe, Y.; Ka oh, T. Eu . J. O g. Chem. 2011, 4985.
116 Fo he syn hesis and biological p ope ies o couma ins see: (a) Bo ges, F.; Rolei a, F.; Milhazes, N.;
San ana, L.; U ia e, E. Cu . Med. Chem. 2005, 12, 887. (b) Musa, M. A.; Coope wood, J. S.; Khan, M. O.
F. Cu . Med. Chem. 2008, 15, 2664. Wagne , B. D. Molecules 2009, 14, 210.
117 Fo he syn hesis o oxepines see: Snyde , N. L.; Haines, H. M.; Peczuh, M. W. Te ahed on 2006, 62,
9301.
Chap e III.
64
Scheme 90. Oxida i e ca bonyla ion o o- inylphenols.
In 2013, Iwasawa epo ed a ela ed ca bonyla ion using CO2 ins ead o CO, while being able
o lowe he gas p essu e o 1 a m. In his wo k hey desc ibe he Palladium-ca alyzed C-H
ac i a ion o he ole in one uni o inylphenol ollowed by coo dina ion by a second
molecule o inylphenol. The e e sible nucleophilic ca boxyla ion o he me allacycle leads
o palladacyle II which eac s wi h ano he molecule o inylphenol and base o a o d he
couma in wi h he egene a ion o he cyclome alla ed in e media e I. 131
Scheme 91. Oxida i e ca bonyla ion o o- inylphenols.
131 Sasano, K.; Takaya, J.; Iwasawa, N. J. Am. Chem. Soc. 2013, 135, 10954.
Chap e III.
65
F om he abo e discussion i seems clea ha , eadily a ailable phenols and de i a i es can
be ans o med in o a a ie y o p oduc s, including se e al oxacycles, using ca aly ic
p ocesses in ol ing C-H ac i a ions, gene ally di ec ed by he phenolic OH g oup. Howe e ,
he numbe o ans o ma ions is s ill limi ed, and many challenges ela ed wi h syn he ic
and mechanis ic aspec s o hese ans o ma ions emain o be app oached.
Chap e III.
67
2– Objec i es.
Conside ing he p eceden s on he C-H unc ionaliza ion o phenols, i was unce ain o us
which would be he eac i i y o o- inylphenols in he p esence o an alkyne when ea ed
unde condi ions ha p omo e C-H ac i a ions. As indica ed in scheme 92, inylphenols
con ain se e al po en ially clea able ca bon-hyd ogen bonds and depending on he p ocess,
di e en possible annula ion p oduc s could be o med. 120,123,132 In pa icula , and aking in o
accoun he p eceden o ca bonyla ion eac ions, we we e pa icula ly a ac ed by he
possibili y o ac i a ing he e minal C-H bonds and in his way, gaining access o
benzoxepines, which had no been ob ained using his chemis y.
In p inciple we en isioned o in es iga e he pe o mance o hese subs a es in p esence o
Rh (III) ca alys s since hey had p o en hei u ili y in o he annula ions wi h alkynes.
Scheme 92. Gene al objec i e.
Al e na i ely, he use o ca bon monoxide as eac ion pa ne migh p o ide an a ac i e,
a om economical and mild en y o couma ins.
Scheme 93. Syn hesis o couma ins.
120 Miu a, M.; Tsuda, T.; Sa oh, T.; Nomu a, M. Chem. Le . 1997, 11, 1103.
123 Ku am, M. R.; Bhanuchand a, M.; Sahoo, A. K. Angew. Chemie. In . Ed. 2013, 52, 4607.
132 Hu, J.; Hi ao, H.; Li, Y.; Zhou, J. Angew. Chemie. In . Ed. 2013, 52, 8676.
Chap e III.
69
3– Resul s and discussion.
3.1 Op imiza ion o he eac ion condi ions.
To s udy he iabili y o he eac ion, we syn hesized model he subs a e 23a by a Wi ig
eac ion om comme cially a ailable salicylaldehyde in 96% yield.
Scheme 94. Syn hesis o model subs a e 23a.
Wi h he model subs a e in hand we s a ed o explo e i s pe o mance unde di e en
condi ions wi h diphenylace ylene as eac ion pa ne . As shown in able 2, using Rh
ca alysis we obse ed he o ma ion o he benzoxepin p oduc . The eac ion wo ks in a
a ie y o sol en s (en ies 1,4, 5) being ace oni ile he one ha gi es be e yield ising om
51 o 91% e en educing he amoun o coppe (en y 6). I is also possible o educe he
equi alen s o alkyne oxidan o 1.5, which e en allowed o sligh ly inc ease he yield o an
excellen 96% (en y 7). Dec easing he amoun o Coppe ace a e o 10 mol% he eac ion is
slowe and he yield d ops o an 87% (en y 8). O he me als ailed o yield he oxepin, ei he
due o lack o con e sion wi h an i idium Cp* complex (en y 2) o decomposi ion o he
inylphenol wi h a Ru ca alys (en y 3). We also con i med ha he hodium is c ucial o
he eac ion since i s omission leads o no con e sion o he s a ing ma e ials.
Table 2. Sc eening o he eac ion condi ions
En y
Ca alys
38a (equi )
Sol en
T (°C)
Yield (%)b
1
[Cp*RhCl2]2
2
Toluene
100
52
2
[Cp*I Cl2]2
2
Toluene
100
0c
3
[Ru(p-cymene)Cl2]2
2
Toluene
100
T acesd
4
[Cp*RhCl2]2
2
DMF
100
72
5
[Cp*RhCl2]2
2
-AmOH
100
83
6
[Cp*RhCl2]2
2
CH3CN
85
91e
7
[Cp*RhCl2]2
1.5
CH3CN
85
97e
8
[Cp*RhCl2]2
1.5
CH3CN
85
87
9
none
1.5
CH3CN
85
0c
a Reac ion condi ions: 32a (0.33 mmol), ca alys (2.5 mol %), Cu(OAc)2·H2O (2.1 equi ), sol en (2 mL). b Isola ed
yield. c Reco e y o he s a ing ma e ials. d Complex mix u e. e 0.5 equi o Cu(OAc)2·H2O/ai balloon we e
used. 0.1 equi o Cu(OAc)2·H2O/ai balloon we e used, 16h.
Chap e III.
70
3.2 Subs a e scope.
Wi h he op imized condi ions in hand, we p oceeded o s udy he scope o he eac ion wi h
ega d o he alkyne. Symme ical alkynes bea ing elec on- ich o elec on-poo subs i uen s
e icien ly pa icipa e in he eac ion leading o he desi ed oxepines in good yields (25ab and
25ac), alkynes bea ing alipha ic subs i uen s can also be used, al hough he yield d ops o
abou 50% (25ad and 25ae). I is also possible o use alkynes wi h silyloxy subs i uen s as
well wi h es e s o ee hyd oxyl g oups (25a , 25ah and 25ai). In e es ingly unsymme ical
alkynes a o d he co esponding p oduc s wi h selec i i ies up o 14:1 (25ag).
a Reac ion condi ions: 23 (0.33 mmol), 29 (1.5 equi ), [Cp*RhCl2]2 (2.5 mol%), Cu(OAc)2·H2O (0.5 equi ), CH3CN (2
mL), 85°C. b Isola ed yields based on 29.
Scheme 95. Scope o he alkynes.
To examine he scope wi h espec o he phenols, we syn hesized se e al hyd oxys y enes
using he same p ocedu e shown in scheme 94.133 As disclosed abo e, eac ion ole a es
di e en elec onically biased a oma ic ings wi h subs i u ion a di e en posi ions. When
elec on-dona ing g oups a e placed a he pa a posi ion o he hyd oxyl, he expec ed
oxepines a e ob ained in good o excellen yields (25ba-25da). The same scena io happens o
elec on-wi hd awing subs i uen s (25ea-25ga). The o ho posi ion o he phenol can also be
subs i u ed wi h no changes in he eac i i y. Mo eo e , he eac ion is also una ec ed by
subs i u ion a he pa a posi ion o he double bond leading o p oduc s (25ha-25ka) in good
o excellen yields. Howe e , when he in e nal posi ion o he alkene is subs i u ed wi h a
me hyl g oup he oxepin is ob ained in low yields in a o o wo di e en byp oduc s
133 In collabo a ion wi h Noelia Casano a
Chap e III.
71
(25na). In e es ingly he eac ion is no e icien when he e is subs i u ion a he o ho
posi ion o he ole in o a he double bond leading o an 8% yield and a complex mix u e o
p oduc s espec i ely (25ma, 25oa).
a Reac ion condi ions: 23 (0.33 mmol), 29 (1.5 equi ), [Cp*RhCl2]2 (2.5 mol%), Cu(OAc)2·H2O (0.5 equi ), CH3CN (2
mL), 85°C. b Isola ed yields based on 29. c Complex mix u e. d Isola ed wi h wo di e en byp oduc s.
Scheme 96. Scope o he o- inylphenols.
The s uc u e o he p oduc s was unambiguously con i med by X-Ray di ac ion o oxepine
25aa as seen below.
Fig 5. S uc u e o 25aa ob ained by X-Ray di ac ome y.
To elucida e he egiochemis y o he p oduc s a isen om when unsymme ical alkynes
whe e used, we ca ied ou nOe expe imen s be ween he alipha ic side chain o he alkyne
and he hyd ogen a C4, as exempli ied below.
Chap e III.
72
Fig 6. De e mina ion o he egiochemis y o 25ag by nOe.
In summa y, we ha e desc ibed a new and a ac i e me hod o making a a ie y o
benzoxepines om i ial s a ing ma e ial.
3.3 (5+1) annula ion owa ds couma ins.
A e he good esul s o he (5+2) annula ion, we wonde ed whe he i was possible o use
ca bon monoxide as coupling pa ne in o de o ob ain couma ins. G a i yingly, when o-
inylphenol was ea ed unde he eac ion condi ions in an a mosphe e o ca bon monoxide
and 1.2 equi alen s o coppe ace a e, he co esponding couma in was ob ained (28a). The
eac ion also wo ks e icien ly wi h elec on-poo o elec on- ich subs i uen s (28b and 28c).
In e es ingly, in con as o he annula ions o alkynes, he ca bonyla ion ole a es
subs i u ion a he in e nal posi ion and he e o e, couma in 28d can be isola ed in an 84%
yield.
a Reac ion condi ions: 27 (0.5 mmol), [Cp*RhCl2]2 (2.5 mol%), Cu(OAc)2·H2O (1.2 equi ),
CH3CN (2 mL), 85°C. o e nigh .
Fig 7. Scope o he ca bonyla ion.
3.4 Mechanis ic in es iga ions.
In an e o o ob ain mechanis ic in o ma ion abou his ans o ma ion, we ca ied ou
se e al expe imen s. Fi s o all we pe o med a compe i ion be ween phenols 23a and 23 .
When bo h a e mixed oge he , he elec on poo 23 eac s p e e en ially leading o an 8:1
mix u e o bo h oxepines.
Chap e III.
73
Scheme 97. Compe i ion be ween 25aa and 25 a.
Howe e , when he eac ions a e ca ied ou in sepa a e essels he o ma ion o 25aa is
as e . This di e gence can be explained in e ms o an i e e sible o ma ion o a phenoxide-
Rh complex ha should be easie o mo e acidic p o ons while, u he s eps could be
a o able o mo e elec on- ich subs a es.
Scheme 98. Reac ion yields a e 10 min o eac ion o 25aa and 25 a.
We also measu ed he ela i e eac ion a es be ween s anda d inylphenol and an elec on-
poo coun e pa , wi h a i luo ome hyl subs i uen pa a o he ole in. Like in he p e ious
25aa
25 a
Chap e IV.
81
1– P eceden s.
1.1 Isola ion o he spi ocycle.
As commen ed be o e, while wo king on he annula ion o o- inylphenols and alkynes, we
obse ed ha , when a me hyl subs i uen was loca ed a he in e nal posi ion o he double
bond only a 15% o he benzoxepin was obse ed in a o o wo di e en byp oduc s.
Isola ion o hose p oduc s allowed us o cha ac e ize he as he dea oma ized spi ocycle
31aa and he azulenone 32aa.
Scheme 105. Di e en p oduc s a ising om he oxida i e annula ion o alkenylphenols wi h alkynes.
This unexpec ed and in iguing eac i i y p omp ed us o u he in es iga e his
ans o ma ion o u he op imize i and unde s and he mechanism.
1.2 Dea oma iza ion o phenols.
Al hough ene ge ically un a o able, he dea oma iza ion o a oma ic ings is a powe ul way
o ob aining new s uc u es wi h inc eased molecula complexi y o m simple plana
s uc u es.137 In pa icula , phenols a e common subs a es o hese ans o ma ions since
he lone pai o he he e oa om allows o an easie b eaking o he a oma ici y.138 An
example o his app oach is he syn hesis o he co e o Ryanodine by Deslongchamps in
1969.139
Scheme 106. Syn he ic app oach owa ds Ryanodine.
Among he many ways o inducing he dea oma iza ion o phenols, he oxida ion o
quinones140 and he gene a ion o quinone me hides141 s and ou o hei e sa ili y and
137(a) Mande , L. N. Synle 1991, 134. (b) Roche, S. P.; Po co, J. A. Angew. Chemie. In . Ed. 2011, 50, 4068.
138 Quideau, S.; Pouységu, L.; De ïeux, D. Synle 2008, No. 4, 467.
139 Be ney, D.; Deslongchamps, P. Can. J. Chem. 1969, 47, 515.
140 Magdziak, D.; Meek, S. J.; Pe us, T. R. R. Chem. Re . 2004, 104, 1383.
Chap e IV.
82
nume ous p oduc s ha e been syn hesized by using hese me hodologies. An example can
be seen in he o al syn hesis o Elisaeb hin A by he g oup o Mulze in 2003.142 Thei
p ocedu e in ol es he gene a ion o a highly eac i e dea oma ized quinone ha unde goes
a as in amolecula Diels-Alde cycloaddi ion o p oduce he co e o he na u al p oduc .
Scheme 107. Key s ep in he o al syn hesis o Elisabe hin A.
The use o o ho quinone me hides is exempli ied in he o al syn hesis o (±)-Alboa in by
Baldwin and co-wo ke s which also in ol es a Diels-Alde cycliza ion al hough in his case,
he quinone is he diene ins ead o he dienophile.143 O he me hods o he dea oma iza ion
o phenols ely on pho oisome iza ions, oxida ions o acid o base-media ed elimina ion.138
Scheme 108. Key s ep in he o al syn hesis o (±)-Alboa in.
141 Van de Wa e , R. W.; Pe us, T. R. R. Te ahed on 2002, 58, 5367. To e a, M. M.; Richa d, J. P. Ad .
Phys. O g. Chem. 2011, 45, 39
138 (a) Mande , L. N. Synle 1991, 134. (b) Roche, S. P.; Po co, J. A. Angew. Chemie. In . Ed. 2011, 50,
4068.
142 Heck od , T. J.; Mulze , J. J. Am. Chem. Soc. 2003, 125, 4680.
143 Rod iguez, R.; Adling on, R. M.; Moses, J. E.; Cowley, A.; Baldwin, J. E. O g. Le . 2004, 6, 3617.
Chap e IV.
83
In addi ion o he a o emen ioned me hods, ansi ion me als can also p omo e eac ions ha
in ol e he dea oma iza ion o phenolic de i a i es.144 In 2011, Buchwald and co-wo ke s
de eloped an a yla i e dea oma iza ion ca alyzed by Pd (0). They also demons a ed ha he
eac ion could be pe o med in an enan ioselec i e manne by using chi al phosphines.145
Scheme 109. Pd(0)-ca alyzed dea oma izing a yla ion o phenols.
La e , while we we e wo king in he syn hesis o he oxepines and couma ins, Luan and co-
wo ke s published a Ru(II)-ca alyzed dea oma izing oxida i e annula ion o naph hols wi h
alkynes. Al hough no explana ion is gi en, in he same communica ion hey epo ha ,
when phenols a e used ins ead o naph hols, he eac ion deli e s less han a 5% o he
spi ocyle146
Scheme 110. Ru(II)-ca alyzed dea oma izing annula ion o naph hols.
Thei mechanis ic hypo hesis s a s wi h he o ma ion o he ac i e ca aly ic species
ollowed by a hyd oxyl di ec ed C-H ac i a ion. A mig a o y inse ion o he alkyne leads o
he eigh -membe ed me allacycle II which, o elease he s ain, e ol es h ough ke o
au ome iza ion owa ds he u henacyle III. A inal educ i e elimina ion yields he
spi ocyle and he educed ca alys which is u he eoxidized by he coppe ace a e.
144 Fo selec ed examples see (a) Wiegand, S.; Scha e , H. J. Te ahed on 1995, 51, 5341. (b) Nemo o, T.;
Ishige, Y.; Yoshida, M.; Kohno, Y.; Kanema su, M.; Hamada, Y. O g. Le . 2010, 12, 5020. (c) Wu, Q.;
Liu, W.; Zhuo, C.; Rong, Z.; Ye, K.; You, S. Angew. Chem. In . Ed. 2011, 50, 4455.
145 Rousseaux, S.; Ga cía-Fo ane , J.; Del Aguila Sanchez, M. A.; Buchwald, S. L. J. Am. Chem. Soc.
2011, 133, 9282.
146 Nan, J.; Zuo, Z.; Luo, L.; Bai, L.; Zheng, H.; Yuan, Y.; Liu, J.; Luan, X.; Wang, Y. J. Am. Chem. Soc.
2013, 135, 17306.
Chap e IV.
84
Scheme 111. Mechanis ic hypo hesis.
1.3 Hyd oxyl-di ec ed syn hesis o spi ocycles by oxida i e annula ion.
A ela ed example was de eloped a he g oup o Lam by using u henium ca alysis and 1,3
dike ones ha ac as masked enols.147
Scheme 112. Ru(II)-ca alyzed dea oma izing annula ion o designed dike ones.
The p oposed mechanism s a s wi h a ke o-enol au ome iza ion and hyd oxyl-di ec ed C-H
ac i a ion o gi e in e media e I. This u henacyle e ol es ia mig a o y inse ion leading o
he oxa-π-allyl u henium, which can also be depic ed as he C- o O- bound o ms. Finally a
C-C educ i e elimina ion a o ds he spi odike one and he educed Ru henium ca alys .
Coppe ace a e may oxidize he Ru (0) o Ru (II) which is einco po a ed in o he ca aly ic
cycle
147 Chidipudi, S. R.; Khan, I.; Lam, H. W. Angew. Chem. In . Ed. 2012, 51, 12115.
Chap e IV.
85
Scheme 113. Mechanis ic hypo hesis.
The same g oup epo ed an in e es ing ca alys -dependan di e gen eac i i y. Using
sligh ly di e en subs a es, hey we e able o assemble icyclic ch omenes wi h u henium
while a palladium-ca bene based ca alys a o ded he p e iously desc ibed spi ocycles. In
hei communica ion, he au ho s we e unable o cla i y he eason behind his ca alys -
dependan di e gence.148
Scheme 114. Di e gen oxida i e annula ion o speci ic dike ones.
The g oup o Wang also epo ed a palladium-ca alyzed (2+2+1) annula ion be ween
hyd oxycouma ins and alkynes leading o spi ocyclopen adienech oman-2-4,diones. In hei
epo hey explain he eac ion in e ms o he ac i a ion o he ole inic C-H bond o he
couma in ollowed by wo consecu i e mig a o y inse ions leading o in e media e I which,
a e a cyclopallada ion d i en by he con e sion o he enol in o a ke one, yields he six-
membe ed in e media e III. This in e media e unde goes educ i e elimina ion eleasing he
148 Dooley, J. D.; Reddy Chidipudi, S.; Lam, H. W. J. Am. Chem. Soc. 2013, 135, 10829.
Chap e IV.
86
spi ocycle and eoxida ion o he ca alys o eini ia e he cycle.149 This me hodology was
la e applied by Luan using naph hols as he one-a om componen .150
Scheme 115. (2+2+1) oxida i e annula ion o he syn hesis o spi ocycles.
1.3 Spi ocycles as a syn he ic goal.
Spi ocyclic compounds a e ele an ,151 no only due o hei unique s uc u al p ope ies
which ha e been used in o de o build chi al ligands, 152 bu also because o hei p esence in
se e al na u al p oduc s. 153 In pa icula , spi o[5.4]nonane sys ems a e qui e common in
many e penes o na u al o igin. This is why me hods leading o hem a e o high in e es .154
Scheme 116. Na u ally occu ing p oduc s and chi al ligand con aining spi ocycles.
149 Peng, S.; Gao, T.; Sun, S.; Peng, Y.; Wu, M. Ad . Syn h. Ca al. 2014, 356, 319.
150 Gu, S.; Luo, L.; Liu, J.; Bai, L.; Zheng, H. O g. Le . 2014, No. Ii, 10.
151 (a) K apcho, P. A. Syn hesis. 1974, 383. (b) Sannig ahi, M. Te ahed on 1999, 55, 9907.
152 Ding, K.; Han, Z.; Wang, Z. Chem. Asian. J. 2009, 4, 32.
153 Rios, R. Chem. Soc. Re 2012, 41, 1060.
154 Quasdo , K. W.; O e man, L. E. Na u e 2014, 516, 181.
Chap e IV.
87
2– Objec i es.
Conside ing he p eceden s shown abo e, we aimed o u he s udy dea oma izing (3+2)
oxida i e annula ion o o-alkenylphenols wi h alkynes, ying o enhance he selec i i y o
he p ocess owa ds he o ma ion o he spi ocycle.
Scheme 117. Objec i e.
We also wan ed o in es iga e he mechanis ic pa hway and he eason why he subs i uen
o he ole in changes he eac i i y owa ds he spi ocycle. Finally, we also need o p o ide
an explana ion o he o ma ion o he azulenone 32aa.
Chap e IV.
89
3– Resul s and discussion.
3.1 Op imiza ion o he eac ion condi ions.
To accomplish ou goals we s a ed wi h he syn hesis o alkenylphenol 27a as desc ibed
ea lie .
Scheme 118. Syn hesis o model subs a e 47a.
Wi h he model subs a e in hand, we explo ed i s eac i i y agains diphenylace ylene
unde di e en condi ions in o de o imp o e he selec i i y o he ans o ma ion. The
esul s o his sc eening a e summa ized in he able below.
Table 3. Sc eening o he eac ion condi ions.
Yield (%)b
En y
Ca alys
Sol en
T (°C)
50
53aa
54aa
1
[Cp*RhCl2]2
CH3CN
85
15
51
25
2
[Cp*RhCl2]2
-AmOH
100
12
18
15
3
[Cp*RhCl2]22
Toluene
100
8
19
17
4
[Cp*RhCl2]2
CH3CN
44
4
5
[Cp*RhCl2]2
CH3CN
40
97c
T aces
6
[Cp*RhCl2]2
CH3CN
40
91d
8
7
[Ru(p-cymene)Cl2]2
CH3CN
40
15
5e
8
Pd(OAc)2
CH3CN
40
<10
-e
9
none
CH3CN
85
-
-
-
a Reac ion condi ions: 27a (0.33 mmol), ca alys (2.5 mol %), alkyne (1.5 equi ), Cu(OAc)2·H2O (0.5 equi ), sol en (2
mL), ai balloon. b Isola ed yield. c In 2h. d 0.1 equi o Cu(OAc)2·H2O/ai balloon we e used, 16h. e
Decomposi ion o he alkenylphenol. b S a ing ma e ials we e eco e ed.
As seen abo e, he eac ion wo ks p oduc i ely in ace oni ile, and leads o lowe o e all
yields when o he sol en s a e used (en ies 1-3). The eac ion also wo ks a oom
empe a u e al hough he yield d ops o a 44% bu , in his case, no benzoxepin is o med
(en y 4). When he eac ion is ca ied ou a 40 °C and s opped a e wo hou s, only he
spi ocycle 53aa is o med wi h aces o he azulenone 54aa (en y 5). I is e en possible o
lowe he amoun o coppe oxidan o 10 mol % by inc easing he eac ion ime wi hou
diminishing he o e all yield, al hough a sligh ly highe p opo ion o he azulenone is
Chap e IV.
96
This in e con e sion be ween spi ocycle and azuleneone can be explain in e ms o he
o ma ion o a zwi e ionic species and he subsequen ing-opening o he esul ing
icycle.158
Scheme 131. Fo ma ion o he azulenone.
158 (a) a [1,5] sigma opic ea angemen o a adical-based mechanism a e also plausible: Spangle , C.
W. Chem. Re . 1976, 76, 187. (b) Fo a ecen , ela ed ea angemen see: Li, X.-Y.; Yang, Y.-F.; Peng, X.-
R.; Li, M.-M.; Li, L.-Q.; Deng, X.; Qin, H.-B.; Liu, J.-Q.; Qiu, M.-H. O g. Le . 2014, 16, 2196.
Chap e IV.
97
4- Conclusions.
In conclusion we ha e de eloped a mild o mal (3+2) annula ion be ween o- inylphenols
and alkynes p omo ed by hodium (III) ca alysis ha p o ides s uc u ally in e es ing
spi ocycles. This ans o ma ion con eys a clea age o he O-H and a C-H bond, and he
dea oma iza ion o he phenolic ing. The eac ion akes place wi h excellen chemo and
egioselec i i y gene a ing chi ali y o m simple, plain s uc u es.
Scheme 132. Oxida i e annula ion o o- inylphenol.
Scheme 133. Di e gence o ou comes depending on he subs i u ion.
Ou s udies also sugges ha om eadily a ailable subs a es, namely o-alkenylphenols and
alkynes i is possible o ob ain ele an and s uc u ally un ela ed p oduc s such as
azulenones.159
Scheme 134. Syn hesis o azulenones o m o-alkenylphenols.
159 These esul s we e published in: Seoane, A.; Casano a, N.; Quiñones, N.; Masca eñas, J. L.; Gulías,
M. J. Am. Chem. Soc. 2014, 136, 7607.
CHAPTER V: Oxida i e annula ions o
o-
alkenylanilines.
Chap e V.
101
1– In oduc ion
A e de eloping he annula ion chemis y o o-alkenylphenols, we wonde ed whe he i was
possible o ansla e hei chemis y o ni ogen-con aining molecules. The mo i a ions
behind his goal ely on he p e alence o ni ogen a oms in d ugs and bioac i e compounds.
In ac , i we could o eplica e he same (5+2) annula ion pe o med wi h phenols o anilines
we would be able o access o benzazepines, a common mo i in se e al pha maceu icals and
na u al p oduc s.160
Scheme 135. Biologically ac i e and na u ally occu ing [1] benzazepines.
1.2 Reac i i y o o-alkenylanilines.
Unlike p e iously desc ibed o- inylphenols, which whe e sca cely used in he li e a u e,
he e a e se e al p eceden s o he use o o-alkenylanilines in syn hesis. Thei use s a ed
wi h he pionee ing wo k o Dewa and Die z whe e hey ea ed hem wi h bo on
ichlo ide which allowed he isola ion o a cyclic compound isos e ic o naph halene.161
Scheme 136. Syn hesis o he naph halene isos e e.
La e , Hegedus and co-wo ke s desc ibed ha ea men o alkenylanilines, ei he ee o
osyl p o ec ed, unde Palladium ca alysis a o ded indoles by cycliza ion. Thei mechanis ic
hypo hesis s a s wi h he coo dina ion o he palladium o he ole in and nucleophilic a ack
160 Shah, J. H.; Hindupu , R. M.; Pa i, H. N. Cu . Bioac . Compd. 2015, 11, 170.
161 Dewa , M. J. S.; Die z, R. J. Chem. Soc. 1959, 2728.
Chap e V.
102
by he ni ogen. Finally, a β-hyd ide elimina ion and eoxida ion o he ca alys close he
cycle and yields he indoles in a mode a e yield.162
Scheme 137. Palladium-ca alyzed cycliza ion o o-alkenylanilines.
The g oup o La ock imp o ed he ca aly ic sys em by using Palladium ace a e and oxygen
as oxidan . Wi h hose condi ions, hey we e able o expand he scope o di e en amines
albei in lowe yields. In e es ingly, when ha ing a me hyl a he inne posi ion o he double
bond, he eac ion can be pe o med a lowe empe a u es and he 3-me hylene-2,3-
dihyd oindole 34 is ob ained ins ead o he expec ed indole.163
Scheme 138. La ock’s syn hesis o indoles.
Following his wo k, o he me als164 we e used o ca y ou his syn hesis. Pho oca aly ic165
and e en me al- ee condi ions166 we e also de eloped by di e en esea ch g oups.
La ock and co-wo ke s also designed a me hod o syn hesizing dihyd oquinolinones by
using he same osylanilides and inylic (pseudo)halides in a o mal (5+1) annula ion.167
162 (a) Hegedus, L. S.; Allen, G. F.; Bozell, J. J.; Wa e man, E. L. J. Am. Chem. Soc. 1978, 100, 5800. (b)
Ha ing on, P. J.; Hegedus, L. S. J. O g. Chem. 1984, 49, 2657.
163 La ock, R. C.; High owe , T. R.; Has old, L. A.; Pe e son, K. P. J. O g. Chem. 1996, 61, 3584.
164 (a) Coleman, C. M.; O’Shea, D. F. J. Am. Chem. Soc. 2003, 125, 4054. (b) Liwosz, T. W.; Chemle , S. R.
Chem. Eu . J. 2013, 19, 12771. (c) Youn, S. W.; Ko, T. Y.; Jang, M. J.; Jang, S. S. Ad . Syn h. Ca al. 2015,
357, 227.
165 Mai y, S.; Zheng, N. Angew. Chemie. In . Ed. 2012, 51, 9562.
166 Jang, Y. H.; Youn, S. W. O g. Le . 2014, 16, 3720.
167 (a) La ock, R. C.; High owe , T. R.; Has old, L. A.; Pe e son, K. P. J. O g. Chem. 1996, 61, 3584. (b)
La ock, R. C.; Pace, P.; Yang, H. Te ahed on Le . 1998, 39, 2515.
Chap e V.
103
Scheme 139. La ock’s o mal (5+1) annula ion.
Thei mechanis ic explana ion consis s o an ini ial educ ion o palladium ace a e and
oxida i e addi ion o he a yl (pseudo)halide. Subsequen mig a o y inse ion and β-hyd ide
elimina ion lead o he diene II. F om his in e media e, he palladium mig a es o he ou e
ole in, which unde goes a mig a o y inse ion leading o π-allyl V. This species su e s a
nucleophilic a ack om he amine eleasing he p oduc and he educed ca alys , which is
now able o een e he cycle by adding on o he C-X bond.
Scheme 140. Mechanis ic hypo hesis.
The g oup o Takemo o employed an oxida i e addi ion o di ec he palladium C-H
ac i a ion in he syn hesis o indolinones. Thei mechanis ic hypo hesis s a s wi h he
oxida i e addi ion o he Pd (0) in o he C-CN bond on he anilide which is ollowed by he
Chap e V.
104
mig a o y inse ion o he alkenyl uni . A inal educ i e elimina ion a o ds he indolinone
and eleases he ac i e ca alys .168
Scheme 141. Palladium-ca alyzed syn hesis o indolinones.
In 2010, Buchwald and co-wo ke s also ook ad an age o an oxida i e addi ion-di ec ed
s a egy o syn hesize se e al ni ogen-con aining he e ocycles. They we e able o con ol he
selec i i y o he C-H ac i a ion by he use o di e en phosphines. In hei communica ion,
hey also explained he o ma ion o he dibenzazepine 35 in e ms o a palladium-induced
dea oma iza ion/ ea oma iza ion mechanism.169
168 Kobayashi, Y.; Kamisaki, H.; Takeda, H.; Yasui, Y.; Yanada, R.; Takemo o, Y. Te ahed on 2007, 63,
2978.
169 Ts elikho sky, D.; Buchwald, S. L. J. Am. Chem. Soc. 2010, 132, 14048.
Chap e V.
105
Scheme 142. Di e gen syn hesis o he e ocycles om (N-a yl) inylanilines.
You e al. de eloped an in e es ing wo k on he allyla ion o inylanilines by using I (I)
ca alysis and allylic ca bona es. They we e also able o couple he allyla ion wi h an
in amolecula amina ion o he syn hesis o dihyd obenzazepines.170
Scheme 143. I (I)-ca alyzed allyla ion and andem allyla ion-cycliza ion o o- inylanilines wi h allylic
ca bona es.
170 (a) He, H.; Liu, W. B.; Dai, L. X.; You, S. L. J. Am. Chem. Soc. 2009, 131, 8346. (b) He, H.; Liu, W. B.;
Dai, L. X.; You, S. L. Angew. Chemie. In . Ed. 2010, 49, 1496. (c) (d) Ye, K.-Y.; Dai, L.-X.; You, S.-L. Asian
J. O g. Chem. 2013, 2, 244.
Chap e V.
112
Fig 8. X-Ray s uc u e o naph hylamides 39aa and 39aa’.
3.2 Op imiza ion o he eac ion condi ions.
Once es ablished ha he i la e g oup was p o iding he app op ia e elec onics o he
eac i i y, we s a ed o in es iga e he bes condi ions o achie e his unusual
ans o ma ion.
Table 5. Sc eening o ca alys .a
En y
Ca alys
Yield 61aa (%)b
Yield 61aa’ (%)b
1
[Cp*RhCl2]2
28
16
2
RhCl3· xH2O
0
0c
3
Rh(PPh3)3Cl
T aces
T acesc
4
[Cp*I Cl2]2
0
0c
5
[(p-cymene) RuCl2]2
0
0c
6
Pd(OAc)2
0
0c
a Reac ion condi ions: 37a (0.33 mmol), 29a (1 equi ), ca alys (5 mol %), Cu(OAc)2·H2O (1 equi ), ace oni ile (2
mL). b Isola ed yield. c S a ing ma e ial was mos ly eco e ed.
We s a ed by iden i ying he app op ia e p eca alys o his ans o ma ion. To do so, we
es ed se e al me al complexes wi h only [Cp*RhCl2]2 leading o app eciable con e sions
(en y 1). F om he o he p eca alys s sc eened, I and Ru complexes as well as RhCl3· xH2O
did no lead o any p oduc and s a ing ma e ials we e mos ly eco e ed (en ies 2, 4, 5).
Wilkinson’s ca alys wo ked sligh ly be e p o iding aces o he cycloadduc s along wi h
s a ing ma e ial, while palladium ace a e led o he decomposi ion o he anilide and a
complex mix u e o p oduc s.
Chap e V.
113
Table 6. Sc eening o condi ions.a
En y
Sol en
Ca alys
Addi i e
(equi )
Yield 39aa
(%)b
Yield 39aa’
(%)b
1
Toluene
[Cp*RhCl2]2
-
32
12
2
E OH
[Cp*RhCl2]2
-
32
14
3
TFE
[Cp*RhCl2]2
-
18
7
4
AcOH
[Cp*RhCl2]2
-
0
0
5
-AmOH
[Cp*RhCl2]2
-
30
16
6c,d
DMF
[Cp*RhCl2]2
-
35
17
7c
DMF
[Cp*RhCl2]2
-
T aces
T aces
8
Dioxane
[Cp*RhCl2]2
-
60
19
9
Dioxane
[Cp BuRhCl2]2
-
21
9
10
Dioxane
[CpiP RhCl2]2
-
38
29
11
Dioxane
[Cp*RhCl2]2
AcOH (2)
57
20
12
Dioxane
[Cp*RhCl2]2
Pi OH (2)
56
21
13
Dioxane
[Cp*RhCl2]2
CsOAc (2)
35
17
14
Dioxane
[Cp*RhCl2]2
CsOPi (2)
56
23
15
Dioxane
[Cp*RhCl2]2
AgSbF6 (0.2)
0
0
16e
Dioxane
[Cp*RhCl2]2
19
5
17
Dioxane
[Cp*RhCl2]2
57
24
18
Dioxane
0
0
a Reac ion condi ions: 37a (0.33 mmol), 29a (1 equi ), ca alys (5 mol %), Cu(OAc)2·H2O (1 equi ), addi i e, sol en
(2 mL). b Isola ed yield. c Reac ion pe o med a 110 °C, s a ing ma e ial was eco e ed. d AgOAc (1 equi ) was
used ins ead o Coppe ace a e. e Reac ion pe o med a 60 °C. 0.5 equi o Coppe ace a e we e used.
A e inding he bes ca alys o he ans o ma ion, we es ed di e en sol en s and
addi i es o u he imp o e he eac ion. Among he sc eened sol en s, he bes one p o ed
o be dioxane leading o a 79% o e all yield in a 3:1 a io o egioisome s (en y 8) unde his
condi ions, he eplacemen o he Cp*Rh p eca alys wi h he analogous Cp Bu and CpiP led
o lowe yields (en ies 9, 10). Also, he addi ion o ei he acids o bases did no a ec he
pe o mance o he eac ion (en ies 11-14) while he use o a sil e sal as chlo ine sca enge
a o ded he decomposi ion o he anilide. Lowe ing he empe a u e o 60 °C esul ed in he
o e all yield d opping o a 24% (en y 16) and educing he amoun o coppe ace a e o 0.5
equi alen s does no a ec he eac ion (en y 17). Finally we con i med he equi emen o
he ca alys since, in i s absence, s a ing ma e ials a e mos ly eco e ed (en y 18)
We nex sough o check he equi emen o he oxidan by omi ing hem om he eac ion.
To ou su p ise he eac ion could be ca ied ou e en in he absence o coppe sal s as
shown below.
Chap e V.
114
Table 7. Con ol expe imen s.a
En y
Base (equi )
Yield 39aa
(%)b
Yield 39aa’
(%)b
Obse a ions
1
Cu(OAc)2 (0.5)
57
24
2
CsOAc (2)
57
15
3
CsOAc (1)
54
16
4
CsOAc (1)
56
15
Unde A a mosphe e
5
NaOAc (2)
57
16
6
NaOAc (0.5)
53
15
7
CsCO3
0
0
Reco e y o s a ing ma e ial
8
AcOH
0
0
Reco e y o s a ing ma e ial
9
CsOAc (2)
0
0
No Rh, eco e y o s a ing
ma e ial
a Reac ion condi ions: 37a (0.33 mmol), 29a (1 equi ), [Cp*RhCl2]2 (5 mol %), Base, Dioxane (2 mL). b Isola ed yield.
When coppe was omi ed om he eac ion media and cesium ace a e was used as base, he
eac ion s ill ook place ca aly ically a o ding he co esponding naph hylamides in simila
yield o he one ob ained wi h coppe (en ies 1, 2). To ule ou he possibili y ha oxygen
was ac ing ou as an oxidan , we ca ied ou he eac ion wi h a ca e ul ex usion o ai in
deoxygena ed dioxane, ob aining he same esul as be o e. Sodium ace a e was used due o
i s lowe hyg oscopici y and, e en in a ca aly ic way, ep oduced he p e ious esul s
(en ies 4, 5). Nei he cesium ca bona e no ace ic acid we e able o p omo e he eac ion
(en ies 6, 7). Finally, when no hodium ca alys is used unde hese new condi ions, no
con e sion is obse ed and he s a ing ma e ial is eco e ed.
We inally ied he eac ion in THF unde he coppe - ee condi ions which allowed us o
educe he empe a u e and s ill obse e a sligh ly imp o emen o he yield. These
condi ions we e he ones conside ed as op imal o he s udy o he scope.
Scheme 150. “Coppe ee” oxida i e annula ion wi h alkenylanilides.
Chap e V.
115
3.3 Subs a e scope.
Fo s udying he scope o he eac ion we syn hesized di e en anilides. The syn he ic ou e
used was as ollows: When he 2’-aminoace ophenones we e a ailable, a Wi ig eac ion
ollowed by i la ion a o ded he co esponding annula ion p ecu so . When he ke one
was no comme cial we syn hesized i by he addi ion o a G igna d o he co esponding
benzoni ile.
Scheme 151. Syn hesis o he i lylanilides.
When submi ed o he op imized condi ions, di e en ly subs i u ed alkynes unde go he
oxida i e annula ion wi h he model anilide o ob ain he co esponding naph hylamides.
Elec on- ich and elec on-poo dia ylace ylenes a e well ole a ed a o ding he
co esponding egioisome s (39ab and 39ac). In e es ingly, unsymme ical alipha ic and
a oma ic alkynes p o ide only wo o he ou possible egioisome s, his p e e ence,
p obably aking place du ing he mig a o y inse ion, is simila o he one obse ed o he
annula ions wi h phenols in he p e ious chap e s (39ai and 39ag). Alipha ic alkynes
pa icipa e in he eac ion showing highe egioisome ic a ios, all o hem abo e 10:1 (39ad
and 39ae). Despi e he lack o coppe in he eac ion, which migh eac wi h e minal
alkynes, alkynes wi h a hyd ogen subs i uen led o no con e sion a e 16h and he s a ing
ma e ials we e mos ly eco e ed (39al).
Chap e V.
116
a Reac ion condi ions: 39a (0.33 mmol), 29 (1 equi ), [Cp*RhCl2]2 (5 mol %), CsOAc (0.5 equi ), THF (2 mL). b
Isola ed yield. c S a ing ma e ial was eco e ed.
Scheme 152. Scope o he alkynes.
Rega ding he anilides, he eac ion equi es subs i u ion a he in e nal posi ion o he ole in
since, when o- inylanilide was submi ed o he eac ion condi ions, no p og ess was
obse ed and s a ing ma e ial was mos ly eco e ed (39bd). Mechanis ically in e es ing,
when an isop opyl g oup is eplacing he me hyl o he alkene, no p oduc is obse ed
ins ead, we could isola e he isome ized (42) in a 47% while when he subs i uen is an a yl
mo i , ega dless o i s elec onic na u e, he naph hylamides a e isola ed in 66-90% yield
(39dd–39 d). I he e is a me hyl a he e minal posi ion o he alkene, whe he cis o ans
he eac ion does no p oceed a all and s a ing ma e ial is eco e ed (39gd). Same scena io
is obse ed when 2-phenylanilide is used. When he hyd ogen a he pa a posi ion o he
amide is eplaced by a me hyl g oup, he esul ing naph hylamide is isola ed in a 72% yield
(39id). Conce ning he pa a posi ion o he double bond, a me hyl g oup a o ds a sa is ac o y
yield o 59% (39jd) and he s ongly elec on-wi hd awing i luo ome hyl also yields 39kd
in a 61% yield al hough he egioisome ic p opo ion d ops o 5:1. In all o he cases 4-oc yne
was used as he coupling pa ne due o he easie iden i ica ion o he p oduc s and he
ob en ion o highe egioisome ic a ios.
Chap e V.
117
Reac ion condi ions: 37 (0.33 mmol), 29d (1 equi ), [Cp*RhCl2]2 (5 mol %), CsOAc (0.5 equi ), THF (2 mL). b Isola ed
yield. c S a ing ma e ial was eco e ed.
Scheme 153. Scope o he anilides.
3.4 Mechanis ic hypo hesis.
Al hough s ill mo e s udies ha e o be made in o de o es ablish a plausible mechanism, ou
cu en wo king model consis s o he o ma ion o he ac i e ca aly ic species by clea age o
he hodium dime and ligand exchange wi h he ace a es. Ano he ligand exchange wi h he
NH g oup ollowed by he C-H ac i a ion would lead o me allacycle I which, upon
mig a o y inse ion o he alkyne and subsequen p o odeme alla ion, deli e s he open
alkenyl hodium complex II. A second p o odeme alla ion a o ds he diene III which can be
coo dina ed o a Rh (III) species. This in e media e may unde go a ni ogen-media ed
nucleophilic a ack o he hodium a o ding imine IV which, a e β-hyd ide elimina ion
yields spi ocycle V. Rea angemen o his species migh lead o bo h naph hylamines
depending on which bond mig a es178. The hodium hyd ide complex can now eac wi h he
ace ic acid o med in he eac ion eleasing hyd ogen and egene a ing he ca alys .179
178 A simila ea angemen has been desc ibed in a Palladium-media ed s oichiome ic eac ion
ega ding N,N-dime hyla ed o-phenylanilines: Dupon , J.; P e e , M.; Theu el, L.; Ro eel, M. A.; De
Cian, A.; Fische , J. New J. Chem. 1991, 15, 551.
179 This p o ona ion o hyd ides is desc ibed o Manganese in He, R.; Huang, Z. T.; Zheng, Q. Y.;
Wang, C. Angew. Chemie. In . Ed. 2014, 53, 4950.
Chap e V.
118
Scheme 154. Mechanis ic hypo hesis.
O he mechanisms could also be ope a ing. Ano he possibili y is he p o odeme alla ion o
spi ocycle IV ha may elease he ca alys and dihyd onaph hylamides VI and VII which, in
p esence o he oxygen du ing he wo kup, apidly oxidize o he naph hylamides.
Scheme 155. Al e na i e mechanis ic hypo hesis.
A hi d possibili y is a mechanism analogous o he one o he ob en ion o spi ocycles wi h
phenols (see in scheme 129 he p e ious chap e ) leading di ec ly o V which ea angemen
a o ds he naph hylamines. The educed complex could be egene a ed ia oxida i e
Chap e V.
119
addi ion o he ace ic acid and p o ona ion o he Rhodium hyd ide as seen in he i s
mechanism.
Scheme 156. Oxida ion o Rh(I) by coppe ace a e.
Chap e V.
121
4- Conclusions
In conclusion, we ha e de eloped an unp eceden ed Rh (III)-ca alyzed (4+2) oxida i e
annula ion be ween i lyl-p o ec ed o ho-alkenyl anilides o a o d naph hylamines. The
eac ion equi es app op ia e subs i u ion a he ni ogen and leads o he o ma ion o
di e en egioisome s a ising om an appa en 1,2 mig a ion o he alkenyl uni p io o he
annula ion.
We ha e also p o en ha his ans o ma ion occu s e en in he absence o oxygen o coppe
sal s and sodium ace a e alone is able o accomplish his ask. Finally, we ha e p oposed
di e en plausible mechanis ic pa hways o he eac ion, al hough mo e expe imen s ha e
o be done in o de o dis inguish among hose possibili ies.
Chap e VI.
128
ch oma og aphy hexanes:e hyl ace a e 1:3) o ob ain he co esponding a ene 10a (112 mg,
80%).
N-(5-Phenylpen -4-yn-1-yl)benzamide (10): whi e solid. 1H NMR (300 MHz, CDCl3) δ 7.86 –
7.60 (m, 2H), 7.51 – 7.13 (m, 8H), 6.53 (b s, 1H), 3.57 (dd, J = 12.6,
6.4 Hz, 2H), 2.48 ( , J = 6.7 Hz, 2H), 1.99 – 1.77 (m, 2H). 13C NMR
(75 MHz, CDCl3) δ 167.5 (C), 134.5 (C), 131.5 (CH), 131.3 (CH),
128.5 (CH), 128.2 (CH), 127.8 (CH), 126.8 (CH), 123.4 (C), 89.2
(C), 81.6 (C), 39.7 (CH2), 28.2 (CH2), 17.5 (CH2).LRMS (m/z, I) 263
(87), 262 (43) 235 (27) HRMS calcula ed o C18H17NO 263.1310, ound 263.1318.
4-Me hoxy-N-(5-phenylpen -4-yn-1-yl)benzamide (10b): yellow solid. 1H NMR (300 MHz,
CDCl3) δ 7.74 – 7.54 (m, 2H), 7.42 – 7.09 (m, 5H), 6.83 – 6.66
(m, 2H), 6.51 (b s, 1H), 3.73 (s, 3H), 3.53 (d , J = 13.9, 6.9
Hz, 2H), 2.46 ( , J = 6.8 Hz, 2H), 1.92 – 1.80 (m, 2H). 13C
NMR (75 MHz, CDCl3) δ 167.2 (C), 162.1 (C), 131.7 (CH),
128.8 (CH), 128.4 (CH), 127.9 (CH), 126.9 (C), 123.6 (C),
113.72 (CH), 89.5 (C), 81.7 (C), 55.4 (CH3), 39.8 (CH2), 28.4 (CH2), 17.6 (CH2). LRMS (m/z, I)
293 (16), 292 (25), 291 (291), 277 (4).
N-(5-Phenylpen -4-yn-1-yl)-4-( i luo ome hyl)benzamide (10c): yellow solid. 1H NMR (300
MHz, CDCl3) δ 7.82 (d, J = 8.6 Hz, 2H), 7.53 (d, J = 8.5 Hz,
2H), 7.40 – 7.22 (m, 5H), 6.90 (b s, 1H), 3.65 (dd, J = 12.5, 6.3
Hz, 2H), 2.55 ( , J = 6.7 Hz, 2H), 2.08 – 1.83 (m, 2H). 13C
NMR (75 MHz, CDCl3) δ 166.4 (C), 137.9 (C), 133.1 (q, J =
32.8 Hz, C), 131.6 (CH), 128.4 (CH), 128.1 (CH), 127.5 (CH),
125.6 (q, J = 3.5 Hz, CH), 123.4 (C), 120.1 (q, J = 272.4 Hz, C), 89.4 (C), 81.9 (C), 40.2 (CH2), 28.1
(CH2), 17.7 (CH2). LRMS (m/z, I) 331 (74), 330 (27), 312 (13), 302 (23), 277 (15). HRMS
calcula ed o C19H16NOF3 331.1184, ound 331.1187
4-B omo-N-(5-phenylpen -4-yn-1-yl)benzamide (10d): whi e solid. 1H NMR (300 MHz,
CDCl3) δ 7.66 – 7.06 (m, 8H), 6.80 (b s, 1H), 3.53 (dd, J =
12.5, 6.3 Hz, 2H), 2.46 ( , J = 6.7 Hz, 2H), 2.03 – 1.64 (m, 2H).
13C NMR (75 MHz, CDCl3) δδ 166.7 (C), 133.5 (C), 131.7
(CH), 131.6 (CH), 128.6 (CH), 128.4 (CH), 128.0 (CH), 126.1
(C), 123.4 (C), 89.4 (C), 81.8 (C), 40.0 (CH2), 28.2(CH2), 17.6
(CH2).LRMS (m/z, I) 341 (28), 313 (9). HRMS calcula ed o C18H16NOB 341.0415, ound
341.0428.
Chap e VI.
129
3-me hyl-N-(5-phenylpen -4-yn-1-yl)benzamide (10e): whi e solid. 1H NMR (300 MHz,
CDCl3) δ 7.60 – 7.47 (m, 1H), 7.40 – 7.30 (m, J = 6.7, 3.1 Hz,
1H), 7.30 – 7.17 (m, 2H), 6.49 (s, 1H), 3.63 (dd, J = 12.6, 6.4 Hz,
1H), 2.54 ( , J = 6.8 Hz, 1H), 2.30 (s, 1H), 2.01 – 1.86 (m, J = 6.7
Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 167.9 (C), 138.5 (C),
134.7 (C), 132.2 (CH), 131.7 (CH), 128.4 (CH), 128.4 (CH), 127.9
(CH), 127.7 (CH), 124.0 (CH), 123.6 (C), 89.4 (C), 81.7 (C), 39.8 (CH2), 28.4 (CH2), 21.3 (CH3),
17.6 (CH2).
3-me hoxy-N-(5-phenylpen -4-yn-1-yl)benzamide (10 ): whi e solid . 1H NMR (300 MHz,
CDCl3) δ 7.40 – 7.30 (m, 3H), 7.30 – 7.15 (m, 5H), 7.02 – 6.95
(m, 1H), 6.61 (s, 1H), 3.79 (s, 3H), 3.62 (dd, J = 12.6, 6.5 Hz,
2H), 2.53 ( , J = 6.8 Hz, 2H), 1.99 – 1.86 (m, 2H). 13C NMR
(75 MHz, CDCl3) δ 167.6 (C), 159.9 (C), 136.2 (C), 131.7
(CH), 129.6 (CH), 128.3 (CH), 127.9 (CH), 123.6 (C), 118.7
(CH), 117.7 (CH), 112.4 (CH), 89.3 (C), 81.7 (C), 55.5 (CH3), 39.8 (CH2), 28.4 (CH2), 17.5 (CH2).
N-(5-Phenylpen -4-yn-1-yl)-1-naph hamide (10g): whi e solid. 1H NMR (300 MHz, CDCl3) δ
8.34 – 8.13 (m, 1H), 7.90 – 7.69 (m, 2H), 7.61 – 7.11 (m, 9H), 6.60
(b s, 1H), 3.59 (dd, J = 12.6, 6.4 Hz, 2H), 2.50 ( , J = 6.9 Hz,
2H), 2.00 – 1.75 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 170.1
(C), 134.9 (C), 134.0 (C), 131.9 (CH), 130.8 (CH), 130.5 (C), 128.7
(CH), 128.2 (CH), 127.4 (CH), 126.8 (CH), 125.8 (CH), 125.3
(CH), 125.1 (CH),124.0 (C), 89.6 (C), 82.0 (C), 39.9 (CH2), 28.8(CH2), 17.8 (CH2). LRMS (m/z, I)
313 (57), 312 (90), 285 (40).
N-(5-(o-Tolyl)pen -4-yn-1-yl)benzamide (10h): b own oil. 1H NMR (300 MHz, CDCl3) δ 7.77
– 7.52 (m, 2H), 7.48 – 6.89 (m, 8H), 6.53 (b s, 1H), 3.58 (dd, J =
12.5, 6.7 Hz, 2H), 2.61 – 2.40 (m, 2H), 2.32 (s, 3H), 1.97 – 1.77 (m
2H). 13C NMR (75 MHz, CDCl3) δ 167.7 (C), 140.1 (C), 134.6 (C),
132.0 (CH), 131.5 (CH), 129.5 (CH), 128.6 (CH), 127.9 (CH), 127.0
(CH), 125.6 (CH), 123.3 (C), 93.2 (C), 80.6 (C), 39.8 (CH2), 28.6
(CH2), 20.9 (CH3), 17.7 (CH2). LRMS (m/z, I) 277 (59), 259 (28). HRMS calcula ed o
C19H19NO 277.1467, ound 277.1455.
Chap e VI.
130
N-(5-(3,5-Dime hylphenyl)pen -4-yn-1-yl)benzamide (10i): b own solid. 1H NMR (300
MHz, CDCl3) δ 7.66 (dd, J = 7.9, 6.7 Hz, 2H), 7.42 – 7.32 (m,
1H), 7.31 – 7.20 (m, 2H), 6.92 (s, 2H), 6.84 (s, 1H), 6.59 (b s,
1H), 3.56 (dd, J = 12.6, 6.3 Hz, 2H), 2.46 (dd, J = 8.4, 5.0 Hz,
2H), 2.18 (s, 3H), 1.92 – 1.78 (m, 2H). 13C NMR (75 MHz,
CDCl3) δ 168.0 (C), 138.3 (C), 135.1 (C), 131.8 (CH), 130.3 (CH),
129.8 (CH), 129.0 (CH), 127.4 (CH), 123.6 (C), 89.0 (C), 82.5 (C), 40.3 (CH2), 28.8 (CH3), 21.6
(CH2), 18.1 (CH2). LRMS (m/z, I) 291 (55), 263 (20). HRMS calcula ed o C20H21NO 291.1623,
ound 291.1622.
N-(5-(p-Tolyl)pen -4-yn-1-yl)benzamide (10j): b own solid. 1H NMR (300 MHz, CDCl3) 7.66
(dd, J = 6.2, 5.2 Hz, 2H), 7.37 (dd, J = 10.6, 4.1 Hz, 1H), 7.31 –
7.16 (m, 4H), 7.00 (d, J = 8.0 Hz, 2H), 6.54 (b s, 1H), 3.56 (q, J =
6.3 Hz, 2H), 2.53 – 2.39 (m, 2H), 2.26 (s, 3H), 1.95 – 1.78 (m,
2H).13C NMR (75 MHz, CDCl3) δ 168.1 (C), 138.4 (C), 135.1
(C), 132.0 (CH), 131.9 (CH), 129.6 (CH), 129.0 (CH), 127.4 (CH),
120.9 (C), 89.0 (C), 82.3 (C), 40.3 (CH2), 28.8 (CH2), 22.0 (CH3), 18.0 (CH2). LRMS (m/z, I) 277
(33), 262 (6) 249 (6) HRMS calcula ed o C19H19NO 277.1467, ound 277.1455.
N-(5-(4-Me hoxyphenyl)pen -4-yn-1-yl)benzamide (10k): b own solid. 1H NMR (300 MHz,
CDCl3) δ 7.68 (dd, J = 8.3, 1.2 Hz, 2H), 7.47 – 7.11 (m, 5H),
6.82 – 6.67 (m, 2H), 6.56 (b s, 1H), 3.69 (d, J = 23.8 Hz, 3H),
3.55 (d , J = 22.2, 10.9 Hz, 2H), 2.48 (dd, J = 12.6, 6.0 Hz,
2H), 2.03 – 1.77 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 167.6
(C), 159.3 (C), 134.7 (C), 133.1 (CH), 131.7 (C), 131.5 (CH),
128.6 (CH), 127.0 (CH), 114.0 (CH), 87.8 (C), 81.5 (C), 55.4 (CH3), 39.9 (CH2), 28.4 (CH2), 17.6
(CH2). LRMS (m/z, I) 293 (45), 262 (6). HRMS calcula ed o C19H19NO2 293.1416, ound
293.1420.
N-(5-(Naph halen-1-yl)pen -4-yn-1-yl)benzamide (10l): b own solid. 1H NMR (300 MHz,
CDCl3) δ 8.24 (dd, J = 7.9, 1.1 Hz, 1H), 7.96 – 7.00 (m, 11H), 6.64 (b s, 1H), 3.72 – 3.46 (m, 2H),
2.56 (d , J = 31.6, 6.8 Hz, 2H), 2.15 – 1.80 (m, 2H). 13C NMR (75
MHz, CDCl3) δ 167.7 (C),134.5 (C), 133.4 (C), 133.2 (C), 131.4
(CH), 130.3 (CH), 128.5 (CH), 128.3 (CH), 127.0 (CH), 126.8
(CH), 126.5 (CH), 126.4 (CH), 126.2 (CH), 125.3 (CH), 121.2 (C),
94.4 (C), 79.7 (C), 39.9 (CH2), 28.6(CH2), 17.9(CH2). LRMS (m/z, I) 313 (47), 262 (7). HRMS
calcula ed o C22H19NO 313.1467, ound 313.1470.
Chap e VI.
131
N-(5-(4-(T i luo ome hyl)phenyl)pen -4-yn-1-yl)benzamide (10m): whi e solid. 1H NMR
(300 MHz, CDCl3) δ 7.87 – 7.04 (m, 9H), 6.85 (s, 1H), 3.52
(dd, J = 12.7, 6.7 Hz, 2H), 2.44 ( , J = 6.9 Hz, 2H), 2.00 – 1.70
(m, 2H). 13C NMR (75 MHz, CDCl3) δ 167.8 (C), 134.5 (C),
131.8 (CH), 131.4 (CH), 129.4 (q, J = 32.6 Hz, C), 128.5 (CH),
127.5 (C), 127.0 (CH), 125.2 (q, J = 3.8 Hz, CH), 124.0 (q, J =
272.3 Hz, C), 92.1 (C), 80.3 (C), 39.6 (CH2), 28.3 (CH2), 17.4 (CH2). LRMS (m/z, I) 331 (44), 330
(33), 303 (8), 262 (9). HRMS calcula ed o C19H16NOF3 331.1184, ound 331.1182.
N-(Hex-4-yn-1-yl)benzamide (10o)180: whi e solid. 1H NMR (300 MHz, CDCl3) δ 7.88 – 7.65
(m, 2H), 7.55 – 7.30 (m, 3H), 6.55 (d, J = 35.7 Hz, 1H), 3.56 (dd, J =
12.6, 6.5 Hz, 2H), 2.37 – 2.13 (m, 2H), 1.85-1.70 (m, 5H). 13C NMR
(75 MHz, CDCl3) δ 167.5(C), 134.7(C), 131.3 (CH), 128.5 (CH),
126.9 (CH), 78.4 (C), 76.6 (C), 39.7 (CH2), 28.3 (CH3), 16.7 (CH2),
3.5(CH2). LRMS (m/z, I) 201 (24), 200 (93) 173 (38). HRMS
calcula ed o C13H15NO201.1154, ound 201.1114.
N-(6-Phenylhex-5-yn-1-yl)benzamide (10p): whi e solid. 1H NMR (300 MHz, CDCl3) δ 7.76 –
7.61 (m, 2H), 7.53 – 7.01 (m, 8H), 6.48 (b s, 1H), 3.39 (d , J =
6.7, 3.8 Hz, 2H), 2.35 (dd, J = 9.3, 4.2 Hz, 2H), 1.80 – 1.44 (m,
4H). 13C NMR (75 MHz, CDCl3) δ 167.7 (C), 134.8 (C), 131.7
(CH), 131.5 (CH), 128.7 (CH), 128.3 (CH), 127.8 (CH), 127.0
(CH), 123.9 (C), 89.8 (C), 81.3 (C), 39.7 (CH2), 29.0 (CH2), 26.2
(CH2), 19.2 (CH2). LRMS (m/z, I) 277 (32), 261 (50), 249 (12). HRMS calcula ed o C19H17NO
275.1310, ound 275.1312
N-(7-Phenylhep -6-yn-1-yl)benzamide (10q): yellow oil. 1H NMR (300 MHz, CDCl3) δ 7.79 –
7.54 (m, 2H), 7.47 – 7.22 (m, 5H), 7.23 – 7.12 (m, 3H), 6.31 (b
s, 1H), 3.47 – 3.26 (m, 2H), 2.34 ( , J = 6.7 Hz, 2H), 1.70 – 1.36
(m, 6H). 13C NMR (75 MHz, CDCl3) δ 167.7 (C), 134.9 (C),
131.6 (CH), 131.4 (CH), 128.6 (CH), 128.3 (CH), 127.6 (CH),
126.9 (CH), 124.0 (C), 90.0 (C), 80.1(C), 40.0 (CH2), 29.3
(CH2), 28.4 (CH2), 26.2 (CH2), 19.4 (CH2). LRMS (m/z, I) 291 (36), 277 (16). HRMS calcula ed
o C20H19NO 291.1623, ound 291.1624.
180 This subs a e was p epa ed using 4-hexyn-1-ol as s a ing ma e ial o he Mi sunobu eac ion ollowing he
gene al p ocedu e o he syn hesis o benzamides.
Chap e VI.
132
2.2 P ocedu e o he syn hesis o alkynylbenzamides (14a-14d), exempli ied
o 14a.
Ac yloyl chlo ide (0.2 mL, 2.4 mmol) was s i ed in CH2Cl2 (10 mL) wi h ie hylamine (0.46
mL, 0.36 mmol) a o 10 min. Addi ion o comme cial a ailable 4-pen ynamine (200 mg,
2.40 mmol) was ollowed by s i ing o 5 h. The CH2Cl2 was emo ed in acuo, and he
emaining esidue was dissol ed in e hyl ace a e. The solu ion was washed wi h 10% HCl
and b ine, d ied o e magnesium sul a e and il e ed. The sol en was emo ed and he
p oduc was pu i ied by column ch oma og aphy (hexanes:E OAc; 1:1) o a o d N-(pen -4-
yn-1-yl)ac ylamide (13) (208 mg, 63%).
In a Schlenk lask con aining Pd(PPh3)4 (87 mg, 5 mol %) and CuI (14 mg, 5 mol%) a , N-
(pen -4-yn-1-yl)ac ylamide (206 mg, 1.5 mmol) and E 3N (10 mL) we e added wi h s i ing.
Then iodobenzene (0.16 mL, 1 equi .) was added and he mix u e was hea ed o 60 ºC. A e
5 hou s he sol en was emo ed and he p oduc was pu i ied by column ch oma og aphy
(hexanes:e hyl ace a e; 1:1) o a o d he p oduc 14a (262 mg, 82%).
N-(5-Phenylpen -4-yn-1-yl)ac ylamide (14a): yellow oil. 1H NMR (300 MHz, CDCl3) δ 7.42 –
7.21 (m, 5H), 6.48 (s, 1H), 6.25 (d, J = 17.0 Hz, 1H), 6.11 (dd, J = 17.0,
10 Hz, 1H), 5.57 (d, J = 10.0 Hz, 1H), 3.47 (q, J = 6.4 Hz, 2H), 2.45 ( , J
= 6.9 Hz, 2H), 1.83 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 165.7 (C),
131.4 (CH), 130.8 (CH), 128.1 (CH), 127.6 (CH), 126.1 (CH2), 123.5 (C),
88.9 (C), 81.3 (C), 38.8 (CH2), 28.2 (CH2), 17.0 (CH2). LRMS (m/z, I)
157 (50), 140 (69).
N-(5-Phenylpen -4-yn-1-yl)me hac ylamide (14b): yellow solid 1H NMR (300 MHz, CDCl3)
δ 7.44 – 7.34 (m, 2H), 7.33 – 7.22 (m, 3H), 6.14 (s, 1H), 5.71 – 5.64
(m, 1H), 5.33 – 5.26 (m, 1H), 3.49 (dd, J = 12.7, 6.7 Hz, 2H), 2.49 ( , J
= 6.9 Hz, 2H), 1.99 – 1.92 (m, 3H), 1.86 (p, J = 6.9 Hz, 2H).13C NMR
(75 MHz, CDCl3) δ 168.5 (C), 140.1 (C), 131.5 (CH), 128.2 (CH),
127.8 (CH), 123.5 (C), 119.3 (CH2), 89.0 (C), 81.5 (C), 39.1 (CH2),
28.2 (CH2), 18.6 (CH3), 17.3 (CH2). LRMS (m/z, I) 212 (7), 199 (40). HRMS calcula ed o
C15H17NO 227.1310, ound 227.1312.
Chap e VI.
133
N-(5-Phenylpen -4-yn-1-yl)cyclohex-1-eneca boxamide (14d): yellow oil. 1H NMR (300
MHz, CDCl3) δ 7.41 – 7.34 (m, 2H), 7.31 – 7.24 (m, 3H), 6.66 –
6.54 (m, 1H), 6.03 (s, 1H), 3.49 (dd, J = 12.6, 6.5 Hz, 2H), 2.49 ( , J
= 6.8 Hz, 2H), 2.23 – 2.16 (m, 2H), 2.08 (dd, J = 6.1, 2.4 Hz, 2H),
1.85 (p, J = 6.7 Hz, 2H), 1.67 – 1.50 (m, 4H).13C NMR (75 MHz,
CDCl3) δ 168.6 (C), 133.3 (CH), 133.1 (C), 131.5 (CH), 128.2 (CH),
127.7 (CH), 123.5 (C), 89.2 (C), 81.5 (C), 39.1 (CH2), 28.3 (CH2), 25.3 (CH2), 24.3 (CH2), 22.1
(CH2), 21.5 (CH2), 17.4 (CH2). LRMS (m/z, I) 250 (11), 239 (30).
2.3 P ocedu e o syn hesis o hexynamides 18a and 18b, exempli ied o
18b.
To a solu ion o hex-5-ynoic acid (1.1 mL, 10 mmol) in CH2Cl2 (50 mL) a oom empe a u e
unde a gon we e added dime hylaminopy idine (DMAP, 12 mg, 0.10 mmol), N,N'-
Dicyclohexylca bodiimide (DCC, 2.06 g, 10 mmol) and naph halen-1-amine (1.43 g, 10.0
mmol). The mix u e was s i ed 10 min. a his empe a u e and hen hea ed a e lux o 5
hou s. CH2Cl2 (20 ml) was added and he p ecipi a e il e ed o . The esul ing homogeneous
solu ion was washed wi h 10% HCl (20 ml) and sa u a ed NaHCO3 (20 ml). The sol en was
e apo a ed and he c ude p oduc pu i ied by lash ch oma og aphy (Hexanes:E OAc; 3:1) o
gi e N-(naph halen-1-yl)hex-5-ynamide (1.28 g, 54 %) as a whi e solid.
In a Schlenk lask con aining Pd(PPh3)4 (232 mg, 5 mol %) and CuI (37 mg, 5 mol%), N-
(naph halen-1-yl)hex-5-ynamide (744 mg, 4 mmol) and E 3N (20 mL) we e s i ed a oom
empe a u e. Then iodobenzene (0.43 mL, 1 equi .) was added and he mix u e was hea ed
o 60 ºC. A e 5 hou s he sol en was emo ed and he c ude p oduc was pu i ied by
column ch oma og aphy (hexanes:die hyle he ; 1:1) o a o d he p oduc 18b (511 mg, 59%).
N,6-Diphenylhex-5-ynamide (18a): 1H NMR (300 MHz, CDCl3) δ 7.67 (s, 1H), 7.60 – 7.21 (m,
9H), 7.16 – 6.96 (m, 1H), 2.68 – 2.41 (m, 4H), 2.09 – 1.95 (m, 2H).13C NMR (75
MHz, CDCl3) δ 170.8 (C), 137.9 (C), 131.5 (CH), 128.9 (CH), 128.2 (CH), 127.7
(CH), 124.1 (CH), 123.6 (C), 119.9 (CH), 88.9 (C), 81.6 (C), 36.2(CH2), 24.2
(CH2), 18.8 (CH2).LRMS (m/z, I) 220 (18), 159 (34). HRMS calcula ed o
C18H17NO 263.1310, ound 263.1309.
Chap e VI.
134
N-(Naph halen-1-yl)-6-phenylhex-5-ynamide (18b): 1H NMR (300 MHz, CDCl3) δ 8.04 (s,
1H), 7.89 – 7.79 (m, 2H), 7.71 (dd, J = 33.9, 7.8 Hz, 2H), 7.53 – 7.21 (m, 8H),
2.59 ( , J = 7.2 Hz, 2H), 2.50 ( , J = 6.9 Hz, 2H), 2.07 – 1.95 (m, 2H).13C NMR
(75 MHz, CDCl3) δ 171.5 (C), 133.9 (C), 132.2 (C), 131.5 (CH), 128.4 (CH),
128.2 (CH), 127.7 (CH), 127.4 (C), 126.0 (CH), 125.8 (CH), 125.4 (CH), 123.6
(C), 121.3 (CH), 121.0 (CH), 89.0 (C), 81.7 (C), 35.8 (CH2), 24.4 (CH2), 18.7
(CH2). LRMS (m/z, I) 183 (19), 128 (27). HRMS calcula ed o C27H19NO 313.1467, ound
313.1465.
2.4 P ocedu e o ca aly ic eac ions o alkynylbenzamides 11a-11q.
In a Schlenk lask equipped wi h a s i ba we e added 10 (0.25 mmol), [Cp*RhCl2]2 (3.9 mg,
2.5% mol) and Cu(OAc)2 (91 mg, 0.52 mmol) wi hou any pa icula p ecau ions o ex ude
oxygen o mois u e. -AmOH (2.0 mL) was hen added and he lask sealed and placed in a
p e-hea ed (110 °C) block. The eac ion was s i ed o 16 hou s, cooled o oom empe a u e
and checked by TLC. The sol en was emo ed in acuo and he emaining esidue was
pu i ied by lash column ch oma og aphy on silica gel (hexanes:e hyl ace a e) o a o d he
co esponding p oduc 11.
10-Phenyl-2,3-dihyd opy olo[1,2-b]isoquinolin-5(1H)-one (11a): whi e solid. 1H NMR (300
MHz, CDCl3) δ 8.48 (ddd, J = 7.9, 1.5, 0.5 Hz, 1H), 7.58 – 7.34 (m, 5H), 7.34 –
7.22 (m, 3H), 4.31 – 4.20 (m, 2H), 2.93 ( , J = 7.6 Hz, 2H), 2.14 (d , J = 14.8, 7.5
Hz, 2H). 13C NMR (75 MHz, CDCl3) δ 161.0 (C), 141.2 (C), 138.0 (C), 136.3
(C), 131.8 (CH), 130.5 (CH), 128.6 (CH), 127.5 (CH), 127.3 (CH), 125.5 (CH),
124.9 (C), 124.2 (CH), 113.6 (C), 48.5 (CH2), 31.0 (CH2), 21.8 (CH2) .LRMS
(m/z, I) 261 (100), 260 (75) HRMS calcula ed o C18H15NO 261.1154, ound
275.1160.
8-Me hoxy-10-phenyl-2,3-dihyd opy olo[1,2-b]isoquinolin-5(1H)-one (11b): b own solid.
1H NMR (300 MHz, CDCl3) δ 8.31 (d, J = 8.9 Hz, 1H), 7.66 – 7.12 (m,
6H), 7.04 – 6.82 (m, 1H), 6.55 (d, J = 2.5 Hz, 1H), 4.28 – 4.02 (m, 2H), 3.63
(s, 3H), 2.82 ( , J = 7.6 Hz, 2H), 2.04 (d , J = 14.9, 7.5 Hz, 2H).13C NMR
(75 MHz, CDCl3) δ 162.6 (C), 160.9 (C), 142.1 (C), 140.3 (C), 136.5 (C),
130.6 (CH), 129.5 (CH), 128.8 (CH), 127.6 (CH), 119.1 (C), 114.5 (CH),
Chap e VI.
135
113.4 (C), 106.0 (CH), 55.3 (CH3), 48.4 (CH2), 31.2 (CH2), 21.9 (CH2).LRMS (m/z, I) 291 (100),
277 (30). LRMS (m/z, I) 341 (28), 313 (9), 212 (38). HRMS calcula ed o C19H17NO2 291.1259,
ound 291.1266
10-Phenyl-8-( i luo ome hyl)-2,3-dihyd opy olo[1,2-b]isoquinolin-5(1H)-one (11c): g een
solid. 1H NMR (300 MHz, CDCl3) δ 8.52 (d, J = 8.4 Hz, 1H), 7.63 – 7.31
(m, 5H), 7.31 – 7.15 (m, 2H), 4.23 ( , J = 7.2 Hz, 2H), 2.89 ( , J = 7.6 Hz,
2H), 2.25 – 2.03 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 160.3 (C), 143.2
(C), 138.1 (C), 135.3 (C), 133.53 (q, J = 32.1 Hz, C), 130.4 (CH), 129.1 (CH),
128.6 (CH), 128.1 (CH), 127.0 (C), 123.9 (q, J = 273.0 Hz, C), 121.6 (q, J =
3.4 Hz, CH), 113.6 (C), 48.8 (CH2) , 31.3 (CH2), 21.8 (CH2). LRMS (m/z, I)
329 ([M] 100), 328 (38) HRMS calcula ed o C19H14NOF3 329.1027, ound 329.1019.
8-B omo-10-phenyl-2,3-dihyd opy olo[1,2-b]isoquinolin-5(1H)-one (11d): g een solid 1H
NMR (300 MHz, CDCl3) δ 8.23 (d, J = 8.6 Hz, 1H), 7.32 (ddd, J = 46.4,
25.7, 6.7 Hz, 7H), 4.16 ( , J = 7.2 Hz, 2H), 2.84 ( , J = 7.6 Hz, 2H), 2.29 – 1.92
(m, 2H).13C NMR (75 MHz, CDCl3) δ 160.6 (C), 143.0 (C), 139.7 (C), 135.6
(C), 130.5 (CH), 129.3 (CH), 129.0 (CH), 128.9 (CH), 127.9 (CH), 127.4 (C),
126.8 (CH), 123.7 (C), 112.8 (C), 48.7 (CH2), 31.3 (CH2), 21.8 (CH2).LRMS
(m/z, I) 341 (28), 313 (9), 212 (38) HRMS calcula ed o C18H14NOB
339.0259, ound 339.0259.
7-me hyl-10-phenyl-2,3-dihyd opy olo[1,2-b]isoquinolin-5(1H)-one (11e): yellow solid. 1H
NMR (300 MHz, CDCl3) δ 8.28 (s, 1H), 7.53 – 7.22 (m, 6H), 7.18 (d, J = 8.3
Hz, 1H), 4.30 – 4.22 (m, 2H), 2.92 ( , J = 7.6 Hz, 2H), 2.46 (s, 3H), 2.20 – 2.07
(m, 2H). 13C NMR (75 MHz, CDCl3) δ 161.1 (C), 140.4 (C), 136.6 (C), 135.9
(C), 135.7 (C), 133.5 (CH), 130.7 (CH), 128.8 (CH), 127.5 (CH), 127.1 (CH),
125.0 (C), 124.3 (CH), 113.7 (CH), 48.6 (CH2), 31.03 (CH2), 22.1 (CH2), 21.3
(CH3).
7-me hoxy-10-phenyl-2,3-dihyd opy olo[1,2-b]isoquinolin-5(1H)-one (11 ): yellow solid.
1H NMR (300 MHz, CDCl3) δ 7.88 (d, J = 2.7 Hz, 1H), 7.58 – 7.33 (m,
3H), 7.33 – 7.10 (m, 4H), 4.32 – 4.23 (m, 2H), 3.93 (s, 3H), 2.92 ( , J = 7.6
Hz, 2H), 2.21 – 2.09 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 160.7 (C),
157.9 (C), 138.8 (C), 136.4 (C), 132.2 (C), 130.5 (CH), 128.6 (CH), 127.4
(C), 126.1 (C), 125.9 (CH), 122.3 (CH), 113.7 (C), 107.1 (CH), 55.6 (CH3),
48.6 (CH2), 30.7 (CH2), 22.0 (CH2).
Chap e VI.
136
9-me hoxy-10-phenyl-2,3-dihyd opy olo[1,2-b]isoquinolin-5(1H)-one (11 ’): yellow solid.
1H NMR (300 MHz, CDCl3) δ 8.13 (dd, J = 8.1, 1.0 Hz, 1H), 7.47 – 7.12 (m,
6H), 6.97 (dd, J = 7.8, 0.7 Hz, 1H), 4.37 – 4.11 (m, 2H), 3.35 (s, 3H), 2.79 ( , J =
7.7 Hz, 2H), 2.22 – 1.98 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 160.8 (C),
155.9 (C), 141.9 (C), 141.0 (C), 129.5 (CH), 128.5 (C), 127.5 (CH), 126.9 (C),
126.3 (CH), 126.2 (CH), 120.0 (CH), 114.1 (CH), 112.1 (C), 55.9 (CH3), 48.9
(CH2), 31.6 (CH2), 21.7 (CH2).
Assignmen o egioisome s by 1H-NMR
The wo egioisome s we e assigned based on he coupling cons an s. As expec ed, in he 1H-
NMR spec um o 11 , Ha appea s as a double (d) wi h a small Jac = 2.7 Hz cha ac e is ic o
his long dis an couplings. Meanwhile, in he 1H-NMR spec um o 11 ’, Ha is a double o
double s (dd) wi h a Jab = 8.1 Hz and a small Jac = 1 Hz, which a e also cha ac e is ic o hese
couplings.
7-Phenyl-9,10-dihyd obenzo[h]py olo[1,2-b]isoquinolin-12(8H)-one (11g): yellow solid. 1H
NMR (300 MHz, CDCl3) δ 10.25 (d, J = 8.7 Hz, 1H), 8.02 – 6.98 (m, 10H),
4.44 – 4.13 (m, 2H), 2.84 ( d, J = 7.7, 2.5 Hz, 2H), 2.25 – 1.88 (m, 2H). 13C
NMR (75 MHz, CDCl3) δ 161.6 (C), 143.2 (C), 139.5 (C), 136.8 (C), 133.1
(CH), 132.3 (C), 131.7 (C), 130.9 (CH), 128.8 (CH), 128.2 (CH), 128.0 (CH),
127.6 (CH), 127.4 (CH), 126.0 (CH), 122.8 (CH), 117.9 (C), 114.2 (C), 49.5
(CH2), 31.6 (CH2), 21.4 (CH2). LRMS (m/z, I) 313(57), 312 (89), 285 (40)
HRMS calcula ed o C22H17NO311.1309, ound 311.1310
10-(o-Tolyl)-2,3-dihyd opy olo[1,2-b]isoquinolin-5(1H)-one (11h): pale yellow solid. 1H
NMR (300 MHz, CDCl3) δ 8.54 – 8.38 (m, 1H), 7.71 – 7.20 (m, 5H), 7.16 (d, J =
7.0 Hz, 1H), 6.99 (dd, J = 8.1, 0.9 Hz, 1H), 4.38 – 4.17 (m, 2H), 2.98 – 2.60 (m,
2H), 2.28 – 2.06 (m, 2H), 2.04 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 161.4 (C),
141.2 (C), 138.1 (C), 137.8 (C), 135.6 (C), 132.1 (CH), 131.0 (CH), 130.4 (CH),
128.2 (CH), 127.6 (CH), 126.4 (CH), 125.7 (CH), 125.0 (C), 124.2 (CH), 113.0
(C), 48.6 (CH2), 30.8 (CH2), 21.9 (CH2), 19.8 (CH3). LRMS (m/z, I) 275 (100),
260 (3), 246 (7). HRMS calcula ed o C19H17NO275.1310, ound 275.1316.
Chap e VI.
137
10-(3,5-Dime hylphenyl)-2,3-dihyd opy olo[1,2-b]isoquinolin-5(1H)-one (11i): yellow
solid. 1H NMR (300 MHz, CDCl3) δ 8.40 (d, J = 8.0 Hz, 1H), 7.72 – 7.11 (m,
3H), 6.93 (d, J = 21.7 Hz, 1H), 6.84 (s, 2H), 4.35 – 4.08 (m, 2H), 2.87 ( , J = 7.6
Hz, 2H), 2.54 – 2.17 (m, 6H), 2.07 (d , J = 15.2, 7.5 Hz, 2H). 13C NMR (75 MHz,
CDCl3) δ 161.2 (C), 141.1 (C), 138.3 (2xC), 136.2 (C), 131.9 (CH), 130.7 (C),
129.2 (CH), 128.3 (2xCH), 127.4 (CH), 125.6 (CH), 125.0 (C), 124.5 (CH), 114.1
(C), 48.6 (CH2), 31.2 (CH2), 22.0 (CH2), 21.5 (CH3).LRMS (m/z, I) 289 (100), 274
(7). HRMS calcula ed o C20H19NO289.1467, ound 289.1467.
10-(Naph halen-1-yl)-2,3-dihyd opy olo[1,2-b]isoquinolin-5(1H)-one (11j): b own oil. 1H
NMR (300 MHz, CDCl3) δ 8.58 – 8.47 (m, 1H), 7.95 (d, J = 7.8 Hz, 2H), 7.63 –
7.32 (m, 7H), 6.98 – 6.88 (m, 1H), 4.42 – 4.24 (m, 2H), 2.94 – 2.78 (m, 1H), 2.63
(ddd, J = 17.0, 8.2, 6.8 Hz, 1H), 2.23 – 2.03 (m, 2H).13C NMR (75 MHz, CDCl3)
δ 161.9 (C), 142.8 (C), 139.2 (C), 134.4 (C), 134.2 (C), 133.2 (C), 132.5 (CH),
129.2 (CH), 129.0 (CH), 128.9 (CH), 127.9 (CH), 126.9 (CH), 126.6(CH), 126.3
(CH), 126.2 (CH), 126.1 (CH), 125.3 (C), 125.1 (CH), 111.9 (C), 49.1 (CH2), 31.3
(CH2), 22.2 (CH2). LRMS (m/z, I) 311 (100) 282 (5) HRMS calcula ed o C22H17NO311.1310,
ound 275.1310
10-(p-Tolyl)-2,3-dihyd opy olo[1,2-b]isoquinolin-5(1H)-one (11k): yellow solid. 1H NMR
(300 MHz, CDCl3) δ 8.39 (d, J = 7.9 Hz, 1H), 7.48 – 7.27 (m, 3H), 7.21 (dd, J =
8.1, 4.3 Hz, 2H), 7.11 (d, J = 7.8 Hz, 2H), 4.19 ( , J = 7.2 Hz, 2H), 2.85 ( , J = 7.6
Hz, 2H), 2.35 (s, 3H), 2.13-1.98 (m 2H). 13C NMR (75 MHz, CDCl3) δ 161.2
(C), 141.3 (C), 138.4 (C), 137.3 (C), 133.4 (C), 131.9 (CH), 130.5 (CH), 129.5
(CH), 127.5 (CH), 125.6 (CH), 125.1 (C), 124.4 (CH), 113.8 (C), 48.6 (CH2), 31.2
(CH2), 22.0 (CH2), 21.4 (CH3).LRMS (m/z, I) 275 (100), 261 (24) HRMS
calcula ed o C19H17NO275.1310, ound 275.1304.
10-(4-Me hoxyphenyl)-2,3-dihyd opy olo[1,2-b]isoquinolin-5(1H)-one (11l): yellow oil. 1H
NMR (300 MHz, CDCl3) δ 8.40 (dd, J = 8.0, 1.4 Hz, 1H), 7.50 – 7.09 (m, 5H),
7.03 – 6.88 (m, 2H), 4.29 – 4.12 (m, 2H), 3.80 (s, 3H), 2.86 ( , J = 7.6 Hz, 2H),
2.07 (d , J = 15.3, 7.6 Hz, 2H).13C NMR (75 MHz, CDCl3) δ 161.2 (C), 159.1 (C),
141.5 (C), 138.5 (C), 131.9 (CH), 131.7 (CH), 128.5 (C), 127.5 (CH), 125.6 (CH),
125.0 (C), 124.4 (CH), 114.2 (CH), 113.42 (C), 55.4 (CH3), 48.6 (CH2), 31.2
(CH2), 22.0 (CH2). LRMS (m/z, I) 275 (100), 261 (24) HRMS calcula ed o
C19H17NO2 291.1250, ound 291.1260.
Chap e VI.
240
135.5 (C), 135.4 (C), 128.6 (CH), 128.5 (CH), 128.3 (CH), 127.8 (CH), 127.3 (CH), 126.8 (CH),
126.3 (CH), 75.9 (C), 13.2 (CH3). HRMS (m/z, ESI) calcula ed o C23H18ClO [M+H]+ 345.1047
ound, 345.1041.
con i med by XR-analysis. CCDC 995496 con ains he c ys allog aphic da a o 31ka, which
can be ob ained ia www.ccdc.cam.ac.uk/da a_ eques /ci .
8-chlo o-2-e hyl-4-me hyl-1-phenylspi o[4,5]deca-1,3,7,9- e aen-6-one (31kg): 73% yield,
yellow oil. 1H NMR (300 MHz, CDCl3) δ (ppm): 7.30 – 7.19 (m, 3H), 7.10 –
7.06 (m, 2H), 6.49 – 6.45 (m, 1H), 6.43 – 6.40 (m, 2H), 6.01 – 5.97 (m, 1H),
2.47 (q, J = 7.3 Hz, 2H), 1.76 (d, J = 1.6 Hz, 3H), 1.18 ( , J = 7.2 Hz, 3H). 13C
NMR (75 MHz, CDCl3) δ (ppm): 194.7 (C), 152.9 (C), 149.5 (C), 144.9 (C),
143.1 (CH), 139.9 (C), 135.5 (CH), 135.4 (C), 128.4 (CH), 128.0 (CH), 127.0
(CH), 126.7 (CH), 125.9 (CH), 75.2 (C), 21.7 (CH2), 13.8 (CH3), 13.1 (CH3).
HRMS (m/z, ESI) calcula ed o C19H18ClO [M+H]+ 297.1036 ound, 297.1041.
Assignmen o he egiochemis y
The majo egioisome was assigned based on he HMBC,
HSQC, COSY expe imen s, as well as by he obse a ion o
nOe be ween he CH2OH chain and he hyd ogen o he C3.
5-me hyl-2,3-diphenyl-5´, 6´, 7´, 8´- e ahyd o-1´H-spi o[cyclopen a[2,4]diene-1,2-
naph halen]1´-one (31ma): 78% yield, Yellow oil. 1H NMR (300 MHz, CDCl3) δ (ppm): 7.39 –
7.34 (m, 2H), ), 7.28 ( , J = 2.2 Hz, 1H), 7.27 – 7.25 (m, 2H), 7.16 – 7.11 (m,
3H), 7.07 – 7.02 (m, 2H), 6.57 (q, J = 1.4 Hz, 1H), 6.28 (d, J = 9.3 Hz, 1H),
5.92 (d, J = 9.3 Hz, 1H), 2.47 – 2.33 (m, 4H), 1.81 (d, J = 1.5 Hz, 3H), 1.71
(d , J = 11.5, 4.6 Hz, 4H). 13C NMR (75 MHz, CDCl3) δ(ppm): 196.2 (C),
150.7 (C), 146.1 (C), 144.9 (C), 141.6 (C), 136.6 (CH), 136.2 (C), 135.9 (C),
134.7 (CH), 133.6 (C), 128.6 (CH), 128.4 (CH), 128.3 (CH), 128.1 (CH), 127.4 (CH), 127.3 (CH),
126.8 (CH), 76.0 (C), 30.8 (CH2), 22.1 (CH2), 22.0 (CH2), 13.2 (CH3). LRMS (CI) (m/z, I): 346
(69), 344 (69), 173 (100).
4,8,9-T ime hyl-1,2-diphenylspi o[4,5] deca-1,3,7,9- e aen-6-one (31na): 77% yield, yellow
solid. 1H NMR (300 MHz, CDCl3) δ (ppm): 7.37 – 7.28 (m, 2H), 7.24 (ddd, J
= 6.5, 3.7, 1.1 Hz, 3H), 7.16 – 7.07 (m, 3H), 7.07 – 7.00 (m, 2H), 6.59 – 6.51
(m, 1H), 6.15 (s, 1H), 5.76 (s, 1H), 2.13 (s, 3H), 2.03 (d, J = 1.0 Hz, 3H), 1.81
– 1.78 (m, 3H). 13C NMR (75 MHz, CDCl3) δ(ppm):197.1 (C), 157.3 (C),
146.3 (C), 145.0 (C), 141.6 (C), 136.1 (C), 136 (CH), 135.9 (C), 134.8 (CH),
132.4 (C), 128.6 (CH), 128.4 (CH), 128.2 (CH), 127.4 (CH), 127 (CH), 126.8 (CH), 21.7 (CH3),
Chap e VI.
241
19.2 (CH3), 13.2 (CH3). LRMS (CI) (m/z, I): 339 (60), 338 (39), 275 (71), 257 (100), 246 (86), 149
(91). HRMS calcula ed o C25H23O: 339.1749, ound, 339.1749.
4.5 P ocedu e B o he Rh-ca alyzed annula ions.
To a solu ion o [Cp*RhCl2]2 (5.2 mg, 2.5 mol%) and Cu(OAc)2·H2O (33 mg, 0.5 equi , 0.165
mmol) in CH3CN (2 mL) unde ai a mosphe e was added he alkyne 2 (0.333 mmol)
ollowed by he addi ion o co esponding o ho- inylphenols 27 (0.50 mmol, 1.5 equi ). The
eac ion lask was sealed wi h a ubbe sep um and an ai a mosphe e was injec ed in he
lask wi h a balloon and a needle. The eac ion was hea ed a 60 °C, s i ed un il comple ion
ollowed by TLC and hen cooled o oom empe a u e. The sol en s we e emo ed in acuo
and he emaining esidue was pu i ied by lash column ch oma og aphy on silica gel o
a o d he co esponding spi ocycles 31.
1,2,4- iphenylspi o[4,5]deca-1,3,7,9- e aen-6-one (31ca): 92% yield, o ange solid. 1H NMR
(300 MHz, CDCl3) δ(ppm):7.51 (s, 1H), 7.36 – 7.32 (m, 6H), 7.28 – 7.18 (m,
7H), 7.17 – 7.09 (m, 3H), 6.53 (dd, J = 9.2, 6.0 Hz, 1H), 6.33 (d, J = 9.9 Hz, 1H),
6.28 – 6.23 (m, 1H). 13C NMR (75 MHz, CDCl3) δ(ppm): 196.5(C), 148.2(C),
145.7(C), 143.1(CH), 142.3(C), 141.5(CH), 135(C), 134.9(C), 134.1(CH),
133.6(C), 129.4(CH), 129.2(CH), 128.8(CH), 128.5(CH), 128.3(CH), 128.1(CH),
127.7(CH), 127.7(CH), 125.7(CH), 123.2(CH), 75.5(C). HRMS (m/z, ESI) calcula ed o
C28H21O [M+H]+ 373.1587 ound, 373.1577.
4-(4-me hoxyphenyl)-1,2-diphenylspi o[4.5]deca-1,3,7,9- e aen-6-one (31da): 70% yield,
b own oam. 1H NMR (300 MHz, CD2Cl2) δ 7.35 – 7.15 (m, 11H), 7.14 – 7.06
(m, 3H), 6.89 – 6.80 (m, 2H), 6.48 (dd, J = 9.0, 6.0 Hz, 1H), 6.27 – 6.17 (m, 2H),
3.78 (s, 3H). 13C NMR (75 MHz, CD2Cl2) δ 196.8 (C), 159.8 (C), 148.6 (C), 146.3
(C), 143.6 (CH), 142.1 (CH), 141.9 (C), 135.7 (C), 135.6 (C), 132.5 (CH), 129.8
(CH), 129.5 (CH), 128.9 (CH), 128.8 (CH), 128.5 (CH), 128.1 (CH), 128.0 (CH),
127.4 (CH), 127.1 (C), 123.6 (CH), 114.7 (CH), 75.9 (C), 55.8 (CH3). LRMS (CI)
(m/z, I): 403 (49), 271 (50), 228 (100). HRMS calcula ed o C29H23O2 403.1698,
ound 403.1712
Chap e VI.
242
1,2-diphenyl-4-(4-( i luo ome hyl)phenyl)spi o[4.5]deca-1,3,7,9- e aen-6-one (31ea): 98%
yield, b own oam. 1H NMR (300 MHz, CDCl3) δ 7.62 – 7.51 (m, 3H), 7.39 (d,
J = 8.2 Hz, 2H), 7.36 – 7.16 (m, 8H), 7.16 – 7.07 (m, 3H), 6.52 (dd, J = 9.2, 6.0
Hz, 1H), 6.34 – 6.28 (m, 1H), 6.24 – 6.18 (m, 1H). 13C NMR (75 MHz, CDCl3) δ
196.0 (C), 146.5 (C), 145.6 (C), 143.7 (C), 143.2 (CH), 140.8 (CH), 136.8 (C),
136.5 (CH), 134.6 (C), 134.5 (C), 129.21 (CH), 129.19 (CH), 128.5 (CH), 128.4
(CH), 128.2 (CH), 127.9 (CH), 125.7 (CH), 124.2 (q, J = 271.8 Hz, C) 123.6 (CH),
75.3 (C). LRMS (CI) (m/z, I): 440 (100), 421 (50), 412 (58). HRMS calcula ed
o C29H20OF3 441.1480, ound 441.1466.
8-b omo -4-me hyl-1,2-diphenylspi o[4,5] deca-1,3,7,9- e aen-6-one (31ha): 67% yield, ed
oil. 1H NMR (300 MHz, CDCl3) δ (ppm): 7.32 – 7.22 (m, 4H), 7.17 – 7.13 (m,
4H), 7.11 (d, J = 2.7 Hz, 1H), 7.04 – 7.01 (m, 2H), 6.58 ( , J = 1.6 Hz, 1H), 6.30 (d,
J = 2.6 Hz, 1H), 6.15 (d, J = 10.1 Hz, 1H), 1.86 (d, J = 1.6 Hz, 3H).13C NMR (75
MHz, CDCl3) δ (ppm):194.9 (C), 146.7 (CH), 145.7 (C), 145.0 (C), 140.4 (C),
139.6 (CH), 135.7 (CH), 135.4 (C), 135.2 (C), 130.0 (CH), 128.5 (CH), 128.5 (CH),
128.3 (CH), 127.8 (CH), 127.3 (CH), 114.5 (C), 78.7 (C), 13.4 (CH3). HRMS (m/z, ESI)
calcula ed o C23H18B O [M+H]+ 389.0536 ound, 389.0551.
1,2- iphenylazulen-7-b omo-4(3aH)-one (32ha):188 18% yield, ed solid. 1H NMR (300 MHz,
CDCl3) δ(ppm): 7.41 – 7.35 (m, 2H), 7.30 (dd, J = 2.9, 2.3 Hz, 2H), 7.27 – 7.24
(m, 3H), 7.20 (d, J = 0.7 Hz, 1H), 7.15 – 7.08 (m, 4H), 7.00 – 6.94 (m, 1H), 5.68
(d, J = 12.9 Hz, 1H), 1.46 (s, 3H). 13C NMR (75 MHz, CDCl3) δ (ppm): 197.8
(C), 151.2 (C), 145.8 (C), 143.9 (CH),
140.8 (CH), 139.4 (C), 134.5 (C), 133.9
(C), 133.8 (CH), 130.4 (CH), 128.8 (CH), 128.4(CH),
128.3 (CH), 128.2 (CH), 127.8 (CH), 122.2 (CH), 117.1
(C), 67.6 (C), 24.3 (CH3). LRMS (CI) (m/z, I): 390 (52),
311 (68), 310 (100). calcula ed o C23H18B O [M+H]+
389.0536 ound, 389.0530.
The s uc u e o his compound was u he con i med
by XR-anaylysis. CCDC 995497 con ains he
c ys allog aphic da a o 5ha, which can be ob ained ia
www.ccdc.cam.ac.uk/da a_ eques /ci .
188This compound was isola ed as mino p oduc in he eac ion o xx and xx ollowing gene al
p ocedu e B.
Chap e VI.
243
4.6 Mechanis ic expe imen s.
4.1 KIE measu emen s.
To a solu ion o [Cp*RhCl2]2 (4.5 mg, 2.5 mol%) and Cu(OAc)2·H2O (29 mg, 0.146 mmol, 0.5
equi ) and diphenylace ylene (52 mg, 0,293 mmol) in MeCN (1 mL) unde ai a mosphe e
was added a equimola solu ion o 27 and 27-d2 (0.386 mmol each) in MeCN (1 mL). This
solu ion was p epa ed by mixing 75 mg o 31 and 99 mg o 31-d2 (88% deu e a ed). The
eac ion mix u e was hea ed a 40 °C. A e 45 minu es he eac ion was pou ed in o E 2O
(10mL), he sol en s we e e apo a ed in acuo and he emaining esidue was pu i ied by
lash column ch oma og aphy on silica gel o emo e he emaining s a ing ma e ial. The
esidue was analyzed by H NMR. The KIE alue (app ox 2.3) was ob ained by in eg a ing
he H3 o he spi o 31 and he H9 o he spi o 31 and 31-d. The con e sion (app ox 10%) was
de e mined based on he s a ing ma e ial (27) eco e ed.
4.1 Deu e ium exchange (wi hou alkyne).
To a solu ion o [Cp*RhCl2]2 (5.2 mg, 2.5 mol%) and Cu(OAc)2·H2O (33 mg, 0.5 equi , 0.165
mmol) in CH3CN (1.7 mL) unde ai a mosphe e was added 2-(p op-1-en-2-yl)phenol 27a
H3
H9
Chap e VI.
244
(0.50 mmol, 1.5 equi ) and D2O (0.3 mL). The eac ion was sealed wi h a ubbe sep um and
an ai a mosphe e was injec ed in he lask wi h a balloon and a needle. The eac ion was
hea ed a 40 °C, s i ed o 4 h and hen cooled o oom empe a u e. The sol en s we e
emo ed in acuo and he emaining esidue was pu i ied by lash column ch oma og aphy
on silica gel o gi e 27a and 27a-dn (26 mg, 39% eco e y). 30% deu e a ion on bo h ole inic
p o ons based on 1H-NMR.189
1) 1-H-NMR o s a ing ma e ial 27a
2) 1H-NMR o he s a ing ma e ial 27a-dn - eco e ed (30% deu e a ion)
189No deu e a ion was obse ed in absence o he ei he he hodium ca alys o coppe ace a e.
Chap e VI.
245
4.2 Deu e ium exchange (wi h alkyne).
To a solu ion o [Cp*RhCl2]2 (5.2 mg, 2.5 mol%) and Cu(OAc)2·H2O (33 mg, 0.5 equi , 0.165
mmol) in CH3CN (1.7 mL) unde ai a mosphe e was added diphenylace ylene (59 mg, 1
equi , 0.333 mmol) ollowed by he addi ion o 2-(p op-1-en-2-yl)phenol 27a (0.50 mmol, 1.5
equi ) and D2O (0.3 mL). The eac ion was sealed wi h a ubbe sep um and an ai
a mosphe e was injec ed in he lask wi h a balloon and a needle. The eac ion was hea ed a
40 °C, s i ed o 4 h and hen cooled o oom empe a u e. The sol en s we e emo ed in
acuo and he emaining esidue was pu i ied by lash column ch oma og aphy on silica gel
o a o d he 4-me hyl-1,2-diphenylspi o[4.5]deca-1,3,7,9- e aen-6-one 31aa (12 mg, 11%),
diphenylace ylene 29a (49 mg, 83% eco e ed) and 2-(p op-1-en-2-yl)phenol 27a (44 mg, 66%
eco e ed).
3) 1-H-NMR o p oduc 31aa eco e ed
4) 1H-NMR o 27a- eco e ed
Chap e VI.
246
4.3 Compe i ion be ween alkynes 29b and 29c.
To a solu ion o [Cp*RhCl2]2 (4.6 mg, 2.5 mol%) and Cu(OAc)2·H2O (30 mg, 0.150 mmol, 0.5
equi ) and alkynes 29b (143 mg, 2 equi , 0.6 mmol) and 29c (189 mg, 2 equi , 0.6mmol) in
MeCN (2 mL) unde ai a mosphe e was added 2-(p op-1-en-2-yl)phenol (27a) (40 mg, 1
equi , 0,3 mmol). The eac ion was sealed wi h a ubbe sep um and an ai a mosphe e was
injec ed in he lask wi h a balloon and a needle. The eac ion was hea ed a 40 °C and s i ed
a ha empe a u e. A e 2h, he esul ing mix u e was il e ed h ough silica, washing wi h
die hyle he ; he sol en s we e e apo a ed in acuo and he esidue was analyzed by 1H
NMR in CDCl3 indica ing ~ 1:7 mix u e o 31ab:31ac and a con e sion o app ox 35%, based
on he amoun o s a ing ma e ials eco e ed.
4.4 S oichiome ic expe imen .
To a solu ion o [Cp*RhCl2]2 (50 mg, 0.5 equi ) in CH3CN (1 mL) unde ai a mosphe e was
added diphenylace ylene (29 mg, 1 equi , 0.162mmol) ollowed by he addi ion o 2-(p op-1-
en-2-yl)phenol 27a (22 mg, 1 equi . 0.162 mmol). The eac ion was sealed wi h a ubbe
sep um and an ai a mosphe e was injec ed in he lask wi h a balloon and a needle. The
solu ion was s i ed o 45 min a 40 °C and no con e sion was obse ed h ough TLC, a e
ha , CsOAc (62 mg, 2 equi ) was added and he mix u e s i ed 1h. The sol en s we e
emo ed in acuo and he emaining esidue was pu i ied by lash column ch oma og aphy
on silica gel o a o d he 4-me hyl-1,2-diphenylspi o[4.5]deca-1,3,7,9- e aen-6-one 31aa (43
mg, 86%).
Chap e VI.
247
A simila expe imen was ca ied ou using E 3N (41 µL, 2 equi ) ins ead o CsOAc o a o d
he 4-me hyl-1,2-diphenylspi o[4.5]deca-1,3,7,9- e aen-6-one 31aa (32 mg, 64%) a e 5h o
eac ion.
4.7 The mal ea angemen .
A solu ion o 31aa (31 mg, 0.10 mmol) o 32aa (31 mg, 0.10 mmol) in CH3CN (2 mL) was e luxed o
12h. The sol en s we e emo ed in acuo and he p oduc was isola ed in quan i a i e yield wi hou
u he manipula ion. Analysis o he 1H-NMR shows ap ox. 1:1 mix u e o 31aa and 32aa.
Chap e VI.
249
5- CHAPTER V: Oxida i e annula ions o
o
-alkenylanilines
5.1 Gene al conside a ions
All non comme cial inylanilines we e syn hesized om he co esponding ke one ia Wi ig
eac ion, i he ke one was no a ailable, hen an addi ion o he co esponding G igna d
eagen was done o he app op ia ely subs i u ed 2-aminobenzoni ile.190 Boc191, ace yl,
osyl, isop opyl173, i luo oace yl192 and nosyl193 p o ec ed o-alkenylanilines we e
syn hesized as p e iously desc ibed in he li e a u e. All spec al da a eco ded was in
ag eemen wi h hose in he co esponding communica ion.
5.2 P ocedu e o he syn hesis o i lyl p o ec ed o-alkenylanilides (37a-
37k) exempli ied o 37a.
To a solu ion o o-isop openylaniline (1 mL, 7.34 mmol) in dichlo ome hane (25 mL) unde
A a mosphe e was added ie hylamine (1.228 ml, 1.2 equi ) a 0 ⁰C. Then
i luo ome hanesul onic anhyd ide (1.489 ml, 1.2 equi ) was added d opwise. The eac ion
was s i ed a 0 °C o 1.5 hou s and quenched wi h sa u a ed NH4Cl aqueous solu ion. The
esul ing mix u e was ex ac ed wi h dichlo ome hane and d ied o e anhyd ous sodium
sul a e. E apo a ion o he sol en ollowed by pu i ica ion column lash ch oma og aphy on
silica gel (hexanes:die hyle he ; 8:2) a o ding 1,1,1- i luo o-N-(2-(p op-1-en-2-
yl)phenyl)me hanesul onamide (37a), (1.84g, 94%), as a whi e solid upon eezing. 1H NMR
(300 MHz, CDCl3) δ 7.49 (d, J = 7.9 Hz, 1H), 7.25 – 7.09 (m, 4H), 5.36 (dd, J = 2.7, 1.2 Hz, 1H),
4.92 (s, 1H), 2.00 (d, J = 1.0 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 142.2 (C), 135.9 (C), 130.8
(C), 128.7 (CH), 128.6 (CH), 126.4 (CH), 121.1 (CH), 119.9 (q, J = 323.4 Hz, C), 118.1 (CH2), 24.5
(CH3).
1,1,1- i luo o-N-(2- inylphenyl)me hanesul onamide (37b): 59% yield, pale yellow solid.
1H NMR (300 MHz, CDCl3) δ 7.49 – 7.37 (m, 1H), 7.35 – 7.10 (m, 3H), 6.79 (dd, J
= 17.3, 11.1 Hz, 1H), 6.59 (b s, 1H), 5.63 (d, J = 17.4 Hz, 1H), 5.37 (d, J = 11.0 Hz,
1H). 13C NMR (75 MHz, CDCl3) δ 134.4 (C), 131.1 (CH), 130.8 (C), 129.2 (CH),
190 Jana, S.; Ashokan, A.; Kuma , S.; Ve ma, A.; Kuma , S. O g. Biomol. Chem. 2015, 13, 8411.
191 Kobayashi, K.; Fukamachi, S.; Nakamu a, D.; Mo ikawa, O.; Konishi, H. He e ocycles 2007, 75, 95.
173 Fe guson, J.; Zeng, F.; Alwis, N.; Alpe , H. O g. Le . 2013, 15, 1998.
192 Kobayashi, K.; Miyamo o, K.; Mo ikawa, O.; Konishi, H. Bull. Chem. Soc. Jpn. 2005, 78, 886.
193 Liwosz, T. W.; Chemle , S. R. Synle 2015, 26, 335.
Chap e VI.
256
N-(8-(4-chlo ophenyl)-5,6-dip opylnaph halen-1-yl)-1,1,1- i luo ome hanesul onamide
(39ed) majo egioisome : 90% yield 4:1 mix u e o insepa able
egioisome s, b own solid. 1H NMR (300 MHz, CDCl3) δ 7.75 (dd, J = 8.5, 0.9
Hz, 1H), 7.44 – 7.01 (m, 9H), 3.38 – 3.23 (m, 2H), 2.82 – 2.64 (m, 2H), 1.62 (dd,
J = 15.4, 7.6 Hz, 2H), 1.48 (dd, J = 16.3, 7.5 Hz, 2H), 1.07 – 0.91 (m, 6H). 13C
NMR (75 MHz, CDCl3) δ 141.0 (C), 139.5 (C), 137.9 (C), 134.2 (C), 133.7 (C),
133.5 (C), 131.7 (CH), 131.1 (CH), 129.9 (C), 129.1 (CH), 128.7 (CH), 128.3
(CH), 128.2 (CH), 124.1 (CH), 119.9 (q, J = 323.6 Hz, C), 36.9 (CH2), 31.8
(CH2), 25.6 (CH2), 25.0 (CH2), 14.4 (CH3), 14.1 (CH3). LRMS (EI) (m/z, EI): 471 (19), 469 (50),
338 (34), 336 (100). HRMS calcula ed o C23H23NO2 F3SCl: 469.1090 ound, 469.1080.
N-(5,6-dip opyl-8-(p- olyl)naph halen-1-yl)-1,1,1- i luo ome hanesul onamide (39 d): 90%
yield, b own solid. 1H NMR (300 MHz, CDCl3) δ 7.88 (dd, J = 8.4, 1.3 Hz,
1H), 7.44 (d, J = 7.3 Hz, 1H), 7.30 – 7.19 (m, 6H), 7.08 (b s, 1H), 3.39 – 3.29 (m,
2H), 2.82 – 2.73 (m, 2H), 1.74 – 1.60 (m, 2H), 1.60 – 1.45 (m, 2H), 1.07 ( , J = 7.3
Hz, 3H), 0.99 ( , J = 7.3 Hz, 3H).13C NMR (75 MHz, CDCl3) δ 141.04 (C), 139.2
(C), 138.1 (C), 137.3 (C), 133.8 (C), 133.5 (C), 131.1 (CH), 130.3 (CH), 129.8 (C),
129.5 (CH), 129.2 (CH), 128.6 (C), 127.9 (CH), 123.8 (CH), 119.9 (q, J = 323.7
Hz, C), 36.9 (CH2), 31.8 (CH2), 25.7 (CH2), 25.0 (CH2), 21.3 (CH3), 14.4 (CH3),
14.1 (CH3). LRMS (m/z, EI): 449 (53), 316 (100). HRMS calcula ed o C24H26NO2F3S: 449.1636
ound, 449.1654.
N-(2,8-dime hyl-5,6-dip opylnaph halen-1-yl)-1,1,1- i luo ome hanesul onamide (39hd)
majo egioisome : 60% yield <13:1 mix u e o insepa able egioisome s,
b own solid. 1H NMR (300 MHz, CDCl3) δ 7.93 (d, J = 8.5 Hz, 1H), 7.32 (d, J
= 8.5 Hz, 1H), 7.13 (s, 1H), 6.87 (b s, 1H), 3.35 ( , J = 7.5 Hz, 2H), 2.83 – 2.70
(m, 2H), 2.61 (s, 6H), 1.76 – 1.60 (m, 2H), 1.36 – 1.20 (m, 2H), 1.02 ( , J = 7.3
Hz, 3H), 0.87 ( , J = 7.3 Hz, 3H).13C NMR (75 MHz, CDCl3) δ 140.8 (C), 137.5
(C), 132.8 (C), 132.7 (C), 131.7 (C), 131.2 (C), 130.4 (CH), 127.0 (CH), 126.8 (CH), 125.7 (C),
119.48 (q, J = 323.0 Hz, C), 37.3 (CH2), 31.5 (CH2), 24.9 (CH2), 24.6 (CH2), 19.8 (CH2), 19.7
(CH2), 14.3 (CH3), 14.2 (CH3). LRMS (m/z, EI): 387 (23), 254 (100). HRMS calcula ed o
C19H24NO2F3S: 387.1480 ound, 387.1486.
N-(4,8-dime hyl-5,6-dip opylnaph halen-1-yl)-1,1,1- i luo ome hanesul onamide (39id)
majo egioisome : 72% yield >15:1 mix u e o insepa able egioisome s,
b own solid. 1H NMR (300 MHz, CDCl3) δ 7.28 (d, J = 7.6 Hz, 1H), 7.15 (d, J
= 8.3 Hz, 2H), 7.03 (b s, 1H), 3.36 – 3.23 (m, 2H), 2.86 (s, J = 7.6 Hz, 3H), 2.83
(s, 3H), 2.80 – 2.70 (m, 2H), 1.67 (dq, J = 14.9, 7.4 Hz, 2H), 1.44 (dq, J = 15.0,
7.4 Hz, 2H), 1.11 – 0.92 (m, 6H). 13C NMR (75 MHz, CDCl3) δ 140.5 (C), 138.4
(C), 135.3 (C), 133.7 (CH), 133.6 (C), 132.9 (C), 131.7 (C), 127.6 (CH), 127.1 (C),
Chap e VI.
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126.8 (CH), 119.8 (q, J = 324.0 Hz, C), 36.6 (CH), 32.2 (CH2), 26.4 (CH2), 26.1 (CH3), 24.8 (CH2),
24.8 (CH2), 14.3 (CH3), 14.1 (CH3). LRMS (m/z, EI): 387 (34), 254 (100). HRMS calcula ed o
C19H24NO2F3S: 387.1480 ound, 387.1486 .
N-(3,8-dime hyl-5,6-dip opylnaph halen-1-yl)-1,1,1- i luo ome hanesul onamide (39jd)
majo egioisome : 59% yield >10:1 mix u e o insepa able egioisome s,
b own solid. 1H NMR (300 MHz, CDCl3) δ 7.79 (s, 1H), 7.35 (s, 1H), 7.17 (s,
1H), 7.03 (b s, 1H), 3.34 – 3.23 (m, 2H), 2.78 – 2.70 (m, 2H), 2.61 (s, 3H), 2.50
(s, 3H), 1.75 – 1.41 (m, 4H), 1.16 – 0.97 (m, 6H). 13C NMR (75 MHz, CDCl3) δ
140.1 (C), 134.5 (C), 133.6 (C), 132.1 (C), 132.0 (C), 131.1 (CH), 129.4 (CH),
128.7 (C), 127.6 (C), 126.2 (CH), 119.91 (q, J = 323.7 Hz, C), 36.7(CH2), 31.6 (CH2), 25.7(CH2),
25.0 (CH2), 21.2 (CH2), 20.3 (CH2), 14.4 (CH3), 14.0 (CH3). LRMS (m/z, EI): 387 (45), 254 (100).
HRMS calcula ed o C19H24NO2 F3S: 387.1480 ound, 387.1478 .
N-(3,8-dime hyl-5,6-dip opylnaph halen-1-yl)-1,1,1- i luo ome hanesul onamide (39kd)
majo egioisome : 61% yield 5:1 mix u e o insepa able egioisome s,
b own solid. 1H NMR (300 MHz, CDCl3) δ 8.22 (s, J = 0.8 Hz, 1H), 7.59 (s,
1H), 7.24 (s, 1H), 7.13 (b s, 1H), 3.33 – 3.16 (m, 2H), 2.78 – 2.66 (m, 2H),
2.62 (d, J = 9.6 Hz, 3H), 1.70 – 1.51 (m, 2H), 1.49 – 1.34 (m, 2H), 1.08 – 0.90
(m, 6H).13C NMR (75 MHz, CDCl3) δ 140.1 (C), 134.5 (C), 133.6 (C), 132.1
(C), 132.0 (C), 131.1 (CH), 129.4 (CH), 128.7 (C), 127.6 (C), 126.2 (CH), 119.91 (q, J = 323.7 Hz,
C), 36.7(CH2), 31.6 (CH2), 25.7(CH2), 25.0 (CH2), 21.2 (CH2), 20.3 (CH2), 14.4 (CH3), 14.0 (CH3).
LRMS (m/z, EI): 441 (43), 308 (100). HRMS calcula ed o C19H21NO2 F6S: 441.1197 ound,
442.1199
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CHAPTER VII: Selec ed spec a
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1. Selec ed spec a om chap e II.
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4. Selec ed spec a om chap e V.
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ANNEX I: Resumen
Annex I.
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una eo ganización del espi ociclo. De hecho, se p opone que exis e un equilib io en e
ambos p oduc os en condiciones de eacción ya que, la disolución y calen amien o de
cualquie a de los dos po sepa ado, da luga a una mezcla de espi ociclo y azulenona. Pa a
explica dicho equilib io se echa mano de la o mación de un in e medio icíclico
zwi e iónico consis en e en dos anillos de seis y cinco miemb os usionados o mando un
ciclop opano.
Anelación oxida i a de o-alquenilanilinas.
El úl imo capí ulo de la esis se cen a en aslada la química de alquenil enoles a
alquenilanilinas ya que una g an pa e de los p oduc os a macológicos de in e és, poseen
algún á omo de ni ógeno en su es uc u a.
En p ime luga , se busca iden i ica un sus i uyen e ap opiado pa a el á omo de ni ógeno
que apo e los eque imien os es é icos y elec ónicos necesa ios pa a que la eacción enga
luga . En e los di e sos g upos p obados, se obse a que los elec oa ac o es son más
p opensos a eacciona de o ma p oduc i a. Sin emba go, en luga de las benzazepinas o
espi ominas espe ados, se ob iene una mezcla de na ilaminas egioisomé icas. Es os dos
isóme os p o ienen de una cicloadición o mal (4+2) en e el aminoes i eno y el alquino y
o a cicloadición o mal (4+2) en e ambos sus a os pe o con una mig ación o mal 1,2 del
alqueno p e ia a la anelación.
Una pos e io op imización de las condiciones pe mi e llega a endimien os globales
supe io es al ochen a po cien o. Conc e amen e, cuando se usan 5 mol% de p eca alizado
de odio en dioxano a e lujo con un equi alen e de cob e como oxidan e. So p esi amen e,
se demues a que aunque el ca alizado es, p e isiblemen e, imp escindible pa a que la
eacción ocu a, no lo es así el oxidan e de cob e ya que, su sus i ución po ace a o de sodio
sigue dando luga a una mezcla simila de na ilaminas en endimien os compa ables.
Se demues a, además, que la ans o mación ambién puede se lle ada a cabo en
condiciones más sua es como THF a e lujo sin disminución ap eciable del endimien o
global.
Al igual que en capí ulos an e io es, se es udia el e ec o de la sus i ución en la eac i idad
ob eniéndose que, con espec o al anillo, an o sus i uyen es dado es como a ac o es son
Annex I.
289
acep ados. En el caso de los alquinos empleados se encuen an di e encias signi ica i as
en e los sus i uidos con g upos a ilo o alquilo ya que es os úl imos, gene almen e, dan luga
a mezclas de egiosóme os más a o ables hacia la anelación sin mig ación o mal. También
se desc ibe cómo la eacción es incapaz de p oduci se cuando no hay sus i ución en la
posición in e na del doble enlace o cuando la hay en la ex e na. Asimismo se comen a que la
eacción alla cuando se usan 2- enilanilinas en luga de 2-alquenilanilinas. Po úl imo
desc iben un esul ado in e esan e cuando se usan ole inas sus i uidas con un g upo
isop opilo, que es la isome ización del doble enlace hacia el isop opilo gene ando la ole ina
isus i uida.
En es e caso no se han ealizado es udios mecanís icos pe o sí se p oponen a ias hipó esis
capaces de explica cómo se p oducen ambos isóme os (pa a lo cual se pos ula la o mación
de una espi oimina in e media) y cómo la eacción puede sucede en ausencia de un
oxidan e “clásico” como el ai e o el cob e:
- La p ime a explicación consis e en la hid oa ilación del alquino ca alizada po odio
(III) y la pos e io o mación del espi ociclo mediada po el mismo complejo de odio
y comple ada con una β-eliminación de hid u o. La p o onación del hid u o de odio
gene ado da ía luga a hid ógeno gas y a la ecupe ación del complejo
ca alí icamen e ac i o.
- En segundo luga se p opone la o mación de las dihid ona ilaminas a pa i del
dihid oespi ociclo las cuales, al en a en con ac o con el oxígeno en la elabo ación, se
oxidan dando luga a las na ilaminas co espondien es.
- Po úl imo se pos ula que la eacción sigue un ciclo análogo a los p opues os pa a los
alquenil enoles y la oxidación del complejo de odio (I), o mado en la e apa de
eliminación educ o a, po adición oxidan e al ácido acé ico, o mado en el paso de
ac i ación C-H, y p o onación del hid u o de odio gene ado como en el caso
an e io .
Conclusión gene al.
Como conclusión gene al, en es a esis se desc iben a ios p ocesos de anelación oxida i a
ca alizados po odio (III) dando luga a di e en es p oduc os y ealizando expe imen os
mecanís icos pa a elucida los caminos que siguen las eacciones.
