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T ansi ion-Me al-Ca alyzed Annula ions In ol ing he
Ac i a ion o C(sp3)−H Bonds
Ma c Fon , Moises Gulías, José L. Masca eñas
Pee e iewed e sion
This is he pee e iewed e sion o he ollowing a icle: Fon , M.; Gulías, M.;
Masca eñas, J. L.; (2021), T ansi ion-Me al-Ca alyzed Annula ions In ol ing he Ac i a ion
o C(sp3)−H Bonds. Angew. Chem. In . Ed., 61: e202112848, which has been published in
inal o m a
h ps://doi.o g/10.1002/anie.202112848. This a icle may be used o non-
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A chi ed Ve sions.
How o ci e:
Fon , M.; Gulías, M.; Masca eñas, J. L.; (2021), T ansi ion-Me al-Ca alyzed Annula ions
In ol ing he Ac i a ion o C(sp3)−H Bonds. Angew. Chem. In . Ed., 61: e202112848. doi:
10.1002/anie.202112848
Copy igh in o ma ion:
© 2021 Wiley-VCH. This a icle may be used o non-comme cial pu poses in
acco dance wi h Wiley Te ms and Condi ions o Use o Sel -A chi ed Ve sions
C(sp3)-H Ac i a ion
T ansi ion-Me al-Ca alyzed Annula ions In ol ing he
Ac i a ion o C(sp3)@HBonds
Ma c Fon ,* Mois8sGul&as,* and Jos8Luis Masca eÇas*
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How o ci e: Angew.Chem. In . Ed. 2022,61,e202112848
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Ge man Edi ion: doi.o g/10.1002/ange.202112848
Angew.Chem. In .Ed. 2022,61,e202112848 (1 o 13) T2021 TheAu ho s.Angewand eChemieIn e na ional Edi ionpublished by Wiley-VCHGmbH
1. In oduc ion
Syn he ic echnologies elying on C@Hac i a ion p o-
cesses a e among he mos powe ul ools in mode n o ganic
chemis y,inpa because hey allow a apid and a om-
economical inc ease in molecula complexi y om simple,
un unc ionalized p ecu so s.[1–5] Themos e ec i e ap-
p oaches o pe o m C@Hac i a ion/ unc ionaliza ion eac-
ions ely on he use o ansi ion-me al ca alys s,which in
many cases p omo e C@Hbond clea age by conce ed
me ala ion-dep o ona ion (CMD) o oxida i e addi ion p o-
cesses.[4,5]
Mos o he me al-ca alyzed C@H unc ionaliza ions so a
desc ibed in ol e he ac i a ion o C(sp2)@Hbonds.These
eac ions include oxida ions,c oss-couplings,cycliza ions, and
o mal cycloaddi ions,among o he s.[3,6–10] No iceably,analo-
gous eac ions in ol ing he clea age o C(sp3)@Hbonds a e
much less common and mo e challenging.This is in pa due
o he lowe acidi y o C(sp3)@Hbonds and he o ma ion o
less s able ca bon–me al bonds.[11,12]
None heless,in he las decade he e has been an
inc easing numbe o epo s dealing wi h he in e molecula
unc ionaliza ion o C(alkyl)@Hbonds.[13–17] Rema kably,
simila eac ions enabling annula ion p ocesses—bo h cycli-
za ions and cycloaddi ions,which a e e y a ac i e om
acons uc i e s andpoin —a e much sca ce ,[18,19] and only
ecen ly ha e hey s a ed o inc ease.
This Mini e iew aims o highligh
signi ican ad ances in he de elop-
men o annula ion eac ions based on
he ac i a ion and clea age o C(sp3)@
Hbonds.Wedono in end o be
comp ehensi e,and hus we will only
conside he mos ele an app oaches
en ailing cycliza ions and o mal cyclo-
addi ions ha p oceed h ough me al-
acyclicin e media es,such as hose
ou lined in Scheme 1. Annula ions in-
ol ing he gene a ion o ca be-
noid[20,21] and ni enoid[22] in e medi-
a es,o addi ions o p-allyl in e medi-
a es esul ing om he ac i a ion o C@
Hbonds,[23] will no be discussed. Mos
o he schemes included in his Mini e-
iew ollow acommon o ma : he
gene al eac ion highligh ing (in bold)
he bonds o med in he p ocess,some
key mechanis ic in e media es (shown
in pa en heses), and a ew selec ed p oduc s made using he
me hod.
2. T ansi ion-Me al-Ca alyzed Cycliza ions
P omo ed by he Ac i a ion o C(sp3)@HBonds
2.1. Lac oniza ions and Lac amiza ions
Among he i s examples o ansi ion-me al-ca alyzed
C(sp3)@H unc ionaliza ions,ace oxyla ion eac ions occupy
acen al ole.In2004, he San o d g oup epo ed he di ec
ace oxyla ion o C(alkyl)@Hbonds in subs a es bea ing
oxime o py idine di ec ing g oups,byusing Pd(OAc)2as
aca alys and PhI(OAc)2as an oxidan and ace yl sou ce.[24]
Since his epo , he numbe o me hods o he di ec
con e sion o hyd oca bon p ecu so s in o aluable ace y-
la ed p oduc s has g own signi ican ly.[15,17]
Rela ed in amolecula p ocesses we e i s epo ed in
1991 by Kao and Sen, who obse ed he o ma ion o small
amoun s o b-and g-lac ones upon eac ing alipha ic ca box-
The selec i e unc ionaliza ion o C(sp3)@Hbonds using ansi ion-
me al ca alysis is among he mo e a ac i e ans o ma ions o
mode n syn he ic chemis y.Inaddi ion o i s inhe en a om economy,
such eac ions open uncon en ional e osyn he ic pa hways ha can
s eamline syn he ic p ocesses.Howe e , he ac i a ion o in insically
ine C(sp3)@Hbonds,and he selec ion among e y simila C@H
bonds, ep esen highly challenging goals.In ecen yea s he e has
been no able p og ess ackling hese issues,especially wi h ega d o
he de elopmen o in e molecula eac ions en ailing he o ma ion o
C@Cand C@he e oa om bonds.Con e sely, he assembly o cyclic
p oduc s om simple acyclic p ecu so s using me al-ca alyzed C-
(sp3)@Hbond ac i a ions has been less explo ed. Only ecen ly has he
numbe o epo s on suchannula ions s a ed o g ow.He ein we gi e
an o e iew o some o he mo e ele an ad ances in his exci ing
opic.
Scheme 1. Mechanis ic ou line o a) ansi ion-me al-ca alyzed cycliza-
ions and b) o mal cycloaddi ions in ol ing he ac i a ion o C(sp3)@H
bonds.
[*] D .M.Fon , P o . M. Gul&as, P o . J. L. Masca eÇas
Cen o Singula de In es igaciknenQu&mica Biolkxica eMa e iais
Molecula es (CIQUS)
Depa amen o de Qu&mica O g#nica
Uni e sidade de San iago de Compos ela
15782, San iago de Compos ela (Spain)
E-mail:m[email p o ec ed]
[email p o ec ed]
[email p o ec ed]
The ORCID iden i ica ion numbe o one o he au ho s o his a icle
can be ound unde :h ps://doi.o g/10.1002/anie.202112848.
T2021 The Au ho s. Angewand e Chemie In e na ional Edi ion
published by Wiley-VCH GmbH. This is an open access a icle unde
he e ms o he C ea i e Commons A ibu ion Non-Comme cial
NoDe i s License, which pe mi s use and dis ibu ion in any
medium, p o ided he o iginal wo k is p ope ly ci ed, he use is non-
comme cialand no modi ica ions o adap a ions a e made.
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ylic acids wi h sub-s oichiome ic amoun s o K2P Cl4and
K2P Cl6.[25] Despi e his ea ly obse a ion, p og ess in he
lac oniza ion o ca boxylic acids enabled by C(sp3)@H
ac i a ions has been e y slow,and essen ially limi ed o
o ho-me hylbenzoic acids[26–28] o p ecu so s equipped wi h
abiden a e di ec ing g oup.[29]
Selec i e b-lac oniza ion p ocesses emained elusi e un il
e y ecen ly,when Zhuang and Yu de eloped an e ec i e
s a egy o p omo ing his eac ion om alkyl ca boxylic
acids ha elies on PdII/PdIV ca aly ic cycles (Scheme 2).[30]
Theuse o b-amino acid ligand L1,which chela es he me al
in o asix-membe ed cycle wi h ala ge bi e angle,seems o be
key o acili a e he C@Hac i a ion, as well as o igge he
educ i e elimina ion in he ensuing alkyl-PdIV in e media e
(II,Scheme 2). Theau ho s also demons a ed ha he
esul ing b-lac ones ep esen e sa ile pla o ms o he
selec i e ins alla ion o di e se unc ionali ies a he b
posi ion o he ca boxylic acid. La e on, he same esea ch
g oup epo ed he cycliza ion o alipha ic diacids in o i e- o
se en-membe ed lac one ings.[31]
Alkyl amides can also cyclize o o m g-o b-lac ams,
p o ided hey a e equipped wi h N,N-biden a e di ec ing
g oups,which no only a o he C@Hac i a ion bu also
s abilize high- alen PdIV in e media es.[3,4,32] Chen and co-
wo ke s desc ibed in 2013 he g-lac amiza ion o seconda y
ca boxamides con aining 8-aminoquinoline (AQ) auxilia ies
o gi e py olidinones (Scheme 3a).
Mechanis ically,i has been pos ula ed ha he eac ion
en ails he o ma ion o six-membe ed palladacycle in e -
media es,and in ol es PdII/PdIV edox cycles.[33] In a ela ed
ans o ma ion, he Shi g oup demons a ed ha 2-(py idine-
2-yl)isop opylamine (PIP) auxilia ies a e pa icula ly e i-
cien a p omo ing he ac i a ion o benzylic me hylene C@H
bonds in b-a yl alanines o a o d b-lac ams (Scheme 3b).[34]
Thesame g oup subsequen ly epo ed an upda ed e sion o
he cycliza ion using 5-me hoxyquinolin-8-amineauxilia ies,
which a e easie o emo e han he PIP pendan s.[35]
Ma c Fon s udied chemis y a he Uni e -
si y o Gi ona, whe e he was awa ded his
PhD in 2015 unde he supe ision o P o .
X. Ribas and P o . M. Cos as. His PhD
s udies included esea ch a he Uni e si y
o Cali o nia, Be keley wi h P o . J. F. Ha -
wig. Subsequen ly, he was awa ded aMa ie
Cu ie pos doc o al ellowship o esea ch
wi h P o . I. La osa a he Uni e si y o
Manches e , UK. In 2017, he joined he
Uni e si y o San iago de Compos ela,
whe e he is cu en ly Juan de la Cie a
ellow.His esea ch ocuses on ansi ion-
me al-ca alyzed C@H unc ionaliza ion eac-
ions and hei mechanisms.
Mois8sGul&as ob ained his PhD in 2006 a
he Uni e si y o San iago de Compos ela.
In 2007–2009 he was aMa ie-Cu ie pos -
doc o al ellow in he esea ch g oup o
P o . M. J. Gaun a he Uni e si y o Cam-
b idge, UK. In 2015, he ecei ed he
Spanish Socie y o Chemis y Young In es-
iga o Awa d and, in 2016, he became
pe manen p o esso a he Uni e si y o
San iago de Compos elaand p incipal in es-
iga o a he CIQUS. His cu en esea ch
ocuses on me al-ca alyzed C@H unc ional-
iza ion and asymme ic syn hesis.
Jos8Luis Masca eÇascomple ed his PhD a
he Uni e si y o San iago in 1988. A e
pos doc o al wo k a S an o d Uni e si y
(USA) unde he supe ision o P o . P.
Wende (1989–1990), he mo ed o he
Uni e si y o San iago (pe manen p o esso :
1993 and ull p o esso : 2005). He has been
scien i ic di ec o o CIQUS since 2014. In
2015 he ecei ed he gold medal o he
Spanish Socie y o Chemis y,and in 2016
was appoin ed amembe o he Eu opean
Academy o Sciences. His esea ch combines
disco e ing no el me hods based on me al
ca alysis and chemical biology o de elop syn he ic ools o biological
in e en ion.
Scheme 2. PdII-ca alyzed b-lac oniza ion o alkyl ca boxylic acids.
Scheme 3. a) PdII-ca alyzed g-lac amiza ion o alkyl amides bea ing 8-
aminoquinoline (AQ) di ec ing g oups. b) PdII-ca alyzed b-lac amiza-
ion o alkyl amides bea ing he 2-py idylme hyl (PIP) di ec ing g oup.
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Se e al addi ional examples o ela ed lac amiza ions o
build i e- and six-membe ed lac ams,also based on palla-
dium ca alysis,ha e been desc ibed.[19,36–38] In e es ingly, i s -
ow ansi ion-me al (Co,Ni, and Cu) ca alys s can also
ca alyze he lac amiza ion o amides equipped wi h biden a e
di ec ing g oups.These eac ions p oceed h ough simila
mechanis ic pa hways o hose p oposed o Pd.[19]
Despi e all hese ad ances, he e a e s ill many challenges
ahead, such as he de elopmen o lac amiza ions o sub-
s a es lacking auxilia y di ec ing g oups, he con olled
o ma ion o di e en ing sizes,and he implemen a ion o
enan ioselec i e a ian s.
2.2. Oxa- and Azacycliza ions
The o ma ion o oxacycles by he di ec oxacycliza ion o
alipha ic alcohols has p o en mo e challenging han he
homologous lac oniza ions.This is mainly associa ed wi h he
inabili y o hyd oxy g oups o wo k as di ec ing g oups in he
C@Hac i a ion s ep.Howe e ,some s a egies based on
in oducing designed di ec ing g oups in he subs a es ha e
been success ully implemen ed. In 2015, he Dong g oup
epo ed aPd-ca alyzed syn hesis o cyclic e he s om he
co esponding alipha ic alcohols by using an oxime auxilia y
(Scheme 4a).[39] Theau ho s p oposed ha , a e he C@H
ac i a ion o he e minal me hyl g oup o he subs a e, he e
is an oxida ion o Pd o o m an alkyl-PdIV in e media e,
which unde goes an SN2- ype educ i e elimina ion wi h he
pendan alcohol o gi e he oxacyclic p oduc (usually in
modes yields). Apa allel s a egy, elying on he use o he
PIP auxilia y as adi ec ing g oup,has enabled he ac i a ion
o seconda y C@Hg oups o he assembly o e ahyd o u an
and e ahyd opy an de i a i es.[40]
Using di e en ypes o subs a es equipped wi h an
amide con aining achi al biden a e di ec ing g oup,Hong,
Baik, and co-wo ke s de eloped adias e eoselec i e oxacyc-
liza ion o alipha ic alcohols (Scheme 4b).[41]
In con as o alcohols, ee alipha ic amines can be
di ec ly cyclized using C(sp3)@Hac i a ion eac ions.Gaun
and co-wo ke s ha e demons a ed ex ensi ely ha app o-
p ia ely designed a-me hyla ed seconda y amines,such as
hose shown in Scheme 5, can be eadily con e ed in o
azi idines.[42] The eac ion in ol es aPd-ca alyzed ac i a ion
o he pendan me hyl g oups o gi e ou -membe ed cyclo-
pallada ed in e media es.The ensuing oxida ion o he
palladacycle o aPd
IV species ollowed by educ i e elimi-
na ion yields he azi idine co e.Impo an ly, he in oduc ion
o s e ic bulk a ound he NH moie y is needed o a oid he
o ma ion o o -cycle bis(amine)–palladium complexes.The
au ho s u he demons a ed he syn he ic po en ial o his
me hod by opening he azi idine ings wi h di e en ypes o
nucleophiles.They also epo ed a ollow-up enan ioselec i e
e sion.[43]
In oducing asui able p o ec ing/auxilia y g oup in he
amine seems o acili a e he azacycliza ion.[19] The e o e,in
2009, Glo ius and co-wo ke s demons a ed ha ace yl-
p o ec ed o ho-alkylanilides can be cyclized in o he co e-
sponding indolines unde PdII ca alysis,al hough all he
epo ed examples consis o anilides wi h o ho- e -bu yl (o
e y simila ) subs i uen s.[44] In a ela ed app oach, Nad es
and Daugulis epo ed in 2012 aPd
II-ca alyzed ac i a ion o d-
C@Hbonds in selec ed alkylamides and o ho-me hylanilides
bea ing picolinamide biden a e auxilia ies o a o d py oli-
dines and isoindolines.[45] Chen and co-wo ke s ex ended his
app oach o he p epa a ion o aze idines and py olidines.[46]
An al e na i e en y o py olidines was epo ed by Shi
and co-wo ke s,and in ol es he use o alkyl i lamides as
p ecu so s and sil e sal s as ca alys s.The au ho s pos ula e
ha PhI(OTFA)2induces he oxida ion o he sil e p ecu so
o aAg
III species,which p omo es aCMD-like clea age o
p ima y o seconda y benzylic C(sp3)@Hbonds o he
subs a es.Finally,aC-N educ i e elimina ion gene a es
he py olidine co e (Scheme 6).[47]
Scheme 4. a) PdII-ca alyzed cycliza ion o alcohols bea ing oxime
di ec ing g oups o yield cyclic e he s. b) PdII-ca alyzed cycliza ion o
alcohols bea ing achi al amide di ec ing g oup.
Scheme 5. PdII-ca alyzed azi idina ion o designed seconda y amines.
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2.3. Ca bocycliza ions
In addi ion o me al-ca alyzed he e ocycliza ions,anum-
be o ca bocycliza ion s a egies ha e also been de eloped
o eac ions in ol ing he ac i a ion o C(sp3)@Hbonds.One
o he ea lies and mos p oli ic app oaches is based on he use
o a yl halide o pseudohalide p ecu so s (A -X) and Pd0
ca alys s.This app oach, pionee ed by he g oup o Dyke ,[48]
elies on an ini ial oxida i e addi ion o Pd0 o A @Xbonds o
gene a e a yl-PdII species,which p omo e selec i e C(sp3)@H
ac i a ions in nea by alkyl chains.A inal educ i e elimi-
na ion om he esul ing palladacycles p oduces he desi ed
ca bocycles.
TheBaudoin g oup has been pa icula ly ac i e in
explo ing he po en ial o his s a egy.Thei i s s udies
ocused on he cons uc ion o benzocyclobu anes om o ho-
alkyl b omoa enes,asillus a ed in Scheme 7a.[49,50] Simila
app oaches ha e since been used o he assembly o awide
ange o used ca bocycles and he e ocycles o di e en
sizes,[18,51,52] e en in an asymme ic manne .Fo example,
Kgndig and co-wo ke s de eloped aPd
0-ca alyzed enan io-
selec i e ca bocycliza ion o a yl halides o he syn hesis o
enan ioen iched used indolines by using achi al NHC ligand
(L2,Scheme 7b).[53]
Theca aly ic ca bocycliza ion sequence can also be
igge ed by an ini ial C@Hac i a ion h ough aCMD
mechanism, ollowed by an oxida i e addi ion o an in e nal
a yl halide, ogi e aPd
IV in e media e (Scheme 8a).[54] This
s a egy,which equi es subs a es bea ing 8-aminoquinoline
(AQ) auxilia ies,was la e used in he mac ocycliza ion o
pep ide-like a chi ec u es, he eby enabling he ob en ion o
mac ocycles wi h up o 37 membe s (Scheme 8b).[55] Mo e
ecen ly, ela ed ca bocycliza ion app oaches ha exploi
ansien di ec ing g oups ins ead o semipe manen auxil-
ia ies ha e s a ed o eme ge.[56,57]
In he las ew yea s he e has been an upsu ge in
ca bocycliza ion me hods based on wo old C@Hac i a ions.
Taking as e e ence he seminal wo k by Dyke on he Pd-
ca alyzed dime iza ion/ca bocycliza ion o iodoanisoles
h ough double C@Hac i a ion p ocesses,[58] Baudoin and
co-wo ke s de eloped a e sa ile me hod o build cyclo-
Scheme 6. AgI-ca alyzed cycliza ion o alkyl i limides opy olidines.
Scheme 7. a) Pd0-ca alyzed cycliza ion o a yl b omides o a o d
benzocyclobu anes h ough C(sp3)@Hac i a ion. b) Pd0-ca alyzed
enan ioselec i e cycliza ion o a yl b omides o a o d used indoline
co es.
Scheme 8. a) PdII-ca alyzed in amolecula a yla ion o 8-aminoquino-
line-con aining alkyl chains by chela ion-assis ed C(sp3)@Hac i a ion.
Ring sizes a e lis ed in he scheme. b) PdII-ca alyzed mac ocycliza ion
o pep ide-like s uc u es exempli ied wi h a ipep ide de i a i e.
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p opanes om acyclicp ecu so s using aPd
0-p omo ed
C(sp3)@Hac i a ion cascade.[59]
The eac ion in ol es an ini ial oxida i e addi ion o he
a yl halide o gene a e palladacyclopen ane I,which e ol es
by p o o-depallada ion o gi e species II in a o mal 1,4-Pd
shi (Scheme 9). This in e media e p omo es he clea age o
aC(sp3)@Hbond in an alkyl g oup o he subs a e o a o d
palladacyclobu ane III,which yields he inal cyclop opane by
educ i e elimina ion. In subs a es con aining alkyl chains
wi h b-hyd ogen a oms, b-hyd ide elimina ion pa hways
compe e wi h he cyclop opana ion. Theau ho s ound ha
he use o pi ala es ins ead o ca bona es is key o a o he
desi ed cyclop opana ion pa hway.
O he ca bocyliza ions elying on double C@Hac i a ion
p ocesses ha e also been epo ed by Yu and co-wo ke s.
Thei eac ions,howe e ,a e no ini ia ed by oxida i e
addi ion o Pd0 o haloa enes,bu by aca boxyla e-di ec ed
C(sp3)@Hac i a ion p ocess (Scheme 10).[60] Asubsequen
oxida ion o he in e media e gene a es an alkyl-PdIV com-
plex ha p omo es he C(sp2)@Hac i a ion o he a ene p io
o a ing- o ming C@C educ i e elimina ion. The eac ion,
which is only e ec i e o he ac i a ion o me hyl g oups,was
used in a ou -s ep syn hesis o indane-con aining sesqui e -
pene (:)- ussujaponol D.
In he abo e eac ions, he C(sp3)@Hac i a ion s ep
occu s h ough aCMD- ype mechanism and equi es elec o-
philic me al ca alys s,inmos cases based on PdII.An
al e na i e o pe o ming he C@Hac i a ion s ep elies on
oxida i e addi ion o low- alen ansi ion-me al cen e s.
Indeed, syn he ic me hods based on C(sp3)@Hoxida i e
addi ions ha lead o me al-hyd ide in e media es a e inding
inc easing syn he ic applica ions.This is he case o well-
known RuII-, RhI-, and I I-ca alyzed bo yla ion and silyla ion
eac ions,[61,62] as well as in in e molecula hyd oca bona ion
p ocesses.[63] Con e sely,in amolecula hyd oca bona ions
o build cyclic p oduc s a e much less common. An ea ly
con ibu ion was published by Jones e al. in 1986, which
demons a ed he iabili y o assembling indoles om 2,6-
dialkylphenylisocyanides[64,65] using low- alen u henium
ca alys s.Ano he ele an con ibu ion elying on an i idi-
um-ca alyzed hyd oca bona ion o alkenes was epo ed by
Sames and co-wo ke s in 2004.[66]
TheSuginome g oup has ecen ly desc ibed elegan
examples o ca bocycliza ion eac ions o build indolines
h ough he I -ca alyzed C(sp3)@Hac i a ion o me hylaniline
p ecu so s.The eac ion can e en be pe o med in an
enan ioselec i e ashion by using chi al BINAP de i a i es
as ligands (L4,Scheme 11).[67] This concep has been u he
exploi ed by he au ho s o build benzo u an skele ons.[68]
To conclude his sec ion, we can s a e ha cycliza ion
eac ions igge ed by me al-p omo ed C(sp3)@Hac i a ions
can be anked among he mo e p omising s a egies o build
cyclic p oduc s om simple acyclic p ecu so s.The p og ess
in his opic has been slow bu s eady,and, e y likely,many
new me hods will see he ligh in he yea s o come.
Scheme 9. Pd0-ca alyzed cycliza ion o gem-dialkyl (pseudo)haloa enes
by double C(sp3)@Hac i a ion.
Scheme 10. PdII-ca alyzed cycliza ion o a yl alkyl ca boxylic acids by
wo old C@Hac i a ion. The oxidized in e media es a e indica ed.
Scheme 11. I I-ca alyzed enan ioselec i e cycliza ion o 2-alkenyl-N-
me hylanilines o a o d indolines.
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3. T ansi ion-Me al-Ca alyzed Fo mal Cycloaddi-
ions by C(sp3)@HAc i a ion
F om acons uc i e poin o iew,cycloaddi ions a e e en
mo e appealing han cycliza ions,owing o hei inhe en
complexi y-inc easing cha ac e is ics.T ansi ion-me al ca al-
ysis has demons a ed an eno mous po en ial in he de elop-
men o o mal cycloaddi ions o unsa u a ed p ecu so s.[69–71]
In ecen yea s he e has been asubs an ial inc ease in
cycloaddi ions in ol ing ansi ion-me al-ca alyzed C@Hac-
i a ion, wi h mos o he examples so a epo ed in ol ing
he clea age o C(sp2)@Hbonds.[7] Analogous o mal cyclo-
addi ions en ailing he ac i a ion o C(sp3)@Hbonds is mo e
challenging,and has been much less de eloped. In mos cases,
hese eac ions ollow he gene al pa hways ou lined in
Scheme 12:Ame al-p omo ed C(sp3)@Hac i a ion ollowed
by amig a o y inse ion o an unsa u a ed pa ne , and a inal
educ i e elimina ion ha yields he cycloaddi ion p oduc . In
addi ion o he in insic di icul ies o he C@Hac i a ion s ep,
he o he s eps can also be p oblema ic,inpa because hey
p esen compe ing b-hyd ide elimina ion pa hways
(Scheme 12).[72]
Despi e hese hu dles,me hods o mally in ol ing such
cycloaddi ions a e s a ing o eme ge.
3.1. Fo mal Cycloaddi ions wi h Ca bon Monoxide
Among he i s examples desc ibing o mal cycloaddi-
ions in ol ing he ac i a ion o C(sp3)@Hbonds, hose based
on he use o ca bon monoxide as an annula ion pa ne
occupy ap ominen posi ion. Awide a ie y o me hods o
he cons uc ion o succinimides and lac ams,usually ope a -
ing h ough he mechanis ic p o ile ou lined in Scheme 12,
ha e been epo ed.
The i s epo s based on his app oach appea ed mo e
han en yea s ago,when Yu and co-wo ke s desc ibed aPd-
ca alyzed o mal (4+1) cycloaddi ion o elec on-de icien
alkyl amides and CO (Scheme 13a).[73] Theelec on-poo
na u e o he a oma ic amide is essen ial o he C@H
ac i a ion s ep.
Rela ed annula ions o gi e succinimides ha e also been
de eloped using o he ansi ion me als,such as u henium,[74]
coppe ,[75] cobal ,[76] and nickel.[77] In some cases, hese
me hods use CO su oga es,such as ni ome hane o DMF,
as annula ion pa ne s.Inall hese examples, he p esence o
coo dina ing g oups appended o he amide ni ogen a om
seems c ucial o he C(sp3)@Hac i a ion s ep.
O he han amides,alipha ic ca boxylic acids ha e also
been epo ed o pa icipa e in PdII-ca alyzed ca bonyla ions.
Indeed, Yu and co-wo ke s de eloped a o mal (4+1)
cycloaddi ion using Mo(CO)6as he CO sou ce and b-
amino hioe he L5 as he ligand (Scheme 13b). The eac ion
p oduc s we e isola ed as acyclicdies e de i a i es because
o he high sensi i i y o anhyd ides owa d hyd olysis.[78]
Mo eo e ,p elimina y esul s o an enan ioselec i e e sion
using he b-amino hioe he ligand L6 ha e been epo ed.
Analogous ca bonyla ions o amine p ecu so s con aining
auxilia y di ec ing g oups (oxalyl- o picolinamides) ha e
ecen ly been epo ed.[79,80] Ca e e o and co-wo ke s ha e
exploi ed py idylsul onyl auxilia ies in alkyl amines o
p omo e hei con e sion in o py olidinones unde Pd-
(OAc)2ca alysis,using Mo(CO)6as aCOsu oga e
(Scheme 14).[81]
Gaun and co-wo ke s delinea ed al e na i e ca bonyla-
i e annula ions di ec ly om hinde ed unp o ec ed amines.
They desc ibed ap ac ical en y o a a ie y o b-lac ams by
PdII-ca alyzed ca bonyla ion o amines unde aCO/ai
Scheme 12. Gene al mechanis ic scena io o ansi ion-me al-ca a-
lyzed o mal cycloaddi ion h ough C(sp3)@Hac i a ion p ocesses.
Scheme 13. a) PdII-ca alyzed o mal (4+1) cycloaddi ion o alkyl
amides. b) PdII-ca alyzed o mal (4+1) cycloaddi ion o alkyl ca boxylic
acids.
Scheme 14. PdII-ca alyzed o mal (4+1) cycloaddi ion o py idylsul on-
yl-p o ec ed alkyl amides.
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a mosphe e (Scheme 15).[43] Theau ho s we e e en able o
isola e key azapalladacycle in e media es esul ing om he
C@Hac i a ion.
Less-hinde ed amines con aining e ia y,seconda y,and
e en p ima y ca bon a oms can also engage in his ype o
annula ion, al hough such eac ions ollow di e en mecha-
nis ic pa hways.Compu a ional and expe imen al s udies
sugges ed ha he eac ion en ails he ca bonyla ion o he
amine o gi e an acyl palladium in e media e,which unde -
goes aC(sp3)@Hac i a ion o gene a e species I(Scheme
16a).
A e op imiza ion o he eac ion pa ame e s,
he Gaun
g oup applied he me hod o he p epa a ion o awide ange
o b-lac ams wi h good o excellen yields (Scheme 16a).[82]
This me hod can also be used o he la e-s age ca bonyla ion
o pha maceu icals and o he biologically ac i e p oduc s.
These o mal (3 +1) cycloaddi ions can also be ex ended o
o he seconda y amines[83] o a- e ia y amines[84] ha equi e
he ac i a ion o b-me hylene C@Hg oups.Fu he uning o
he eac ion condi ions allowed he egioselec i i y o hese
p ocesses o be shi ed o ac i a e g-me hyl g oups o
seconda y amines and deli e g-lac ams in a o mal (4 +1)
cycloaddi ion (Scheme 16b). To achie e his selec i i y i is
key o use a eac ion a mosphe e wi h alow con en o CO
(6.25%CO/ai mix u e), and hus p e en he o ma ion o
ca bamoyl-Pd species,as hese eac ions p oceed h ough
i e-membe ed palladacycles (species I,Scheme 16b).[85]
I can be concluded ha he ca bonyla ion o C(sp3)@H
bonds in o mal cycloaddi ion p ocesses has p o en e y
ui ul o building succinimides,succinic anhyd ides,and
lac ams o di e en sizes.Howe e ,mos o hese ans-
o ma ions equi e ca e ul enginee ing o he subs a e o
p e en undesi ed side eac ions,which ep esen s ase ious
limi a ion in e ms o scope and gene ali y.No iceably, ela ed
cycloaddi ions wi h CO,in ol ing he o ma ion o wo C@C
bonds,ha e no ye been epo ed.
3.2. Fo mal Cycloaddi ions wi h Alkenes, Dienes, and Allenes
Fo mal cycloaddi ions in ol ing he ac i a ion o C(sp3)@
Hbonds bu using ole inic pa ne s ins ead o CO a e e y
a ac i e (Scheme 11), al hough hey ep esen asigni ican
challenge.The palladacyclic in e media es esul ing om he
mig a o y inse ion o he alkene end o unde go b-hyd ide
elimina ion p ocesses,which hal s he canonical cycloaddi-
ion. Howe e , he esul ing ole ina ed adduc s can s ill be
con e ed in o cyclic p oduc s h ough an in amolecula
Michael- ype addi ion. This was indeed demons a ed by Yu
and co-wo ke s in 2010 wi h he eac ion be ween alkyl
amides and ac yla es using PdII ca alys s and oxidizing
addi i es.The eac ion is ini ia ed by ac i a ion o aC(sp3)@
Hbond in he bposi ion o an amide o gi e apalladacyclic
in e media e,which e ol es o he inal g-lac am by he
a o emen ioned Heck- ype coupling/Michael addi ion mech-
anism (Scheme 17a).[86] This ans o ma ion could be ex end-
ed o build six-membe ed ings using amide subs a es
bea ing b-qua e na y ca bon a oms.[87]
Mo e ecen ly,Shi and co-wo ke s epo ed aPd
II-ca a-
lyzed alkenyla ion/cycliza ion p ocess o build g-lac ams using
alkyl amides bea ing apy idyl-isop opylamine di ec ing
g oup (PIP) and alkenyl iodide coupling pa ne s (Scheme
17b). In his case, he Pd ca alys p omo es aC(sp3)@H
alkenyla ion o he alkyl amide, ollowed by a syn-amino-
pallada ion (II!III). Finally,ab-hyd ide elimina ion s ep
deli e s he aza-Wacke cyclized p oduc . Theau ho s also
demons a ed ha using BINOL de i a i es as chi al ligands
o Pd enables he eac ion o occu wi h excellen le els o
enan ioselec i i y.[88,89]
Compa ed o amides, ela ed alkenyla ion/cycliza ions o
alkyl ca boxylic acids ha e p o en mo e challenging.As
indica ed in Sec ion 2.1, he C@Hac i a ion o hese p e-
cu so s is a o ed by using alkali me al bases,which exhibi
k2-coo dina ion wi h he acid subs a e and p e en poisoning
o he ca alys .[90]
Scheme 15. PdII-ca alyzed C(sp3)@Hca bonyla ion o hinde ed secon-
da y ee amines.
Scheme 16. a) PdII-ca alyzed b-ca bonyla ion o seconda y bulky
amines ia ca bamoyl-PdII species. The eac ion in e media e Iwas
cha ac e ized by X- ay di ac ion. b) PdII-ca alyzed g-ca bonyla ion o
hinde ed seconda y amines.
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