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Syn hesis o silacyclopen -2-en-4-ols ia in amolecula [2 + 2] pho ocycloaddi ion o
benzoyl(allyl)silanes
© Au ho s, 2019
Published e sion
Vale, Joao R.; Valkonen, A o; A onso, Ca los A. M.; Candeias, Nuno R.
Vale, J. R., Valkonen, A., A onso, C. A. M., & Candeias, N. R. (2019). Syn hesis o silacyclopen -2-
en-4-ols ia in amolecula [2 + 2] pho ocycloaddi ion o benzoyl(allyl)silanes. O ganic Chemis y
F on ie s, 6(22), 3793-3798. h ps://doi.o g/10.1039/C9QO01028A
2019
ORGANIC CHEMISTRY
FRONTIERS
RESEARCH ARTICLE
Ci e his: O g. Chem. F on ., 2019, 6,
3793
Recei ed 21s Augus 2019,
Accep ed 10 h Oc obe 2019
DOI: 10.1039/c9qo01028a
sc.li/ on ie s-o ganic
Syn hesis o silacyclopen -2-en-4-ols ia
in amolecula [2 + 2] pho ocycloaddi ion
o benzoyl(allyl)silanes†
João R. Vale,
a,b
A o Valkonen,
c
Ca los A. M. A onso *
b
and
Nuno R. Candeias *
a
O ganosilicon compounds a e e sa ile uni s wi h a wide ange o uses om medicinal chemis y o he
field o o ganic elec onics. An unp eceden ed me hod o he syn hesis o no el dia yl-subs i u ed silacy-
clopen enols ia blue-ligh p omo ed in amolecula [2 + 2] pho ocycloaddi ion o acyl silanes is he ein
disclosed. Addi ionally, he p esen findings demons a e he influence o he olefin subs i uen s in con-
olling he egioselec i i y o he in amolecula Pa e nò–Büchi eac ion, p o iding silacycles diffe en
om p e iously epo ed ones. The high deg ee o unc ionaliza ion o hese compounds makes hem
a ac i e p ecu so s o o he syn he ically challenging silacyclopen anes.
In oduc ion
The inco po a ion o silicon in o an o ganic molecule can al e
some o i s physical and chemical p ope ies, making o gano-
silicon compounds a ac i e candida es o medicinal
chemis y.
1,2
Al hough silicon is an isos e e o sp
3
-hyb idised
ca bon, eplacing ca bon by silicon can: al e eac i i y,
inc ease lipophilici y, induce diffe en con o ma ions and
inc ease ing sizes.
1
O ganosilicons ha e he endency o o m
pen a- and hexa-coo dina ed species
3,4
and labile Si–O, Si–N
and Si–H bonds in aqueous media. Mo eo e , pola ised C–Si
bounds ha e inc eased eac i i y as compa ed o C–C bounds.
Because o hese ea u es, o ganosilicon compounds ha e
shown conside able po en ial in he medicinal chemis y ield
o e he pas 55 yea s.
1
The i ually simple eplacemen o
ca bon by silicon in a known d ug o scaffold has been widely
explo ed in he design o new bioac i e compounds.
5,6
D as ic
changes in he pha macological p o iles o silicon bioisos e o
enla axine,
7
halope idol
8
and bexa o ene
9
ha e been p e-
iously epo ed, including imp o emen s in he selec i i y
p o ile o lowe oxici y o he d ug me aboli es.
No wi hs anding he ole o silicon in d ug disco e y,
2
o ga-
nosilicon compounds ha e also gained no o ie y in molecula
elec onics
10
and polyme science.
11
Conjuga ed o ganosilicon
ma e ials a e pa icula ly p omising o he o ganic elec onics
and pho onics ield.
12
The inse ion o silicon a oms in conju-
ga ed o ganic mo i s changes he HOMO and LUMO ene gy
le els, c ea ing a new b oad class o impo an semi-
conduc o s. The 5-membe ed conjuga ed silacycle silole is a
pa icula ly in e es ing building block in his esea ch a ea
and in he de elopmen o silicon-con aining polyme s.
13
Gi en he na u al abundance o silicon and i s lack o in insic
oxici y, p ocesses a ge ing he syn hesis o o ganosilanes
14
and he modi ica ion o C–Si bonds a e becoming mo e a ail-
able.
15
Despi e he e sa ili y and impo ance o silacycles,
me hods o hei p epa a ion a e somewha sca ce.
16
Silacyclobu anes (SCBs) a e gene ally syn he ised by he con-
enien in amolecula silyla ion o in si u p epa ed G igna d
eagen s.
16
Due o hei high ing s ain and Lewis acidi y,
SCBs a e o en used as p ecu so s o o he o ganosilicon com-
pounds h ough ing opening/expansion eac ions ca alysed by
ansi ion me als.
16,17
E en hough ing expansion o SCBs can
also p o ide silacyclopen anes unde speci ic condi ions, he
mos di ec me hod o hei syn hesis consis s in he addi ion
o me al ea ed 1,3-bu adienes o dichlo osilanes.
18,19
The
syn hesis o silacyclopen enes h ough palladium-ca alysed
silylene-1,3-diene [4 + 1] cycloaddi ion
20
allows lexibili y on
subs i u ion o he cyclopen ene co e.
Conside ing he impo ance o he cyclopen ane mo i in
bioac i e compounds,
21–26
we easoned ha new me hods o
he p epa a ion o 5 membe ed- ing silacycles a e needed o
se e al ields o molecula sciences. F om a syn he ic pe spec-
†Elec onic supplemen a y in o ma ion (ESI) a ailable: Expe imen al p o ocols
and NMR, compu a ional and X- ay diff ac ion da a. CCDC 1935510 and
1935511. Fo ESI and c ys allog aphic da a in CIF o o he elec onic o ma see
DOI: 10.1039/c9qo01028a
a
Facul y o Enginee ing and Na u al sciences, Tampe e Uni e si y,
Ko keakoulunka u 8, 33101 Tampe e, Finland. E-mail: nuno. a aelca[email p o ec ed]
b
Ins i u o de In es igação do Medicamen o (iMed.ULisboa), Facul y o Pha macy,
Uni e sidade de Lisboa, A . P o . Gama Pin o, 1649-003 Lisboa, Po ugal.
E-mail: ca losa onso@ff.ulisboa.p
c
Depa men o Chemis y, Uni e si y o Jy askyla, P.O. Box 35, 40014 Jy äskylä, Finland
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i e, achie ing he cyclopen ene moie y would be p e e able
due o po en ially u he unc ionaliza ion o he double
bound, such as asymme ic oxida i e ans o ma ions.
27,28
Silacyclopen -2-enes a e especially challenging as he ing is
usually cons uc ed om a highly unc ionalised silane
(Scheme 1a),
29–31
imposing limi a ions on he deg ee o subs i-
u ion on he cyclic co e. Fu he modi ica ions o silacyclo-
pen -2-enes ha e also been epo ed
32–35
bu addi ional
unc ionaliza ion o he cyclopen ene ing is a e and syn he ic
lexibili y on ole in subs i u ion is o en limi ed. Amongs he
a o emen ioned scaffold, silacyclopen -2-enes bea ing an
allylic alcohol a e o pa icula in e es . Tomooka’s g oup has
u ilised such compounds in he syn hesis o a ious unc iona-
lised silacylclopen anes, some p esen ing biological ac i i y,
ia Mi sunobu, Tsuji–T os , and o he ans o ma ions.
34,35
Addi ionally, simila silacyclopen -2-en-4-ols ha e been used in
he syn hesis o a polyol mo i p esen in se e al na u al
p oduc s.
36
In 2008, Po ella e al. epo ed a pho ochemical [2 + 2]
cycloaddi ion o acylsilanes (Scheme 1b).
37
Upon i adia ion,
acyl(allyl)silanes unde go in amolecula Pa e nò–Büchi eac-
ion, p oducing bicyclic oxe anes in mode a e o good yields
and p o iding a new me hod o he syn hesis o SCBs. While
new 1-alky-6-oxa-2-silabicyclo[2.2.0]hexanes could be p epa ed
by his way, i adia ion o benzoyl(allyl)silane esul ed in an
in ac able eac ion mix u e. Since he ela i e s abili y o he
iple bi adical in e media es in he Pa e nò–Büchi eac ion
plays an impo an ole in i s s e eo- and egioselec i i y,
38,39
we en isioned ha subs i u ion on he ole in moie y wi h a
adical s abilising g oup could ame he eac i i y o he in e -
media es, al e ing he eac ion p o ile obse ed by Po ella.
This could al e he egioselec i i y o he cycloaddi ion, and
he subsequen oxe ane ing-opening would e en ually yield
silacyclopen enols (Scheme 1c).
Acylsilanes ha e a ac ed immense scien i ic in e es since
hei i s p epa a ion by B ook in 1957.
40
Despi e he ex ensi e
esea ch conduc ed on hese compounds in he pas ew
decades,
41–43
no el me hodologies ha u ilize acylsilanes as
powe ul eagen s in o ganic chemis y a e s ill being
epo ed.
44–46
Expe imen ally, he use o a oma ic acylsilanes
is pa icula ly a ac i e as hey do no unde go side eac ions
in ol ing he ca bonyl α-ca bon.
47
Mo eo e , hey show an
abso p ion maximum a a ound 425 nm, hus allowing pho o-
exci a ion using isible blue ligh . The handling o acylsilanes
equi es special p ecau ions as hey a e known o unde go
B ook ea angemen o a eac i e ca bene a e pho o-
i adia ion o he mal condi ions. This ca bene has been
shown o unde go inse ion eac ions in pola ised he e oa om-
hyd ogen bounds,
48,49
cycloaddi ions o aldehydes
50
and
alkynes,
51,52
c oss-coupling eac ion wi h o ganobo onic
es e s
53
and e en C–H inse ions
54–56
unde ha she con-
di ions. Ca bene o ma ion and i s subsequen eac ions a e
hen possible compe i i e des uc i e pa hways o he [2 + 2]
pho ocycloaddi ion. This in luence can be minimised by using
d y, ap o ic sol en s and by p o ec ing ee alcohols o amines
in he acylsilane s a ing ma e ial.
Resul s and discussion
To in es iga e ou hypo hesis, cinnamyl silane 3a was syn-
hesised (Scheme 2). Ini ial in es iga ions using he di hiane
umpolung app oach ailed as he ha sh condi ions equi ed
o he dep o ec ion o he di hiane moie y we e incompa ible
wi h he ole in g oup. Inspi ed by Po ella’s success in he syn-
hesis o acyl(allyl)silanes using benzo iazole hemiaminals as
umpolung equi alen s o aldehydes,
37,57
we adop ed a simila
syn he ic pa hway. This s a egy, o iginally de eloped by
Ka i zky,
58
bene i s om acile la e-s age hyd olysis o he
hemiaminals o he co esponding ca bonyls. Ole in c oss-
me a hesis was pe o med on in e media e 2a, as he acylsi-
lane moie y seems o inhibi he G ubbs ca alys .
57
Scheme 1 Me hods o cons uc ion o silacyclopen -2-enes and
pho ocycloaddi ion o acylsilanes. Scheme 2 Syn hesis o benzoylsilanes 3.
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G a i yingly, 3a was ob ained in easonable 53% yield a e
hyd olysis. Compound 3a was i adia ed wi h blue-ligh o
5 hou s in d y hexane, and comple e consump ion o he s a -
ing ma e ial was obse ed (Scheme 3). NMR analysis showed
ha oxe ane 4a was cleanly ob ained as a mix u e o wo dia-
s e eoisome s (syn/an i = 1 : 2), esul ing om he [2 + 2] pho o-
cycloaddi ion eac ion. No ably, e e se egioselec i i y in he
Pa e nò–Büchi eac ion was obse ed by Po ella e al.
37
o
unsubs i u ed acyl(allyl)silanes (Scheme 1b).
Compound 4a p o ed o be uns able o silica column pu i i-
ca ion and o e all acidic condi ions, p oducing alcohol 5a and
o he p oduc s. A e op imiza ion, we ound ha ea ing 4a
wi h ca aly ic NaHSO
4
in e -bu anol leads o comple e and
selec i e isome iza ion o 5a, in 82% o e all yield. I s s uc u e
was p o en h ough es e i ica ion wi h 3,5-dini obenzoylchlo -
ide o yield 6a and ollowing single c ys al X- ay diff ac ion
analysis o he ob ained es e .
Realising he po en ial o he pho ocycloaddi ion–isome i-
za ion sequence as a di ec and selec i e way o ob ain 2,3-a yl-
subs i u ed silacyclopen -2-en-4-ols, we syn hesised a se ies o
acylsilanes 3 o be submi ed o he same ans o ma ion
(Scheme 2). Sila-hemiaminals 2we e ob ained in e y good
yields, con aining a wide ange o unc ional g oups in he a yl
moie y. Ni o-subs i u ed a oma ics howe e ailed o add o
he silylchlo ide eagen , p esumably due o he low nucleo-
philici y o he li hia ed in e media e. Issues ela ed wi h he
ins abili y o he li hia ed anion o 1bea ing elec on- ich
g oups in A
1
we e o e come by BuLi addi ion o a s i ing
solu ion o 1and silyl chlo ide. The syn heses p oceeded wi h
c oss-me a hesis o in e media es 2wi h s y enes. Low o mod-
e a e yields we e ob ained in some cases due o incomple e
con e sion o 2, as he dime iza ion o s y ene o s ilbene was
a as compe i i e eac ion. 2-Py ididyl, 4-cyano- and 4-di-
me hylamine-benzene esul ed in comple e deac i a ion o he
ca alys , as no eac ions we e obse ed a e se e al days a
e lux. The de imen al effec o ni ogen bases and
N-he e ocycles in me a hesis eac ion is known and s ill a p o-
blema ic issue in his ield.
59
Despi e he syn he ic challenges, a se ies o se en een a yl-
subs i u ed acylsilanes 3we e ob ained and es ed in he in a-
molecula [2 + 2] pho ocycloaddi ion eac ion (Scheme 4). The
eac ion scope appea s o be qui e as , wi hs anding elec on
wi hd awing and elec on dona ing subs i uen s, as well as
o ho,me a and pa a subs i u ion. G a i yingly, bo h a ia ions
a 3- and 2-posi ions o he 2,3-dia yl-silacyclopen -2-ene-4-ol
could be pe o med. The eac ion ole a es he p esence o
subs i uen s p one o u he de i a iza ion such as ace yl
(5e), ni ile (5g), aldehyde (5h) and silyl e he (5n). Fo ma ion
o sul u he e ocycle de i a i e 5o con as s wi h i s oxygen
homologue 5p, o which only aces could be obse ed. Also
o ho-me hyl subs i u ion on he ke one side (A
1
) led o he
eco e y o s a ing ma e ial e en a e 8 hou s o i adia ion.
In o de o be e unde s and he d ama ic change in egio-
selec i i y o he [2 + 2] pho ocycloaddi ion o 3a compa ed o
i s e minal ole in analogues, DFT calcula ions we e pe o med
and he ene gies o he possible bi adical in e media es com-
Scheme 3 [2 + 2] pho ocycloaddi ion o cinnamyl silane 3a, acid-
ca alysed isome iza ion o 5a, and c ys al s uc u e o 3,5-dini o-
benzoyla ed 6a.
Scheme 4 Scope o he [2 + 2] pho ocycloaddi ion o benzoylsilanes 3.
a
PPTS (10%) was used ins ead o NaHSO
4
.
b
No acid ea men was
needed.
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pa ed (see ESI† o de ails). The Pa e nò–Büchi pho ocycload-
di ion ypically occu s h ough eac ion o a ca bonyl com-
pound in he exci ed s a e wi h an alkene in he g ound s a e.
Time dependen DFT s udies on 3a and 7show ha he i s
e ical ansi ion co esponds o popula ing he single
exci ed s a e wi h compa able ene gies o bo h molecules (ca.
64 kcal mol
−1
, Scheme 5a), h ough a ca bonyl n →π* an-
si ion be ween HOMO−1 and LUMO, as can be obse ed in
he case o 3a (Scheme 5b). As iple exci ed s a es o bo h
molecules a e gene ally ca. 11 kcal mol
−1
mo e s able han
hei single coun e pa s, hey likely unde go in e sys em spin
c ossing. Analysis o he molecula o bi als o 3a
T1
e i ies ha
LSOMO and HSOMO co espond o he hal -occupied n and π*
ca bonyl o bi als, espec i ely (Scheme 5c).
The wo pa hs conce ning he a ack o he ca bonyl oxygen
o he iple exci ed s a e o he ole in moie y o he allylsilane
we e conside ed‡(Scheme 6). Compa ing he o ma ion o he
wo bi adical species upon ei he exo and endo a acks o he
oxygen o he cinnamyl moie y, a p e e ence would be expec ed
owa ds he o me pa h due o s abiliza ion o he adicals by
he a oma ic ing in 3a :b
5
. The less han 1 kcal mol
−1
diffe -
ence in he s abili ies o he bi adicals de i ed om 7ne e -
heless sugges s wo compe ing mechanisms. Since, when
s a ing om alipha ic acyl(allyl)silanes, Po ella e al.
obse ed he exclusi e o ma ion o he 6-endo- ig cycliza ion-
de i ed p oduc (Scheme 1b), benzoylsilane 7was syn hesised
and i adia ed in o de o de e mine he effec o he ca bonyl
subs i uen on he eac ion ou come.
A e i adia ion o 7in hexane o 8 hou s, we obse ed
comple e and clean con e sion o he s uc u al isome s 8and
9, in 1 o 1.5 a io, espec i ely (Scheme 7). Bo h compounds
p o ed o be uns able o silica column ch oma og aphy.
Indi ec de ec ion o compound 9was possible a e acid ea -
men wi h PPTS and isome iza ion o he isolable allylic
alcohol 10 in 41% o e all yield, which was u he unc iona-
lised wi h 3,5-dini obenzoyl chlo ide o gi e es e 11 o X- ay
diff ac ion analysis (Scheme 7). Despi e he many a emp s in
isola ing compound 8o i s decomposi ion p oduc s, we could
only e i y i s p esence h ough iden i ica ion o cha ac e is ic
peaks in
1
H and
13
C NMR spec a o he eac ion mix u e, in
acco dance wi h p e ious oxe anes cha ac e iza ion by Po ella
e al.
37
(Scheme 1b).
Expe imen ally, he lack o egioselec i i y o he cyclo-
addi ion o compound 7is in ag eemen wi h i s DFT p e-
dic ed eac i i y, highligh ing he need o a adical s abilising
g oup connec ed o he ole in in o de o p omo e comple e
egioselec i i y owa ds he 5-exo- ig pa hway.
In o de o demons a e he e sa ili y o hese unp e-
ceden ed 2,3-disubs i u ed silacyclopen enols as p ecu so s o
o he silacyclopen anes, compound 5a was subjec ed o known
ans o ma ions (Scheme 8). Dias e eoselec i e epoxida ion
wi h m-CPBA quan i a i ely deli e ed 12a, a candida e p ecu -
so o a se ies o polyols. E hanolysis o a ansien ca boca ion
o med a e acid ea men o 5a yielded e he 13a.In
addi ion, ole in educ ion wi h 1 a m o hyd ogen in he p es-
Scheme 6 P oposed mechanism o he in amolecula [2 + 2] pho o-
cycloaddi ion o acylsilanes.
Scheme 7 I adia ion o benzoyl(allyl)silane 7and i s non- egio-
selec i e [2 + 2] cycloaddi ion.
Scheme 5 (a) Ene gy p ofile o exci ed s a es popula ion o acylsilanes
3a and 7. F ee ene gies o he species a e indica ed in i alics (kcal mol
−1
),
e e ing o co esponding acylsilane in g ound s a e. (b) Rep esen a ion
o mos significan molecula o bi als in ol ed in fi s e ical exci a ion
o 3a. (c) Single occupied o bi als o 3a.
‡The possible in e media es in ol ed in he pa hs de i ed om he a ack o he
ca bonyl ca bon o he ole in moie y we e also conside ed, al hough leading o
bi adicals conside ably highe in ene gy (see ESI†).
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ence o ca aly ic palladium on ca bon quan i a i ely yields
he silacyclopen anol 14a as mix u e o wo dias e eoisome s
(syn/an i = 1.4 : 1). Finally, inspi ed by he s uc u al simila i y
o selec i e COX-2 enzyme inhibi o s
60
de i ed om cyclo-
pen ane, he emo al o he hyd oxyl unc ionali y o 5a was
a emp ed. G a e ully, use o Yamamo o’s HSiE
3
/ca aly ic
B(C
6
F
5
)
3
sys em
61
allowed deoxygena ion o 15a in easonable
yield. The use o such compounds as bioisos e es o cyclo-
pen anes could pa e he way in he adop ion o he new in a-
molecula [2 + 2] pho ocycloaddi ion in he silicon/ca bon
swi ch s a egy. Oxida ion o allylic alcohol 5a was accom-
plished using excess MnO
2
in cold DCM, gi ing ke one 16a
quan i a i ely. Low empe a u es a e i al as 16a p o ed o
easily isome ize o he silyl enol e he 17a unde he mal
condi ions.
Conclusions
In conclusion, we ha e de eloped a me hodology o he syn-
hesis o no el 2,3-dia yl silacyclopen -2-en-4-ols. This s a egy
in ol ed he syn hesis o ole in-subs i u ed benzoyl(allyl)
silanes h ough he benzo iazole umpolung and me a hesis
eac ions. Blue-ligh i adia ion o hese molecules p omo es a
[2 + 2] pho ocycloaddi ion eac ion wi h comple e egio-
selec i i y, go e ned by he s abili y o he bi adical in e medi-
a e as suppo ed by compu a ional calcula ions. Acid-p o-
mo ed isome iza ion yields, o he bes o ou knowledge, he
so a una ailable 2,3-disubs i u ed silacyclopen enols.
Mo eo e , his s udy expands he a he sho collec ion o
in amolecula Pa e nò–Büchi eac ion examples while demon-
s a ing he in luence o he ole in subs i uen s in con olling
he egioselec i i y o such eac ion. The ob ained compounds
may be used as e sa ile p ecu so s o o he silacyclopen anes
ha could ind hei use in he silicon/ca bon swi ch app oach
in medicinal chemis y as bioisos e s o bioac i e cyclopen-
anes, o as o ganosilicon mo i s in o ganic elec onics.
Conflic s o in e es
The e a e no con lic s o decla e.
Acknowledgemen s
The Academy o Finland is duly acknowledged o inancial
suppo o N. R. C. (Decisions No. 326487 and 326486) and o
A. V. (No. 314343). Fundação pa a a Ciência e Tecnologia (FCT)
is acknowledged o inancial suppo o JRV (SFRH/BD/
120119/2016). CSC-IT Cen e o Science L d, Finland is
acknowledged o he alloca ion o compu a ional esou ces.
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