Fused heteroaromatic dihydrosiloles: Synthesis and double-fold modification

Article abstract of DOI:10.1021/ol400977r

An efficient method for the synthesis of fused heteroaromatic dihydrosiloles via Ni-catalyzed hydrosilylation/intramolecular Ir-catalyzed dehydrogenative coupling of the Si-H bond with the heteroaromatic C-H bond has been developed. The method is efficient for both electron-deficient and -rich heterocycles. It exhibits high functional group tolerance and good regioselectivity. Fused heteroaromatic dihydrosiloles can be smoothly halogenated and then oxidized or arylated. Application of these transformations allows obtaining highly functionalized heteroaromatic structures. A gram-scale synthesis of dihydropyridinosilole has also been accomplished using reduced amounts of Ni- and Ir-catalysts.

Full text of DOI:10.1021/ol400977r

ORGANIC
LETTERS
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Vol. XX, No. XX
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Fused Heteroaromatic Dihydrosiloles:
Synthesis and Double-Fold Modification
Alexey Kuznetsov, Yoshiharu Onishi, Yoshihiro Inamoto, and Vladimir Gevorgyan*
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street,
Chicago, Illinois 60607-7061, United States
vlad@uic.edu
Received April 8, 2013
ABSTRACT
An efficient method for the synthesis of fused heteroaromatic dihydrosiloles via Ni-catalyzed hydrosilylation/intramolecular Ir-catalyzed
dehydrogenative coupling of the SiꢀH bond with the heteroaromatic CꢀH bond has been developed. The method is efficient for both electron-
deficient and -rich heterocycles. It exhibits high functional group tolerance and good regioselectivity. Fused heteroaromatic dihydrosiloles can be
smoothly halogenated and then oxidized or arylated. Application of these transformations allows obtaining highly functionalized heteroaromatic
structures. A gram-scale synthesis of dihydropyridinosilole has also been accomplished using reduced amounts of Ni- and Ir-catalysts.
Transition-metal-catalyzed CꢀH silylation reactions1 of
aromatic and heteroaromatic systems serve as powerful
toolsfor functionalizationofthese molecules.2ꢀ10 Inrecent
years, a number of methodologies employing Ru,3 Ir,4
Rh,5 Pt,6 Pd,7 Re,8 and Lewis acid9 catalysis, have been
developed for inter- and intramolecular dehydrogenative
SiꢀH/CꢀH coupling reactions. Yet reports on analogous
heteroaromatic CꢀH coupling are exceedingly rare.10
Recently, we reported a one-pot procedure for the efficient
synthesis of dihydrobenzosiloles via hydrosilylation of
(1) For recent reviews on CꢀH silylation reactions, see: (a) Kakiuchi,
F.; Chatani, N. Adv. Synth. Catal. 2003, 345, 1077. (b) Hartwig, J. F.
Acc. Chem. Res. 2012, 45, 864. (c) Kuhl, N.; Hopkinson, M. N.; Wencel-
Delord, J.; Glorius, F. Angew. Chem., Int. Ed. 2012, 51, 10236.
(4) For recent examples of Ir-catalyzed CꢀH silylation reactions, see:
(a) Ishiyama, T.; Sato, K.; Nishio, Y.; Miyaura, N. Angew. Chem., Int.
Ed. 2003, 42, 5346. (b) Saiki, T.; Nishio, Y.; Ishiyama, T.; Miyaura, N.
Organometallics 2006, 25, 6068. (c) Simmons, E. M.; Hartwig, J. F.
J. Am. Chem. Soc. 2010, 132, 17092. (d) Mita, T.; Michigami, K.; Sato, Y.
Org. Lett. 2012, 14, 3462.
(5) For recent examples of Rh-catalyzed CꢀH silylation reactions,
see: (a) Tobisu, M.; Ano, Y.; Chatani, N. Chem.;Asian J. 2008, 3, 1585.
(b) Ureshino, T.; Yoshida, T.; Kuninobu, Y.; Takai, K. J. Am. Chem.
Soc. 2010, 132, 14324. (c) Tobisu, M.; Hasegawa, J.; Kita, Y.; Kinuta,
H.; Chatani, N. Chem. Commun. 2012, 11437. (d) Kuninobu, Y.;
Nakahara, T.; Takeshima, H.; Takai, K. Org. Lett. 2013, 15, 426. (e)
Kuninobu, Y.; Yamauchi, K.; Tamura, N.; Seiki, T.; Takai, K. Angew.
Chem., Int. Ed. 2013, 52, 1520.
(2) For pioneering work on transition-metal-catalyzed silylation
reactions, see: (a) Gustavson, W. A.; Epstein, P. S.; Curtis, M. D.
Organometallics 1982, 1, 884. (b) Sakakura, T.; Tokunaga, Y.; Sodeyama,
T.; Tanaka, M. Chem. Lett. 1987, 2375. (c) Ishikawa, M.; Okazaki, S.;
Naka, A.; Sakamoto, H. Organometallics 1992, 11, 4135. (d) Uchimaru, Y.;
El Sayed, A. M. M.; Tanaka, M. Organometallics 1993, 12, 2065.
(e) Ishikawa, M.; Naka, A.; Ohshita, J. Organometallics 1993, 12, 4987.
(3) For recent examples of Ru-catalyzed CꢀH silylation reactions,
see: (a) Kakiuchi, F.; Igi, K.; Matsumoto, M.; Chatani, N.; Murai, S.
Chem. Lett. 2001, 422. (b) Kakiuchi, F.; Igi, K.; Matsumoto, M.;
Hayamizu, T.; Chatani, N.; Murai, S. Chem. Lett. 2002, 396. (c)
Kakiuchi, F.; Matsumoto, M.; Tsuchiya, K.; Igi, K.; Hayamizu, T.;
Chatani, N.; Murai, S. J. Organomet. Chem. 2003, 686, 134. (d)
Kakiuchi, F.; Tsuchiya, K.; Matsumoto, M.; Mizushima, E.; Chatani,
N. J. Am. Chem. Soc. 2004, 126, 12792. (e) Shima, T.; Hou, Z. Chem.
Lett. 2008, 298. (f) Ihara, H.; Suginome, M. J. Am. Chem. Soc. 2009, 131,
7502. (g) Ihara, H.; Ueda, A.; Suginome, M. Chem. Lett. 2011, 40, 916.
(h) Sakurai, T.; Matsuoka, Y.; Hanataka, T.; Fukuyama, N.; Namikoshi,
T.; Watanabe, S.; Murata, M. Chem. Lett. 2012, 41, 374. (i) Mita, T.;
Michigami, K.; Sato, Y. Org. Lett. 2012, 14, 3462.
(6) For recent examples of Pt-catalyzed CꢀH silylation reactions,
see: (a) Williams, N. A.; Uchimaru, Y.; Tanaka, M. J. Chem. Soc., Chem.
Commun. 1995, 1129. (b) Tsukada, N.; Hartwig, J. F. J. Am. Chem. Soc.
2005, 127, 5022. (c) Fukuyama, N.; Wada, J.-i.; Watanabe, S.; Masuda,
Y.; Murata, M. Chem. Lett. 2007, 36, 910.
(7) For an example of Pd-catalyzed allylic CꢀH silylation, see:
ꢀ
Larsson, J. M.; Zhao, T. S. N.; Szabo, K. J. Org. Lett. 2011, 13, 1888.
r
10.1021/ol400977r
XXXX American Chemical Society

styrenes with diphenylsilane followed by dehydrogenative
cyclization (eq 1).11 However, the heteroaromatic ana-
logues of dihydrobenzosiloles are virtually unknown.12
Given the importance of heteroaromatic molecules in var-
ious fields, herein we wish to report an efficient method for
dehydrogenative SiꢀH/CꢀH cyclization of heteroaromatic
molecules including pyridine, pyrrole, furan, and thiophene
(eq 2). In this work, we also show that the resulted fused
heteroaromatic dihydrosiloles can be readily transformed
into valuable highly functionalized building blocks.
Table 1. Scope of Electron-Deficient Heterocycles in
HydrosilylationꢀDehydrogenative Cyclizationa
First, we attempted to apply the previously developed
conditions11 for the synthesis of dihydropyridinosilole
3a from 4-vinylpyridine (eq 3). However, hydrosilylation
of vinylpyridine 1a with diphenylsilane in the presence of
NiBr2•(PPh3)2 produced traces of 2a. Use of the Ni(cod)2/
PPh3 combination was more effective in this transforma-
tion to give 2a in high yield. A subsequent one-pot addition
of [Ir(cod)(OMe)]2, dtbpy, and norbornene however did
not provide any sufficient amounts of dihydropyridinosi-
lole 3a. Optimization of the dehydrogenative cyclization
of 2a revealed13 that use of 2% [Ir(cod)OMe]2 and 4%
1,10-phenantroline gives a good yield of dihydropyridino-
silole 3a (Table 1, entry 1). We also found that the presence
of PPh3, which is a requisite ligand for the hydrosilyla-
tion reaction, inhibits the cyclization step. Hence, the
hydrosilylation/dehydrogenative coupling sequence was
performed in two steps. Notably, both reactions can be
easily scaled up to a gram-scale synthesis of dihydro-
pyridinosilole 3a, which can be accomplished using lower
amounts of Ni- and Ir-catalysts (Table 1, entry 2).
a Hydrosilylation reaction conditions:
1 (1.0 mmol), H2SiPh2
(1.02 mmol), Ni(cod)2 (5 mol %), PPh3 (20 mol %), and THF (1.0 mL)
were stirred at 90 °C for 2 h under nitrogen. Dehydrogenative coupling
reaction conditions: 2 (0.5 mmol), [Ir(cod)OMe]2 (2 mol %) and 1,10-
phenanthroline (4 mol %), norbornene (1,2 equiv), and THF (1.0 mL)
were stirred at 100 °C for 12 h under nitrogen. b Isolated yield. c Reaction
was performed on 10 mmol scale using 2.5 mol % Ni-catalyst and
0.25ꢀ0.5mol % Ir-catalyst. d 10mol%Ni(cod)2 wasused. e 48 h at100 °C.
Having the optimized conditions for dehydrogenative
cyclization in hand, we examined the scope of the
(8) For an example of Re-catalyzed CꢀH silylation, see: Jiang, Y.;
Blacque, O.; Fox, T.; Frech, C. M.; Berke, H. Chem.;Eur. J. 2009, 15,
2121.
(9) For Lewis acid catalyzed CꢀH silylation examples, see: (a)
Furukawa, S.; Kobayashi, J.; Kawashima, T. J. Am. Chem. Soc. 2009,
131, 14192. (b) Oyamada, J.; Nishiura, M.; Hou, Z. Angew. Chem., Int.
Ed. 2011, 50, 10720. For a Lewis base catalyzed CꢀH silylation example,
see: Fedorov, A.; Toutov, A. A.; Swisher, N. A.; Grubbs, R. H. Chem.
Sci. 2013, 4, 1640.
(10) For heteroaromatic CꢀH silylation examples, see: (a) Ishiyama,
T.; Sato, K.; Nishio, Y.; Saiki, T.; Miyaura, N. Chem. Commun. 2005,
5065. (b) Lu, B.; Falck, J. R. Angew. Chem., Int. Ed. 2008, 47, 7508. (c)
Klare, H. F.; Oestreich, M.; Ito, J.-i.; Nishiyama, H.; Ohki, Y.; Tatsumi,
K. J. Am. Chem. Soc. 2011, 133, 3312.
hydrosilylationꢀdehydrogenative cyclization reaction start-
ing with 4-vinylpyridines bearing a substituent at the C2
position of the ring (Table 1, entries 3ꢀ5). It was found
that both electron-donating and -withdrawing groups
were tolerable at this position leading to a dehydrogenative
SiꢀH/CꢀH coupling reaction at a less hindered site. Hydro-
silylation of 4-methyl-3-vinylpyridine worked well (entry 6).
However, attempts at the cyclization step resulted in traces of
cyclized product only, probably due to the inhibition of the Ir
catalyst by its complexation with the pyridine nitrogen atom.
(11) Kuznetsov, A.; Gevorgyan, V. Org. Lett. 2012, 14, 914.
(12) Tamao, K.; Nakamura, K.; Ishii, H.; Yamaguchi, S.; Shiro, M.
J. Am. Chem. Soc. 1996, 118, 12469.
(13) See Supporting Information for details.
B
Org. Lett., Vol. XX, No. XX, XXXX

On the other hand, 2-methyl-3-vinylpyridine and its deriva-
tives were converted into the cyclization products in good
yield (entries 7ꢀ9). 2-Vinylpyridine underwent a smooth
hydrosilylation reaction, as judged by GC/MS analysis of
the crude reaction mixture; however it decomposed upon
purification into 2-ethylpyridine (entry 10). This result can
be explained by intramolecular pyridine nitrogen-assisted
hydrolysis of the hydrosilylation product 2i. Hence, next, we
examined reactions of more sterically hindered substrates
possessing a substituent at the C6 position of the pyridine
ring. Thus, the hydrosilylation of 6-methyl-2-vinylpyridine
lead to the corresponding hydrosilylation product 2j in
moderate yield (entry 11). A subsequent dehydrogenative
cyclization reaction of 2j allowed 3j to be obtained in low
yield. Introduction of fluorine at the C5 position of 6-methyl-
2-vinylpyridine gave improved results (entry 12). Employ-
ment of substrates possessing MeO- and CF3- groups at
the C6 position of 2-vinylpyridine gave comparable good
yields for both steps (entries 13ꢀ14). Having explored the
dehydrogenative cyclization of pyridine substrates with a
Si-tether at different positions, we turned our attention
to other electron-deficient heterocycles. It was found that
quinoline, isoquinoline, and quinoxaline systems provided
high yields for the hydrosilylation reaction and good yields
for a subsequent cyclization step (entries 15ꢀ18).
Next, we examined the possibility of using substrates
possessing electron-rich heterocycles in this hydrosilylationꢀ
dehydrogenative coupling reaction sequence (Table 2).
We were pleased to find that furan, thiophene, and pyrrole
systems worked well in both reactions producing the corre-
sponding cyclization products in good yields (entries 1ꢀ3).
In the case of pyrrole with a Si-tether at the C4 position, the
cyclization selectively occurred at the C3 position (entry 3).
Expectedly, benzothiophene with a tether at the C3 position
cyclized at the C2 site (entry 4). Cyclization of fused hetero-
aromatic systems at the phenyl ring were efficient, as well.
Thus, employment of benzothiophene with a tether at C5
resulted in the cyclization product at the C6 position as
a major regioisomer (entry 5). Similarly, indole and N-Ts
indazole with an alkylsilyl tether at C5 gave the C6 cycliza-
tion products as major regioisomers (entries 6ꢀ7). On the
other hand, N-Me indazole with a Si-tether at C5 cyclized at
the C6 exclusively (entry 8).
Table 2. Scope of Electron-Rich Heterocycles in Hydrosilylationꢀ
Dehydrogenative Cyclizationa
Finally we explored the synthetic usefulness of this
method by transforming the obtained fused hetero-
aromatic dihydrosiloles into valuable heterocylic building
blocks (Scheme 1). Thus, dihydropyridinosilole 3a upon
t
treatement with BuOOH/KH and TBAF14 can be oxi-
dized into 4-(2-hydroxyethyl)pyridin-3-ol derivative 4 in
Scheme 1. Further Modifications of Dihydropyridinosilole
85% yield. Upon reaction with N-halosuccinimides and
AgF, the C(Het)ꢀSi bond of dihydropyridinosilole 3a
can be cleaved selectively over the C(Ph)ꢀSi bond to pro-
duce 3-halopyridinefluorosilanes 5aꢀc in good yields.
a Hydrosilylation reaction conditions: 1 (1.0 mmol), H2SiPh2 (1.02
mmol), Ni(cod)2 (5 mol %), PPh3 (20 mol %), and THF (1.0 mL) were
stirred at 90 °C for 2 h under nitrogen. Dehydrogenative coupling
reaction conditions: 2 (0.5 mmol), [Ir(cod)OMe]2 (2 mol %) and 1,10-
phenanthroline (4 mol %), norbornene (1,2 equiv), and THF (1.0 mL)
were stirred at 100 °C for 12 h under nitrogen. b Isolated yield.
(14) Jones, G. R.; Landais, Y. Tetrahedron 1996, 52, 7599.
Org. Lett., Vol. XX, No. XX, XXXX
C

The Si-group in 5aꢀc can be further oxidized to 6aꢀc, or
replaced with an aryl-15 group to form 7a,b in good yields.
Compound 7b can undergo efficient intramolecular direct
arylation with formation of tricyclic dihydrobenzoquinoline
8. Moreover, upon reaction with LiAlH4,16 3-chloropyridi-
nefluorosilane 5a was converted to hydrosilane 2a0, which
was cyclized into 3a0 under the Ir-catalyzed dehydrogenative
cyclization reaction conditions. Subsequent dihydrosilole
ring opening with NIS and AgF, and oxidation of the
Si-group in the resulted 3-chloro-5-iodopyridinefluorosi-
followed by the Ir-catalyzed dehydrogenative SiꢀH/CꢀH
coupling sequence. This method proved tobe veryeffective
for electron-defficient and -rich heterocycles. These newly
formed fused heteroaromatic dihydrosiloles can be further
transformed into valuable heterocyclic building blocks,
possessing halogen, hydroxyl, and aryl functionalities.
Acknowledgment. We thank the National Institutes of
Health (GM-64444) and (1P50 GM-086145) for financial
support of this work. The Mass Spectrometry Lab at the
University of Illinois at UrbanaꢀChampaign (UIUC) is
gratefully acknowledged for the acquisition of HRMS data.
t
lane 5d using BuOOH/KH and TBAF, led to the highly
functionalized 2-(3-chloro-5-iodopyridin-4-yl)ethanol 9.
In summary, we developed an efficient method for the
synthesis of fused heteroaromatic dihydrosiloles via the
Ni-catalyzed hydrosilylation of heteroaromatic styrenes,
Supporting Information Available. Detailed experimen-
tal procedures and characterization data for all new
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
(15) Beaulleu, L.-P. B.; Delvos, L. B.; Charette, A. B. Org. Lett. 2010,
12, 1348.
(16) Cheng, A. H.-B.; Lee, M. E.; Rouss, P.; Jones, P. R. Organo-
metallics 1985, 4, 581.
The authors declare no competing financial interest.
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Org. Lett., Vol. XX, No. XX, XXXX