Site-Selective Silylation of Aliphatic C-H Bonds Mediated by [1,5]-Hydrogen Transfer: Synthesis of α-Sila Benzamides

Article abstract of DOI:10.1021/acs.orglett.6b02784

The first example of site-selective silylation of C(sp³)-H bonds mediated by a [1,5]-hydrogen transfer is reported. This reaction occurs selectively at the α-position of benzamides with a combination of tert-butylmagnesium chloride and a catalytic amount of 4,4′-di-tert-butylbipyridine (dtbpy) ligand and provides a facile route for the creation of biologically interesting α-sila benzamides. Late-stage functionalization of the incorporated silyl moieties facilitates the synthesis of N-formyl, cis-enamine, β-hydroxyl, amino, and pyrrole-containing derivatives.

Full text of DOI:10.1021/acs.orglett.6b02784

Letter
pubs.acs.org/OrgLett
Site-Selective Silylation of Aliphatic C−H Bonds Mediated by [1,5]-
Hydrogen Transfer: Synthesis of α‑Sila Benzamides
Pei Liu,† Jinghua Tang,† and Xiaoming Zeng*,†,‡,§
†Center for Organic Chemistry, Frontier Institute of Science and Technology, Xi’an Jiaotong University, Xi’an 710054, China
‡Department of Chemistry, Northeast Normal University, Changchun 130024, China
§State Key Laboratory of Elemento-organic Chemistry, Nankai University, Tianjin 300071, China
S
* Supporting Information
ABSTRACT: The first example of site-selective silylation of
C(sp3)−H bonds mediated by a [1,5]-hydrogen transfer is
reported. This reaction occurs selectively at the α-position of
benzamides with a combination of tert-butylmagnesium
chloride and a catalytic amount of 4,4′-di-tert-butylbipyridine
(dtbpy) ligand and provides a facile route for the creation of
biologically interesting α-sila benzamides. Late-stage function-
alization of the incorporated silyl moieties facilitates the synthesis of N-formyl, cis-enamine, β-hydroxyl, amino, and pyrrole-
containing derivatives.
he unique reactivity, low toxicity, stability, and pharmaco-
logical properties of silicon-containing compounds make
Scheme 1. Strategies for Silylation of Aliphatic C−H Bonds
T
them useful in synthetic1 and medicinal chemistry2 as well as in
materials science.3 For example, compounds I−IV containing a
silyl moiety at the α-position of a benzamide (Figure 1) can be
Figure 1. Examples of α-sila benzamide-bearing bioactive molecules as
angiotensin-converting enzyme inhibitors.
utilized as angiotensin-converting enzyme inhibitors (ACEIs)
for the treatment of hypertension.4 In particular, the silyl
moiety can serve as a synthetic handle that facilitates library
synthesis by its direct functionalization.5
One of the most powerful strategies for the synthesis of
organosilicon compounds is the silylation of C−H bonds.6,7
However, in contrast to the significant achievements in the
construction of C(sp2)−Si bonds from aromatic C−H
bonds,8−10 the silylation of aliphatic C−H bonds is less
developed.11 Dehydrogenative silylation incorporates a silyl
moiety directly into hydrocarbons (Scheme 1, eq 1).12 By
introducing a pyridyl chelation auxiliary, Kakiuchi pioneered
the silylation of benzylic C−H bonds (a general directed
strategy is shown in Scheme 1, eq 2).13,14 Hartwig and co-
workers demonstrated that (hydrido)silyl ethers can be
generated in situ and serve as directing groups to achieve the
silylation of C(sp3)−H bonds.15 Despite the progress, reactions
involving aliphatic C−H bond silylation remain rather limited.
Received: September 15, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02784
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Organic Letters
Letter
There is no methodology that can install a silyl moiety at the α-
position of heteroatoms via C(sp3)−H bond functionalization.
Since its discovery by Curran,16 the functionalization of a
remote C(sp3)−H bond through a [1,5]-hydrogen transfer has
provided a useful tool for the construction of synthetically
appealing molecules, generally by mechanisms involving radical
intermediates.17,18 Here we report the site-selective silylation of
C(sp3)−H bonds mediated by a [1,5]-hydrogen transfer,
allowing the construction of C−Si bonds specifically at the α-
position of benzamides to form α-sila benzamides (Scheme 1,
eq 3).
At the outset, we assumed that the selection of a suitable
metal to chelate the amidyl group would be vital for achieving
the α-silylation of benzamides. The metal was expected to help
abstract the o-halide to generate a persistent aryl radical species
A, thus inducing the hydride shift (Scheme 1, eq 3). Because
main-group metals such as magnesium possess a unique
capacity to activate fluoride,19 commercially available tert-
butylmagnesium chloride was treated in the reaction of 2-
fluorobenzamide 1a with chlorotriethylsilane (Table 1, entry 1).
increase the level of conversion (Table 1, entries 8−10).
However, silylation with MeMgBr, TMSCH2MgCl, or PhMgBr
was inhibited, indicating that β-hydride elimination to form an
active magnesium species can be considered (Table 1, entries
11−13).
The reactions with 2-fluoro-N,N-dimethylbenzamide and 1-
(2-fluorophenyl)-N-methylmethanamine did not take place,
and the fluoride moiety was maintained in these molecules
(Scheme 1c). These results show that chelation of magnesium
to the amidyl group after the deprotonation is required for
fluoride activation.21 Furthermore, the fluoride substituent on
N-(tert-butyl)-2-fluorobenzamide was retained. Silylation with
2-chloro-, 2-bromo-, and 2-iodo-substituted N-methylbenza-
mides gave inferior results (Scheme 2).
Scheme 2. Silylation of 2-Halide-Substituted Benzamides
a
Table 1. Optimization of the Reaction Conditions
We then turned our attention to probing the substrate scope
for the creation of functionalized α-sila benzamides (Scheme
3). 2-Fluorobenzamides containing CF3, F, Cl, Me, or OMe
substituents on the aromatics underwent the silylation
effectively, forming α-sila benzamides 3ab−ag in moderate to
good yields. Appealing functionalities such as amino and
entry
ligand
RMgX
yield of 3aa (%)
1
2
−
Phen
t-BuMgCl
t-BuMgCl
t-BuMgCl
t-BuMgCl
t-BuMgCl
t-BuMgCl
t-BuMgCl
iPrMgCl
12
16
32
37
44
76
13
20
28
14
3
Bpy
Scheme 3. Site-Selective Silylation of Aliphatic C−H Bonds
b
a
4
6,6′-Me2bpy
4,4′-(OMe)2bpy
dtbpy
at the α-Position through [1,5]-Hydrogen Transfer
c
5
6
7
TMEDA
dtbpy
8
9
dtbpy
CyMgCl
10
11
12
13
dtbpy
EtMgBr
d
dtbpy
MeMgBr
TMSCH2MgCl
PhMgBr
nd
d
dtbpy
nd
d
dtbpy
nd
a
Conditions: 1a (0.2 mmol), 2a (0.8 mmol), ligand (0.02 mmol),
b
RMgX (0.8 mmol), THF, 50 °C, 12 h. 6,6′-Dimethyl-2,2′-bipyridine.
c
d
4,4′-Dimethoxy-2,2′-bipyridine. Not detected.
Encouragingly, under these conditions we obtained the desired
α-sila benzamide 3aa in 12% yield. Interestingly, the addition of
10 mol % 1,10-phenanthroline (phen) to the system increased
the reaction rate slightly (Table 1, entry 2). Inspired by this
result, we explored the effect of bidentate nitrogen ligands on
the conversion. In particular, 4,4′-di-tert-butylbipyridine
(dtbpy) greatly promoted the silylation, giving 3aa in 76%
yield (Table 1, entry 6). The coupling reaction of the Grignard
reagent with the C−F bond did not occur. Furthermore,
isoindolinone, which may be derived from the cyclization of
radical B, was not detected (Scheme 1, eq 3).20 Decreasing the
amount of t-BuMgCl led to lower yields (see the Supporting
Information for details). In addition to serving as a base in the
deprotonation of benzamide, we assumed that another 2 equiv
of t-BuMgCl might be consumed for the C−F bond
dissociation and C−Si bond formation. It was found that
isopropyl, cyclohexyl, and ethyl Grignard reagents did not
a
Conditions: 1 (0.2 mmol), 2a (0.8 mmol), dtbpy (0.02 mmol), t-
b
BuMgCl (0.8 mmol), THF, 50 °C, 12 h. The reaction was conducted
on a 10 mmol scale. t-BuMgCl (1.2 mmol). 1 (0.5 mmol).
c
d
B
DOI: 10.1021/acs.orglett.6b02784
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Organic Letters
Letter
hydroxyl groups were well-tolerated under the reaction
conditions (3ah−aj). In addition to the functionalization of
primary C−H bonds, unactivated secondary C−H bonds were
also silylated to produce tertiary C−Si bonds (3ak−ao).22 The
compatibility of double bonds with the reaction conditions
enabled the silylation of allylic C−H bonds, providing a
straightforward construction of γ-silyl-containing allyl scaffolds
(3ap and 3aq), which are important building blocks for the
total synthesis of cyclic peptides TMC-95A; the synthesis of
such motifs previously required a multiple-step reaction
sequence.23 Several silane electrophiles were then examined.
Diverse substituted organosilicon functionalities were incorpo-
rated in a site-selective manner at the α-position of the
benzamide (Scheme 4).24 The silylation proceeded smoothly
on a gram scale to give 3aa in 67% yield (Scheme 3).
The [1,5]-hydrogen transfer in the silylation was then
examined by conducting deuterium experiments with N-
methyl-deuterated benzamide. It was found that almost 100%
of the deuterium was incorporated at the ortho position of the
product 3aa-d3 (Scheme 6, eq 1). Moreover, no intermolecular
Scheme 6. Mechanistic Studies
a
Scheme 4. Synthesis of α-Sila Benzamides
H/D exchange was detected in H/D crossover experiments
(Scheme 6, eq 2), thus providing further evidence for the
intramolecular hydride shift process. To measure the initial
reaction rates, kinetic isotope effect (KIE) studies with two
separate reactions of nondeuterated 3aa and deuterated 3aa-d3
were performed (Scheme 6, eq 3). The results indicated that
cleavage of the α-C(sp3)−H bond, with a KIE value of 4.33, can
be considered as the turnover-limiting step. Notably, the o-C−F
bond on the benzamide was not cleaved without the assistance
of chlorosilane (Scheme 6, eq 4).
In summary, we have developed a novel silylation of aliphatic
C−H bonds that proceeds through a [1,5]-hydrogen transfer.
The approach provides a site-selective and scalable method to
construct C−Si bonds at the α-position of benzamides,
expanding the hydride transfer reactions beyond the con-
struction of C−C, C−O, and C−N bonds. Through the
combined use of a catalytic amount of dtbpy ligand and tert-
butylmagnesium chloride, primary and secondary C−H bonds
were silylated in a site-specific manner to form α-sila
benzamides, which can be further utilized as building blocks
in synthesis by functionalization of the incorporated silyl
scaffolds. Additional efforts to elucidate the reaction mechanism
with the help of theoretical studies are underway.
a
Conditions: 1a (0.2 mmol), 2 (0.8 mmol), dtbpy (0.02 mmol), t-
b
c
BuMgCl (0.8 mmol), THF, 50 °C, 12 h. TMSCN was used. Me2(t-
Bu)SiOTf was used. 1a (0.5 mmol).
d
The installed organosilicon motifs are amenable to trans-
formation by late-stage functionalization. In the presence of
AgF and NBS, conversion of the silylmethyl moiety into the
corresponding aldehyde functionality proceeded smoothly to
give N-formylbenzamide (4) (Scheme 5).25 Direct additions of
α-sila benzamide 3aa to benzaldehyde and an aromatic imine
gave β-hydroxyl- and amino-substituted compound 5 and 6,
respectively.26 Heating α-silyl N-allylbenzamide 3ap in toluene
enabled the preparation of cis-enamide compound 7.27
Furthermore, multiply substituted pyrrole 8 could be
synthesized from 3ca.28
Scheme 5. Functionalization of α-Sila Benzamides
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b02784.
Detailed optimization data; experimental procedures;
characterization data for all new compounds; ORTEP
drawing and crystallographic data for 3ba (PDF)
Crystallographic data for 3ba (CIF)
C
DOI: 10.1021/acs.orglett.6b02784
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Gevorgyan, V. Nat. Chem. 2014, 6, 122−125. (d) Mita, T.; Michigami,
K.; Sato, Y. Org. Lett. 2012, 14, 3462−3465. (e) Kuninobu, Y.;
Nakahara, T.; Takeshima, H.; Takai, K. Org. Lett. 2013, 15, 426−428.
(f) Murai, M.; Takeshima, H.; Morita, H.; Kuninobu, Y.; Takai, K. J.
Org. Chem. 2015, 80, 5407−5414.
(15) (a) Simmons, E. M.; Hartwig, J. F. Nature 2012, 483, 70−73.
(b) Lee, T.; Hartwig, J. F. Angew. Chem., Int. Ed. 2016, 55, 8723−8727.
(c) Li, B.; Driess, M.; Hartwig, J. F. J. Am. Chem. Soc. 2014, 136,
6586−6589.
(16) Curran, D. P.; Kim, D.; Liu, H. T.; Shen, W. J. Am. Chem. Soc.
1988, 110, 5900−5902.
(17) For reviews of [1,5]-hydride shift reactions, see: (a) Majetich,
G.; Wheless, K. Tetrahedron 1995, 51, 7095−7129. (b) Robertson, J.;
Pillai, J.; Lush, R. K. Chem. Soc. Rev. 2001, 30, 94−103. (c) Nechab,
M.; Mondal, S.; Bertrand, M. P. Chem. - Eur. J. 2014, 20, 16034−
16059.
(18) For recent examples, see: (a) Yoshikai, N.; Mieczkowski, A.;
Matsumoto, A.; Ilies, L.; Nakamura, E. J. Am. Chem. Soc. 2010, 132,
5568−5569. (b) Parasram, M.; Chuentragool, P.; Sarkar, D.;
Gevorgyan, V. J. Am. Chem. Soc. 2016, 138, 6340−6343.
(19) For examples of magnesium-promoted fluoride activation, see:
(a) Yoshikai, N.; Matsuda, H.; Nakamura, E. J. Am. Chem. Soc. 2009,
131, 9590−9599. (b) Yoshikai, N.; Mashima, H.; Nakamura, E. J. Am.
Chem. Soc. 2005, 127, 17978−17979. (c) Xiong, Y.; Wu, J.; Xiao, S.;
Xiao, J.; Cao, S. J. Org. Chem. 2013, 78, 4599−4603.
(20) Wertjes, W. C.; Wolfe, L. C.; Waller, P. J.; Kalyani, D. Org. Lett.
2013, 15, 5986−5989.
(21) For proposed N coordination of magnesium with benzamide,
see: Tang, Q.; Xia, D.; Jin, X.; Zhang, Q.; Sun, X.-Q.; Wang, C. J. Am.
Chem. Soc. 2013, 135, 4628−4631.
(22) For selected examples of the formation of tertiary C−Si bonds
by cross-coupling, see: (a) Chu, C. K.; Liang, Y.; Fu, G. C. J. Am.
Chem. Soc. 2016, 138, 6404−6407. (b) Zarate, C.; Martin, R. J. Am.
Chem. Soc. 2014, 136, 2236−2239.
(23) Lin, S.; Yang, Z.-Q.; Kwok, B. H. B.; Koldobskiy, M.; Crews, C.
M.; Danishefsky, S. J. J. Am. Chem. Soc. 2004, 126, 6347−6355.
(24) CCDC 1495032 (3ba) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.
(25) Chernyak, N.; Dudnik, A. S.; Huang, C.; Gevorgyan, V. J. Am.
Chem. Soc. 2010, 132, 8270−8272.
(26) Leiendecker, M.; Hsiao, C.-C.; Guo, L.; Alandini, N.; Rueping,
M. Angew. Chem., Int. Ed. 2014, 53, 12912−12915.
(27) Lin, S.; Yang, Z.-Q.; Kwok, B. H. B.; Koldobskiy, M.; Crews, C.
M.; Danishefsky, S. J. Am. Chem. Soc. 2004, 126, 6347−6355.
(28) Washizuka, K. I.; Minakata, S.; Ryu, I.; Komatsu, M. Tetrahedron
1999, 55, 12969−12976.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: zengxiaoming@mail.xjtu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(21202128 and 21572175) and Beijing National Laboratory for
Molecular Sciences for financial support.
REFERENCES
■
(1) (a) Handbook of Reagents for Organic Synthesis: Reagents for
Silicon-Mediated Organic Synthesis; Fuchs, P. L., Ed.; Wiley: Chichester,
U.K., 2011. (b) Langkopf, E.; Schinzer, D. Chem. Rev. 1995, 95, 1375−
1408.
(2) (a) Franz, A. K.; Wilson, S. O. J. Med. Chem. 2013, 56, 388−405.
(b) Showell, G. A.; Mills, J. S. Drug Discovery Today 2003, 8, 551−556.
(3) Organosilicon Chemistry V: From Molecules to Materials; Auner, N.,
Weis, J., Eds.; Wiley-VCH: Weinheim, Germany, 2004.
(4) (a) Sieburth, S. M.; Mutahi, A. M. PCT Int. Appl. WO 9802578,
1998. (b) Kim, J.; Hewitt, G.; Carroll, P.; Sieburth, S. M. J. Org. Chem.
2005, 70, 5781−5789.
(5) Cheng, C.; Hartwig, J. F. Science 2014, 343, 853−857.
(6) For selected reviews of silylation of C−H bonds, see: (a) Cheng,
C.; Hartwig, J. F. Chem. Rev. 2015, 115, 8946−8975. (b) Hartwig, J. F.
Acc. Chem. Res. 2012, 45, 864−873. (c) Yang, Y.; Wang, C. Sci. China:
Chem. 2015, 58, 1266−1279. (d) Xu, Z.; Huang, W.-S.; Zhang, J.; Xu,
L.-W. Synthesis 2015, 47, 3645−3668. (e) Sharma, R.; Kumar, R.;
Kumar, I.; Singh, B.; Sharma, U. Synthesis 2015, 47, 2347−2366.
(7) For selected reviews of C−H functionalization, see: (a) Sun, C.-
L.; Li, B.-J.; Shi, Z.-J. Chem. Rev. 2011, 111, 1293−1314. (b) Wencel-
Delord, J.; Droge, T.; Liu, F.; Glorius, F. Chem. Soc. Rev. 2011, 40,
̈
4740−4761. (c) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew.
Chem., Int. Ed. 2009, 48, 5094−5115. (d) Lyons, T. W.; Sanford, M. S.
Chem. Rev. 2010, 110, 1147−1169. (e) Zhou, L.; Lu, W. Huaxue
Xuebao 2015, 73, 1250−1274.
(8) For silylation of C(sp2)−H bonds with t-BuOK, see: Toutov, A.
A.; Liu, W.-B.; Betz, K. N.; Fedorov, A.; Stoltz, B. M.; Grubbs, R. H.
Nature 2015, 518, 80−84.
(9) For silylation of C(sp2)−H bonds with B(C6F5)3, see: Ma, Y.;
Wang, B.; Zhang, L.; Hou, Z. J. Am. Chem. Soc. 2016, 138, 3663−3666.
(10) For selected recent examples, see: (a) Cheng, C.; Hartwig, J. F.
J. Am. Chem. Soc. 2015, 137, 592−595. (b) Lee, T.; Wilson, T. W.;
Berg, R.; Ryberg, P.; Hartwig, J. F. J. Am. Chem. Soc. 2015, 137, 6742−
6745. (c) Chen, Q.-A.; Klare, H. F. T.; Oestreich, M. J. Am. Chem. Soc.
2016, 138, 7868−7871. (d) Hua, Y.; Asgari, P.; Avullala, T.; Jeon, J. J.
Am. Chem. Soc. 2016, 138, 7982−7991. (e) Choi, G.; Tsurugi, H.;
Mashima, K. J. Am. Chem. Soc. 2013, 135, 13149−13161. (f) Klare, H.
F. T.; Oestreich, M.; Ito, J.-i.; Nishiyama, H.; Ohki, Y.; Tatsumi, K. J.
Am. Chem. Soc. 2011, 133, 3312−3315. (g) Oyamada, J.; Nishiura, M.;
Hou, Z. Angew. Chem., Int. Ed. 2011, 50, 10720−10723.
(11) For early reports of C(sp3)−H bond silylation, see: (a) Ishikawa,
M.; Okazaki, S.; Naka, A.; Sakamoto, H. Organometallics 1992, 11,
4135−4139. (b) Djurovich, P. I.; Dolich, A. R.; Berry, D. H. J. Chem.
Soc., Chem. Commun. 1994, 1897−1898.
(12) (a) Sadow, A. D.; Tilley, T. D. Angew. Chem., Int. Ed. 2003, 42,
803−805. (b) Sadow, A. D.; Tilley, T. D. J. Am. Chem. Soc. 2005, 127,
643−656. (c) Atienza, C. C. H.; Diao, T.; Weller, K. J.; Nye, S. A.;
Lewis, K. M.; Delis, J. G. P.; Boyer, J. L.; Roy, A. K.; Chirik, P. J. J. Am.
Chem. Soc. 2014, 136, 12108−12118.
(13) Kakiuchi, F.; Tsuchiya, K.; Matsumoto, M.; Mizushima, E.;
Chatani, N. J. Am. Chem. Soc. 2004, 126, 12792−12793.
(14) For recent examples of directed silylation of C(sp3)−H bonds,
see: (a) Li, W.; Huang, X.; You, J. Org. Lett. 2016, 18, 666−668. (b) Li,
Q.; Driess, M.; Hartwig, J. F. Angew. Chem., Int. Ed. 2014, 53, 8471−
8474. (c) Ghavtadze, N.; Melkonyan, F. S.; Gulevich, A. V.; Huang, C.;
D
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