Indium triiodide catalyzed reductive functionalization of amides via the single-stage treatment of hydrosilanes and organosilicon nucleophiles

Article abstract of DOI:10.1021/ol4015317

The indium triiodide catalyzed single-stage cascade reaction of N-sulfonyl amides with hydrosilanes and two types of organosilicon nucleophiles such as silyl cyanide and silyl enolates selectively promoted deoxygenative functionalization to give α-cyanoamines and β-aminocarbonyl compounds, respectively.

Full text of DOI:10.1021/ol4015317

ORGANIC
LETTERS
2013
Vol. 15, No. 13
3452–3455
Indium Triiodide Catalyzed Reductive
Functionalization of Amides via the
Single-Stage Treatment of Hydrosilanes
and Organosilicon Nucleophiles
Yoshihiro Inamoto, Yuta Kaga, Yoshihiro Nishimoto, Makoto Yasuda, and Akio Baba*
Department of Applied Chemistry, Graduate School of Engineering, Osaka University,
2-1 Yamadaoka, Suita, Osaka 565-0871, Japan
baba@chem.eng.osaka-u.ac.jp
Received May 30, 2013
ABSTRACT
The indium triiodide catalyzed single-stage cascade reaction of N-sulfonyl amides with hydrosilanes and two types of organosilicon nucleophiles
such as silyl cyanide and silyl enolates selectively promoted deoxygenative functionalization to give r-cyanoamines and β-aminocarbonyl
compounds, respectively.
Much attention has been paid to the synthesis of func-
tionalized amines. Among them, the reduction of pre-
functionalized carboxamides is a promising tool because
of the wide availability, stability, and the convenient
installation of a variety of functional moieties. Unfortu-
nately, reductions employing general metal hydrides such
as LiAlH4 and NaBH4 have accomplished little achieve-
ment, perhaps because the functional groups can barely
tolerate the harsh reduction conditions.1 In recent ad-
vances, the catalytic reduction of prefunctionalized amides
to the corresponding amines through the use of mild
reducing reagents such as hydrosilanes has been exten-
sively investigated (eq 1).2 However, when using this
method, the preparation of functionalized amides is trouble-
some. An alternative tool is the direct deoxygenative
functionalization of simple amides. To achieve the trans-
formation, in general, two kinds of species, metal hydrides
such as LiAlH4 and carbon nucleophiles such as Grignard
reagents, were separately added under the respective
controlled conditions.3 Recently, two advanced strategies
have been reported as shown in eqs 2 and 3.4,5 One is
a transformation via the iminium triflate intermediate
(eq 2),4 and the other employs a Weinreb amide, which
forms a stable chelation intermediate via a reduction with
DIBALH (eq 3).5 However, even these examples require
the stepwise addition of two different organometallic
(1) (a) Cope, A. C.; Ciganek, E. Org. Synth. 1963, 4, 339–342.
(b) Seyden-Penne, J. In Reductions by the Alumino- and Borohydrides
in Organic Synthesis, 2nd ed.; Wiley-VCH: New York, 1997; p 1.
(2) For selected examples of the catalytic reduction of amides using
hydrosilane, see: (a) Kuwano, R.; Takahashi, M.; Ito, Y. Tetrahedron
Lett. 1998, 39, 1017–1020. (b) Motoyama, Y.; Mitsui, K.; Ishida, T.;
Nagashima, H. J. Am. Chem. Soc. 2005, 127, 13150–13151. (c) Hanada,
S.; Tsutsumi, E.; Motoyama, Y.; Nagashima, H. J. Am. Chem. Soc.
2009, 131, 15032–15040. (d) Sunada, Y.; Kawakami, H.; Imaoka, T.;
Motoyama, Y.; Nagashima, H. Angew. Chem., Int. Ed. 2009, 48, 9511–
9514. (e) Sakai, N.; Fujii, K.; Konakahara, T. Tetrahedron Lett. 2008,
49, 6873–6875. (f) Zhou, S.; Junge, K.; Addis, D.; Das, S.; Beller, M.
Angew. Chem., Int. Ed. 2009, 48, 9507–9510. (g) Das, S.; Addis, D.;
Zhou, S.; Junge, K.; Beller, M. J. Am. Chem. Soc. 2010, 132, 1770–1771.
(3) For selected examples of the addition of Grignard reagents
or organolithium reagents followed by the addition of a hydride, see:
(a) Yamaguchi, M.; Hirao, I. Tetrahedron Lett. 1983, 24, 1719–1722.
(b) Iida, H.; Watanabe, Y.; Kibayashi, C. J. Am. Chem. Soc. 1985, 107,
5534–5535. (c) Vincent, G.; Guillot, R.; Kouklovsky, C. Angew. Chem.,
Int. Ed. 2011, 50, 1350–1353. One example was carried out by using
acyclic amide; see: (d) Hwang, Y. C.; Chu, M.; Flower, F. W. J. Org.
Chem. 1985, 50, 3885–3890. For selected examples of addition of metal
hydride reagents followed by addition of carbon nucleophiles, see:
(e) Overman, L. E.; Lesuisse, D.; Hashimoto, M. J. Am. Chem. Soc.
€
(h) Das, S.; Wendt, B.; Moller, K.; Junge, K.; Beller, M. Angew. Chem.,
Int. Ed. 2012, 51, 1662–1666. (i) Park, S.; Brookhart, M. J. Am. Chem.
Soc. 2012, 134, 640–653. (j) Cheng, C.; Brookhart, M. J. Am. Chem. Soc.
2012, 134, 11304–11307. A part of the references are described here:
(k) Addis, D.; Das, S.; Junge, K.; Beller, M. Angew. Chem., Int. Ed. 2011,
50, 6004–6011.
1983, 105, 5373–5379. (f) Tschinkl, M.; Schier, A.; Riede, J.; Gabbaı,
¨
F. P. Angew. Chem., Int. Ed. 1999, 38, 3545–3547.
r
10.1021/ol4015317
Published on Web 06/25/2013
2013 American Chemical Society

nucleophiles, more than an equimolar amount of addi-
tional reagents, and respective control of reaction tem-
perature, which continues to prevent the introduction of
feasible functional groups.6
Table 1. Optimization of Reductive Cyanation of Amides 1a
Herein, we report a simple, useful, and energy-efficient
single-stagesynthesis of functionalized amines from amides
using hydrosilanes and organosilicon nucleophiles in the
presence of an indium(III) catalyst, wherein hydrosilyla-
tion and functionalization take place automatically in the
desired order (eq 4). This procedure can avoid the pre-
functionalization of amides and the stepwise controlled
treatments. In contrast to a stepwise addition, single-stage
synthesis, however, usually generates two undesired ad-
ducts because the conditions cannot be controlled in
accordance with each of the nucleophiles, as shown in eq 4.
yield (%)b
entry amide 1; R3
HSi (mmol)
InX3
3
4
1c
2c
3
1a; Bn
1b; Boc
1c; Ts
1c; Ts
1c; Ts
1c; Ts
1c; Ts
1c; Ts
1c; Ts
1c; Ts
1c; Ts
1c; Ts
1c; Ts
1c; Ts
1c; Ts
1c; Ts
HSiMe2Ph (1.5) InI3
HSiMe2Ph (1.5) InI3
HSiMe2Ph (1.5) InI3
HSiMePh2 (1.5) InI3
trace
0
trace
0
81
91
58
94
28
77
96 (88)
0
14
4
4
5
HSiEt3 (1.5)
H3SiPh (1.5)
PMHS (1.5)
TMDS (1.5)
H3SiPh (1.0)
H3SiPh (1.0)
H3SiPh (1.0)
H3SiPh (1.0)
H3SiPh (1.0)
HSiEt3 (1.5)
À
InI3
13
6
6
InI3
7
InI3
0
8
InI3
9
9
InI3
4
10c
11
12c
13d
14
15c
16e
InCl3
InBr3
In(OTf)3
InI3
0
92
0
4
0
88
49
0
2
InBr3
InI3
3
0
H3SiPh (1.0)
InI3
À
99
a Reaction conditions: To a solution of 1 (1 mmol), 2 (2 mmol), and
InX3 (0.05 mmol) in dichloromethane (1 mL) was added HSi. The
reaction mixture was stirred for 1 h at rt. b Determined by 1H NMR using
1,1,2,2-tetrachloroethane as an internal standard. Value in parentheses
indicates isolated yield. c >90% of 1 was recovered. d Solvent-free condi-
tions. e No addition of 2. PMHS = polymethylhydrosiloxane, TMDS =
1,1,3,3-tetramethylhydrodisiloxane
We have previously reported the indium(III)-catalyzed
reductive functionalization of esters using HSiMe2Ph
and organosilicon nucleophiles such as allylsilane and
silyl enolates, in which the alkoxy moiety is selectively
substituted.7 Unfortunately, the previous system did not
work in the reductive cyanation of N-benzyl amide 1a and
N-Boc amide 1b (Table 1, entries 1 and 2). Gratifyingly, an
employment of N-tosyl amide 1c afforded R-cyanoamine
3c in an 80% yield along with 10% of undesired amine 4c
via the single-stage treatment, where to a mixture of InI3,
amide 1c, and silyl cyanide 2 in dichloromethane was
added HSiMe2Ph (Table 1, entry 3).8 It was noted that
the final addition of hydrosilane to the reaction mixture
was a crucial procedure. To optimize the reaction condi-
tions, investigations of hydrosilanes and indium(III) cata-
lysts were carried out (Table 1, entries 4À12). H3SiPh gave
a higher yield of 3c than other hydrosilanes (Table 1,
entries 4À8). In addition, the use of a strictly equimolar
amount of H3SiPh gave the best outcome (Table 1, entry 9).
The most appropriate catalyst proved to be InI3, because
it had a high turnover frequency (Table 1, entries 9À12).
In contrast, no reaction was promoted by either InCl3
or In(OTf)3.9 Solvent-free conditions also provided good
results (Table 1, entry 13). The InBr3/HSiEt3 system for
thereductionofamidesreportedbySakai2e gavealowyield
of 3c (Table 1, entry 14). It was notable that no reaction
of N-tosyl amide 1c with silyl cyanide 2 was observed in
the absence of hydrosilane,10 while H3SiPh readily gave
dihydrogenated product 4c in the absence of silyl cyanide 2
ꢀ
(4) (a) Larouche-Gauthier, R.; Belanger, G. Org. Lett. 2008, 10,
ꢀ
4501–4504. (b) Belanger, G.; O’Brien, G.; Larouche-Gauthier, R. Org.
Lett. 2011, 13, 4268–4271. (c) Xiao, K.-J.; Luo, J.-M.; Ye, K.-Y.; Wang,
Y.; Huang, P.-Q. Angew, Chem., Int. Ed. 2010, 49, 3037–3040. (d) Xiao,
K.-J.; Wang, Y.; Ye, K.-Y.; Huang, P.-Q. Chem.;Eur. J. 2010, 16,
12792–12796. (e) Xiao, K.-J.; Wang, A.-E.; Huang, P.-Q. Angew. Chem.,
Int. Ed. 2012, 51, 8314–8317. (f) Huo, H.-H.; Zhang, H.-K.; Xia, X.-E.;
Huang, P.-Q. Org. Lett. 2012, 14, 4834–4937. Metal-free reduction of
amides using Hantzsch ester; see: (g) Barbe, G.; Charette, A. B. J. Am.
Chem. Soc. 2008, 130, 18–19. (h) Pelletier, G.; Bechara, W. S.; Charette,
A. B. J. Am. Chem. Soc. 2010, 132, 12817–12819.
(5) (a) Shirokake, K.; Kurosaki, Y.; Sato, T.; Chida, N. Angew.
Chem., Int. Ed. 2010, 49, 6369–6372. (b) Oda, Y.; Sato, T.; Chida, N.
Org. Lett. 2012, 14, 950–953. The introduction of two kinds of carbon
nucleophiles was achieved; see: (c) Yanagita, Y.; Nakamura, H.;
Shirokane, K.; Kurosaki, Y.; Sato, T.; Chida, N. Chem.;Eur. J.
2013, 19, 678–684.
(6) For a review of the deoxygenative functionalization of carbonyl
compounds, see: (a) Seebach, D. Angew. Chem., Int. Ed. 2011, 50, 96–
101. For selected examples of an amide to a N,O-aminal followed by
nucleophilic addition, see: (b) Ma, D.; Yang, J. J. Am. Chem. Soc. 2001,
123, 9706–9707. (c) Aggarwal, V. K.; Astle, C. J.; Rogers-Evans, M. Org.
Lett. 2004, 6, 1469–1471. For selected examples of the functionalization
of thioamides to produce functionalized amines, see: (d) Murai, T.;
Mutoh, Y.; Ohta, Y.; Murakami, M. J. Am. Chem. Soc. 2004, 126, 5968–
5969. (e) Murai, T.; Asai, F. J. Am. Chem. Soc. 2007, 129, 780–781.
(f) Agosti, A.; Britto, S.; Renaud, P. Org. Lett. 2008, 10, 1417–1420.
(g) Murai, T.; Mutoh, Y. Chem. Lett. 2012, 41, 2–8.
(8) The addition order was important. To a mixture of InI3, amide 1c,
and HSiMe2Ph was added silyl cyanide 2 to give only amine 4c. See
Supporting Information (SI) for the detailed experiment.
(7) (a) Nishimoto, Y.; Inamoto, Y.; Saito, T.; Yasuda, M.; Baba, A.
Eur. J. Org. Chem. 2010, 3382–3386. (b) Inamoto, Y.; Nishimoto, Y.;
Yasuda, M.; Baba, A. Org. Lett. 2012, 14, 1168–1171.
(9) Further optimizations of reaction conditions are shown in the SI.
Org. Lett., Vol. 15, No. 13, 2013
3453

Scheme 1. Reaction of N-Sulfonyl Amides 1 with H3SiPh and
Silyl Cyanide 2a
Scheme 2. Reaction of Amides 1 with Hydrosilanes and Silyl
Enolates 5a
a To a solution of 1 (1 mmol), 2 (2 mmol), and InI3 (0.05 mmol) in
solvent (1 mL) was added H3SiPh. Condition A: dichloromethane, rt.
Condition B: 1,2-dichloroethane, 80 °C. Isolated yield of 3. Values
a To a solution of 1 (1 mmol), 5 (1.5 mmol), and InI3 (0.05 mmol) in
solvent (1 mL) was added HSi. Isolated yield of 6. Values in parentheses
indicate NMR yields of 4. Condition A: H3SiPh (1 mmol), dichloro-
methane, rt. Condition B: H3SiPh (1 mmol), 1,2-dichloroethane, 80 °C.
Condition C: HSiMe2Ph (1.5 mmol), dichloromethane, rt. Condition D:
HSiMe2Ph (1.5 mmol), 1,2-dichloroethane, 80 °C. Condition E: HSiMe2Ph
(1.5 mmol), 1,2-dichloroethane, 50 °C. Condition F: HSiMePh2 (1.5 mmol),
dichloromethane, rt. b H3SiPh (1.5 mmol). c Solvent-free conditions. d dr =
52:48. e 5 (3 mmol). f H3SiPh (2 mmol), 5 (3 mmol), InI3 (0.1 mmol).
b
c
in parentheses indicate NMR yields of 4. H3SiPh (1.5 mmol). InI3
(10 mol %).
(Table 1, entries 15 and 16).11 These results indicate that the
reactivity of hydrosilanes toward amides 1c was apparently
higher than that of silyl cyanide 2. Additionally, it was very
strange and interesting that the second hydride attack was
effectively suppressed to produce the desired cyanation
product 3c.
Scheme 1 summarizes the scope of applicable N-sulfonyl
amides 1. Simple amides were suitable to give the desired
products 3d and 3e in 72 and 87% yields, respectively,
along with a negligible amount of side products 4, which
were easily removed by column chromatography. A hin-
dered amide effectively afforded product 3f under heating
conditions. Functional groups such as chloro-, bromo-,
alkene-, alkyne-, methoxy-, and hydroxy-groups were
compatible with this system to give the corresponding func-
tionalized amines 3gÀlin high yields. The use of N-allylamide
and N-benzylamide gave high yields of R-cyanoamines 3m
and 3n, respectively, without deprotection of the allyl-
and benzyl-moieties. Five-membered lactam was also
applicable to provide cyclic R-cyanoamine 3o in an
81% yield. Generally, a nosyl (o-nitrobenzenesulfonyl)
group on the nitrogen atom can be more easily removed
than a tosyl group under mild conditions.12 To our delight,
N-nosyl amide 1p also reacted with H3SiPh and silyl
cyanide 2 in the presence of 10 mol % of InI3 to give the
corresponding product 3p in 75% yield.
Next, we demonstrated a Mannich-type reaction by
the application of silyl enolate 5 instead of silyl cyanide 2
(Scheme 2). To the best of our knowledge, there has been
no study into the reductive functionalization of amides
using an enolate as a nucleophile.13 The single-stage treat-
ment of an N-tosyl amide with H3SiPh and a ketene silyl
acetal 5a successfully gave β-amino ester 6da in a 93%
yield.14 The bromo and alkenyl groups were compatible
with this system to produce amines 6ha and 6ia. Moreover,
allyl, benzyl, and phenyl substituents on the nitrogen atom
(12) Kan, T.; Fukuyama, T. Chem. Commun. 2004, 353.
(13) The addition of an enolate into formamide followed by reduc-
tion using NaBH(OAc)3 is reported in the literature. See ref 4a.
(14) See the SI concerning the opimization of reaction conditions.
(10) See the SI concerning the reaction of amide 1c with silyl cyanide 2
in the presence of an InI3 catalyst.
(11) A quantitative yield of 4c indicated that two hydrogens of
H3SiPh were introduced.
3454
Org. Lett., Vol. 15, No. 13, 2013

did not suppress this reaction, furnishing 6ma, 6na, and
6qa, respectively. The reaction of aromatic amides 1r and
1s gave the corresponding products 6ra and 6sa, respec-
tively, under the usual conditions, whereas 1t possessing an
electron-donating group required solvent-free conditions
to give the product 6ta. When the treatments of dialkyl-
and monoalkyl-ketene silyl acetals (5b and 5c) were con-
ducted, desired amines 6db and 6dc were obtained in high
yields, respectively. Silyl enol ether 5d had a nucleophilicity
that was lower than ketene silyl acetal 5aÀ5c15 and
also furnished adduct 6dd, which was achieved by using
the mild reducing reagent HSiMePh2 instead of H3SiPh
or HSiMe2Ph to suppress the generation of byproduct 4d.
Interestingly, N-phenyl amide was applicable instead of
N-tosyl amide to provide amine 6ua under harsh conditions.
Six-membered lactam 1v also gave the cyclic amine
6va in a 90% yield, which was further transformed to fused
bicyclic β-lactam 7va via deprotection of the tosyl moiety by
sodium naphthalenide (Scheme 3). This procedure is the first
transformation from a lactam to a fused bicyclic β-lactam.16
activation of amide 1 and iminium cation 10, the sulfonyl
group plays an important role in the selective release
of a siloxy group from N,O-acetal 9 via a decrease in the
interaction of the amine moiety with the indium(III)
catalyst.17 Although the cause of the predominant attack
of silyl cyanide 2 and silyl enolate 5 over hydrosilylation is
unclear, it may be the high reactivity of NuSi2 2 (5) toward
the highly polarized iminium cation 10.
Scheme 4. Plausible Reaction Mechanism
Scheme 3. Transformation from Six-Membered Lactam 1v to
Fused Bicyclic β-Lactam 7va
In conclusion, we have established the synthesis
of functionalized amines from N-sulfonyl amides using
hydrosilanes and organosilicon nucleophiles such as silyl
cyanide and silyl enolates in the presence of an indium
triiodide catalyst. In contrast to conventional methods,
this step-economical system is a practical “single-stage”
introduction of two kinds of nucleophiles into amides.
A plausible reaction mechanism is illustrated in Scheme 4.
First, as noted in Table 1, entries 15 and 16, a completely
exclusive hydrosilylation over the reaction with organosili-
con nucleophile 2 (5) takes place to afford N,O-acetal
intermediate 9. Second, the selective elimination of the
siloxy group generates iminium cation 10. Finally, the
resultant 10 predominantly reacts with 2 (5) over hydro-
silane (HSi1) to produce the functionalized amine 3 (6)
along with the regeneration of the InI3 catalyst. Besides the
Acknowledgment. This work was supported by the
Ministry of Education, Culture, Sports, Science and
Technology (Japan).
Supporting Information Available. Experimental pro-
cedures and characterization. This material is available
free of charge via the Internet at http://pubs.acs.org.
(17) Our previous report, which conducted the indium(III)-catalyzed
allylation of imines, shows that the introduction of a tosyl group gave
good results; see: Onishi, Y.; Ito, T.; Yasuda, M.; Baba, A. Tetrahedron
2002, 58, 8227–8235.
(15) For the reactivity order of organosilicon nucleophiles, see:
Mayr, H.; Kempf, B.; Ofial, A. R. Acc. Chem. Res. 2003, 36, 66–77.
(16) For selected examples of the construction of fused bicyclic
β-lactam 7va, see: (a) Shono, T.; Tsubata, K.; Okinaga, N. J. Org.
Chem. 1984, 49, 1056–1059. (b) Beckwith, A. L. J.; Boate, D. R.
Tetrahedron Lett. 1985, 26, 1761–1764.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 13, 2013
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