Nucleophilic addition of α-(dimethylsilyl)nitriles to aldehydes and ketones

Article abstract of DOI:10.1021/ol401663u

α-Alkylated (dimethylsilyl)acetonitriles (Me₂HSiCR ³R⁴CN) react spontaneously with aldehydes in DMSO to give β-hydroxynitriles in good to high yields. The addition to ketones is effectively promoted by using MgCl₂

Full text of DOI:10.1021/ol401663u

ORGANIC
LETTERS
2013
Vol. 15, No. 14
3750–3753
Nucleophilic Addition of
r‑(Dimethylsilyl)nitriles to
Aldehydes and Ketones
Takaaki Jinzaki,† Mitsuru Arakawa,‡ Hidenori Kinoshita,† Junji Ichikawa,‡ and
Katsukiyo Miura*,†
Department of Applied Chemistry, Graduate School of Science and Engineering,
Saitama University, Sakura-ku, Saitama 338-8570, Japan, and Division of Chemistry,
Faculty of Pure and Applied Sciences, University of Tsukuba, Tsukuba,
Ibaraki 305-8571, Japan
kmiura@apc.saitama-u.ac.jp
Received June 12, 2013
ABSTRACT
R-Alkylated (dimethylsilyl)acetonitriles (Me2HSiCR3R4CN) react spontaneously with aldehydes in DMSO to give β-hydroxynitriles in good to high
yields. The addition to ketones is effectively promoted by using MgCl2 or CaCl2. (Dimethylsilyl)acetonitrile (Me2HSiCH2CN) shows lower reactivity
than the R-alkylated analogues. However, the parent reagent adds efficiently to aldehydes and ketones under catalysis by AcOLi or MgCl2.
β-Hydroxynitriles are versatile synthetic intermediates
because the cyano group is convertible to various func-
tionalities. Carbonyl addition of R-metallonitriles has fre-
quently beenused for the synthesisof β-hydroxynitriles.1ꢀ4
The conventional methods include successive deprotona-
tionꢀcarbonyl addition of nitriles using strong bases and
the Reformatsky reaction of R-halonitriles.1 These meth-
ods are not necessarily efficient due to the reversibility
of the carbonyl addition as well as condensation leading
to R,β-unsaturated nitriles. Therefore, recent attention
has been focused on Lewis base-promoted addition of
R-(trimethylsilyl)nitriles (R-TMS-nitriles), stable equiva-
lents of R-cyano carbanions. Several methods for this
silicon-mediated carbonyl addition have been reported.4c,5ꢀ8
However, these studies mostly deal with the reaction of
TMS-acetonitrile (Me3SiCH2CN). There are only a few
examples for carbonyl addition of sterically congested
R-TMS-nitriles.6 Additionally some silicon-basedmethods
have limited scope of available carbonyls. There is still
much room for development of a new silicon-based meth-
od for efficient synthesis of various β-hydroxynitriles.
(5) (a) Latouche, R.; Texier-Boullet, F.; Hameli, J. Tetrahedron Lett.
1991, 32, 1179. (b) Palomo, C.; Aizpurua, J. M.; Lopez, M. C.; Lecea, B.
J. Chem. Soc., Perkin Trans. 1 1989, 1692.
† Saitama University.
‡ University of Tsukuba.
(1) (a) Arseniyadis, S.; Kyler, K. S.; Watt, D. S. Org. React. 1984,
31, 1. (b) Kaiser, E. W.; Hauser, C. R. J. Org. Chem. 1968, 33, 3402.
(2) (a) Zhou, J. J. P.; Zhoug, B.; Silverman, R. B. J. Org. Chem. 1995,
60, 2261. (b) Li, N.-S.; Yu, S.; Kabalka, G. W. J. Org. Chem. 1995, 60,
5973. (c) Araki, S.; Yamada, M.; Butsugan, Y. Bull. Chem. Soc. Jpn.
1994, 67, 1126. (d) Takai, K.; Ueda, T.; Ikeda, N.; Morikawa, T. J. Org.
Chem. 1996, 61, 7990.
(6) Mukaiyama and co-workers have reported carbonyl addition of
TMS-acetonitrile under catalysis by AcOLi. In addition, they have
found that R-alkylated TMS-acetonitriles add efficiently to benzalde-
hyde under catalysis by AcOCs (three examples). Kawano, Y.; Kaneko,
N.; Mukaiyama, T. Chem. Lett. 2005, 34, 1508.
(7) (a) Wadhwa, K.; Verkade, J. G. J. Org. Chem. 2009, 74, 5683. (b)
Matsukawa, S.; Kitazaki, E. Tetrahedron Lett. 2008, 49, 2982. (c) Jolivet,
S.; Abdallah-El Ayoubi, S.; Mathe, D.; Texier-Boullet, F.; Hamelin, J.
J. Chem. Res. Synop. 1996, 6, 300.
(8) For enantioselective carbonyl addition of silyl ketene imines, see:
Denmark, S. E.; Wilson, T. W.; Burk, M. T.; Heemsta, J. R., Jr. J. Am.
Chem. Soc. 2007, 129, 14864.
(9) (a) Miura, K.; Ebine, M.; Ootsuka, K.; Ichikawa, J.; Hosomi, A.
Chem. Lett. 2009, 38, 832. (b) Miura, K.; Nakagawa, T.; Hosomi, A.
Synlett 2003, 2068. (c) Miura, K.; Nakagawa, T.; Hosomi, A. J. Am.
Chem. Soc. 2002, 124, 536.
(3) Electrochemical reactions: (a) Bianchi, G.; Feroci, M.; Rossi, L.
Eur. J. Org. Chem. 2009, 3863. (b) Barhdadi, R.; Gal, J.; Heintz, M.;
ꢀ
Troupel, M.; Peichon, J. Tetrahedron 1993, 49, 5091.
(4) Catalytic reactions: (a) Goto, A.; Endo, K.; Ukai, J.; Irle, S.;
Saito, S. Chem. Commun 2008, 2212. (b) Kumagai, N.; Matsunaga, S.;
Shibasaki, M. J. Am. Chem. Soc. 2004, 126, 13632. (c) Suto, Y.;
Kumagai, N.; Matsunaga, S.; Kanai, M.; Shibasaki, M. Org. Lett.
2003, 5, 3147. (d) Kisanga, P.; McLeod, D.; D’Sa, B.; Verkade, J.
J. Org. Chem. 1999, 64, 3090.
r
10.1021/ol401663u
Published on Web 07/09/2013
2013 American Chemical Society

In our study on synthesis and synthetic use of dimethyl-
silyl (DMS)-protected carbon nucleophiles,9 we have dis-
closed that ethyl DMS-acetate (Me2HSiCH2CO2Et) and
other R-DMS-esters add smoothly to various aldehydes
and ketones in the presence of metal chlorides such as LiCl,
CaCl2, and MgCl2.10 In contrast, ethyl TMS-acetate is
insensitive to carbonyls under the same conditions. Thus,
the DMS-protected carbon nucleophiles show much high-
er reactivity than the TMS analogues. With this finding,
our interest was next focused on synthetic use of R-DMS-
nitriles. We herein report nucleophilic addition of R-DMS-
nitriles to carbonyl compounds.
R-DMS-nitriles 1aꢀc were prepared by treatment of a
diethyl ether solution of the corresponding nitrile and chlor-
odimethylsilane (DMS-Cl) with LDA (eq 1 in Scheme 1).
The reaction of in situ generated R-lithionitriles with DMS-Cl
provided better results than a stepwise method via depro-
tonation and subsequent silylation. We failed to obtain
pure DMS-acetonitrile (1d) from acetonitrile by the LDA-
mediated method shown in eq 1. After many attempts, we
succeeded in an efficient preparation of pure 1d by the
reaction among chloroacetonitrile, DMS-Cl, and zinc
powder (eq 2).11
2bꢀe were efficiently converted into β-hydroxynitriles
(entries 1ꢀ4). The addition of 1a to p-nitrobenzaldehyde
(2f) resulted in a low yield of 3af, and competitive reduction
leading to p-nitrobenzyl alcohol was observed (entry 5). An
excess amount of 1a was required for complete conversion
of 4-hydroxybenzaldehyde (2g) into 3ag (entry 6). This is
probably due to desilylation of 1a by the acidic hydroxy
group. Enolizable aldehydes 2h and 2i also underwent
spontaneous addition of 1a (entries 7 and 8). The reaction
of cinnamaldehyde (2j) mainly gave 1,2-adduct 3aj along
with 1,4-adduct 4aj (entry 9). Although ketones are generally
less reactive toward nucleophilic addition than aldehydes, 1a
showed enough reactivity for the addition to acetophenone
(2k) and cyclohexanone (2l) (entries 10 and 11). Use of
MgCl2 effectively promoted the reaction of 2l. R,β-Unsatu-
rated ketone 2m as well as 2j underwent both 1,2- and 1,4-
addition in favor of 1,2-addition (entry 12).
Table 1. Reaction of 1a with Aldehydes and Ketonesa
Scheme 1. Synthesis of R-DMS-nitriles
carbonyl compound
entry
R1
R2
product isolated yield (%)
1
4-MeOC6H4
4-MeC6H4
4-BrC6H4
4-ClC6H4
4-O2NC6H4
4-HOC6H4
Ph(CH2)2
c-C6H11
H
H
H
H
H
H
H
H
H
2b
2c
2d
2e
2f
3ab
3ac
3ad
3ae
3af
90
2
86
3
86
4
90
5
24b
22, 92c
71
6
2g
2h
2i
3ag
3ah
3ai
7
8
99
9
(E)-PhCHdCH
Ph
2j
3aj
59,d,e
90
10
11
12
Me 2k
3ak
3al
(CH2)5
2l
72, 99f
62d
We initially examined solvent effect on the reaction of 1a
with benzaldehyde (2a). The carbonyl addition of 1a proceeded
spontaneously at 30 °C in DMSO and DMF (Scheme 2).
Particularly the reaction in DMSO gave β-hydroxynitrile
3aa in high yield following treatment with acidic MeOH.
Other solvents (THF, CH2Cl2, PhMe, hexane) did not
promote the carbonyl addition. In the presence of CaCl2 or
LiCl (1 equiv), the reaction in DMSO was complete in 1 h.
(E)-PhCHdCH Me 2m
3am
a Unless otherwise noted, all reactions were carried out with 2
(0.50 mmol) and 1 (0.60 mmol) in DMSO (1.0 mL) at 30 °C for 24 h.
b p-Nitrobenzyl alcohol was also obtained in 53% NMR yield. c With
1.2 mmol of 1a. d 1,4-Adducts 4aj (entry 9) and 4am (entry 12) were
obtained in 9% and 27% yields, respectively. e The reaction time was 48 h.
f With 0.50 mmol of MgCl2.
Scheme 2. Solvent Effect on Reaction of R-DMS-nitrile 1a
We next examined the reaction of R-DMS-nitrile 1b with
aldehydes and ketones (Table 2). The addition of 1b to
aldehydes 2a and 2i proceeded slowly without additive
(entries 1 and 2). However, prolonged reaction time
brought about high yields of the desired adducts. In the
presence of CaCl2, the addition to 2a was completed in 24 h.
(10) Miura, K.; Nakagawa, T.; Hosomi, A. Synlett 2005, 1917.
(11) A similar Zn-mediated method is valuable for the synthesis of
TMS-acetonitrile. For the original method, see: Matsuda, I.; Murata, S.;
Ishii, Y. J. Chem. Soc., Perkin Trans. 1 1979, 26.
The results of the reaction of 1a with various carbonyl
compounds are summarized in Table 1. Aromatic aldehydes
Org. Lett., Vol. 15, No. 14, 2013
3751

The uncatalyzed reaction of ketones was rather slow, and
use of metal chlorides (CaCl2 or MgCl2) was essential to
efficient addition of 1b (entries 3 and 4).
utility of DMS-acetonitrile (1d). In addition, we aimed to
disclose the effect of the R-alkyl groups on the reactivity of
R-DMS-nitriles 1aꢀc. Initially, the reaction of 1d with 2a
was carried out in DMSO (Table 4). The desired carbonyl
addition proceeded spontaneously but more slowly than the
reactions of 1aꢀc (entries 1 and 2). MgCl2 was effective in
promoting the addition of 1d (entry 3). Catalysis by LiOAc,
as introduced by Mukaiyama and co-workers,6 brought
about a rapid addition leading to β-hydroxynitrile 3da
(entry 4). The reaction using 2.5 mol % of LiOAc was
completed in 1 h at 0 °C to give 3da in 93% yield.
R-DMS-nitrile 1c, derived from butanenitrile, added
smoothly to aromatic aldehydes (entries 1ꢀ5 in Table 3).
The desired adducts were obtained as diastereomeric
mixtures with low stereoselectivity. The reaction of 1c with
aliphatic aldehydes proceeded slowly and needed prolonged
reaction time (entries 6 and 7). The uncatalyzed reaction
with ketones 2k and 2l was very sluggish (entries 8 and 9).
Adding MgCl2 effectively accelerated the addition of 1c to
aliphatic aldehydes and ketones.
Table 4. Reaction of 1d with Benzaldehydea
Table 2. Reaction of 1b with Aldehydes and Ketonesa
additive
(/equiv)
NMR
yieldb (%)
entry
solvent
time (h)
carbonyl compound
1
2
3
4
none
DMSO
DMSO
DMSO
DMF
24
48
24
1
40
56
74
93c
none
entry
R1
R2
product isolated yield (%)
MgCl2 (1)
AcOLi (0.025)
1
2
3
4
Ph
H
2a
2i
3ba
3bi
3bk
3bl
45, 87,b 89c
71, 80b
c-C6H11
Ph
H
a Unless otherwise noted, all reactions were carried out with 2a
(0.50 mmol) and 1d (0.65 mmol) in solvent (1 mL) at 30 °C. b Determined
by 1H NMR analysis of the crude product. c At 0 °C.
Me
2k
2l
35, 87c
(CH2)5
23, 74d
a See footnote a in Table 1. b The reaction time was 48 h. c With 0.50
mmol of CaCl2. d With 0.50 mmol of MgCl2.
Table 5. Reaction of 1d with Aldehydesa
Table 3. Reaction of 1c with Aldehydes and Ketonesa
AcOLi time
isolated
entry
R1
(equiv)
(h)
product yield (%)
carbonyl compound
1
2
3
4
5
6
7
4-MeOC6H4
4-ClC6H4
Ph(CH2)2
Ph(CH2)2
c-C6H11
2b 0.025
3
3
3db
3de
3dh
3dh
3di
3di
3dj
90
isolated
product yield (%) syn:antib
2e
0.025
95
entry
R1
R2
2h 0.05
2h 0.05
24
24
24
6
65
67b
71
1
2
3
4
5
6
7
8
9
Ph
H
H
H
H
H
H
H
2a
2b
2c
2d
2e
2h
2i
3ca
3cb
3cc
3cd
3ce
3ch
3ci
98
56:44
59:41
58:42
57:43
55:45
55:45d,e
60:40d
62:38e
2i
2i
0.05
0.05
0.05
4-MeO-C6H4
4-Me-C6H4
4ꢀBr-C6H4
4ꢀCl-C6H4
Ph(CH2)2
c-C6H11
95
c-C6H11
87b
84
96
(E)-PhCHdCH 2j
24
85
a Unless otherwise noted, all reactions were carried out with 2
(0.50 mmol), 1d (0.65 mmol), and AcOLi (0.013 or 0.025 mmol) in
DMF (1 mL) at 0 °C. b In DMSO at 30 °C.
92
80, 73c
56, 87c
94c
Ph
Me 2k
3ck
3cl
(CH2)5
2l
79c
The scope of the LiOAc-catalyzed addition of 1d was
examined with several aldehydes (Table 5). Similar to the
TMS-analogue 1d0, 1d added smoothly to aromatic alde-
hydes (entries 1 and 2). The reaction of linear and R-branched
aliphatic aldehydes, 2h and 2i, also gave the corresponding
β-hydroxynitriles in good isolated yields (entries 3ꢀ6). In
contrast to the case of 1a, 1,2-addition of 1d to 2j proceeded
efficiently without 1,4-addition (entry 7). These results are
comparable with those of the addition of 1d0.6
a See footnote a in Table 1. The reaction time was 6 h (entries 1ꢀ5) or
48 h (entries 6ꢀ7). b Determined by 1H NMR analysis of the isolated
product. c With 0.50 mmol of MgCl2 for 24 h. d The same diastereomeric
ratio was observed in the absence and presence of MgCl2. e The relative
configuration of the major isomer was not determined.
As described above, TMS-acetonitrile (Me3SiCH2CN, 1d0)
is well-known to serve as a cyanomethyl anion equivalent.
We were therefore interested in the reactivity and synthetic
3752
Org. Lett., Vol. 15, No. 14, 2013

Table 6. Reaction of 1d with Ketonesa
Scheme 3. Reactivity of R-TMS-nitrile 1a0
ketone
promoter (entry 4). Conjugated ketones 2m and 2n underwent
efficient cyanomethylation with 1d (entries 5 and 6).
isolated
time (h) product yield (%)
entry
R1
R2
To gain a mechanistic insight, we attempted the reaction
of R-TMS-nitrile 1a0 with 2a (Scheme 3). In sharp contrast
with 1a, 1a0 did not add to 2a in DMSO even in the
presence of CaCl2. Judging from this result, nucleophilic
activation of the DMS-based reagents 1 by DMSO or
counteranions of metal salts would promote the present
reaction.10,13 The low reactivity of 1a0 can be rationalized
by the steric hindrance around silicon, which inhibits the
nucleophilic activation. Our efforts to detect a reactive species
generated from 1a by NMR analysis were not successful. As
described above, the addition of R-DMS-nitriles 1 is applic-
able to enolizable ketones. The less basic behavior of 1
indicates that a highly coordinated silicate is more likely than
a naked R-cyano carbanion as the reactive species.14
1
2
3
4
5
6
Ph
Ph
Me 2k
Me 2k
2l
24
24
24
48
6
3dk
3dk
3dl
60b
69b,c
40d
72c,d
75
(CH2)5
(CH2)5
2l
3dl
(E)-PhCHdCH Me 2m
4-O2NC6H4 Me 2n
3dm
3dn
6
92
a Unless otherwise noted, all reactions were carried out with 2
(0.50 mmol), 1d (0.65ꢀ0.75 mmol), and AcOLi (0.025 mmol) in DMSO
(1 mL) at 30 °C. b R,β-Unsaturated nitrile 5k was obtained in 15%
(E:Z = 1:1, entry 1) and 17% (E:Z = 3:2, entry 2) NMR yields. c MgCl2
(0.50 mmol) was used instead of AcOLi. d R,β-Unsaturated nitrile 5l was
obtained in 32% (entry 3) and 13% (entry 4) NMR yields.
In conclusion, we have developed new reagents that serve
as R-cyano carbanion equivalents for carbonyl addition.
R-DMS-nitriles 1 added to various aldehydes and ketones
spontaneously or in the presence of metal salts. In particular,
R-alkylated DMS-acetonitriles 1aꢀc showed high reactivity,
which enabled an efficient synthesis of sterically congested
β-hydroxynitriles. The present method is complementary to
the known method using TMS-acetonitrile, which is valuable
for the synthesis of less congested β-hydroxynitriles. It is also
interesting that DMS-acetonitrile 1d is much less reactive
than sterically congested R-DMS-nitriles 1aꢀc although the
reason is not clear at present.
Ketones were also subjected to the reaction with 1d
(Table 6). When 2k was employed, 3dk and dehydrated
product 5k were formed in 75% combined yield (entry 1).
This result indicates that, unlike the case of 1d0, the
carbonyl addition of 1d is faster than R-deprotonation of
2k under catalysis by AcOLi.12 Although the reaction was
carried out under neutral conditions using MgCl2 instead
of AcOLi, our efforts to suppress the formation of 5k was not
successful (entry 2). Similarly, the addition to 2l was accom-
panied by the subsequent elimination to 5l (entry 3). However,
the side reaction was inhibited effectively by using MgCl2 as
Acknowledgment. This work was partly supported by a
Grant-in-Aid for Scientific Research from the Ministry of
Education, Culture, Sports, Science and Technology, Japan.
(12) Mukaiyama and co-workers reported that the AcOLi-catalyzed
reaction of 2k with 1d0 resulted in a low yield of 3dk due to competitive
deprotonation affording the TMS enolate of 2k. See ref 6.
Supporting Information Available. Experimental details
and characterization data (1H NMR, 13C NMR, IR, MS).
This material is available free of charge via the Internet at
http://pubs.acs.org.
(13) For DMSO-promoted carbonyl addition of TMS-protected
carbon nucleophiles, see: (a) Iwanami, K.; Oriyama, T. Synlett 2006,
ꢀ
112. (b) Genisson, Y.; Gorrichon, L. Tetrahedron Lett. 2000, 41, 4881. In
these cases, MS 4A as well as DMSO were used for effcient addition.
(14) Naked enolates generated from ester silyl enolates and R-silyl esters
deprotonate enolizable ketones efficiently. Kuwajima, I.; Nakamura, E.
Acc. Chem. Res. 1985, 18, 181.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 14, 2013
3753