Efficient synthesis of α-tertiary α-silylamines from aryl sulfonylimidates via one-pot, sequential C-Si/C-C bond formations

Article abstract of DOI:10.1021/ol301194e

An efficient and flexible route for the synthesis of α-tertiary (α,α-dibranched) α-silylamines via sequential reactions of sulfonylimidates using readily available phenyldimethylsilyllithium and Grignard reagents is described. The procedure allows successive formation of C-Si/C-C bonds in a single flask.

Full text of DOI:10.1021/ol301194e

ORGANIC
LETTERS
2012
Vol. 14, No. 11
2906–2909
Efficient Synthesis of r-Tertiary
r-Silylamines from Aryl Sulfonylimidates
via One-Pot, Sequential CꢀSi/CꢀC
Bond Formations
Xiao-Jun Han, Ming Yao, and Chong-Dao Lu*
Xinjiang Technical Institute of Physics & Chemistry, Chinese Academy of Sciences,
Urumqi 830011, China and Graduate University of the Chinese Academy of Sciences
clu@ms.xjb.ac.cn
Received May 1, 2012
ABSTRACT
An efficient and flexible route for the synthesis of R-tertiary (R,R-dibranched) R-silylamines via sequential reactions of sulfonylimidates using
readily available phenyldimethylsilyllithium and Grignard reagents is described. The procedure allows successive formation of CꢀSi/CꢀC bonds
in a single flask.
R-Silylamines, also called silylmethylamines (SMAs),
and their derivatives have attracted considerable attention
due to their biological activities and their applications in
synthetic transformations1 ever since they were first de-
scribed in 1951.2 Although numerous SMAs have been
characterized and used in various applications, few reports
exist of R-tertiary amines containing R-silyl groups (R2SMA),
in part because they cannot be prepared efficiently by current
methods.
To access such hindered R-silylamines, conventional
methods for the synthesis of typical tertiary amines3
cannot be easily applied. This strategy involves the addi-
tion of carbanions to ketimines, but the equivalent addi-
tion of silyl nucleophiles to ketimines has not given satis-
factory yields.4 In 2011, the Oestreich group achieved
CuCN-catalyzed addition of Me2PhSiꢀBpin (pin =
pinacolate) to ketimines (Scheme 1, path 1).5 However,
the need for toxic copper(I) cyanide and the somewhat
tedious procedures to prepare the nucleophilic silyl reagent,
Me2PhSiꢀBpin,6 make this approach less practical. An
alternative approach to producing R-tertiary R-silylamines
would be to couple carbanions with imines derived from
acylsilanes (C-silylimines) or their functional equivalents
(1) For a review of the chemistry and biological activities of silyl-
methylamines and their derivatives, see: Picard, J.-P. Adv. Organomet.
Chem. 2005, 52, 175.
(2) (a) Noll, J. E.; Speier, J. L.; Daubert, B. F. J. Am. Chem. Soc.
1951, 73, 3867. (b) Sommer, L. H.; Rocket, J. J. Am. Chem. Soc. 1951, 73,
5130.
(3) For additions of nonsilylated nucleophiles to ketimines, see:
(a) Ramon, D. J.; Yus, M. Curr. Org. Chem. 2004, 8, 149. (b) Cogan, D. A.;
Ellman, J. A. J. Am. Chem. Soc. 1999, 121, 268. (c) Davis, F. A.; Lee, S.;
Zhang, H.; Fanelli, D. L. J. Org. Chem. 2000, 65, 8704. (d) Ogawa, C.;
Sugiura, M.; Kobayashi, S. J. Org. Chem. 2002, 67, 5359. (e) Berger, R.;
Duff, K.; Leighton, J. L. J. Am. Chem. Soc. 2004, 126, 5686.
(f) Dhudshia, B.; Tiburcio, J.; Thadani, A. N. Chem. Commun. 2005,
5551. (g) Garcia Ruano, J. L.; Aleman, J.; Parra, A. J. Am. Chem. Soc.
2005, 127, 13048. (h) Lauzon, C.; Charette, A. B. Org. Lett. 2006, 8,
2743. (i) Wada, R.; Shibuguchi, T.; Makino, S.; Oisaki, K.; Kanai, M.;
Shibasaki, M. J. Am. Chem. Soc. 2006, 128, 7687. (g) Canales, E.;
Hernandez, E.; Soderquist, J. A. J. Am. Chem. Soc. 2006, 128, 8712.
(k) Wang, J.; Hu, X.; Jiang, J.; Gou, S.; Huang, X.; Liu, X.; Feng, X.
Angew. Chem., Int. Ed. 2007, 46, 8468. (l) Wang, J.; Wang, W.; Li, W.;
Hu, X.; Shen, K.; Tan, C.; Liu, X.; Feng, X. Chem.;Eur. J. 2009, 15,
11642. (m) Shintani, R.; Takeda, M.; Tsuji, T.; Hayashi, T. J. Am. Chem.
Soc. 2010, 132, 13168.
(4) For examples of low-yield reactions, see: (a) The addition of
dimethylphenylsilyllithium to acetophenone-derived imine to afford the
desired silylmethylamine in 11% yield: Ballweg, D. M.; Miller, R. C.;
Gray, D. L.; Scheidt, K. A. Org. Lett. 2005, 7, 1403. (b) The addition of
diphenylmethylsilyllithium to acetone-derived imine gives a 31% yield:
Nielsen, L.; Lindsay, K. B.; Faber, J.; Nielsen, N. C.; Skrydstrup, T.
J. Org. Chem. 2007, 72, 10035.
€
(5) Vyas, D. J.; Frohlich, R.; Oestreich, M. Org. Lett. 2011, 13, 2094.
(6) Suginome, M.; Matsuda, T.; Ito, Y. Organometallics 2000, 19,
4647.
r
10.1021/ol301194e
Published on Web 05/23/2012
2012 American Chemical Society

(Scheme 1, path 2). However, a common method of
synthesizing ketimines, i.e., condensation of amines with
all-carbon ketones, is inappropriate when acylsilanes are
used as substrates. In this case, the reaction does not afford
the desired silyl azomethines; instead, it usually results in
the loss of silyl groups due to silyl migration (1,2-Brook
rearrangement).7,8
Scheme 1. Strategies to Synthesize R2SMA
Our interest in the chemistry of sulfonylimidates and
silicon-containing compounds9 led us to speculate that
addition of a silyl nucleophile to the azomethine of sulfo-
nylimidates could furnish N-sulfonyl-C-silylimines or their
functional equivalents,3h,10 which would then combine with
carbanions to afford the desired R-tertiary R-silylamines
(Scheme 1, path 2, RM = organometallic reagents).11ꢀ13
Here we report an efficient and flexible method for the
synthesis of R-tertiary R-silylamines in which silyllithium
reagents and Grignard reagents are sequentially added to
sulfonylimidates in one pot.
To test the reactivity of sulfonylimidates, we chose
PhMe2SiLi,14 which is the most commonly used silyl-
lithium reagent due to its easy preparation and handling.
To our delight, the addition of silyllithium 2 to methyl
N-Ts-phenylimidate 1a proceeded smoothly at ꢀ78 °C to
give the silyl N,O-aminal product 4 in 90% yield after
quenching with aqueous NaHCO3 (Scheme 2), while
phenyl acylsilane 5 was obtained in 85% yield under
strongly acidic quenching conditions (6 N aqueous HCl).15
Interestingly, quenching the reaction with 1.0 N aqueous
HCl gave acylsilane-derived imine 7 in moderate yield
(68%), as well as 5 in 20% yield. No double addition was
observed even when excess silyllithium was used. Adding
1.5 equiv of allylmagnesium bromide directly to the reaction
mixture and warming it to ꢀ45 °C over 2.5 h gave the R,R-
(7) Brook, A. G.; Yu, Z. Organometallics 2000, 19, 1859.
(8) Brook, A. G.; Golino, C.; Matern, E. Can. J. Chem. 1978, 56,
2286.
(9) (a) Yao, M.; Lu, C.-D. Org. Lett. 2011, 13, 2782. (b) Liu, B.; Lu,
C.-D. J. Org. Chem. 2011, 76, 4205.
Scheme 2. Preliminary Results for the Reaction of Sulfonyli-
midate 1a, PhMe2SiLi, and AllylMgBr
(10) Adams, R.; Reifschneider, W. J. Am. Chem. Soc. 1956, 78, 3825.
(11) Selected examples of sequential introduction of two different or
identical nucleophiles to ketones, thioamides, amides, or lactim ethers
are described below. Some of the reactions must be facilitated by
preactivating transformations, oxophilic metal derivatives, or Lewis
acids. For ketones, see: (a) Reetz, M. T.; Westermann, J. J. Org. Chem.
1983, 48, 254. For thioamides, see: (b) Murai, T.; Mutoh, Y.; Ohta, Y.;
Murakami, M. J. Am. Chem. Soc. 2004, 126, 5968. (c) Murai, T.; Asai, F.
J. Am. Chem. Soc. 2007, 129, 780. (d) Agosti, A.; Britto, S.; Renaud, P.
Org. Lett. 2008, 10, 1417. (e) Murai, T.; Ui, K.; Narengerile J. Org.
Chem. 2009, 74, 5703. For amides, see: (f) Larouche-Gauthier, R.;
ꢀ
Belanger, G. Org. Lett. 2008, 10, 4501. (g) Xiao, K.-J.; Luo, J.-M.; Ye,
K.-Y.; Wang, Y.; Huang, P.-Q. Angew. Chem., Int. Ed. 2010, 49, 3037.
(h) Shirokane, K.; Kurosaki, Y.; Sato, T.; Chida, N. Angew. Chem., Int.
Ed. 2010, 49, 6369. (I) Seebach, D. Angew. Chem., Int. Ed. 2011, 50, 96
and references therein. (j) Vincent, G.; Guillot, R.; Kouklovsky, C.
Angew. Chem., Int. Ed. 2011, 49, 3037.
(12) For coupling of two identical nucleophiles to lactim ethers
(cyclic imidates), see: (a) Cervinka, O. Collect. Czech. Chem. Commun.
1959, 24, 1146. (b) Lukes, R.; Cerny, M. Collect. Czech. Chem. Commun.
1961, 26, 2886. (c) Sernmelhack, M. F.; Chong, B. P.; Stauffer, R. D.;
Rogerson, T. D.; Chong, A.; Jones, L. D. J. Am. Chem. Soc. 1975, 97,
2507. (d) Zezza, C. A.; Smith, M. B.; Ross, B. A.; Arhin, A.; Cronin,
P. L. E. J. Org. Chem. 1984, 49, 4397.
(13) Substitutions of the cyano group in 1-piperidinocyclohexane-
carbonitrile by arylmagnesium halides have been described; see:
Maddox., H.; Godefroi, E. E.; Parcell, R. F. J. Med. Chem. 1965, 8, 230.
(14) (a) Fleming, I.; Newton, T. W.; Roessler, F. J. Chem. Soc.,
Perkin Trans. 1 1981, 2527. (b) George, M. V.; Peterson, D. J.; Gilman,
H. J. Am. Chem. Soc. 1960, 82, 403. (c) Fleming, I. In Organocopper
Reagents: A Practical Approach; Taylor, R. J. K., Ed.; Oxford University
Press: Oxford, 1994; p 257. (d) Ilardi, E. A.; Stivala, C. E.; Zakarian, A.
Org. Lett. 2008, 10, 1727. (e) Herrmann, A. T.; Martinez, S. R.;
Zakarian, A. Org. Lett. 2011, 13, 3636.
(15) Similarly, methyl N-Tf-phenylimidate underwent the addition
reaction and gave phenyl acylsilane 5 in 84% yield. This method for
synthesizing aryl acylsilanes can be considered complementary to
Scheidt’s protocol. Scheidt’s protocol is efficient for preparing alkyl
acylsilanes using silyllithium species; however, it offers limited possibi-
lities for aryl acylsilanes due to the undesired Brook rearrangement and
subsequent transformations. See: Clark, C. T.; Milgram, B. C.; Scheidt,
K. A. Org. Lett. 2004, 6, 3977.
disubstituted R-silylamine 6a in 89% yield. Notably, no silyl
group migration (aza-Brook rearrangement)16 occurred in
this one-pot, streamlined synthesis of R-tertiary R-silyla-
mines. Addition of 1.0 equiv of allylmagnesium bromide to
the solution of 1a prior to introduction of the silyllithium 2
resulted in the formation of a substantial amount of Ph-
(allyl)2CꢀNHTs, formed by double addition of a Grignard
reagent to 1a, in addition to the desired product 6a. More-
over, PhMe2SiꢀBpin was inert toward sulfonylimidate
when the reaction conditions described previously were
(16) (a) Brook, A. G.; Duff, J. M. J. Am. Chem. Soc. 1974, 96, 4692.
(b) Duff, J. M.; Brook, A. G. Can. J. Chem. 1977, 55, 2589.
Org. Lett., Vol. 14, No. 11, 2012
2907

used,5 and no CꢀSi bond formation occurred. Control experi-
ments indicated that both N,O-aminal 4and acylsilane-derived
imine 7 are extremely reactive to Grignard reagents. For
example, compounds 4and 7reacted with 3 equiv of MeMgBr
to give the R-tertiary R-silylamine PhMe(PhMe2Si)CꢀNHTs
in yields of 90% and 95%, respectively.
Table 1. Synthesis of R-Tertiary R-Silylamines (ArRSMA) via
Three-Component Couplinga
The scope and limitations of this three-component
coupling protocol were investigated in the reactions of a
series of aryl tosylimidates and Grignard reagents with
PhMe2SiLi (Table 1). When allylmagnesium bromide was
used, aryl N-Ts-imidates bearing electron-withdrawing (1b
and 1c) or electron-donating substituents (1d and 1e) on
the phenyl groups were viable participants in the coupling
reaction, providing R,R-disubstituted R-silylamine 4bꢀe in
yields of 88ꢀ93% (entries 2ꢀ5), while moderate to low
yields were obtained in the cases of 1-naphthyl sulfonyli-
midate 1f and heteroaromatic sulfonylimidates 1g and 1h
(entries 6ꢀ8). A 1-g scale preparation of 6a gave an even
higher yield than the microscale reaction (entry 1, 95% vs
89%). In addition to allylMgBr, alkyl and aryl Grignard
reagents proved effective in the three-component cou-
plings, allowing efficient access to diverse products
(entries 10ꢀ16). Freshly prepared vinylmagnesium bro-
mide was also a suitable coupling partner and showed
good reactivity, giving the desired product 6i in 60% yield
(entry 9). Vinyl silylamines are precursors for silicon-
containing R-amino acids17 that have important functions
in peptidomimetic strategies.18 It should be noted that the
quality of Grignard reagents is crucial to successful cou-
pling. When the reaction was set up using 3.0 equiv of
commercially available vinylmagnesium bromide19 from a
freshly opened bottle and incubated at ꢀ78 °C for 3 h, no
desired product was obtained. Instead, the reaction exclu-
sively gave the N-sulfonyl-C-silyl-phenylimine 7 due to the
decomposition of a tetrahedral intermediate (Scheme 2).20
The failure of the commercial vinylmagnesium bromide
may be at least partially due to the reagent’s degradation.
Not unexpectedly, using bulky Grignard reagents pos-
sessing a β-hydrogen atom in the reactions reduced the
yields of R,R-disubstituted R-silylamines; these Grignard
reagents can also act as reducing agents in combination
with sterically hindered electrophiles.21 Thus, using iso-
propylmagnesium chloride or cyclohexylmagnesium bro-
mide (entries 16 and 17) gave the side product, R-branched
R-silylamines (RSMA) 6r (Ar = Ph and R = H), due to
hydride transfer from the Grignard reagents along with
moderate to low yields of the desired products 6p and 6q.
Grignard
reagents
yield
(%)b
entry
imidates (Ar)
products
1
Ph (1a)
allylMgBr
allylMgBr
6a
6b
6c
6d
6e
6f
89 (95c)
91
2
4-MeC6H4 (1b)
3
4-MeOC6H4 (1c) allylMgBr
88
4
4-FC6H4 (1d)
4-ClC6H4 (1e)
1-naphthyl (1f)
2-furyl (1g)
2-thienyl (1h)
Ph (1a)
allylMgBr
allylMgBr
allylMgBr
allylMgBr
allylMgBr
vinylMgBr
MeMgBr
EtMgBr
93
5
90
6
60
7
6g
6h
6i
54
8
35
9d
11
12
13
14
15e
60
Ph (1a)
6j
86
Ph (1a)
6k
6l
88
Ph (1a)
BnMgBr
71
Ph (1a)
Ph-MgBr
4-FC6H4-
MgBr
6m
6n
66
Ph (1a)
54
16e
Ph (1a)
4-MeOC6H4-
MgBr
6o
58
17
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
iso-propylMgCl
6p þ 6r 54 þ 38
18f
19e
20g
cyclohexylMgBr 6q þ 6r 26 þ 57
tBuMgCl
6r
8
84
88
allylMgBr
a All reactions were carried out in THF with 1.2 equiv of phenyldi-
methylsilyllithium and 1.5 equiv of Grignard reagents unless otherwise
noted; see the Supporting Information for details. b Isolated yield after silica
gel chromatography. c 1-g scale reaction. d 3.0 equiv of freshly prepared
vinylmagnesium bromide were used. e 10.0 equiv of Grignard reagent were
used. f The desired product 6q was obtained in 55% yield when 10 mol %
zinc(II) chloride was used. g Ph2MeSiLi was used instead of PhMe2SiLi.
When used in conjunction with 10 mol % zinc chloride,21a,22
cyclohexylmagnesium bromide tended to transfer the
cyclohexyl group rather than the β-hydride, increasing the
yield of three-component coupling product 6q to 55%.
When the bulkier tert-butylmagnesium chloride was used,
the reductive pathway predominated, giving the R-second-
ary R-silylamine 6r as the sole product in 84% yield.
We further examined this protocol using other silyl-
lithium reagents and sulfonylimidates. Diphenylmethylsi-
lyllithium (Ph2MeSiLi)23 underwent a similar reaction as
PhMe2SiLi to afford coupling product 8 in 88% yield. We
also observed the very efficient three-component coupling
of 1a, PhLi, and allylMgBr, affording R,R-disubstituted
amine Ph2(allyl)CꢀNHTs (9) in nearly quantitative yield
(97%). However, trimethylsilyllithium (Me3SiLi) was not
compatible with this coupling protocol.24 Similarly, eno-
lizable alkyl sulfonylimidates possessing an R-proton were
(17) For oxidative cleavage of amino alkenes to amino acids, see:
(a) Yoshida, K.; Yamaguchi, K.; Sone, T.; Unno, Y.; Asai, A.;
Yokosawa, H.; Matsuda, A.; Arisawa, M.; Shuto, S. Org. Lett. 2008, 10,
3571. (b) Almansa, R.; Guijarro, D.; Yus, M. Tetrahedron 2009, 50, 4188.
(18) For review, see: Mortensen, M.; Husmann, R.; Veri, E.; Bolm, C.
Chem. Soc. Rev. 2009, 38, 1002.
(19) For differences in reaction behavior of freshly prepared and
commercially available vinylMgBr, see: Ushakov, D. B.; Navickas, V.;
Strobele, M.; Maichle-Mossmer, C.; Sasse, F.; Maier, M. E. Org. Lett.
2011, 13, 2090.
(20) Evans, D. A.; Borg, G.; Scheidt, K. A. Angew. Chem., Int. Ed.
2002, 41, 3188 and references therein.
(21) (a) Hatano, M.; Suzuki, S.; Ishihara, K. J. Am. Chem. Soc. 2006,
128, 9998. (b) Tramontini, M. Synthesis 1982, 605.
(22) Hevia, E.; Chua, J. Z.; Garcia-Alvarez, P.; Kennedy, A. R.;
McCall, M. D. Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 5294.
(23) (a) Gilman, H.; Lichtenwalter, G. D. J. Am. Chem. Soc. 1958, 80,
607. (b) George, M. V.; Peterson, D. J.; Gilman, H. J. J. Am. Chem. Soc.
1960, 82, 403.
(24) Magnus, P.; Moursounidis, J. J. Org. Chem. 1991, 56, 1529.
2908
Org. Lett., Vol. 14, No. 11, 2012

not suitable candidates for this transformation, presum-
ably due to the potential Neber-type rearrangement in-
itiated by the deprotonation of alkyl sulfonylimidates by
silyllithium.25
Acknowledgment. This work was supported by the Na-
tional Natural Science Foundation of China (20972182
and 21172251), the “Western Light” program (XBBS200820),
and the Chinese Academy of Sciences.
In summary, an efficient method for the synthesis of
R-tertiary R-silylamines has been developed. The three-
component coupling of aryl tosylimidates, silyllithium,
and Grignard reagents in a single flask enables the rapid
construction of diverse bulky R-silylamine derivatives.
Supporting Information Available. Experimental de-
tails and characterization data. This material is available
free of charge via the Internet at http://pubs.acs.org.
(25) Still, W. C. J. Org. Chem. 1976, 41, 3063.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 11, 2012
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