Formation and utility of azasilacyclopentadienes derived from silacyclopropenes and nitriles

Article abstract of DOI:10.1021/ol802412b

(Chemical Equation Presented) The copper-catalyzed insertions of nitriles into the Si-C bonds of silacyclopropenes provide azasilacyclopentadienes, which can be converted to allylic amines after reduction and protodesilylation. The enamine functionality o

Full text of DOI:10.1021/ol802412b

ORGANIC
LETTERS
2009
Vol. 11, No. 2
425-428
Formation and Utility of
Azasilacyclopentadienes Derived from
Silacyclopropenes and Nitriles
Laura L. Anderson and K. A. Woerpel*
Department of Chemistry, UniVersity of California, IrVine, California 92697
kwoerpel@uci.edu
Received October 19, 2008
ABSTRACT
The copper-catalyzed insertions of nitriles into the Si-C bonds of silacyclopropenes provide azasilacyclopentadienes, which can be converted
to allylic amines after reduction and protodesilylation. The enamine functionality of azasilacyclopentadienes also participates in 1,4-addition
reactions and undergoes a hydroboration and oxidation sequence to form an allylic 1,2-amino alcohol.
Allylic amines are useful intermediates in organic synthesis,
and a number of methods have been developed for preparing
these compounds.1 Because the insertion of carbonyl com-
pounds into silacyclopropenes provides a method for the
synthesis of allylic alcohols,2 we considered that reactions of
silacyclopropenes with C-N multiple bonds could lead to a
synthesis of allylic amines. Although the photochemical reac-
tions of nitriles with a silacyclopropene have been reported,3,4
the insertion products underwent further reactions in modest
yields, and applications of these reactions in synthesis were
not described.3 In this paper, we report the copper-catalyzed
insertions of nitriles into the Si-C bonds of silacyclopro-
penes to form azasilacyclopentadienes. These compounds can
be functionalized by reductions, 1,4-additions, and hydrobo-
rations to form allylic amines and allylic amino alcohols.5
Copper salts proved to be efficient catalysts for the insertions
of nitriles into silacyclopropenes. When a 1:1 mixture of
acetonitrile and silacyclopropene 1a in C6D6 was treated with
5 mol % of Cu(OTf)2, silacyclopropene 1a disappeared over
24 h, and enamine 2a was formed as a single regioisomer
(Scheme 1). Preference for the 1,2-insertion product, which was
Scheme 1. Insertion of Acetonitrile into the Si-C Bond of 1a
(1) For reviews that include methods for the synthesis of allylic amines,
see: (a) Johannsen, M.; Jørgensen, K. A. Chem. ReV. 1998, 98, 1698–1708.
(b) Trost, B. M.; Crawley, M. L. Chem. ReV. 2003, 103, 2921–2943. (c)
Carpenter, N. E. In Organic Reactions; Overman, L. E., Ed.; Wiley: New
York, 2005; Vol. 66, pp 1-107. For examples of different methods for
allylic amine synthesis, see: (d) Wipf, P.; Kendall, C.; Stephenson, C. R. J.
J. Am. Chem. Soc. 2003, 125, 761–768. (e) Anderson, C. E.; Overman,
L. E. J. Am. Chem. Soc. 2003, 125, 12412–12413. (f) Yamashita, Y.;
Gopalarathnam, A.; Hartwig, J. F. J. Am. Chem. Soc. 2007, 129, 7508–
7509. (g) Ngai, M.-Y.; Barchuk, A.; Krische, M. J. J. Am. Chem. Soc. 2007,
129, 12644–12645. (h) Lalic, G.; Krinsky, J. L.; Bergman, R. G. J. Am.
Chem. Soc. 2008, 130, 4459–4465. (i) Kinder, R. E.; Zhang, Z.; Widen-
hoefer, R. A. Org. Lett. 2008, 10, 3157–3159.
confirmed by a 1H-1H NOESY experiment, is consistent with
the regioselectivity of insertions of carbonyl compounds into
silacyclopropenes and silacyclopropanes.2,6 The imine tautomer
of 2a was not observed in the product mixure or at any time
during the transformation. A subsequent catalyst screen for
the acetonitrile insertion of silacyclopropene 1a showed that
Cu(OTf)2 and (CuOTf)2·tol were more efficient catalysts than
(2) Clark, T. B.; Woerpel, K. A. J. Am. Chem. Soc. 2004, 126, 9522–
9523.
(3) Sakurai, H.; Kamiyama, Y.; Nakadaira, Y. J. Chem. Soc., Chem.
Commun. 1978, 80–81
(4) For a related insertion of an imine, see: Seyferth, D.; Duncan, D. P.;
Shannon, M. L. Organometallics 1984, 3, 579–583
.
(5) For the synthesis of an allylic amine via a silaaziridine intermediate,
see: Neva´rez, Z.; Woerpel, K. A. Org. Lett. 2007, 9, 3773–3776.
.
10.1021/ol802412b CCC: $40.75
Published on Web 12/10/2008
2009 American Chemical Society

Table 1. Insertions of Nitriles into Monosubstituted
Silacyclopropenes
Table 2. Insertions of Nitriles into Disubstituted
Silacyclopropenes
entry
R1
Ph
Ph
Ph
Ph
SiMe3
X
R2
product, % yield
1
2
3
H
Me
Ph
2a, 82
2b, 86
2c, 84
2d, 83
2e, 65
2f, 82
entry
R1
R2
Ph
Et
X
R3
A:B
product, % yield
1
2
3
4
5
Me
Et
Me
Me
n-Bu
Ph
Ph
Me
Ph
Ph
10:1
na
3:2
3:1
>10:1
5a, 85
5b, 86
5c, 96
5d, 83
5e, 85
4
CH2OTBDMS
5a
6
Ph
Ph
X
OTIPS
a Cu(OTf)2 was used as a catalyst. X ) CH(Ph)(OSiEt3).
a X ) CH(i-Pr)(OTIPS).
CuBr2 or CuI. When the transformation was performed on a
1 mmol scale, (CuOTf)2·tol gave higher yields than Cu(OTf)2
(Table 1, entry 1).
(CuOTf)2·tol as the catalyst. As with the analogous reactions
of monosubstituted silacyclopropenes, a number of functional
groups were tolerated. Consistent with the results described in
Table 1, insertions into disubstituted silacyclopropenes favored
the 1,2-regioisomer and Z-enamine products, although the
regioselectivity of these insertions was lower than for the
monosubstituted silacyclopropene reactions. Only a small
degradation in regioselectivity was observed for 1-phenylpro-
pyne-derived silacyclopropene 4a, but a further decrease in
regioselectivity was observed for the silyloxy-substituted sila-
cyclopropene 4c. These results suggest that steric effects are
not the only factor contributing to regioselectivity.
A two-step, one-flask synthesis of azasilacyclopentadienes
was developed to avoid the isolation of air-sensitive silacyclo-
propenes.9 With internal alkenes, a single metal salt, Cu(OTf)2,
was employed to catalyze both silylene transfer and insertion,
as shown in Scheme 3. With terminal alkynes, Ag3PO4 was
The insertion of a nitrile into a monosubstituted silacyclo-
propene was general for a number of nitriles and silacyclopro-
penes (Table 1). Nitriles with alkyl, aryl, and silyloxy groups
(Table 1, entries 1-4) and silacyclopropenes with silyl- and
silyloxy substituents (Table 1, entries 5 and 6) were tolerated
by the reaction conditions.7 In all cases, the 1,2-insertion product
and the Z-enamine were observed exclusively.8 The imine
tautomer of the azasilacyclopentadiene was only observed for
the insertion of isobutyronitrile into the Si-C bond of silacy-
clopropene 1a (Scheme 2). The formation of the enamine
Scheme 2. Insertion of Isobutyronitrile into 1a
Scheme 3
.
Two-Step, One-Flask, Single-Catalyst Synthesis of
Azasilacyclopentadienes
tautomer in this case may be disfavored because it would be
destablized by interactions between the resulting isopropylidene
group and the phenyl substituent.
The copper-catalyzed insertion of nitriles was also successful
for disubstituted silacyclopropenes (Table 2). These transforma-
tions required mild heating but proceeded smoothly with
(6) (a) Franz, A. K.; Woerpel, K. A. J. Am. Chem. Soc. 1999, 121, 949–
957. (b) Franz, A. K.; Woerpel, K. A. Angew. Chem., Int. Ed. 2000, 39,
4295–4299.
(7) All of the insertion products shown in Tables 1 and 2 were isolated
and purified by a hexane extraction from an acetonitrile solution of the
reaction mixture in an inert atmosphere glovebox. This procedure allowed
the products to be separated from the copper catalyst and avoided hydrolysis
of the Si-N bonds of these sensitive products. Additional confirmation of
structure was obtained for the corresponding hydrolysis products; details
are provided as Supporting Information.
employed for silylene transfer,2 and after filtration of the reaction
mixture through glass fiber filter paper, copper salts were added
to catalyze the insertion of the nitrile.10
(9) For transition-metal-mediated reductive coupling reactions of alkynes
and imines, see: (a) Reference 1d. (b) Barchuk, A.; Ngai, M.-Y.; Krische,
M. J. J. Am. Chem. Soc. 2007, 129, 8432–8433. (c) Reference 1g.
(8) The enamine stereochemistry was determined by 1H-1H NOESY
experiments.
426
Org. Lett., Vol. 11, No. 2, 2009

Reduction of the enamine moiety of the nitrile insertion
products served as the first step of a synthesis of allylic amines.
Although metal-catalyzed hydrogenation reduced both the
alkene and enamine functional groups,10 the enamine function-
ality could be reduced selectivity by NaBH4 in the presence of
camphorsulfonic acid (CSA).11 After aqueous workup, hydroly-
sis of the Si-N bond occurred to form the aminosilanols 6a-e
(Table 3). The unpurified products of these transformations were
aminosilanols was investigated. Although protodesilylation
under acidic conditions was not successful, treatment of 6a
with KO(t-Bu) and Bu4NF in a mixture of DMSO and THF
(4:1)2,5 provided the desired allylic amine 9a. This procedure
was general for the synthesis of a range of allylic amines
and amides (Table 4).
Table 4. Protodesilylations of Allylic Aminosilanols
Table 3. Reduction of Azasilacyclopentadienes
entry
R1
R2
R3
R4
% yield
1
2
3
4
5
H
H
H
Et
Me
Ph
Ph
Ph
Et
Ph
Ph
Me
Ph
Ph
H
9a, 74
9b, 55
9c, 74
9d, 58
9e, 54
entry
R1
R2
Ph
Ph
Ph
Et
OTIPS
R3
product, % yielda
COMe
COMe
H
1
2
3
4
5
H
H
Me
Et
n-Bu
Ph
Me
Ph
Ph
Ph
6a, 90 (59)
6b, 95 (60)
6c, 80 (32)
6d, 82
Ph
H
6e, 88
a Isolated yields of unpurified products are reported. Yields after
chromatography are shown in parentheses.
The enamine functionality of the azasilacyclopentadiene
provided a handle to functionalize the nitrile insertion products.
1,4-Additions13 of azasilacyclopentadiene 2a to acrylonitrile
gave a tautomeric mixture of the addition product 10, but addi-
tions to methyl acrylate and crotononitrile were selective for
the enamine tautomer (Scheme 5). Hydroboration of azasila-
isolated in high yields and were of sufficient purity (>90% as
1
estimated by H NMR spectroscopy) to use in subsequent
transformations. The purification of these compounds by
chromatography, however, was challenging because of their
amphiphilic nature.12 Protection of the amino group of the
products was investigated to facilitate purification of the
reduction products, but the success of this approach was
substrate-dependent (Scheme 4).
Scheme 5. 1,4-Addition Reactions of 2a
Scheme 4. Enamine Reduction and Amine Protection
Once conditions for the reduction of azasilacyclopenta-
dienes had been determined, the protodesilylation of allylic
(10) Details are provided as Supporting Information.
(11) For recent examples of reductive amination under acidic conditions,
see: (a) Reddy, P. S.; Kanjilal, S.; Sunitha, S.; Prasad, R. B. N. Tetrahedron
Lett. 2007, 48, 8807–8810. (b) Heydari, A.; Arefi, A.; Esfandyari, M. J.
Mol. Catal. A: Chem. 2007, 274, 169–172.
cyclopentadiene 2c followed by oxidation with NaOH and H2O2
provided allylic amino alcohol 13 as a single stereoisomer
Org. Lett., Vol. 11, No. 2, 2009
427

(Scheme 6).14,15 These transformations showed that azasila-
cyclopentadienes can be functionalized at the enamine
position to provide highly substituted allylic amine deriva-
tives.
well as a hydroboration and oxidation procedure to form an
allylic amino alcohol.
Acknowledgment. This research was supported by the
National Institute of General Medical Sciences of the Na-
tional Institutes of Health (GM-54909). L.L.A. thanks the
National Institutes of Health for a postdoctoral fellowship
(GM-57688). K.A.W. thanks Amgen and Lilly for awards
to support research. We would like to thank Dr. John Greaves
and Ms. Shirin Sorooshian (UCI) for assistance with mass
spectrometry and Dr. Phil Dennison (UCI) for help with
NMR spectroscopy.
Scheme 6. Hydroboration and Oxidation of 2c
Supporting Information Available: Complete experi-
mental procedures and product characterization. This material
is available free of charge via the Internet at http://pubs.acs.org.
In summary, a procedure for the synthesis of azasilacy-
clopentadienes has been developed based on insertions of
nitriles into the Si-C bonds of silacyclopropenes. The
synthetic utility of these reactions has been demonstrated
by conversions of the products to allylic amines and allylic
amino alcohols. The azasilacyclopentadiene insertion prod-
ucts were also shown to undergo 1,4-addition reactions as
OL802412B
(13) For examples of additions of enamines to acrylonitrile and methyl
acrylate, see: (a) de Jeso, B.; Pommier, J.-C. J. Chem. Soc., Chem. Commun.
1977, 565–566. (b) Jones, R. C. F.; Hirst, S. C. Tetrahedron Lett. 1989,
30, 5361–5364. (c) Pfau, M.; Ughetto-Monfrin, J. Tetrahedron 1979, 35,
1899–1904. (d) Fourtinon, M.; de Jeso, B.; Pommier, J.-C. J. Organomet.
Chem. 1985, 289, 239–246.
(14) For examples of enamine hydroboration, see: (a) Butler, D. N.;
Soloway, A. H. J. Am. Chem. Soc. 1966, 88, 484–487. (b) Goralski, C. T.;
Hasha, D. L.; Nicholson, L. W.; Zakett, D.; Fisher, G. B.; Singaram, B.
Tetrahedron Lett. 1994, 35, 3251–3254.
(12) A purified sample of 6a was resubjected to chromatography
conditions, and only 78% of the pure material was recovered. This
observation suggested that a similar loss in yield occurred during the initial
purification and accounted for the discrepancy between the unpurified and
purified yields shown in Table 3. Attempts to solve the purification problems
by buffering the eluant with Et3N or using silanized silica gel or alumina
did not improve the purification.
(15) The allylic amino alcohol was isolated in 85% yield with >90%
purity. This compound was of sufficient purity to be used in subsequent
reactions. Purification by chromatography provided a 44% yield of the allylic
amino alcohol.
428
Org. Lett., Vol. 11, No. 2, 2009