Catalytic asymmetric vinylogous mannich reaction of W-(2-thienyl) sulfonylimines

Article abstract of DOI:10.1021/ol8019082

(Chemical Equation Presented) Both cyclic and acyclic silyl dienol ethers participate efficiently in the asymmetric vinylogous Mannich reaction of N-2-thienylsulfonylimines catalyzed by copper(l) complexes of Fesulphos ligands. This procedure displays wid

Full text of DOI:10.1021/ol8019082

ORGANIC
LETTERS
2008
Vol. 10, No. 19
4335-4337
Catalytic Asymmetric Vinylogous
Mannich Reaction of
N-(2-Thienyl)sulfonylimines
Alvaro Salvador Gonza´lez, Ramo´n Go´mez Arraya´s, Marta Rodríguez Rivero, and
Juan C. Carretero*
Departamento de Química Orga´nica, Facultad de Ciencias, UniVersidad Auto´noma de
Madrid, Cantoblanco, 28049 Madrid, Spain
juancarlos.carretero@uam.es
Received August 14, 2008
ABSTRACT
Both cyclic and acyclic silyl dienol ethers participate efficiently in the asymmetric vinylogous Mannich reaction of N-2-thienylsulfonylimines
catalyzed by copper(I) complexes of Fesulphos ligands. This procedure displays wide imine and nucleophile versatility, high enantiocontrol,
and complete γ-regioselectivity in most cases examined. The mild sulfonamide deprotection allows the resulting products to be readily
transformed into optically active δ-lactams or 5-hydroxy-2-piperidone derivatives.
The γ-addition of dienolate equivalents to imines, known
as vinylogous Mannich-type reaction (VMR), provides rapid
access to δ-amino-R,ꢀ-unsaturated carbonyl derivatives, a
valuable class of intermediates for the synthesis of alkaloids
and other nitrogen-containing compounds.1 However, in
contrast to the much more developed vinylogous aldol
reaction,2 the catalytic asymmetric variant of this transforma-
tion has been little explored. The first report by Martin et
al.3 on VMR of 2-silyloxy furans was later improved by
Hoveyda, Snapper, and Carswell4 using chiral silver-based
catalysts and by Akiyama et al.5 with a binol-based phos-
phoric acid catalyst. The direct reaction of γ-butenolides with
imines has been achieved by Shibasaki et al.6 combining
Bro¨nsted acid and chiral metal catalysis. The groups of Chen7
and Jorgensen8 have reported asymmetric organocatalytic
protocols for the γ-selective addition of R,R-dicyanoolefins
to imines. Aside from these elegant approaches leading to
optically active butenolides and dicyanoolefins, there is
plenty of room for the development of asymmetric protocols
showing high nucleophile versatility, especially with more
general and truly vinylogous enolate equivalents such as
acyclic silyl dienol ethers. Very recently, Schneider’s group9
has described the first VMR of an acyclic, ester derived, silyl
dienolate using a binol-based phosphoric acid catalyst, which
occurs with complete γ-site regiocontrol and high asymmetric
(1) For reviews on vinylogous Mannich-type reaction including synthetic
applications, see: (a) Bur, S. K.; Martin, S. F. Tetrahedron 2001, 57, 3221.
(b) Martin, S. F. Acc. Chem. Res. 2002, 35, 895.
(2) For a comprehensive review on catalytic asymmetric vinylogous aldol
reaction, see: (a) Denmark, S. E.; Heemstra, J. R., Jr.; Beutner, L. Angew.
Chem., Int. Ed. 2005, 44, 4682. See also: (b) Casiraghi, G.; Zanardi, F.;
Appendino, G.; Rassu, G. Chem. ReV. 2000, 100, 1929. (c) Soriente, A.;
De Rosa, M.; Villano, R.; Scettri, A. Curr. Org. Chem. 2004, 8, 993. (d)
Kalesse, M. Top. Curr. Chem. 2005, 244, 43.
(5) Akiyama, T.; Honma, Y.; Itoh, J.; Fuchibe, K. AdV. Synth. Catal.
2008, 350, 399.
(6) Yamaguchi, A.; Matsunaga, S.; Shibasaki, M. Org. Lett. 2008, 10,
2319.
(7) Liu, T.-Y.; Cui, H.-L.; Long, J.; Li, B.-J.; Wu, Y.; Ding, L.-S.; Chen,
Y.-C. J. Am. Chem. Soc. 2007, 129, 1878.
(3) Martin, S. F.; Lopez, O. D. Tetrahedron Lett. 1999, 40, 8949.
(4) Carswell, E. L.; Snapper, M. L.; Hoveyda, A. H. Angew. Chem.,
Int. Ed. 2006, 45, 7230.
(8) Niess, B.; Jørgensen, K. A. Chem. Commun. 2007, 1620.
(9) Sickert, M.; Schneider, C. Angew. Chem., Int. Ed. 2008, 47, 3631.
10.1021/ol8019082 CCC: $40.75
Published on Web 09/09/2008
2008 American Chemical Society

induction (80-90% ee). This work prompted us to disclose
our own results in this area.
adduct 7 with complete γ-selectivity in 85% isolated yield and
94% ee. In contrast, no reaction was observed in the case of
the 2-pyridylsulfonylimine 414 (entry 5).
Complete γ-addition selectivity and good yields were also
observed in the reaction of the silyl dienolate 5 with a survey
of N-(2-thienyl)sulfonylimines (9-16, entries 1-8 in Table
2). In all cases, the corresponding R,ꢀ-unsaturated δ-(2-
Herein, we report an efficient metal-catalyzed asymmetric
VMR procedure compatible with both cyclic and acyclic silyl
dienol ethers that relies on the use of N-(2-thienyl)sulfo-
nylimines as substrates and CuI-Fesulphos complexes as
catalysts. Wide imine and nucleophile versatility, high
enantiocontrol, and complete γ-site selectivity are key
features of this method.
We have recently reported that the readily available CuI
complex of the bulky Fesulphos ligand10 1b ([1b·CuBr]2,
Scheme 1) is a very efficient catalyst for Mannich11 and formal
Table 2. Catalytic Asymmetric VMR of Acyclic Silyl Dienol
Ethersa
Scheme 1. Synthesis of the Copper(I) Complexes [1·CuBr]2
yieldb
eec
(%)
entry
R1 (imine)
R2 R3 diene product (%)
1
2
3
4
5
6
7
8
9
m-ClC6H4 (9)
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
5
5
17
18
19
20
21
22
23
24
27
28
29
30
31
32
33
35
38
39
40
41
42
84
62
68
81
66
83
83
72
72
91
p-OMeC6H4 (10) H
94
o-MeC6H4 (11)
1-Naph (12)
2-Naph (13)
PhCHdCH (14)
Cy (15)
i-Pr (16)
Ph (3)
H
5
93
H
5
89
H
5
92
90 (99)d
65
aza Diels-Alder reactions12 of N-sulfonylimines. On the other
hand, N-(2-thienyl)sulfonylimines were previously found by
others13 and us11 to provide enhanced reactivity and selectivity
toward Mannich-type reactions compared to typically substituted
sulfonylimines such as N-tosylimines. Both the superiority of
the N-(2-thienyl)sulfonyl group and the higher performance of
phosphine 1b over the parent ligand 1a was confirmed in the
model reaction of the N-sulfonylimines 2-4 with the com-
mercially available silyloxy-1,3-butadiene 5 under our optimized
conditions11 [combination of [1·CuBr]2 (5.1 mol %) and AgClO4
(10 mol %) in CH2Cl2 at rt]. As depicted in Table 1, the
H
5
H
5
H
5
66 (99)d
83
OMe
25
25
25
25
25
25
25
10 p-OMeC6H4 (10) OMe
62e 95
11 1-Naph (12)
12 2-Naph (13)
13 PhCHdCH (14) OMe
14 Cy (15)
15 2-thienyl (26)
16 Ph (3)
17 Ph (3)
18 2-Naph (13)
19 1-Naph (12)
20 p-CF3C6H4 (36) OMe Me 37
21 Cy (15) OMe Me 37
OMe
OMe
70
74
83
84
76
91
75
85
87
86
88
91
78 (95)d
80 (99)d
75
OMe
OMe
Oi-Pr Me 34
OMe Me 37
OMe Me 37
OMe Me 37
66
71
80
77
80
75
82
a 2-4 equiv of dienol ether was used. b After chromatographic
purification. c Determined by chiral HPLC. d After a single recrystallization
e 14% of the R-addition product was also obtained (see the Supporting
Information).
Table 1. CuI-Fesulphos-Catalyzed Asymmetric VMR of
N-Sulfonylimines 2-4 with Silyl Dienol Ether 5
thienyl)sulfonylamino aldehyde (17-24) was the only re-
gioisomer detected by NMR in the reaction mixture. High
enantiocontrol (89-94% ee) was consistently achieved with
aromatic imines of varied electronic and steric nature (entries
1-5). Notably, R,ꢀ-unsaturated imines (entry 6), yet unex-
plored in VMR, and aliphatic imines (entries 7 and 8), which
have been seldom used in VMR,5-7 did also participate in
the VMR quite efficiently, although the enantioselectivity
was significantly lower in the case of the aliphatic imines.
a
entry R (imine)
ligand R-:γ-
product yieldb (%) eec (%)
1
2
3
4
5
p-Tol (2)
p-Tol (2)
1a
1b
34d:66
25d:75
<2:>98
<2:>98
NR
6
6
7
7
8
37
44
65
85
30
42
78
94
2-thienyl (3) 1a
2-thienyl (3) 1b
2-pyridyl (4) 1a or 1b
Other silyl dienol ethers with additional substituents at C-1
(R2) or C-2 (R3) of the 1,3-diene moiety proved also to be
suitable nucleophiles. For instance, the more electronically
a Determined by NMR from the crude reaction mixture. b Isolated yield
of the γ-isomer after chromatography. c Of the γ-isomer, by chiral HPLC.
d As a mixture of diastereomers.
(10) García Manchen˜o, O.; Priego, J.; Cabrera, S.; Go´mez Arraya´s, R.;
Llamas, T.; Carretero, J. C. J. Org. Chem. 2003, 68, 3679.
(11) Salvador Gonza´lez, A.; Go´mez Arraya´s, R.; Carretero, J. C. Org.
Lett. 2006, 8, 2977.
2-thienylsulfonyl group was essential for achieving high reactiv-
ity and δ-regioselectivity (entries 3 and 4), while the copper(I)
complex of the bulky ligand 1b was superior to 1a in terms of
enantiocontrol (entry 4). Thus, the combined choice of substrate
3 and ligand 1b led to the corresponding vinylogous Mannich
(12) García Manchen˜o, O.; Go´mez Arraya´s, R.; Carretero, J. C. J. Am.
Chem. Soc. 2004, 126, 456.
(13) Morimoto, H.; Lu, G.; Aoyama, N.; Matsunaga, S.; Shibasaki, M.
J. Am. Chem. Soc. 2007, 129, 9588.
4336
Org. Lett., Vol. 10, No. 19, 2008

biased methyl ester-derived silyl enol ether 2515 underwent
smooth VMR with a variety of aromatic and aliphatic imines
to afford with complete γ-selectivity the corresponding R,ꢀ-
unsaturated δ-amino esters (27-33) in good yield (72-84%)
and high enantioselectivity (75-95% ee, Table 2, entries 9-15).
The only exceptions to this general trend were the electron-
rich imine 10, leading to a small amount of the R-addition
product (entry 10), and the decreased asymmetric induction
observed in the case of the heteroaryl imine 26 (R1 ) 2-thienyl,
66% ee, entry 15). In contrast, the silyl dienolate 34, derived
from a more sterically encumbered ester, provided a lower
asymmetric induction than the parent methyl ester (compare
entries 9 and 16). The presence of an additional substituent at
C-2 (diene 37)16 led to similar results in terms of γ-selectivity
and chemical yields, although with slightly lower enantiocontrol
(77-82% ee, entries 17-21). Among the reactions performed
with diene 37, the aliphatic imine 15 provided the highest
asymmetric induction (82% ee, entry 21). Most of the sulfona-
mide products are crystalline solids, and its enantiopurity can
be significantly enhanced by a single recrystallization (from
66-90% ee to 95-99% ee, entries 6, 8, 12, and 13).17
(80-94.5% ee) after chromatography. The reaction of the R,ꢀ-
unsaturated imine 14 provided the product 48, with an additional
double bond susceptible of further functionalization, with 94.5%
ee (entry 5). The enantiopurity of 44 and 48 was raised to >99%
ee upon single recrystallization.17
A synthetically relevant advantage of using the 2-thienyl-
sulfonyl group is the facile deprotection of the sulfonamide
products by simple treatment with Mg in MeOH. For
example, adducts 27 and 28 were converted to the δ-lactams
4918 and 50,19 respectively, by hydrogenation of the double
bond and subsequent deprotection (Scheme 2). In a similar
Scheme 2. Amine Deprotection and Chemical Correlations
To further extend the scope of this protocol, a cyclic diene,
the 2-trimethylsilyloxyfuran, was also examined. As shown in
Table 3. Catalytic Asymmetric VMR of
2-Trimethylsilyloxyfuran
fashion, γ-butenolide 44 was transformed into the 5-hydroxy-
2-piperidone (+)-5120 in 68% yield through the hydrogena-
tion/deprotection sequence. The preparation of the known
piperidines (+)-49 and (+)-51 allowed us to establish the
absolute configuration of the starting adducts 27 and 44 and,
by analogy, that of the rest of VMR products.
In summary, we have developed a catalytic asymmetric
VMR procedure applicable to both acyclic and cyclic silyl
dienol ethers. The high enantiocontrol and nearly complete
γ-selectivity displayed by the combination of CuI-Fesulphos
catalyst and N-(2-thienyl)sulfonylimines provides a ready
access to optically active R,ꢀ-unsaturated δ-amino carbonyl
derivatives in good yields.
yieldb
(%)
eec
(%)
entry
R (imine)
Ph (3)
p-OMeC6H4 (10)
p-ClC6H4 (43)
2-Naph (13)
product
dra
1
2
3
4
5
44
45
46
47
48
93:7
85
79
87
84
87
88 (99)c
81:19
90:10
93:7
94
90
89
PhCH)CH (14)
91:9
94.5 (>99)c
a Determined by NMR from the crude reaction mixture. b Of the major
diastereomer after chromatography. c Of the major diastereomer, determined
by chiral HPLC. d After a single recrystallization.
Acknowledgment. Financial support by the Ministerio de
Educacio´n y Ciencia (MEC, CTQ2006-01121) and the UAM/
Consejer´ıa de Educacio´n de la Comunidad Auto´noma de
Madrid (CCG07-UAM/PPQ-1799) is gratefully acknowledged.
A.S.-G. and M.R.R. also thank the MEC for a predoctoral
fellowship and a Juan de la Cierva contract, respectively.
Table 3, the higher reactivity of this nucleophile allowed the
reaction to be performed at -40 °C, giving the corresponding
chiral aminoalkyl γ-substituted γ-butenolides in excellent yields
and high diastereocontrol (from 81:19 to 93:7). The major
isomer was isolated in 79-87% yield and high enantiocontrol
Supporting Information Available: Experimental pro-
cedures and characterization data of new compounds; copies
of NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
(14) For very recent applications of 2-pyridylsulfonylimines in metal-
catalyzed reactions, see: (a) Esquivias, J.; Gome´z-Arraya´s, R.; Carretero,
J. C. J. Am. Chem. Soc. 2007, 129, 1480. (b) Esquivias, J.; Gome´z-Arraya´s,
R.; Carretero, J. C. Angew. Chem., Int. Ed. 2007, 46, 9257. (c) Nakamura,
S.; Nakashima, H.; Sugimoto, H.; Sano, H.; Hattori, M.; Shibata, N.; Toru,
T. Chem.sEur. J. 2008, 14, 2145.
OL8019082
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J. E. J. Org. Chem. 1991, 56, 91.
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(17) The recrystallization yields were typically in the range of 65-75%
(usually from CH2Cl2-hexane mixtures).
(20) Yoon, Y.-J.; Joo, J.-E.; Lee, K.-Y.; Kim, Y.-H.; Oh, C.-Y.; Ham,
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Org. Lett., Vol. 10, No. 19, 2008
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