Copper(I)-fesulphos Lewis acid catalysts for enantioselective Mannich-type reaction of N-sulfonyl imines

Article abstract of DOI:10.1021/ol060866v

Copper(I) complexes of Fesulphos ligands are efficient chiral Lewis acid catalysts in the Mannich-type addition of silyl enol ethers of ketones, esters, and thioesters to N-(2-thienyl)sulfonyl aldimines. The corresponding optically active β-amino carbonyl

Full text of DOI:10.1021/ol060866v

ORGANIC
LETTERS
2006
Vol. 8, No. 14
2977-2980
Copper(I)-Fesulphos Lewis Acid
Catalysts for Enantioselective
Mannich-Type Reaction of N-Sulfonyl
Imines
Alvaro Salvador Gonza´lez, Ramo´n Go´mez Arraya´s, and Juan C. Carretero*
Departamento de Qu´ımica Orga´nica, Facultad de Ciencias, UniVersidad Auto´noma de
Madrid, Cantoblanco, 28049 Madrid, Spain
juancarlos.carretero@uam.es
Received April 10, 2006
ABSTRACT
Copper(I) complexes of Fesulphos ligands are efficient chiral Lewis acid catalysts in the Mannich-type addition of silyl enol ethers of ketones,
esters, and thioesters to N-(2-thienyl)sulfonyl aldimines. The corresponding optically active -amino carbonyl derivatives were obtained in
â
good yields (58
−91%) and with moderate to good enantioselectivity (61−93% ee). Removal of the N-activating group was achieved under mild
conditions by simple treatment of the products with Mg in methanol.
The catalytic enantioselective Mannich-type addition of
enolate anion equivalents to imines represents an extremely
powerful strategy for the preparation of chiral nonracemic
â-amino carbonyls, which are key structural units in biologi-
cally relevant compounds such as â-lactams and â-amino
acids.1 Consequently, the development of organocatalysts2
and metal-based chiral catalysts3-7 to promote this reaction
has received a great deal of attention in recent years. Despite
the impressive progress achieved in this reaction there is still
room for improvement, especially toward developing novel
procedures displaying a wide structural scope with regard
to the substitution at the two reaction partners, imine and
enolate. Thus, although there are some very efficient asym-
metric metal-catalyzed protocols for the addition of enolate
reagents to N-aryl imines,3 N-acyl imines,4 N-acyl hydra-
zones,5 and N-phosphinoyl imines,4d-e,6 the use of sulfonyl
(1) For reviews, see: (a) Kobayashi, S.; Ishitani, H. Chem. ReV. 1999,
99, 1069. (b) Co´rdova, A. Acc. Chem. Res. 2004, 37, 102. (c) Marques, M.
M. B. Angew. Chem., Int. Ed. 2006, 45, 348.
(3) For recent examples with N-aryl imines of aromatic and aliphatic
aldehydes, see: (a) Xue, S.; Yu, S.; Deng, Y.; Wulff, W. D. Angew. Chem.,
Int. Ed. 2001, 40, 2271. (b) Yamashita, Y.; Ueno, M.; Kuriyama, Y.;
Kobayashi, S. AdV. Synth. Catal. 2002, 344, 929. (c) Ueno, M.; Ishitani,
H.; Kobayashi, S. Org. Lett. 2002, 4, 3395. (d) Kobayashi, S.; Kobayashi,
J.; Ishitani, H.; Ueno, M. Chem. Eur J. 2002, 8, 4185. (e) Trost, B. M.;
Terrell, L. R. J. Am. Chem. Soc. 2003, 125, 338. (f) Jaber, N.; Carre´e, F.;
Fiaud, J.-C.; Collin, J. Tetrahedron: Asymmetry 2003, 14, 2067. (g)
Kobayashi, S.; Ueno, M.; Saito, S.; Mizuki, Y.; Ishitani, H.; Yamashita, Y.
Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5476. (h) Josephsohn, N. S.;
Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2004, 126, 3734. (i)
Josephsohn, N. S.; Carswell, E. L.; Snapper, M. L.; Hoveyda, A. H. Org.
Lett. 2005, 7, 2711. (j) Ihori, Y.; Yamashita, Y.; Ishitani, H.; Kobayashi,
S. J. Am. Chem. Soc. 2005, 127, 15528. For a Reformatsky-type reaction,
see: (k) Cozzi, P. G.; Rivalta, E. Angew. Chem., Int. Ed. 2005, 44, 3600.
(2) For recent reviews on organocatalysis, see: (a) Dalko, P. I.; Moisan,
L. Angew. Chem., Int. Ed. 2004, 43, 5138. (b) Seayad, J.; List, B. Org.
Biomol. Chem. 2005, 3, 719. For selected references on asymmetric Mannich
reactions using organocatalysts, see: (c) Mitsumori, S.; Zhang, H.; Cheong,
P. H.-Y.; Houk, K. N.; Tanaka, F.; Barbas, C. F., III. J. Am. Chem. Soc.
2006, 128, 1040. (d) Ibrahem, I.; Zou, W.; Xu, Y.; Co´rdova, A. AdV. Synth.
Catal. 2006, 348, 211. (e) Rodr´ıguez, B.; Bolm, C. J. Org. Chem. 2006,
71, 2888. (f) Taylor, M. S.; Tokunaga, N.; Jacobsen, E. N. Angew. Chem.,
Int. Ed. 2005, 44, 6700. (g) Okada, A.; Shibuguchi, T.; Ohshima, T.; Masu,
H.; Yamaguchi, K.; Shibasaki, M. Angew. Chem., Int. Ed. 2005, 44, 4564.
(h) Poulsen, T. B.; Alemparte, C.; Saaby, S.; Bella, M.; Jørgensen, K. A.
Angew. Chem., Int. Ed. 2005, 44, 2896. (i) Lou, S.; Taoka, B. M.; Ting,
A.; Schaus, S. E. J. Am. Chem. Soc. 2005, 127, 11256. (j) Enders, D.;
Grondal, C.; Vrettou, M.; Raabe, G. Angew. Chem., Int. Ed. 2005, 44, 4079.
10.1021/ol060866v CCC: $33.50
© 2006 American Chemical Society
Published on Web 06/17/2006

imines as electrophiles is limited mainly to the case of the
highly electronically activated R-tosyliminoesters.7 However,
as a result of their great synthetic availability, stability, and
structural variety, aryl, alkenyl, and alkyl N-sulfonyl imines
are very appealing N-protected electrophiles in Mannich-
type reactions.8 To the best of our knowledge, there are only
two precedents concerning the use of nonactivated N-sulfonyl
imines, in particular tosylimines, both involving the partici-
pation of a particular type of nucleophile partner: enolates
of glycine Schiff bases9 and N-(2-hydroxyacetyl)pyrrole.10
We recently described that the readily available and air-
stable copper(I) complexes of sulfenylphosphino-ferrocenes
(Fesulphos ligands),11 particularly the bulky bis(1-naphthyl)-
phosphine derivative [1a‚CuBr]2 (Scheme 1), in combination
Tosylimines are by far the type of N-sulfonyl imines most
used in organic synthesis. However, in recent years, we14
and others15 have shown that the substitution at sulfur,
especially when heteroaryl groups are used, can dramatically
affect the chemical behavior of N-sulfonyl imines, paving
the way for the development of novel reactive patterns of
great synthetic value. Thus, we first focussed on searching
for the optimal N-sulfonyl protecting group. In this pursuit,
several sulfonyl imines of benzaldehyde (2a-e) were readily
prepared16 and subjected to the reaction with 1-tert-butyldi-
methylsilyloxy-1-tert-butylthioethene (3) under our optimized
catalyst system,12 a combination of [1a‚CuBr]2 (5.1 mol %)
and AgClO4 (10 mol %) in CH2Cl217 at room temperature18
for 5 h. Table 1 highlights the important role of the nature
Table 1. Screening of Different N-Sulfonyl Groups
Scheme 1. Synthesis of the Copper(I) Complex [1a‚CuBr]2
conv
ee
entry
R
imine (%)a yield (%)b product (%)c
with AgClO4, behave as highly efficient chiral Lewis acid
catalysts for the formal aza Diels-Alder reaction of N-
sulfonyl imines with Danishefsky diene under very mild
reaction conditions.12 Extending the interest of this novel P,S-
copper complex in asymmetric catalysis,13 we report herein
its efficiency as general catalyst in the enantioselective
Mannich-type reaction of a broad structural variety of
N-sulfonyl imines and silyl enolates.
1
2
3
4
5
NMe2
p-NO2C6H4
p-Tol
2-pyridyl
2-thienyl
2a
2b
2c
2d
2e
0
20
50
90
95
4a
4b
4c
4d
4e
39
65
80
90
39
91
a Determined by 1H NMR analysis of the crude reaction mixture (the
remaining product is starting material). b Isolated yield after chromatographic
purification. c Determined by HPLC using chiral stationary phases.
of the sulfonyl group on the reactivity and enantioselectivity
of the process. While imines 2a and 2b led to the recovery
of the starting material or were hardly reactive (entries 1
and 2), the N-tosyl imine 2c reached 50% conversion under
identical conditions, affording the addition product 4c with
39% yield and 90% ee (entry 3). Heteroarylsulfonyl imines
2d14b and 2e showed enhanced reactivity, the reaction being
almost completed after 5 h (90-95% conversion, entries 4
and 5). However, whereas the N-(2-pyridyl)sulfonyl imine
2d gave 4d with low enantioselectivity (39% ee), the N-(2-
thienyl)sulfonyl derivative 2e produced 4e with 91% ee.
At this point, we confirmed the superiority of the complex
[1a‚CuBr]2 over the copper(I) bromide complexes of other
(4) (a) Kobayashi, S.; Matsubara, R.; Kitagawa, H. Org. Lett. 2002, 4,
143. (b) Kobayashi, S.; Matsubara, R.; Nakamura, Y.; Kitagawa, H.; Sugiura,
M. J. Am. Chem. Soc. 2003, 125, 2507. (c) Nakamura, Y.; Matsubara, R.;
Kiyohara, H.; Kobayashi, S. Org. Lett. 2003, 5, 2481. (d) Matsunaga, S.;
Yoshida, T.; Naoya, M.; Kumagai, N.; Shibasaki, M. J. Am. Chem. Soc.
2004, 126, 8777. (e) Trost, B. M.; Jaratjaroonphong, J.; Reutrakul, V. J.
Am. Chem. Soc. 2006, 128, 2778.
(5) (a) Kobayashi, S.; Hamada, T.; Manabe, K. J. Am. Chem. Soc. 2002,
124, 5640. (b) Hamada, T.; Manabe, K.; Kobayashi, S. Chem. Eur. J. 2006,
12, 1205.
(6) (a) Matsunaga, S.; Kumagai, N.; Harada, S.; Shibasaki, M. J. Am.
Chem. Soc. 2003, 125, 4712. (b) Yoshida, T.; Morimoto, H.; Kumagai, N.;
Matsunaga, S.; Shibasaki, M. Angew. Chem., Int. Ed. 2005, 44, 3470. (c)
Sugita, M.; Yamaguchi, A.; Yamagiwa, N.; Handa, S.; Matsunaga, S.;
Shibasaki, M. Org. Lett. 2005, 7, 5339.
(7) For N-tosyl R-iminoesters, see: (a) Ferraris, D.; Young, B.; Dudding,
T.; Lectka, T. J. Am. Chem. Soc. 1998, 120, 4548. (b) Ferraris, D.; Young,
B.; Cox, C.; Dudding, T.; Drury, W. J., III; Ryzhkov, L.; Taggi, A. E.;
Lectka, T. J. Am. Chem. Soc. 2002, 124, 67. (c) Marigo, M.; Kjærsgaard,
A.; Juhl, K.; Gathergood, N.; Jørgensen, K. A. Chem. Eur. J. 2003, 9, 2359.
(8) The deprotection of commonly used phenyl- and tolyl-sulfonamides
are typically somewhat troublesome because of the required harsh reaction
conditions (see, for instance: Sharma, A. K.; Hergenrother, J. P. Org. Lett.
2003, 5, 2107).
(13) For the application of Fesulphos ligands in other metal-promoted
transformations, see: (a) Garc´ıa Manchen˜o, O.; Go´mez Arraya´s, R.;
Carretero, J. C. Organometallics 2005, 24, 557. (b) Cabrera, S.; Go´mez
Arraya´s, R.; Alonso, I.; Carretero, J. C. J. Am. Chem. Soc. 2005, 127, 17938.
(c) Cabrera, S.; Go´mez Arraya´s, R.; Carretero, J. C. J. Am. Chem. Soc.
2005, 127, 16394. See also ref 11.
(14) (a) Esquivias, J.; Go´mez Arraya´s, R.; Carretero, J. C. J. Org. Chem.
2005, 70, 7451. (b) Esquivias, J.; Go´mez Arraya´s, R.; Carretero, J. C. Angew.
Chem., Int. Ed. 2006, 45, 629.
(9) Bernardi, L.; Gothelf, A. S.; Hazell, R. G.; Jørgensen, K. A. J. Org.
Chem. 2003, 68, 2583.
(10) Harada, S.; Handa, S.; Matsunaga, S.; Shibasaki, M. Angew. Chem.,
Int. Ed. 2005, 44, 4365.
(11) Garc´ıa Manchen˜o, O.; Priego, J.; Cabrera, S.; Go´mez Arraya´s, R.;
Llamas, T.; Carretero, J. C. J. Org. Chem. 2003, 68, 3679.
(12) Garc´ıa Manchen˜o, O.; Go´mez Arraya´s, R.; Carretero, J. C. J. Am.
Chem. Soc. 2004, 126, 456. The reaction of Danishefsky diene with
N-tosylimines catalyzed by [1‚CuBr]2/AgClO4 occurs mainly by a stepwise
process: initial Mannich-type addition followed by in situ acid-catalyzed
cyclization to the formal aza Diels-Alder adduct.
(15) Sugimoto, H.; Nakamura, S.; Hattori, M.; Ozeki, S.; Shibata, N.;
Toru, T. Tetrahedron Lett. 2005, 46, 8941.
(16) See Supporting Information for details.
(17) DCE provided similar results, whereas toluene led to lower yields
and enantioselectivities. The use of coordinating solvents such as THF or
DMF resulted in no reaction.
(18) Lower temperature (0 °C) led to unpractical conversions.
2978
Org. Lett., Vol. 8, No. 14, 2006

members of the Fesulphos family of ligands (1b-e). The
diphenylphosphine (1b, 60%, 47% ee), the bis(o-tolyl)-
phosphine (1c, 81%, 59% ee), the dicyclohexylphosphine
(1d, 74%, 76% ee), and the difurylphosphine (1e, 68%, 53%
ee) ligands provided poorer results in the reaction of imine
2e with 3 (Scheme 2). On the other hand, the chloride
Table 2. Mannich-Type Reaction of Imines 5e-15e with 3
Scheme 2. Copper(I) Bromide Complexes of Other FeSulfOs
Ligands [(1b-e)‚CuBr]2 in the Mannich-Type Reaction of 2e
with 3
time
yield
ee
entry
R
imine (h) product (%)a
(%)b
1
2
3
4
5
6
7
8
9
Ph
2e
5e
19
22
72
14
12
12
13
19
28
43
12
17
4e
16e
17e
18e
19e
20e
21e
22e
23e
24e
25e
26e
80 91 (>99)c
60 82
58 81
(p-F)C6H4
(p-OMe)C6H4
o-Tol
(m-OMe)C6H4
(m-Cl)C6H4
1-naphth
2-naphth
2-furyl
6e
7e
8e
9e
77 93
91 83 (94)c
80 88 (98)c
86 88
10e
11e
12e
13e
71 91
87 49
40 71
83 60
70 76 (88)c
10
11
12
PhCHdCH
(2-furyl)CHdCH 14e
Cy 15e
complex [1a‚CuCl]2 led to similar results (79%, 90% ee) as
[1a‚CuBr]2 in this model reaction, albeit it was less reactive.
a Isolated yield after chromatographic purification. b Determined by
HPLC using chiral stationary phases. c In parentheses is % ee after one
recrystallization
From a practical point of view, it is important to note that
these sulfonamide products are stable crystalline solids,
enabling thereby an enhancement of their enantiomeric purity
by recrystallization. For instance, a single recrystallization
from hexane/CH2Cl2 of a 91% ee sample of 4e resulted in
enantiomerically pure 4e (ee > 99%).19 In addition, crystals
of this product suitable for X-ray crystallographic analysis
allowed its absolute configuration (R) to be unequivocally
established.16
asymmetric Mannich reaction of 3 in the presence of [1a‚
CuBr]2/AgClO4, affording the addition product 26e in 70%
yield and 76% ee (entry 12). As shown in four cases the
enantiopurity of the Mannich products can be significantly
increased after a single recrystallization19 (entries 1, 5, 6,
and 12; 88-99% ee).
The generality of the process with regard to the silyl enol
Having established the optimal sulfonyl protecting group20
and the catalyst system, we next evaluated the scope of the
reaction of 3 with differently substituted N-(2-thienyl)sulfonyl
imines. As shown in Table 2, a number of representative
aryl imines underwent addition with consistently high
enantioselectivity, regardless of their steric or electronic
nature (81-93% ee, entries 1-6). Both electron-withdrawing
(F, Cl) and electron-donating (Me, OMe) substituents, as well
as ortho-, meta-, and para-substitution, were well tolerated.
In contrast, the N-(2-thienyl)sulfonyl imine of 2-furyladehyde
(12e) resulted in a significant decrease of the enantioselec-
tivity (49% ee, entry 9). Besides the aromatic aldimines, we
next evaluated alkenyl- and alkyl-substituted imines, a kind
of substrate much less studied in catalytic asymmetric
Mannich-type reactions. Cinnamyl aldimine 13e showed
decreased reactivity, affording the addition product in
moderate 40% yield and 71% ee (entry 10), whereas the
substrate 14e, vinylogous of 2-furyl derivative 12e, showed
higher reactivity (83% yield) but modest asymmetric induc-
tion (60% ee, entry 11). The aliphatic enolizable imine of
cyclohexanecarbaldehyde (15e) did also participate in the
ether nucleophile is summarized in Table 3. Gratifyingly,
Table 3. Mannich-Type Addition of Silyl Enol Ethers of
Esters and Ketones to Imine 2e
entry
R1
R2
R3 product yield (%)a ee (%)b
1
2
3
4
5
TBDMS OMe
TBDMS OMe
H
Me
H
H
H
27e
28e
29e
30e
31e
75
77
71
80
90
80
86
93
85
86
TMS
TMS
TMS
Ph
(p-OMe)C6H4
2-Naph
a Isolated yield after chromatographic purification. b Determined by
HPLC using chiral stationary phases.
not only thioester-derived nucleophiles but also silyl enol
ethers of esters (entries 1 and 2) and silyl enol ethers of
ketones (entries 3-5) underwent smooth addition reaction
to imine 2e, leading to the corresponding â-amino derivatives
in good yields (71-90%) and high enantioselectivities (80-
93% ee).
(19) The recrystallization yields were typically in the range of 70-90%.
(20) Further confirmation of the superiority of N-(2-thienyl)sulfonyl
imines over the N-tosyl derivatives resulted from the comparative reaction
of 3 with the naphthyl imine 11e and its N-tosyl derivative 11c. Thus, while
imine 11e led to the addition product 22e with 71% yield and 91% ee (Table
2, entry 8), 11c afforded 22c in 36% yield and 81% ee.
Org. Lett., Vol. 8, No. 14, 2006
2979

From a synthetic applicability point of view, it is important
to note that the resulting 2-thienylsulfonyl-protected amino
ester and thioester derivatives21 can be readily deprotected
in high yields under mild reaction conditions by treatment
with magnesium in methanol (Table 4).22 Under these
of the enantiomeric purity (>99% and 98% ee, respectively).
Similarly, deprotection of the ester 28e (86% ee) afforded
the â-aminoester 343a in 83% yield with the same enantio-
meric excess (86% ee, entry 3). In the case of the known
compounds 3223 and 34,3a comparison of their optical rotation
value with that reported in the literature allowed us to confirm
the absolute configuration of the Mannich products previ-
ously established by X-ray diffraction analysis of 4e.
In summary, we have shown that the combination of CuI-
Fesulphos as catalyst and 2-thienylsulfonyl imines as sub-
strates provides a highly enantioselective and broad structural
procedure for the Mannich-type reactions of silyl enolates.
This novel methodology displays a wide tolerance with
respect to both the substitution at the imine substrate (aryl,
alkenyl, and alkyl imines) and the nucleophile (silyl enolates
of thioesters, esters, and ketones). Further investigation to
clarify the exact role of the 2-thienylsulfonyl group and
application of this strategy to the vinylogous Mannich-type
reaction and other enantioselective reactions of N-sulfo-
nylimines are currently in progress in our lab.
Table 4. Deprotection of the (2-Thienyl)sulfonamide Group
substrate,
ee (%)a
yield product
entry
R1
R2
X
(%)b
ee (%)a
1
2
3
4e, >99
20e, 98
28e, 86
Ph
m-ClC6H4
Ph
H
H
S-t-Bu
S-t-Bu
83
84
87
32, >99
33, 98
34, 86
Me OMe
a Determined by HPLC using chiral stationary phases. b Isolated yield
after chromatographic purification.
Acknowledgment. Financial support of this work by the
Ministerio de Ecucacio´n y Ciencia (MEC, project BQU2003-
0508), Consejer´ıa de Educacio´n de la Comunidad Auto´noma
de Madrid (CAM, Project GR/MAT/0016/2004), and UAM-
CAM (Project 08/PPQ/001) is gratefully acknowledged.
A.S.G. and R.G.A. thank the MEC for a predoctoral
fellowship and a Ramo´n y Cajal contract, respectively. We
acknowledge with pleasure the contribution of Jose´ L. Rolda´n
to the early stage of this project.
reaction conditions recrystallized samples of thioesters 4e
and 20e (>99% and 98% ee, respectively) underwent the
cleavage of the sulfonamide moiety and methanolysis of the
thioester group to give the methyl â-aminoesters 3223 and
33 in good yields (83-84%, entries 1 and 2) without erosion
(21) Unfortunately, this N-deprotection method is not suitable for ketone
derivatives. For example, complete disappearance of starting material was
observed upon treatment of compounds 30e and 31e with Mg in MeOH
for 4 h, but only decomposition products were detected in the reaction
mixture.
(22) These reductive reaction conditions had been reported for the
cleavage of 2-pyridylsulfonyl-protected amines: Pak, C. S.; Lim, D. S.
Synth. Commun. 2001, 2209.
Supporting Information Available: Full experimental
details, copies of 1H NMR and 13C NMR of all new
compounds, and X-ray crystallography data of (R)-4e. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(23) Hata, S.; Iguchi, M.; Iwasawa, T.; Yamada, K.-i.; Tomioka, K. Org.
Lett. 2004, 6, 1721.
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