Direct catalytic asymmetric mannich-type reaction of thioamides

Full text of DOI:10.1002/anie.200901588

Communications
DOI: 10.1002/anie.200901588
Asymmetric Catalysis
Direct Catalytic Asymmetric Mannich-Type Reaction of Thioamides**
Yuta Suzuki, Ryo Yazaki, Naoya Kumagai,* and Masakatsu Shibasaki*
Thioamides are widely utilized as useful precursors for the
synthesis of a broad range of heterocyclic compounds by
exploiting their ambident nucleophilic character at both the
sulfur and nitrogen atoms.[1] They are, however, rarely
ized.[11] A commonly accepted interpretation is the greater
contribution of the canonical structure B in Scheme 1, where
more pronounced charge transfer from N to S is antici-
À
recognized as carbon pronucleophiles in enantioselective C
C bond-forming reactions. Yoshida and co-workers disclosed
that the exposure of thioamides to a stoichiometric amount of
strong base selectively generated a Z enolate, thus affording
syn-aldol products upon the addition of aldehydes.[2] Lithium
thioamide enolates and thioketene S-silyl N,S-acetals were
successively reported as activated nucleophiles for Michael,[3]
aldol,[4] and Mannich-type reactions.[5] Later the aldol reac-
tion was rendered asymmetric under stoichiometric condi-
tions, although only one example with benzaldehyde was
described.[6] In this context, there are no reports on the
catalytic generation of active carbon nucleophiles from
Scheme 1. Catalytic generation of the thioamide enolate by soft Lewis
acid/hard Brønsted base cooperative catalysis.
pated.[12] Higher acidity of the a proton of thioamides
compared to that of amides may also be ascribed to better
accommodate the negative charge at the sulfur atom.[13] We
hypothesized that chemoselective coordination of the sulfur
atom to a cationic soft Lewis acid would accommodate the
partial negative charge and enhance the acidity of the
a proton of thioamides, thus leading to a facile catalytic
generation of thioamide enolates by a mild Brønsted base
(Scheme 1). Initially, we selected N,N-dimethylthioacetamide
(2a), which is a commercially available thioamide pronucleo-
phile,[14] and it was subjected to a direct Mannich-type
reaction with N-Dpp imine 1a (Table 1). The catalyst
prepared from [Cu(CH3CN)4]PF6, (R,R)-Ph-BPE, and
Li(OC6H4-p-OMe) showed better catalytic turnover than
that prepared from [Cu(CH3CN)4]ClO4, and afforded 3aa
with encouraging enantioselectivity (Table 1, entries 1 and 2).
The reaction in CH2Cl2 or DME resulted in a lower yield
despite the higher solubility of 1a (Table 1, entries 3 and 4).
Toluene offered a suitable reaction medium for the present
catalysis in terms of both catalytic turnover and ee value
(Table 1, entry 5). The reaction in the absence of the CuI salt
or base did not proceed at all, thus verifying the crucial
cooperative nature of the soft Lewis acid and hard Brønsted
base to generate the active nucleophile from 2a (Table 1,
entries 6 and 7). The reaction can be carried out in the
presence of 1 mol% of catalyst at À208C without any loss of
enantioselectivity (Table 1, entry 8).
À
thioamides and their integration into enantioselective C C
bond-forming processes. Such an approach would be more
advantageous than the preceding stoichiometric reactions in
terms of both atom and step economy.[7] Herein, we report a
direct catalytic asymmetric Mannich-type reaction of thio-
amides and N-diphenylphosphinoyl (Dpp) imines[8] under
proton-transfer conditions by soft Lewis acid/hard Brønsted
base cooperative catalysis, to afford enantiomerically
enriched b-amino thioamides. Divergent transformation of
the thioamides ensures the synthetic utility of the product.
The direct catalytic asymmetric Mannich-type reaction
has attracted much attention as a useful protocol to provide
optically active b-amino carbonyl units under proton-transfer
conditions.[9] We recently reported a catalytic system com-
prising [Cu(CH3CN)4]ClO4/(R,R)-Ph-BPE/LiOAr that was
particularly effective for catalytic generation of nucleophiles
from otherwise unreactive pronucleophiles bearing soft Lewis
basic functionality.[10] We envisioned employing thioamides as
carbon pronucleophiles in this catalytic system. The thio-
amide functionality has an even larger rotational barrier and
dipole moment than the corresponding amides, although the
=
=
C S bond, unlike the C O bond, is intrinsically not polar-
[*] Y. Suzuki, R. Yazaki, Dr. N. Kumagai, Prof. Dr. M. Shibasaki
Graduate School of Pharmaceutical Sciences
The University of Tokyo
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
Fax: (+81)3-5684-5206
E-mail: nkumagai@mol.f.u-tokyo.ac.jp
mshibasa@mol.f.u-tokyo.ac.jp
The investigation of the substrate scope with the present
system was our next focus. N,N-diallyl 2b and N,N-bisPMB 2c
variants, whose nitrogen substituents can be removed at the
product elaboration stage, were used as thioamide pronu-
cleophiles. In the reaction using 2b, b elimination of the N-
Dpp group occurred occasionally at 08C, which was circum-
vented by lowering the reaction temperature to À208C and
using Li(OC6H4-o-OMe) as the base.[15] The reaction of 1a
and 2b proceeded smoothly with 3 mol% of the catalyst, and
Homepage: http://www.f.u-tokyo.ac.jp/~kanai/e_index.html
[**] This work was financially supported by a Grant-in-Aid for Scientific
Research (S) and a Grant-in-Aid for Young Scientist (B). Dr. M. Shiro
at Rigaku Corporation is gratefully acknowledged for technical
assistance with the X-ray crystallographic analysis of 3ab.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200901588.
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Table 1: Direct catalytic asymmetric Mannich-type reaction of N-Dpp imine 1a and thioamides 2a with
lower enantioselectivity (Table 2,
soft Lewis acid/hard Brønsted base cooperative catalysis.[a]
entry 4). Excellent enantioselectiv-
ity was maintained with imines
bearing either bromide or methoxy
substituents in the para position
(Table 2, entries 5 and 6). Notably,
high
enantioselectivity
was
Entry
Soft Lewis acid
Base
Solvent
x
t
[h]
Yield
[%][b]
ee
[%]
observed even for imines bearing
soft Lewis basic 2-thienyl or 2-
pyridyl groups (Table 2, entries 8
and 9). Although the yield was
moderate with 1h likely owing to a
competitive coordination to CuI. In
view of the synthetic utility of the
product, a Mannich-type reaction
was conducted with imines bearing
aliphatic or alkenyl substituents and
[mol%]
1
2
3
4
[Cu(CH3CN)4]ClO4
[Cu(CH3CN)4]PF6
[Cu(CH3CN)4]PF6
[Cu(CH3CN)4]PF6
[Cu(CH3CN)4]PF6
–
Li(OC6H4-p-OMe)
Li(OC6H4-p-OMe)
Li(OC6H4-p-OMe)
Li(OC6H4-p-OMe)
Li(OC6H4-p-OMe)
Li(OC6H4-p-OMe)
–
THF
THF
DME
CH2Cl2
toluene
toluene
toluene
toluene
10
10
10
10
10
10
10
1
20
20
20
20
20
20
20
72
60
72
60
46
95
0
87
89
93
88
95
–
5
6[c]
7[c]
8[d]
[Cu(CH3CN)4]PF6
[Cu(CH3CN)4]PF6
0
–
96
Li(OC6H4-p-OMe)
88[e]
[a] 1a (0.2 mmol), 2a (0.24 mmol). [b] Determined by 1H NMR with Bn2O as an internal standard. [c] In
the absence of (R,R)-Ph-BPE. [d] Run with 1.5 equivalents of 2a at À208C. [e] Yield of isolated product.
THF=tetrahydrofuran, DME=1,2-dimethoxyethane.
reasonable
were observed (Table 2, entries 10
enantioselectivities
and 11). Thioamide 2c also served
as
afford 3ac in excellent yield and
enantioselectivity (Table 2,
entry 12). The reactions using thio-
a suitable pronucleophile to
the reaction also reached completion with as little as 1 mol%
of catalyst over an extended period of time (Table 2, entries 1
and 2).[16] The methyl group at the ortho position of the imine
did not interfere with the enantioselectivity (Table 2, entry 3),
whereas an imine derived from 1-naphthaldehyde gave a
amides 2d,e derived from propionic or butyric acids were
sluggish and required Li(OC6H4-p-OMe) as a stronger base,
and afforded the product in high anti-diastereoselectivity and
in moderate to good enantioselectivity (Table 2, entries 13–
16). A plausible transition state model is depicted in
Scheme 2. The (R,R)-Ph-BPE/Cu(OC6H4-o-OMe) complex,
which would be formed by mixing (R,R)-Ph-BPE, [Cu-
(CH3CN)4]PF6, and Li(OC6H4-o-OMe),[17] serve as a soft
Lewis acid and a hard Brønsted base to generate thioamide
enolates, which would be in equilibrium between E/Z isomers
through protonation/deprotonation. Taking severe steric
constraint into account, the reaction would proceed through
the transition state where the N,N-dialkyl and C-alkyl groups
Scheme 3. Transformation of the Mannich products. TFA=trifluoro-
acetic acid, TFAA=trifluoroacetic anhydride.
Scheme 2. Proposed transition state.
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Communications
Table 2: Direct catalytic asymmetric Mannich-type reaction of N-Dpp imine 1 and thioamides 2.[a]
In summary, we have devel-
oped a direct catalytic asymmetric
Mannich-type reaction of N-Dpp
imines and thioamides.
A soft
Lewis acid/hard Brønsted base
cooperative system worked effi-
ciently to generate the active
carbon nucleophile from thioa-
mides by exploiting the soft Lewis
basic nature of the sulfur atom. The
reaction can be performed with as
little as 1 mol% of catalyst and
excellent enantioselectivity as well
as high anti-diastereoselectivity
was observed. Divergent transfor-
mation of thioamide functionality
highlights the utility of the meth-
odology presented here.
Entry Imine 1 R1
Thioamide 2
x
Product
T
t
anti/syn[b] Yield ee
[mol%]
[8C] [h]
[%][c] [%]
1
1a
2b
3
3ab
À20 20
–
95
97
2
3
1a
1b
2b
2b
1
3
3ab
3bb
À20 72
À20 48
–
–
99
88
95
95
4
1c
2b
3
3cb
À20 20
–
96
84
5
6
1d
1e
2b
2b
3
3
3db
3eb
À20 20
À20 48
–
–
94
89
95
95
Experimental Section
A
typical procedure for the direct
catalytic asymmetric Mannich-type
reaction of N-Dpp imine 1a and thio-
amide 2b described in Table 2, entry 1:
A flame-dried 20 mL test tube equip-
ped with a magnetic stirring bar was
charged N-Dpp imine 1a (61.1 mg,
0.2 mmol) and was dried under
vacuum for 10 min. The test tube was
back-filled with argon and dry toluene
(2.0 mL) was added in an argon atmos-
phere. Then a premixed solution of
[Cu(CH3CN)4]PF6 and (R,R)-Ph-BPE
in THF (60 mL, 0.006 mmol, 0.1m) was
added at room temperature. After cool-
ing the reaction mixture to À208C,
7
8
9
1 f
1g
1h
2b
2b
2b
3
3
3
3 fb
3gb
3hb
À20 48
À20 48
À20 48
–
–
–
95
90
54
93
90
88
10
11
1i
1j
2b
2b
3
3
3ib
3jb
À20 48
À20 48
–
–
60
66
78
81
12
1a
2c
3
3ac
À20 48
–
99
94
13[d,e] 1a
14[d,e] 1a
15[d,e] 1a
16[d,e] 1d
2d
2d
2e
2d
10
10
10
10
3ad
3ad
3ae
3dd
À20 72
89/11
90/10
90/10
89/11
57
89
84
89
88[f]
74[f]
53[f]
71[f]
Li(OC6H4-o-OMe)
(30 mL,
0.006 mmol, 0.2m/THF) and thioamide
2b (47.7 mL, 0.3 mmol) were subse-
quently added. After stirring at the
same temperature for 20 h, 1n HCl
(1.0 mL) was added and the resulting
biphasic mixture was extracted with
AcOEt three times. The combined
organic layers were washed with satu-
rated aqueous NaHCO3 and brine, then
dried over Na2SO4. The volatiles were
removed under reduced pressure and
the resulting residue was purified by
0
0
0
72
72
42
[a] 1 (0.2 mmol), 2 (0.3 mmol). [b] Determined by 1H NMR analysis. [c] Yield of isolated product.
[d] Li(OC6H4-p-OMe) was used instead of Li(OC6H4-o-OMe). [e] THF was used as the solvent.
[f] Enantioselectivity of the anti diastereomer. PMB=p-methoxybenzyl.
of the E enolate and the P,P-diphenyl groups of 1 occupy the
column chromatography on silica gel to give Mannich product 3ab as
a colorless solid (87.5 mg, 0.19 mmol, 95% yield). The enantioselec-
tivity was determined by HPLC on a chiral stationary phase using a
Daicel Chiralcel OD-H column (f 0.46 ꢀ 25 cm); eluent: n-hexane/2-
propanol = 4/1; flow rate: 0.5 mLminÀ1; detection at 254 nm; tR =
12.0 min ((S) minor), 16.6 ((R) major).
vacant space of the asymmetric architecture provided by
(R,R)-Ph-BPE, thereby affording (2S,3R)-3 predominantly.
The rich chemistry of thioamides enabled functional
group manipulation of the Mannich product (Scheme 3).
Treatment of 3ab with MeI in the presence of H2O under
acidic conditions gave methyl thioester 4a in quantitative
yield.[18] Meanwhile, anhydrous conditions and the addition of
HCl·NH2OBn provided benzyloxyamidine 5ab as a single
geometric isomer. Facile conversion into amide 6ab was
achieved by TFAA in CH2Cl2.[19] Desulfurization of 3ac with
Raney-Ni generated the N,N-bisPMB-protected diamine 7ac
in 75% yield.
Received: March 23, 2009
Published online: May 26, 2009
Keywords: asymmetric catalysis · copper · Mannich reactions ·
proton transfer · thioamides
.
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Angew. Chem. 2008, 120, 151; Angew. Chem. Int. Ed. 2008, 47,
145.
[1] T. S. Jagodzinski, Chem. Rev. 2003, 103, 197, and references
therein.
[2] a) Y. Tamaru, T. Harada, S.-I. Nishi, M. Mizutani, T. Hioki, Z.-I.
Yoshida, J. Am. Chem. Soc. 1980, 102, 7806; b) Y. Tamaru, T.
Hioki, Z.-I. Yoshida, Tetrahedron Lett. 1984, 25, 5793.
[3] C. Goasdoue, N. Goasdoue, M. Gaudemar, M. Mladenova, J.
Organomet. Chem. 1982, 226, 209.
[4] a) C. Goasdoue, N. Goasdoue, M. Gaudemar, Tetrahedron Lett.
1983, 24, 4001; b) C. Goasdoue, N. Goasdoue, M. Gaudemar,
Tetrahedron Lett. 1984, 25, 537.
[5] C. Goasdoue, M. Gaudemar, Tetrahedron Lett. 1985, 26, 1015.
[6] N. Iwasawa, T. Yura, T. Mukaiyama, Tetrahedron 1989, 45, 1197.
[7] a) B. M. Trost, Science 1991, 254, 1471; b) P. A. Wender, V. A.
Verma, T. J. Paxton, T. H. Pillow, Acc. Chem. Res. 2008, 41, 40.
[8] For the utility of N-diphenylphosphinoyl imines, see: a) S. M.
Weinreb, R. K. Orr, Synthesis 2005, 1205; b) G. K. Friestad,
A. K. Mathies, Tetrahedron 2007, 63, 2541.
[11] Sulfur has an electronegativity close to that for carbon: a) L.
Pauling in The Nature of Chemical Bond, 3rd ed., Cornel
University, Ithaca, NY, 1960, pp. 88; for rotational barriers of
thioamides, see: b) C. M. Lee, W. D. Kumler, J. Org. Chem. 1962,
27, 2052; c) K. A. Jensen, Acta Chem. Scand. 1963, 17, 551; d) A.
Loewenstein, A. Melera, P. Rigny, W. Walter, J. Phys. Chem.
1964, 68, 1597; e) W. E. Stewart, T. H. Siddall III, Chem. Rev.
1970, 70, 517.
[12] a) K. B. Wiberg, P. R. Rablen, J. Am. Chem. Soc. 1995, 117, 2201;
b) D. Lauvergnat, P. C. Hiberty, J. Am. Chem. Soc. 1997, 119,
9478; c) B. Galabov, S. Ilieva, B. Hadjieva, E. Dinchova, J. Phys.
Chem. A 2003, 107, 5854.
[13] H-CH2C(S)NMe2 (pKa = 25.7 in DMSO; F. G. Bordwell, H. E.
Fried, J. Org. Chem. 1991, 56, 4218) compared to the corre-
sponding amide H-CH2C(O)NEt2 (pKa = 35 in DMSO; M. L.
Hlavinka, J. F. Greco, J. R. Hagadorn, Chem. Commun. 2005,
5304).
[9] For recent reviews on direct Mannich(-type) reactions, see:
a) M. M. B. Marques, Angew. Chem. 2006, 118, 356; Angew.
Chem. Int. Ed. 2006, 45, 348; b) A. Ting, S. E. Schaus, Eur. J. Org.
Chem. 2007, 5797; c) J. M. M. Verkade, L. J. C. van Hemert,
P. J. L. M. Quaedflieg, F. P. J. T. Rutjes, Chem. Soc. Rev. 2008, 37,
29; for general reviews on catalytic asymmetric Mannich
reactions, see: d) S. Kobayashi, M. Ueno in Comprehensive
Asymmetric Catalysis, Supplement 1 (Eds.: E. N. Jacobsen, A.
Pfaltz, H. Yamamoto), Springer, Berlin, 2004, Chapter 29.5,
p. 143; e) G. Friestad, A. K. Mathies, Tetrahedron 2007, 63, 2541.
[10] a) Y. Suto, R. Tsuji, M. Kanai, M. Shibasaki, Org. Lett. 2005, 7,
3757; b) Y. Asano, K. Hara, H. Ito, M. Sawamura, Org. Lett.
2007, 9, 3901; c) R. Yazaki, T. Nitabaru, N. Kumagai, M.
Shibasaki, J. Am. Chem. Soc. 2008, 130, 14477; d) R. Yazaki,
N. Kumagai, M. Shibasaki, J. Am. Chem. Soc. 2009, 131, 3195; for
[14] As of May 2009, this commercially available C2 unit sells for
E85.7 per 5 g from A Better Choice for Research Chemicals.
[15] Lower basicity of LiOC6H4-o-OMe (pKa = 17.8 in DMSO)
compared with LiOC6H4-p-OMe (pKa = 19.1 in DMSO) would
avoid undesirable b elimination.
[16] The absolute configuration of 3ab was determined by single X-
ray crystallographic analysis. Mr= 475.67, colorless block; a =
13.9241(3), b = 19.8931(4), c = 21.3053(4) ꢂ, a = 64.6031(10)8,
b = 118.497(7)8, g = 88.5534(11)8. V= 5228.95(19) ꢂ3, T= 103 K,
triclinic, space group P1, Z = 8, Rigaku RAXIS-RAPID, l(Cu
Ka) = 1.54187 ꢂ, qmax = 68.258. The crystallographic data
(CCDC-720992) can be obtained free of charge from The
Cambridge Crystallogrpahic Data Center via www.ccdc.cam.
ac.uk/data_request/cif.
[17] Mixing three catalyst components would afford Ph-BPE/
Cu(OC6H4-o-OMe) and LiPF6. For the formation of CuOAr
upon addition of an alkali metal aryloxide to CuI salt, see: P. G.
Eller, G. J. Kubas, J. Am. Chem. Soc. 1977, 99, 4346.
[18] D. C. Harrowven, M. C. Lucas, P. D. Howes, Tetrahedron 1999,
55, 1187.
À
selected examples of catalytic asymmetric formation of C C or
À
C B bonds using Cu/alkoxides, see: e) B. L. Pagenkopf, J.
Krꢁger, A. Stojanovic, E. M. Carreira, Angew. Chem. 1998,
110, 3312; Angew. Chem. Int. Ed. 1998, 37, 3124; f) H. Ito, C.
Kawakami, M. Sawamura, J. Am. Chem. Soc. 2005, 127, 16034;
g) R. Wada, T. Shibuguchi, S. Makino, K. Oisaki, M. Kanai, M.
Shibasaki, J. Am. Chem. Soc. 2006, 128, 7687; h) J.-E. Lee, J. Yun,
[19] R. Masuda, M. Hojo, T. Ichi, S. Sasano, T. Kobayashi, C. Kuroda,
Tetrahedron Lett. 1991, 32, 1195.
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