Enantioselective Pd-catalyzed hydrogenation of enesulfonamides

Article abstract of DOI:10.1039/c1cc10313j

Asymmetric hydrogenation of cyclic enesulfonamides affords chiral cyclic sulfonamides using Pd(OCOCF₃)₂/diphosphine complexes as catalysts with up to 98% ee.

Full text of DOI:10.1039/c1cc10313j

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Enantioselective Pd-catalyzed hydrogenation of enesulfonamidesw
Chang-Bin Yu, Kao Gao, Duo-Sheng Wang, Lei Shi and Yong-Gui Zhou*
Received 17th January 2011, Accepted 8th March 2011
DOI: 10.1039/c1cc10313j
Asymmetric hydrogenation of cyclic enesulfonamides affords
chiral cyclic sulfonamides using Pd(OCOCF3)2/diphosphine
complexes as catalysts with up to 98% ee.
Chiral amines are important structure motifs in synthetic
chemistry, medicinal chemistry, and materials industries.1
Scheme 2 Synthesis of chiral sulfonamides.
Compounds containing the sulfonamide skeleton have gained
wide attention.2 Cyclic sulfonamide (sultams) analogs are
atom efficiency (Scheme 2). In the past few years, cyclic
N-sulfonylimines have been hydrogenated successfully by us6
useful structures in drug active compounds due to their wide
and other groups.7 However, to the best of our knowledge, the
chemical and biological activities including anti-HIV, anti-
asymmetric hydrogenation of cyclic enesulfonamides 2 and 4
inflammatory, anti-malarial, and so on (Scheme 1).3
has not been reported.
In the past decades, numerous strategies4 have been devel-
Recently, chiral palladium complexes have been successfully
oped to synthesize sultams, they are generally obtained by
applied to asymmetric hydrogenation of activated imines
Friedel–Craft reactions, [3+2] cycloadditions, dianion
(especially for the activated N-sulfonylimines), functionalized
reactions, and Diels–Alder reactions, ring-closing metathesis
ketones and unprotected indoles.6,8,9 Considering enesulfon-
(RCM), Heck reactions, as well as Rh-, Au- and Cu-catalyzed
cyclizations.5 However, to date only a few examples of the
amide could tautomerize to the corresponding N-sulfonyl-
imines under the acidic conditions (Scheme 2), this instance
asymmetric catalytic versions have been reported despite its
inspired us to conjecture that enesulfonamides would be good
synthetic significance. Toward further investigation of new
substrates for palladium-catalyzed asymmetric hydrogenation.
biological activities of sulfonamides, a more practical and
Herein, we present our results on the Pd-catalyzed hydrogenation
general route to sultams, particularly for their optically pure
of enesulfonamides, up to 98% ee was obtained.
enantiomers, is highly attractive. According to the retro-
Enesulfonamides (2 and 4) can be conveniently synthesized
synthetic analysis, we envisioned that asymmetric hydro-
from 2-methyl substituted arylsulfonamides and saccharins by
slightly modified literature procedures (Scheme 3).10
genation of the corresponding cyclic N-sulfonylimines or
enesulfonamides is also the convenient and efficient route to
Asymmetric hydrogenation of enesulfonamide 2a was
obtain chiral cyclic sulfonamides in terms of simplicity and
chosen as the model reaction and initial hydrogenation
experiment was performed in trifluoroethanol (TFE) using
Pd(OCOCF3)2/(S,S)-f-Binaphane at room temperature. How-
ever, no product was obtained (entry 1, Table 1). When the
reaction temperature was elevated to 70 1C, 96% yield and
moderate 82% ee were obtained (entry 2, Table 1). Next, the
ligand effect was screened (entries 3–6, Table 1). Fortunately,
up to 97% ee was achieved using (R,Sp)-JosiPhos (entry 6,
Table 1). Slightly low enantioselectivities were obtained under
the low hydrogen pressure (entries 7–9, Table 1).
Scheme 1 Biologically active sultams.
State Key Laboratory of Catalysis, Dalian Institute of Chemical
Physics, Chinese Academy of Sciences, 457 Zhongshan Road,
Dalian 116023, China. E-mail: ygzhou@dicp.ac.cn
w Electronic supplementary information (ESI) available: Experimental
details. CCDC 808553. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c1cc10313j
Scheme 3 Synthesis of cyclic enesulfonamides 2 and 4.
c
5052 Chem. Commun., 2011, 47, 5052–5054
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Table 1 Pd-catalyzed asymmetric hydrogenation of 2aa
When an electron-donating or electron-withdrawing group is
present on the aromatic ring of substrates, the corresponding
cyclic sulfonamides can be achieved successfully in high ees
(95–98% ee, entries 5–7, Table 2). Substrate 2h with a substi-
tuent at the 7-position could also be hydrogenated smoothly,
and 96% ee was observed (entry 8, Table 2). In the case of the R2
group being 2-furyl, full conversion and 81% ee were obtained
(entry 9, Table 2). However, for 2k containing the n-propyl
group, only moderate 69% ee was obtained under the above
standard conditions. Fortunately, when ligand (R,Sp)-JosiPhos
was replaced by (R,RP)-WalPhos, a significant increase in the ee
value was observed (96% ee, entry 11, Table 2). Under the
optimum conditions, for substrates with a variety of alkyl
substituents, there was no remarkable influence on reactivity
and enantioselectivity regardless of the chain length (90–98% ee,
entries 10–13, Table 2).
Entry
L*
H2 (atm)
Yieldb (%)
eec (%)
1d
2
3
4
5
6
7
8
9
L1
L1
L2
L3
L4
L5
L5
L5
L5
42
42
42
42
42
42
28
14
1
—
96
86
96
93
98
98
94
99
—
82
79
67
49
97
98
96
93
A single crystal of sulfonamides 3c (499% ee) was obtained
by recrystallization from DCM/hexane, and its absolute
configuration was unambiguously assigned as (R)-3c by
X-ray diffraction analysis (see ESIw).11
In addition to endo-cyclic-enesulfonamides 2, we also explored
the asymmetric hydrogenation of exo-cyclic-enesulfonamides 4
with the above Pd catalyst system. Interestingly, when the Pd
catalyst containing the (S,S)-f-Binaphane ligand was used in the
asymmetric hydrogenation of 4a full conversion and 92% ee
value were obtained. Inspired by the result, a series of exo-
enesulfonamides 4 were synthesized from the saccharin. Fortu-
nately, all substrates were transformed completely and good to
excellent ee values were obtained. The results are summarized in
Table 3. High enantioselectivities were obtained for alkyl ester
bearing ethyl and tert-butyl groups (92% and 96%, entries 2–3,
Table 3). Albeit methyl and benzyl ester (4a and 4d) gave slightly
lower ee values (86% and 87%, entries 1 and 4, Table 3).
Substrate 4e with a substituent at the 5-position could also be
smoothly hydrogenated with 87% ee (entry 5, Table 3).
a
The reaction was carried out with 2a (0.125 mmol), Pd(OCOCF3)2
(0.0025 mmol), ligand (0.003 mmol), and 3 mL TFE under 70 1C for 16 h.
Isolated yield. ee was determined by HPLC analysis. The reaction
was run at room temperature.
b
c
d
Under the optimal reaction conditions, a variety of enesulfon-
amides 2 was explored to examine the substrates scope. As
shown in Table 2, substrates with steric difference in aryl resulted
in similar enantioselectivities (97–98% ee, entries 1–4, Table 2).
To investigate the process of the hydrogenation reaction,
three isotopic labeling experiments were carried out. When 2a
was subjected to hydrogenation with D2, one deuterium atom
was incorporated to the a-position, and deuterium at the
b-position was not observed (eqn (1), Scheme 4). When the
hydrogenation was carried out in CF3CH2OD with full
Table 2 Pd-catalyzed asymmetric hydrogenation of 2a
Entry
R1 of 2
R2 of 2
L*
Yieldb (%)
eec,d (%)
Table 3 Pd-catalyzed asymmetric hydrogenation of 4a
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
Me
H
H
H
H
H
Ph
L5
L5
L5
L5
L5
L5
L5
L5
L5
L6
L6
L6
L6
96 (3a)
97 (3b)
97 (3c)
99 (3d)
97 (3e)
99 (3f)
97 (3g)
97 (3h)
99 (3i)
99 (3j)
92 (3k)
90 (3l)
75 (3m)
98 (+)
98 (+)
97 (R)
97 (+)
95 (+)
98 (+)
98 (+)
96 (+)
81 (+)
98 (À)
96 (À)
90 (À)
96 (À)
2-Me-C6H4
3-Me-C6H4
4-Me-C6H4
4-MeO-C6H4
4-F-C6H4
4-Cl-C6H4
Ph
2-Furyl
Me
n-C3H7
n-C5H11
C6H5CH2CH2
Entry
R1 of 4
R2 of 4
Yieldb (%)
eec (%)
9
10
11e
12e
13e
1
2
H
H
H
H
Me
Me
Et
t-Bu
Bn
Et
97 (5a)
97 (5b)
97 (5c)
97 (5d)
99 (5e)
86 (À)
92 (À)
96 (+)
87 (À)
87 (À)
3
4d
5e
a
The reaction was carried out with 2 (0.125 mmol), Pd(OCOCF3)2
(0.0025 mmol), ligand (0.003 mmol), and 3 mL TFE under directed
a
The reaction was carried out with 4 (0.125 mmol), Pd(OCOCF3)2
(0.0025 mmol), (S,S)-f-Binaphane (0.003 mmol), and 3 mL TFE under
b
conditions for 16 h. Isolated yield. ee was determined by HPLC
d
analysis. The absolute configuration of the major enantiomer of 3c
c
b
directed conditions for 16 h. Isolated yield. ee was determined by
c
d
e
HPLC. The reaction was conducted under 70 1C. The reaction was
run at 60 1C.
was determined by X-ray analysis. Other products’ absolute config-
e
urations were assigned by analogy to 3c. Determined by H NMR.
1
c
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J. Org. Chem., 2004, 69, 6377; (i) L. A. Paquette, R. D. Dura and
I. Modolo, J. Org. Chem., 2009, 74, 1982; (j) A. Vasudevan,
P. S. Tseng and S. W. Djuric, Tetrahedron Lett., 2006, 47, 8591;
(k) E. S. Sherman, P. H. Fuller, D. Kasi and S. R. Chemler, J. Org.
Chem., 2007, 72, 3896.
5 (a) C. Fruit and P. Muller, Helv. Chim. Acta, 2004, 87, 1607;
¨
(b) K. H. Ahn, H. H. Baek, S. J. Lee and C. W. Cho, J. Org. Chem.,
2000, 65, 7690; (c) C. Fruit and P. Muller, Tetrahedron:
Asymmetry, 2004, 15, 1019; (d) A. H. Zhou and P. R. Hanson,
Org. Lett., 2008, 10, 2951; (e) I. R. Greig, M. J. Tozer and
P. T. Wright, Org. Lett., 2001, 3, 369; (f) U. Chiacchio,
A. Corsaro, A. Rescifina, M. Bkaithan, G. Grassi, A. Piperno,
T. Privitera and G. Romeo, Tetrahedron, 2001, 57, 3425; (g) J. Lee,
Y. L. Zhong, R. A. Reamer and D. Askin, Org. Lett., 2003, 5,
4175; (h) J. Zhang, P. W. H. Chan and C.-M. Che, Tetrahedron
Lett., 2005, 46, 5403; (i) W. Zeng and S. R. Chemler, J. Am. Chem.
Soc., 2007, 129, 12948; (j) P. Desos, B. Serkiz, P. Morain,
J. Lepagnol and A. Cordi, Bioorg. Med. Chem. Lett., 1996, 6,
3003; (k) D. Enders, A. Moll and J. W. Bats, Eur. J. Org. Chem.,
2006, 1271; (l) D. N. Zalatan and J. D. Bois, J. Am. Chem. Soc.,
2008, 130, 9220; (m) T. Miura, M. Yamauchi, A. Kosaka and
M. Murakami, Angew. Chem., Int. Ed., 2010, 49, 4955;
(n) J. L. Liang, S. X. Yuan, J. S. Huang, W. Y. Yu and C. M.
Che, Angew. Chem., Int. Ed., 2002, 41, 3465; (o) J. L. Liang,
S. X. Yuan, J. S. Huang and C. M. Che, J. Org. Chem., 2004, 69,
3610.
6 (a) Y. Q. Wang and Y. G. Zhou, Synlett, 2006, 1189;
(b) Y. Q. Wang, S. M. Lu and Y. G. Zhou, J. Org. Chem., 2007,
72, 3729; (c) Y. Q. Wang, C. B. Yu, D. W. Wang, X. B. Wang and
Y. G. Zhou, Org. Lett., 2008, 10, 2071; (d) C. B. Yu, D. W. Wang
and Y. G. Zhou, J. Org. Chem., 2009, 74, 5633; (e) M. W. Chen,
Y. Duan, Q. A. Chen, D. S. Wang, C. B. Yu and Y. G. Zhou, Org.
Lett., 2010, 12, 5075.
7 (a) W. Oppolzer, M. Wills, C. Starkemann and G. Bernardinelli,
Tetrahedron Lett., 1990, 31, 4117; (b) J. M. Mao and D. C. Baker,
Org. Lett., 1999, 1, 841; (c) K. H. Ahn, C. Ham, S. K. Kim and
C. W. Cho, J. Org. Chem., 1997, 62, 7047; (d) C. J. Cobley,
E. Foucher, J. P. Lecouve, I. C. Lennon, J. A. Ramsden and
G. Thominot, Tetrahedron: Asymmetry, 2003, 14, 3431;
(e) Y. C. Chen, T. F. Wu, J. G. Deng, H. Liu, X. Cui, J. Zhu,
Y. Z. Jiang, M. C. K. Choi and A. S. C. Chan, J. Org. Chem., 2002,
67, 5301; (f) P. N. Liu, P. M. Gu, J. G. Deng, Y. Q. Tu and
Y. P. Ma, Eur. J. Org. Chem., 2005, 3221; (g) J. S. Wu, F. Wang,
Y. P. Ma, X. Cui, L. F. Cun, J. Zhu, J. G. Deng and B. L. Yu,
Chem. Commun., 2006, 1766; (h) S. Kang, J. Han, E. S. Lee,
E. B. Choi and H. K. Lee, Org. Lett., 2010, 12, 4184.
Scheme 4 Isotopic labeling experiments using D2 and CF3CH2OD.
conversion of substrate, (eqn (2), Scheme 4), 1H NMR analysis
of the hydrogenated product showed that one deuterium atom
was incorporated to the b-position. However, when incom-
plete conversion was carried out, 1H NMR analysis of the
crude hydrogenated product showed that one deuterium atom
was incorporated to the b-position, while no deuterium
atom was observed in the recovered starting material 2a
(eqn (3), Scheme 4). The above experiments confirmed that
the hydrogenation of enesulfonamides was conducted via
N-sulfonylimine intermediates, and the tautomerization
process of enesulfonamides to N-sulfonylimine intermediates
was slower than the hydrogenation.
In conclusion, we have developed an efficient and highly
enantioselective Pd-catalyzed hydrogenation of enesulfon-
amides, which led to the facile synthesis of chiral cyclic sultams
in good to excellent enantioselectivities. Further exploring the
applications of this method in asymmetric synthesis of some
biologically active compounds is currently underway.
Financial support of National Natural Science Foundation
of China (21032003 and 20872140), and National Basic
Research Program of China (2010CB833300).
Notes and references
1 (a) B. G. Main and H. Tuker, in Medicinal Chemistry,
ed. C. R. Genellin and S. M. Roberts, Academic Press, New York,
8 (a) Y. Q. Wang, S. M. Lu and Y. G. Zhou, Org. Lett., 2005, 7,
3235; (b) Y. G. Zhou, Acc. Chem. Res., 2007, 40, 1357;
(c) D. S. Wang, Q. A. Chen, W. Li, C. B. Yu, Y. G. Zhou and
X. M. Zhang, J. Am. Chem. Soc., 2010, 132, 8909.
1993, p. 187; (b) H. Groger, O. May, H. Werner, A. Menzel and
¨
J. Altenbuchner, Org. Process Res. Dev., 2006, 10, 666;
(c) R. Bloch, Chem. Rev., 1998, 98, 1407.
2 (a) L. Levy, Drugs Future, 1992, 17, 451; (b) A. Scozzafava,
T. Owa, A. Mastrolorenzo and T. C. Supuran, Curr. Med. Chem.,
2003, 10, 925; (c) R. Matsubara, T. Doko, R. Uetake and
S. Kobayashi, Angew. Chem., Int. Ed., 2007, 46, 3047.
3 (a) C. Valent, R. C. Guedes, R. Moreia, J. Iley, J. Gut and
P. J. Rosenthal, Bioorg. Med. Chem. Lett., 2006, 16, 4115;
(b) L. Zhuang, J. S. Wai, M. W. Embrey, T. E. Fisher,
M. S. Egbertson, L. S. Payne, J. P. Guare, J. P. Vacca,
D. J. Hazuda, P. J. Felock, A. L. Wolfe, K. A. Stilmock,
M. V. Witmer, G. Moyer, W. A. Schleif, L. J. Gabryelski,
Y. M. Leonard, J. J. Lynch, S. R. Michelson and S. D. Young,
J. Med. Chem., 2003, 46, 453; (c) Y. Misu and H. Togo, Org.
Biomol. Chem., 2003, 11, 1342; (d) K. H. Ahn, S. K. Kim and
C. Ham, Tetrahedron Lett., 1998, 39, 6321.
9 (a) H. Abe, H. Amii and K. Uneyama, Org. Lett., 2001, 3, 313;
(b) P. Nanayakkara and H. Alper, Chem. Commun., 2003, 2384;
(c) A. Suzuki, M. Mae, H. Amii and K. Uneyama, J. Org. Chem.,
2004, 69, 5132; (d) R. P. Laura, F. P. F. Javier, P. Sharma,
L. Velasco and A. Cabrera, Org. Lett., 2009, 11, 265;
(e) N. S. Goulioukina, G. N. Bondarenko, A. V. Bogdanov,
K. N. Gavrilov and I. P. Beletskaya, Eur. J. Org. Chem., 2009,
510; (f) Y. Tsuchiya, Y. Hamashima and M. Sodeoka, Org. Lett.,
2006, 8, 4851; (g) D. Monguchi, C. Beemelmanns, D. Hashizume,
Y. Hamashima and M. Sodeoka, J. Organomet. Chem., 2008, 693,
867; (h) Q. Yang, G. Shang, W. Z. Gao, J. G. Deng and
X. M. Zhang, Angew. Chem., Int. Ed., 2006, 45, 3832.
10 (a) Z. P. Liu, N. Shibata and Y. Takeuchi, J. Org. Chem., 2000,
65, 7583; (b) F. A. Davis, J. C. Towson, D. B. Vashi,
R. ThimmaReddy, J. P. McCauley, M. E. Harakal and
D. J. Gosciniak, J. Org. Chem., 1990, 55, 1254; (c) C. Wallinder,
4 (a) R. D. Bravo and A. A. Canepa, Synth. Commun., 2002, 1, 1342;
(b) H. Hamaguchi, S. Kosaka, H. Ohno and T. Tanaka, Angew.
Chem., Int. Ed., 2005, 44, 1513; (c) H. Hamaguchi, S. Kosaka,
H. Ohno, N. Fujii and T. Tanaka, Chem.–Eur. J., 2007, 13, 1692;
M. Botros, U. Rosenstrom, M. O. Guimond, H. Beaudry,
¨
F. Nyberg, N. Gallo-Payet, A. Hallberg and M. Alterman, Bioorg.
Med. Chem., 2008, 16, 6841; (d) J. G. Lombardino, J. Org. Chem.,
1971, 36, 1843.
(d) M. Jimenez-Hopkins and P. R. Hanson, Org. Lett., 2008, 10,
´
2223; (e) L. A. Paquette, R. D. Dura, N. Fosnaugh and
S. Marshall, J. Org. Chem., 2006, 71, 8438; (f) X. Y. Liu,
C. H. Li and C. M. Che, Org. Lett., 2006, 8, 2707; (g) S. Merten,
R. Frohlich, O. Kataeva and P. Metz, Adv. Synth. Catal., 2005,
¨
347, 754; (h) A. Padwa, A. C. Flick, C. A. Leverett and T. Stengel,
11 Selected bond lengths [A] and angles [1]: C8–N1, 1.497(4); C8–C9,
1.520(5); C9–C10, C7–C8, 1.521(4); 1.370(5); N1–S1, 1.598(3);
C6–C7–C8, 114.3(3); N1–C8–C9, 109.1(3); N1–C8–C7, 110.0(3);
C9–C8–C7, 114.6(3); N1–C8–H8,107.6; C9–C8–H8, 107.6;
C7–C8–H8,107.6.
c
5054 Chem. Commun., 2011, 47, 5052–5054
This journal is The Royal Society of Chemistry 2011