Synthesis of enantiopure sulfinimines (Thiooxime S-oxides) catalyzed by Yb(OTf)3 from p-toluenesulfinamide and aldehydes in mild reaction conditions

Article abstract of DOI:10.1021/jo048597e

(Chemical Equation Presented) Enantiomerically pure sulfinimines as important building blocks in the asymmetric synthesis of amine derivatives are prepared in good to excellent yields from chiral p-toluene-sulfinamide with aromatic, heteroaromatic, and al

Full text of DOI:10.1021/jo048597e

acids,4 R- and â-amino phosphonates,5 and heterocycles.6
Their achievements have triggered various groups to
develop new asymmetric syntheses by using these sulfin-
imines as chiral induction groups.7 Among the several
methods to synthesize these sulfinimines,1,2 the straight-
forward one is the direct condensation of chiral sulfin-
amides with aldehydes under fairly drastic conditions.
To mitigate the seemingly forced conditions required for
making sulfinimines, several improved procedures have
emerged.8-10 Ellman realized the condensation of N-tert-
butanesulfinimines with aldehydes using MgSO4,8a
CuSO4,8a,b and Ti(OEt)4.8b,c At the same time, Davis
reported the condensation of N-p-toluenesulfinamide with
aldehydes using CsF,9a Ti(OEt)4,9a,b and molecular sieves.9b
Recently, Cs2CO3 was reported as an activating and
dehydrating reagent to facilitate the transformation.10
Although the reported methods rendered the preparation
of sulfinimines much easier, excess Lewis acid or sto-
ichiometric base had to be used.
Synthesis of Enantiopure Sulfinimines
(Thiooxime S-Oxides) Catalyzed by
Yb(OTf)3 from p-Toluenesulfinamide and
Aldehydes in Mild Reaction Conditions
Zhi-Yong Jiang,† W. H. Chan,* and A. W. M. Lee
Department of Chemistry and Central Laboratory of the
Institute of Molecular Technology for Drug Discovery and
Synthesis,‡ Hong Kong Baptist University,
Hong Kong, China
whchan@hkbu.edu.hk
Received August 11, 2004
To further simplify the preparation route of the titled
compounds, under the mediation of microwave we found
the condensation could be effected in good to excellent
yields.11 On the other hand, an excess amount of Ti(OEt)4
was adopted by many investigators as the reagent of
choice to promote the condensation reaction. Its removal
after the reaction sometimes is problematic, however, and
Enantiomerically pure sulfinimines as important building
blocks in the asymmetric synthesis of amine derivatives are
prepared in good to excellent yields from chiral p-toluene-
sulfinamide with aromatic, heteroaromatic, and aliphatic
aldehydes. The unprecedented feature of the reported pro-
cedure is that the formation of the sulfinimines was achieved
by the catalytic action of Yb(OTf)3 in THF at room temper-
ature. The reaction conditions were also applicable to
Ellman’s sulfinimines.
(4) (a) Davis, F. A.; Srirajan, V. J. Org. Chem. 2000, 65, 3248. (b)
Davis, F. A.; Srirajan, V.; Fanelli, D. L.; Portonovo, P. J. Org. Chem.
2000, 65, 7663. (c) Davis, F. A.; Lee, S.; Zhang, H. M.; Fanelli, D. L. J.
Org. Chem. 2000, 65, 8704.
(5) (a) Davis, F. A.; Wu, Y. Z.; Yan, H. X.; Prasad, K. R.; McCoull,
W. Org. Lett. 2002, 4, 655. (b) Davis, F. A.; Wu, Y, Z.; Yan, H. X.;
McCoull, W.; Prasad, K. R. J. Org. Chem. 2003, 68, 2410. (c) Davis, F.
A.; Prasad, K. R. J. Org. Chem. 2003, 68, 7249. (d) Evans, J. W.;
Ellman, J. A. J. Org. Chem. 2003, 68, 9948.
Asymmetric synthesis of functionalized amino com-
pounds has been the subject of intensive studies, partly
because a majority of drugs and drug candidates are
incorporating amine functionality. A particularly vener-
able synthetic route toward the preparation of homochiral
amine derivatives is the elaboration of chiral sulfinimines
pioneered by Davis1 and Ellman.2 The two important
sulfinimines, N-p-toluenesulfinimines and N-tert-butane-
sulfinimines, developed by them, respectively, have been
demonstrated as versatile intermediates for the asym-
metric syntheses of amine derivatives,1-3 R- and â-amino
(6) (a) Davis, F. A.; Mohanty, P. K. J. Org. Chem. 2002, 67, 1290.
(b) Li, B.-F.; Zhang, M.-J.; Hou, X.-L.; Dai, L.-X. J. Org. Chem. 2002,
67, 2902. (c) Degoey, D. A.; Chen, H.-J.; Flosi, W. J.; Grampovnik, D.
J.; Yeung, C. M.; Klein, L. L.; Kempf, D. J. J. Org. Chem. 2002, 67,
5445. (d) Yang, X.-F.; Zhang, M.-J.; Hou, X.-L.; Dai, L.-X. J. Org. Chem.
2002, 67, 8097. (e) Davis, F. A.; Ramachandar, T.; Wu, Y. Z. J. Org.
Chem. 2003, 68, 6894. (f) Sorochinsky, A.; Voloshin, N.; Markovsky,
A.; Belik, M.; Yasuda, N.; Uekusa, H.; Ono, T.; Berbasov, D. O.;
Soloshonok, V. A. J. Org. Chem. 2003, 68, 7448. (g) Viso, A.; Ferna´ndez
de la Pradilla; Garc´ıa, A.; Tortosa, M.; Flores, A.; Mart´ınez-Ripoll, A.;
Fonseca, I.; Andre´, I.; Rodr´ıguez, A. Chem.-Eur. J. 2003, 9, 2867.
(7) (a) Davis, F. A.; Wu, Y. Org. Lett. 2004, 6, 1269. (b) Cook, G. R.;
Maity, B. C.; Kargbo, R. Org. Lett. 2004, 6, 1741. (c) Morton, D.;
Pearson, D.; Field, R. A.; Stockman, R. A. Org. Lett. 2004, 6, 2377. (d)
Viso, A.; Fernandez de la Pradilla, R.; Lopez-Rodriguez, M. L.; Garcia,
A.; Flores, A.; Alonso, M. J. Org. Chem. 2004, 69, 1542. (e) Davis, F.
A.; Lee, S. H.; Xu, H. J. Org. Chem. 2004, 69, 3774. (f) Jacobsen, M.
F.; Ionita, L.; Skrydstrup, T. J. Org. Chem. 2004, 69, 4792. (g) Ribiere,
P.; Enjalbal, C.; Aubagnac, J.-L.; Yadav-Bhatnagar, N.; Martinez, J.;
Lamaty, F. J. Comb. Chem. 2004, 6, 464. (h) Kennedy, A.; Nelson, A.;
Perry, A. Synlett 2004, 967. (i) Chemla, F.; Ferreira, F. Synlett 2004,
983. (j) Alajarin, M.; Pastor, A.; Cabrera, J. Synlett 2004, 995.
(8) (a) Liu, G.; Cogan, D. A.; Ellman, J. A. J. Am. Chem. Soc. 1997,
119, 9913. (b) Cogan, D. A.; Ellman, J. A. J. Am. Chem. Soc. 1999,
121, 268. (c) Liu, G.; Cogan, D. A.; Owens, T. D.; Tang, T. P.; Ellman,
J. A. J. Org. Chem. 1999, 64, 1278.
† Postdoctoral Fellow from Zhejiang University.
‡ An Area of Excellence of the University Grants Committee, Hong
Kong, China.
(1) Davis, F. A.; Zhou,-P.; Chen, B.-C. Chem. Soc. Rev. 1998, 27,
13.
(2) Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002,
35, 984.
(3) (a) Chan, W. H.; Lee, A. W. M.; Xia, P. F.; Wong, W. Y.
Tetrahedron Lett. 2000, 41, 5725. (b) Ruano, J. L. G.; Alcudia, A.; Prado,
M. D.; Barros, D.; Maestro, M. C.; Fernandez, I. J. Org. Chem. 2000,
65, 2856. (c) Dragoli, D. R.; Burdett, M. T.; Ellman, J. A. J. Am. Chem.
Soc. 2001, 123, 10127. (c) Viso, A.; Ferna´ndez de la Pradilla, R.; Lopez-
Rodriguez, M. L.; Garc´ıa, A.; Tortosa, M. Synlett 2002, 755. (d) Wipf,
P.; Nunes, R. L.; Ribe, S. Helv. Chim. Acta 2002, 85, 3478. (e) Schopohl,
M. C.; Bergander, K.; Kataeva, O.; Frohlich, R.; Waldvogel, S. R.
Synthesis 2003, 2689. (f) Mukade, T. Dragoli, D. R.; Ellman, J. A. J.
Comb. Chem. 2003, 5, 590. (g) Ruano, J. L. G.; Aleman, J.; Soriano, J.
F. Org. Lett. 2003, 5, 677. (h) Ruano, J. L. G.; Aleman, J. Org. Lett.
2003, 5, 4513. (i) Jacobsen, M. F.; Skrydstrup, T. J. Org. Chem. 2003,
68, 7112.
(9) (a) Davis, F. A.; Reddy, R. E.; Szewczyk, J. M.; Reddy, G. V.;
Portonovo, P. S.; Zhang, H.; Fanelli, D.; Reddy, R. T.; Zhou, P.; Carroll,
P. J. J. Org. Chem. 1997, 62, 2555. (b) Davis, F. A.; Zhang, Y.;
Andemichael, Y.; Fang, T.; Fanelli, D. L.; Zhang, H. J. Org. Chem.
1999, 64, 1403. (c) Fanelli, D. L.; Szewczyk, J. M.; Zhang, Y.; Reddy,
G. V.; Burns, D. M.; Davis, F. A. Org. Synth. 1999, 77, 50.
(10) Higashibayashi, S.; Tohmiya, H.; Mori, T.; Hashimoto, K.;
Nakata, M. Synlett 2004, 457.
(11) Unpublished results.
10.1021/jo048597e CCC: $30.25 © 2005 American Chemical Society
Published on Web 01/08/2005
J. Org. Chem. 2005, 70, 1081-1083
1081

TABLE 1. Condition Optimization for Synthesis of
Sulfinimine from p-Toluenesulfinamide and
Benzaldehyde
TABLE 2. Synthesis of Sulfinimine 3 from
p-Toluenesulfinamide 1 and Several Aromatic Aldehydes
entry
R
ratio 1:3a
product
yield (%)b
1
p-CN
<1:>99
1:99
3a
3b
3c
3d
3e
3f
3g
3h
3i
91
81
91
84
85
84
94
90
57
f
ratio
equiv of
ratio
2
o-NO2
p-CHO
m-CHO
p-F
entry
solvent
sulfinamide:aldehyde Yb(OTf)3
1:3a
3
1:99
4
1:99
1
dioxane
toluene
DMF
1:3.5
1:3.5
1:3.5
1:3.5
1:3.5
1:3.5
1:3.5
1:3.5
1:3.5
1:1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.5
1.0
1.0
2.0
3.0
7:93
31:69
30:70
23:77
21:79
49:51
6:94
1:99
2:98
27:73
10:90
<1:>99
5
10:90
12:88
2:98
2
6
p-Cl
3
7
p-Br
4
CH2Cl2
CH3CN
CHCl3
THF
8
p-H
1:99
5
9
p-MeOc
p-MeOd
p-MeOe
p-MeS
37:63
30:70
23:77
46:54
6
10
11
12
7
f
8
THF
3j
41
9
THF
10
11
12
THF
a Determined by 1H NMR analysis of the crude product. All
reactions proceeded cleanly without decomposition, as indicated
by TLC and 1H NMR). b Isolated yield based on sulfinamide used.
c 0.1 equiv of Yb(OTf)3. d 0.5 equiv of Yb(OTf)3. e 1.0 equiv of
Yb(OTf)3. f Not determined.
THF
1:1
1:1
THF
a The ratio of 1:3 was based on 1H NMR analysis of the crude
product. All reactions proceeded cleanly without decomposition,
as indicated by TLC and 1H NMR.
TABLE 3. Synthesis of Sulfinimine 3 from
p-Toluenesulfinamide 1 with Several Heteroaromatic
and Complex Aromatic Aldehydes
the high reaction temperature at refluxing THF may
cause the decomposition of some unstable adducts.3f The
popular use of ytterbium(III) triflate as catalysts in recent
literature for a number of transformations prompted us
to undertake the investigation whereby expeditious
formation of chiral sulfinimines could be realized.6b,12 We
describe in this report that the facile condensation of N-p-
toluenesulfinamide and aldehydes could be realized by
using catalytic amount of Yb(OTf)3 at very mild condi-
tions. Under systematic studies, the optimized reaction
condition for making sulfinimines exemplified by ben-
zaldehyde emerged. First, THF emerged as the solvent
of the choice for the transformation (Table 1, entries
1-7). In the presence of 0.1 equiv of Yb(OTf)3 in THF at
room temperature, benzaldehyde (3.5 equiv) reacted
smoothly with 1 equiv of N-p-toluenesulfinamde 1, af-
fording the product with a minimum amount of the
starting material left (Table 1, entry 7). The reaction rate
of the condensation could be expedited by increasing the
amount of Yb(OTf)3 to 0.5 or more (Table 1, entries 8 and
9). If only a 1:1 ratio of aldehyde to sulfinamide was used,
3.0 equiv of Yb(OTf)3 had to be employed to drive the
reaction to completion (Table 1, entries 10-12). It was
later found that such condition is not suitable for the
preparation of sulfinimines from aliphatic aldehydes, as
well as aromatic aldehydes possessing electron-donating
groups.
equiv of
ratio
yield
(%)b
entry
1
R
Yb(OTf)3 product
1:3a
0.1
0.1
0.5
3k
c
58
2
3
3l
c
76
3m
1:99d 52
4
5
0.5
0.1
3n
3o
41:59
8:92
47
79
6
0.1
3p
1:99
72
To define the scope of the procedure, monosubstituted
aromatic aldehydes were subjected to the condensation
conditions, and consistent with the mechanism, the
electronic nature of the second substituent exerted a
dominant impact on the yield of the products. Aromatic
a The ratio of 1:3 was based on 1H NMR analysis of the crude
product. b Isolated yield. c The ratio could not be determined.
d Other byproducts were found.
aldehydes bearing an electron-withdrawing group con-
densed more effectively with sulfinamide than those
bearing an electron-donating group (Table 2, entries 1-7
versus 9-12).
(12) Li, G. G.; Wei, H.-X.; Hook, J. D. Tetrahedron Lett. 1999, 40,
4611.
1082 J. Org. Chem., Vol. 70, No. 3, 2005

TABLE 4. Synthesis of Monosulfinimine 4 from
TABLE 6. Synthesis of Sulfinimines 7 from
p-Toluenesulfinamide 1 and Several Bisaldehydes
tert-Butanesulfinamide 6 and Aldehydes
entry
R′
product
ratio 1:7a
yield (%)b
1
2
3
Ph
7a
7b
7c
1:99
7:93
1:99
84
87
87
2-butyl
(E)-CH3CHdCH-
ratio equiv of
T
reaction yield
a The ratio of 1:7 was based on 1H NMR analysis of the crude
entry bisaldehydes 1:5 Yb(OTf)3
(°C)
time (h) of 4b
product. b Isolated yield.
1
2
3
4
5
6
7
o-CHO
m-CHO
m-CHO
m-CHO
p-CHO
p-CHO
p-CHO
1:3.5
1:3.5
6:1
0.1
0.1
0.1
0.5
0.1
0.1
0.5
rta
12
12
12
24
12
12
24
nr
84
77
72c
91
57
78
rt
rt
steric hindrance of o-phthalaldehyde completely re-
stricted the formation of the condensed product (Table
4, entry 1). Furthermore, the preparation of mono-
sulfinimines from both m- and p-phthalaldehyde could
be accomplished, using the developed reaction protocol
(Table 4, entries 2 and 5). Neither by increasing the
amount of the sulfinamide/Yb(OTf)3 nor by prolonging the
heating time of the reaction was any trace amount of
desirable bis-product obtained (Table 4, entries 3, 4, 6
and 7).
8:1
reflux
rt
1:3.5
6:1
8:1
rt
reflux
a rt ) room temperature. b Isolated yield. c Trace bis-sulfin-
imines were found from TLC and 1H NMR.
TABLE 5. Synthesis of Sulfinimines 5 from
p-Toluenesulfinamide and Aliphatic Aldehydes
On the other hand, it is gratifying to find that the
reaction conditions developed can be also used to syn-
thesize sulfinimines from p-toluenesulfinimine and a
variety of aliphatic aldehydes. In the presence of 0.1 equiv
of Yb(OTf)3, excess of aldehyde was used to react with
the sulfinamide, affording good to excellent yield of the
product. Remarkably, Yb(OTf)3 was shown to be highly
effective in promoting the reaction even for sterically
hindered aliphatic aldehydes (Table 5, entries 4, 5, and
7). Finally, in the case of the Ellman sulfinimine 6,
sulfinamides were obtained in equally good yields under
the same conditions (Table 6, entries 1-3).
In summary, a general, mild, and effective method for
the synthesis of chiral sulfinimines from N-p-toluene-
sulfinamide and aldehydes was developed. The advan-
tages of this method are the easy workup procedure, very
mild reaction conditions, and the need of using only a
catalytic amount of Lewis acid.
entry
R′
product
ratio 1:5
yield (%)b
1
2
3
4
5
6
7
CH3CH2-
CH3CH2CH2-
2-butyl
5a
5b
5c
5d
5e
5f
<1:>99
7:93
1:99
1:99
c
99:1
c
87
77
80
81
62
81
86
c-C6H11
-
t-Bu
(E)-CH3CHdCH-
5g
a The ratio of 1:5 was based on 1H NMR analysis of the crude
Acknowledgment. The work described in this paper
was fully supported by a grant from the University
Grants Committee of the Hong Kong Special Adminis-
trative Region, China (Project AoE/P-10/01).
product. b Isolated yield. c The ratio could not be determined.
The protocol has been extended to the preparation of
sulfinimines from heteroaromatics (Table 3, entries 1 and
2), polysubstituted aromatics (Table 3, entries 3 and 4),
a polyaromatic (Table 3, entry 5), and cinnamaldehyde
(Table 3, entry 6). Modest to good yield of the products
was invariantly obtained in each of the cases.
Supporting Information Available: Detailed experi-
mental procedures and compound characterization data (1H
and 13C spectra of every compound and HRMS spectra of new
compounds). This material is available free of charge via the
Internet at http://pubs.acs.org.
In contrast, our attempt to prepare bis-sulfinimines
from the three phthalaldehydes was unfruitful. First, the
JO048597E
J. Org. Chem, Vol. 70, No. 3, 2005 1083