Synthesis of Sulfinimines by Direct Condensation of Sulfinamides with Aldehydes Using Cs2CO3 as an Activating and Dehydrating Reagent

Article abstract of DOI:10.1055/s-2004-815409

Chiral sulfinimines were prepared from chiral sulfinamides and aldehydes in CH₂Cl₂ in the presence of cesium carbonate as an amine-activating and dehydrating reagent.

Full text of DOI:10.1055/s-2004-815409

LETTER
457
Synthesis of Sulfinimines by Direct Condensation of Sulfinamides with
Aldehydes Using Cs2CO3 as an Activating and Dehydrating Reagent
Synthesis of
S
h
ulfinimines
b
u
y Direct Co
h
eSulfinamii
Department of Applied Chemistry, Faculty of Science and Technology, Keio University, 3-14-1 Kohoku-ku, Hiyoshi, Yokohama 223-8522,
Japan
Fax +81(45)5661551; E-mail: msynktxa@applc.keio.ac.jp
Received 9 December 2003
During the course of our synthetic studies on the thios-
Abstract: Chiral sulfinimines were prepared from chiral sulfina-
trepton family of peptide antibiotics,6 we used the three-
mides and aldehydes in CH2Cl2 in the presence of cesium carbonate
as an amine-activating and dehydrating reagent.
component one-pot coupling of the Davis chiral sulfina-
mide 1,5 aldehyde 2, and dehydropyrrolidine
4
Key words: sulfinimines, sulfinamides, cesium carbonate, dehy-
(Scheme 2). In this case, the mixture of LiClO4-triethyl-
amine was very effective for not only the condensation of
1 with 2 but also the stereoselective addition of the azome-
thine ylide derived from 4 to sulfinimine 3, giving a good
yield of 5. However, it was found that the mixture of
LiClO4-triethylamine was not an effective reagent for the
condensation of sulfinimines with more simple aldehydes.
In general, Lewis acids are used to realize this condensa-
tion as carbonyl activation reagents and water scavengers.
Among them, the most effective reagent seems to be
Ti(OEt)4.1,2 However, the drawback of this titanium re-
agent is its removal from the reaction mixture.7 It is ex-
pected that the condensation would be also accelerated if
the amino group of the sulfinamides is activated with ba-
sic reagents instead of a carbonyl activation and such
bases have the capability as water scavengers. In this let-
ter, we report that Cs2CO3 is an effective reagent along
these lines.
drations, amine activation
Enantiomerically pure sulfinimines are versatile interme-
diates for the asymmetric syntheses of amine derivatives.
A variety of nucleophiles add to chiral sulfinimines in a
highly diastereoselective manner; after addition, the sulfi-
nyl group can be removed by brief treatment with an acid
to afford chiral amine derivatives (Scheme 1).1,2 Two
enantiomerically pure sulfinimines have been widely
used: N-p-toluenesulfinimines (R1 = p-tolyl, Scheme 1)
pioneered by Davis1, and N-t-butanesulfinimines (R1 = t-
butyl, Scheme 1) developed by Ellman.2,3 Among the sev-
eral methods to synthesize these sulfinimines,1,2 the
straightforward one is the direct condensation of chiral
sulfinamides with aldehydes. However, the lower nucleo-
philicity of the nitrogen in sulfinamides than that in
amines makes the synthesis of sulfinimines more difficult
than the synthesis of imines. To overcome this, several
precedents have been reported.1,2,4,5 Ellman realized this
condensation using MgSO4,4 CuSO4,4b,c and Ti(OEt)4.4b,c
Davis also reported this method using CsF,5a Ti(OEt)4,5b,c
and molecular sieves.5b In all these cases, however, excess
amounts of reagents (typically 2–5 molar amounts, some-
times 10 molar amounts) were needed in order to com-
plete the condensation reactions.
CHO
N
H
S
O
S
Me
N
p-Tolyl
HN
O
O
N
H
S
O
2
3
S
LiClO4, Et3N,
THF, r.t., 5 h
Me
H2N
p-Tolyl
HN
O
1
O
H
H
O
O
+
S
S
R1
NH2
O
R2
- H2O
R1
N
R2
S
S
N
-25 °C, 1
d,
65%
sulfinamides
aldehydes
sulfinimines
N
N
EtO2C
CO2Et
4
H
H
O
Nu
R2
Nu
R2
∗
∗
S
S
N
S
Nu
R1
N
acid
H2N
H
N
N
EtO2C
CO2Et
Scheme 1
NH
H
S
O
S
N
H
p-Tolyl
Me
HN
O
5
O
SYNLETT 2004, No. 3, pp 0457–0460
Advanced online publication: 12.01.2004
1
8.
0
2.
2
0
0
4
DOI: 10.1055/s-2004-815409; Art ID: U25703ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 2

458
S. Higashibayashi et al.
LETTER
Since strong bases are considered to be unsuitable for the Table 2 Solvent Optimization for Synthesis of Sulfinimine 6 from
p-Toluenesulfinamide 1 and Benzaldehyde
condensation, carbonate bases were the first choice of our
experiments. The suspension of the Davis sulfinamide 15
Cs2CO3
(1 mol amt)
H
H
O
O
(1 molar amount), benzaldehyde (1 molar amount), and a
carbonate base (1 molar amount) in CH2Cl2 (0.2 M for 1)
was vigorously stirred at 40–45 °C for 4 hours. The results
are summarized in Table 1. Although the use of Li2CO3,
Na2CO3, and K2CO3 resulted in no reaction under these
conditions (entries 1–3), an acceptable result was obtained
when Cs2CO3 was used, giving a 3:7 mixture of 1 and 6
(entry 4). After 8 hours at 40–45 °C, the reaction proceed-
ed almost completely (entry 6). Excess amounts of
Cs2CO3 have practically no effect on the result.
+
S
S
NH2
O
Ph
N
Ph
40–45 °C,
4 h
(1 mol amt)
1
6
Me
Me
(1 mol amt)
Entry
Solvent
Benzene
Toluene
DME
Ratio of 1:6a
63:37
1
2
3
4
5
6
7
8
56:44
60:40
Table 1 Synthesis of Sulfinimine 6 from p-Toluenesulfinamide 1
and Benzaldehyde Using Several Carbonate Bases
THF
58:42
CH2Cl2
ClCH2CH2Cl
DMF
30:70
H
H
O
O
in CH2Cl2
40–45 °C
36:64
+
S
S
NH2
O
Ph
N
Ph
(1 mol amt)
48:52
1
6
Me
Me
(1 mol amt)
Reagent
Li2CO3
Na2CO3
K2CO3
CH3CN
41:59
Entry
Time (h)
Ratio of 1:6a
NRb
a The ratio of 1:6 was based on 1H NMR analysis of the crude product.
All reactions proceeded cleanly without decomposition (checked by
TLC and 1H NMR).
1
2
3
4
5
6
4
4
4
4
6
8
NR
NR
Table 3 Synthesis of Sulfinimine 6 from p-Toluenesulfinamide 1
and Several Aldehydes
Cs2CO3
Cs2CO3
Cs2CO3
30:70c
12:88c
<1:>99c
Cs2CO3
(1 mol amt)
H
H
O
O
+
S
S
p-Tolyl
NH2
O
p-Tolyl
N
CH2Cl2,
40–45 °C,
8 h
1
6
a The ratio of 1:6 was based on 1H NMR analysis of the crude product.
b No reaction.
R
R
(1 mol amt)
(1 mol amt)
R
c All reactions proceeded cleanly without decomposition (checked by
TLC and 1H NMR).
Entry
Ratio of 1:6a
<1:>99
15:85
7:93
1
2
3
4
5
6
7
8
H
Next, solvent optimization was investigated using a 1 mo-
lar amount of Cs2CO3 at 40–45 °C8 for 4 hours (Table 2),
indicating that CH2Cl2 proved to be the best solvent.
p-OMe
m-OMe
p-Br
4:96
Under these optimized conditions, several aldehydes were
subjected to the condensation reactions. These results are
compiled in Table 3 and Table 4. Although in the case of
p-methoxybenzaldehyde (entry 2, Table 3), the yield of
the sulfinimine slightly decreased (1:6 = 15:85), the elec-
tron-donating (entry 3, Table 3) and electron-withdrawing
(entries 4–8, Table 3) substituents on benzaldehyde did
not affect the yields of the sulfinimines, thus producing
good to excellent yields of the sulfinimines. Moreover, in
the case of heteroaromatic compounds (entries 1–5,
Table 4) and cinnamaldehyde (entry 6, Table 4), good to
excellent yields of the sulfinimines were obtained.
m-Br
6:94
m-Cl
3:97
p-NO2
m-NO2
<1:>99
1:99
a The ratio of 1:6 was based on 1H NMR analysis of the crude product.
All reactions proceeded cleanly without decomposition (checked by
TLC and 1H NMR).
yield than 6 (entries 1 and 2) and in a comparable yield to
6 (entries 3–5).
With the satisfactory results using the Davis sulfinamide
1 in hand, our next concern was its application to the Ell-
man sulfinamide 7.4a,9 t-Butanesulfinamide (7) and sever-
al representative aldehydes were subjected to our
condensation conditions and the results are shown in
Table 5. Sulfinimines 8 were obtained in a slightly lower
We next investigated the Cs2CO3 conditions for the con-
densation of sulfinamides with aliphatic aldehydes. These
data are compiled in Table 6. In the case of the Davis
sulfinamide 1, unfortunately, but not unexpectedly, our
Synlett 2004, No. 3, 457–460 © Thieme Stuttgart · New York

LETTER
Synthesis of Sulfinimines by Direct Condensation of Sulfinamides
459
Table 6 Synthesis of Sulfinimines from Sulfinamides and Aliphatic
Aldehydes
Table 4 Synthesis of Sulfinimine 6 from p-Toluenesulfinamide 1
and Several Aldehydes
Cs2CO3
(1 mol amt)
Cs2CO3
(1 mol amt)
H
H
H
H
O
O
O
O
+
S
S
+
S
S
R1
NH2
O
R2
R1
N
R2
p-Tolyl
NH2
O
R
p-Tolyl
N
R
CH2Cl2,
40–45 °C
CH2Cl2,
40–45 °C,
8 h
(1 mol amt)
(1 mol amt)
1 or 7
(1 mol amt)
6 or 8
1
6
(1 mol amt)
Entry R1
R2
Time
(h)
Ratio of
Yield of
Entry
R
Ratio of 1:6a
<1:>99
1:99
1:6 or 7:8a 6 or 8 (%)b
1
2
3
4
5
6
2-Pyridyl
3-Pyridyl
4-Pyridyl
2-Furyl
c
1
2
3
4
5
6
7
8
9
p-Tolyl
p-Tolyl
p-Tolyl
t-Bu
n-Pentyl
8
8
–
16
15
45
65
46
52
73
76
59
c
2-Propyl
t-Bu
–
1:99
8
52:48
24:76
49:51
40:60
10:90
17:83
35:65
7:93
n-Pentyl
2-Propyl
t-Bu
8
2-Thiazolyl
PhCH=CH–
1:99
t-Bu
8
7:93
t-Bu
8
a The ratio of 1:6 was based on 1H NMR analysis of the crude product.
All reactions proceeded cleanly without decomposition (checked by
TLC and 1H NMR).
t-Bu
n-Pentyl
2-Propyl
t-Bu
16
16
16
t-Bu
t-Bu
conditions were not suitable for enolizable aliphatic alde-
hydes, causing aldehyde decompositions and giving
sulfinimines in low isolated yields (entries 1 and 2). In
contrast, in the case of the Ellman sulfinamide 7, sulfin-
imines were obtained in moderate yields together with a
small amount of aldehyde decomposition products (en-
tries 4 and 5); the longer the reaction time, the better the
isolated yields (entries 4, 5, 7, and 8). The bulky trimeth-
ylacetaldehyde gave a moderate yield of sulfinimines
(entries 3, 6, and 9).
a The ratio of 1:6 (or 7:8) was based on 1H NMR analysis of the crude
product.
b Since these reactions (except for entries 3, 6, and 9) were contami-
nated with some decomposition products, the isolated yields after
silica-gel (flash) column chromatography were determined.
c The ratio could not be determined.
In summary, we have achieved the synthesis of chiral
sulfinimines from the Davis and/or Ellman sulfinamides
(1 molar amount) and aldehydes (1 molar amount) in
CH2Cl2 in the presence of Cs2CO3 (1 molar amount). The
merits of this method are the easy workup procedure (fil-
tration) and no need to use excess amounts of activating
and dehydrating reagents.10
Table 5 Synthesis of Sulfinimine 8 from t-Butanesulfinamide (7)
and Several Aldehydes
Cs2CO3
(1mol amt)
H
H
O
O
+
S
S
t-Bu
NH2
O
R
t-Bu
N
R
Acknowledgment
CH2Cl2,
40–45 °C,
8 h
(1 mol amt)
7
8
This research was supported by a Grant-in Aid for Scientific Re-
search on Priority Areas (A) ‘Exploitation of Multi-Element Cyclic
Molecules’ from the Ministry of Education, Culture, Sports,
Science and Technology, Japan.
(1 mol amt)
Entry
R
Ratio of 7:8a
15:85
1
2
3
4
5
Phenyl
p-Methoxyphenyl
p-Nitrophenyl
4-Pyridyl
45:55b
<1:>99
1:99
References
(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) See also: Garcia Ruano, J. L.; Fernandez, I.; del Catalina, M.
P.; Cruz, A. A. Tetrahedron: Asymmetry 1996, 7, 3407.
(4) (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.
2-Thiazolyl
7:93
a The ratio of 7:8 was based on 1H NMR analysis of the crude product.
All reactions proceeded cleanly without decomposition (checked by
TLC and 1H NMR).
b The ratio of 7:8 was based the isolated yield after silica-gel (flash)
column chromatography.
Synlett 2004, No. 3, 457–460 © Thieme Stuttgart · New York

460
S. Higashibayashi et al.
LETTER
(5) (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.
(6) Higashibayashi, S.; Hashimoto, K.; Nakata, M. Tetrahedron
Lett. 2002, 43, 105.
(7) Recently, the modified procedure to remove titanium
materials was reported by the Ellman group, see: Mukade,
T.; Dragoli, D. R.; Ellman, J. A. J. Comb. Chem. 2003, 5,
590.
(8) At the reflux temperature of each solvent, considerable
decomposition occurred (except CH2Cl2).
(9) (a) Cogan, D. A.; Liu, G.; Kim, K.; Backes, B. J.; Ellman, J.
A. J. Am. Chem. Soc. 1998, 120, 8011. (b) Weix, D. J.;
Ellman, J. A. Org. Lett. 2003, 5, 1317.
(10) Representative Experimental Procedure (Table 3, Entry
1): To a solution of 15 (80.0 mg, 0.515 mmol) in CH2Cl2 (2.6
mL) were added Cs2CO3 (168 mg, 0.515 mmol) and
benzaldehyde (0.0523 mL, 0.515 mmol). The resulting
suspension was vigorously stirred at 40–45 °C for 8 h. The
reaction mixture was filtered with Celite and the filter cake
was washed with CH2Cl2. The filtrates and washings were
combined and concentrated. The residue was
The ee of 6 was 97% determined by chiral HPLC analysis
(Daicel Chiralcel OD column, 4.6 × 250 mm, 99.5:0.5
hexane–IPA; 1 mL/min, 254 nm, tR = 36.6 min; enantiomer
of 6, t = 32.7 min), which was identical with that of 1 used
(Daicel Chiralcel OD column, 4.6 × 250 mm, 90:10 hexane–
IPA; 1 mL/min, 254 nm, tR = 18.0 min; enantiomer of 1,
tR = 14.9 min). Compound 6: mp 78–79 °C (lit.5a,b 77–78 °C,
lit.5c 80–81 °C); [a]D29 +114 (c 1.00, CHCl3) {lit.5a [a]D
20
+117.3 (c 1.77, CHCl3), lit.5b [a]D20 +117.5 (c 1.6, CHCl3),
lit.5c [a]D20 +122.8 (c 1.2, CHCl3)}. 1H NMR (300 MHz,
CDCl3, TMS = 0 ppm): d = 2.40 (3 H, s), 7.32 (2 H, d,
J = 8.0 Hz), 7.41–7.52 (3 H, m), 7.64 (2 H, d, J = 8.0 Hz),
7.82–7.87 (2 H, m), 8.75 (1 H, s). Sulfinimine 8 (Table 5,
entry 1) was obtained after silica-gel(flash) column
chromatography (CH2Cl2) in 80% isolated yield by the same
procedure as described above. The ee of 8 was 99%
determined by chiral HPLC analysis (Daicel Chiralcel OD
column, 4.6 × 250 mm, 95:5 hexane–IPA; 1 mL/min, 254
nm, tR = 5.51 min; enantiomer of 6, tR = 6.96 min), which
was identical with that of 7 used (Daicel Chiralcel OD
column, 4.6 × 250 mm, 96:4 hexane–IPA; 1 mL/min, 222
nm, tR = 41.6 min; enantiomer of 7, tR = 35.5 min).
Compound 8: [a]D28 +103 (c 1.00, CHCl3) {lit.3 [a]D20 +104
(c 1.00, CHCl3); enantiomer of 8, lit.4c [a]D23 –122 (c 1.00,
CHCl3)}. 1H NMR (300 MHz, CDCl3, TMS = 0 ppm):
d = 1.28 (9 H, s), 7.44–7.55 (3 H, m), 7.83–7.89 (2 H, m),
8.59 (1 H, s).
chromatographed on silica gel (flash) with hexane–
EtOAc = 9:1 to afford sulfinimine 6 (119 mg) in 95% yield.
Synlett 2004, No. 3, 457–460 © Thieme Stuttgart · New York