KHSO4-mediated condensation reactions of tert-butanesulfinamide with aldehydes. Preparation of tert-butanesulfinyl aldimines

Article abstract of DOI:10.1055/s-2005-865234

Optically pure tert-butanesulfinyl aldimines 1 were prepared by direct condensation of chiral tert-butanesulfinamide 3 with aldehydes 2 in high yields in the presence of KHSO₄. The main advantage of KHSO₄ is that it is applicable to the condensation reactions of a variety of aldehydes, including electron deficient and electron rich (hetereo)aromatic aldehydes, as well as aliphatic aldehydes.

Full text of DOI:10.1055/s-2005-865234

1334
LETTER
KHSO4-Mediated Condensation Reactions of tert-Butanesulfinamide with
Aldehydes. Preparation of tert-Butanesulfinyl Aldimines
K
HS
O
-Media
t
h
edCondensa
i
tion Re
y
a
ctionsof te
a
rt
-
Butanesu
n
lfinamide
w
ith Ald
H
ehydes uang, Min Zhang, Yin Wang, Yong Qin*
4
Department of Chemistry of Medicinal Natural Products, West China School of Pharmacy, Sichuan University, Chengdu 610041,
P. R. China
E-mail: yanshuqin@yahoo.com
Received 3 March 2005
O
O
Abstract: Optically pure tert-butanesulfinyl aldimines 1 were
prepared by direct condensation of chiral tert-butanesulfinamide 3
with aldehydes 2 in high yields in the presence of KHSO4. The main
advantage of KHSO4 is that it is applicable to the condensation
reactions of a variety of aldehydes, including electron deficient and
electron rich (hetereo)aromatic aldehydes, as well as aliphatic alde-
hydes.
2 equiv, KHSO4
45 °C, toluene
S
S
H2N
CHO
+
N
R
R
2 (2 equiv)
3 (1 equiv)
1
Scheme 1 The condensation reactions of tert-butanesulfinamide
with aldehydes catalyzed by KHSO4.
Key words: tert-butanesulfinamide, aldehyde, tert-butanesulfinyl
aldimines, potassium hydrogen sulfate, condensation
In the previous study,7 we found that KHSO4 activated the
addition reactions of indole to aldimines 1 efficiently to
afford bisindolylalkanes in excellent yields. This observa-
tion encouraged us to investigate the usefulness of KHSO4
in the condensation reaction of 3 with aldehydes to afford
aldimines 1. Initial work showed that when 1 equivalent
of (S)-tert-butanesulfinamide 3 was stirred with 1.1 equiv-
alents of benzaldehyde at room temperature in CH2Cl2 in
the presence of two equivalents of KHSO4 for 24 hours,
the desired aldimine 1a (R = Ph) was obtained in 61%
yield. Our study was then directed to explore the effects of
different solvents on the condensation reaction. The re-
sults are depicted in Table 1. For the majority of solvents,
the condensation reactions proceeded smoothly to give
desired 1a in good yields (Table 1, entries 1–6). Toluene
and (i-Pr)2O gave the highest yields (over 80%; Table 1
entries 7 and 8). The yield was slightly improved (from
81% to 86%) when the reaction temperature was in-
creased by 20 °C from 25 °C to 45 °C under the same con-
ditions in toluene (Table 1, entries 9 and 10). When 2
equivalents of benzaldehyde were used in order to drive
the reaction to completion, the yield was further improved
from 86% to 91% (Table 1, entries 9 and 10; 45 °C). In-
creasing the reaction temperature from 45 °C to 80 °C
resulted in a lower yield (Table 1, entry 11, 65%) owing
to the competitive decomposition of 1a.
Optically pure tert-butanesulfinyl aldimine 1 has been
shown to be an important intermediate for the asymmetric
syntheses of chiral amine derivatives through the addition
reactions of nucleophilic reagents in recent years.1 The
practical preparation of 1 is the key issue in relation to its
application in asymmetric synthesis.
Optically pure aldimines 1 were usually prepared by di-
rect condensations of chiral tert-butanesulfinamide 32
with aldehydes in the presence of an activator such as
MgSO4(PPTS),3,4 Ti(OEt)4,4 CuSO4,4 and Cs2CO3.5 All of
the above reagents are useful in their own right, but each
suffers from one or more limitations. For example,
MgSO4(PPTS) was not effective for most aldehydes,
while CuSO4 was not effective with electron-deficient ar-
omatic aldehydes nor with sterically hindered aliphatic al-
dehydes, and Cs2CO3 was expensive and less effective
with electron-rich aromatic aldehydes. Although Ti(OEt)4
can promote the condensation reactions of 3 with elec-
tron-deficient and electron-rich aromatic aldehydes, and
aliphatic aldehydes in high yields, it is a moisture-sensi-
tive reagent and lacks an easy workup procedure. More re-
cently, a catalytic procedure has been developed using
Yb(OTf)3 as a catalyst for the condensation reaction,6 it
still seems highly desirable to find a simple, efficient, eco-
nomical, and general method for the preparation of 1. In
this communication, we report that inexpensive KHSO4
can serve as a highly efficient and mild catalyst for the
condensation reactions of 3 with all types of aldehydes in
high to excellent yields (Scheme 1).
Next we examined the scope of the KHSO4-mediated con-
densation reaction of 3 with a variety of aldehydes, using
the optimum conditions [toluene, 45 °C, KHSO4 (2
equiv)].8 The results are shown in Table 2. In general for
aromatic aldehydes, condensation reactions usually af-
forded the corresponding aldimines 1 in over 80% yields
(Table 2, entries 1–7). KHSO4 was as effective when
compared with CuSO4 for both electron rich and electron
deficient aromatic aldehydes, and was superior to Cs2CO3
for electron rich aromatic aldehydes5 (Table 2, entries 3,
5, and 6 compared with entry 4). When conjugated alde-
hydes were subjected to this reaction, KHSO4 was found
SYNLETT 2005, No. 8, pp 1334–1336
1
7.
0
5.
2
0
0
5
Advanced online publication: 21.04.2005
DOI: 10.1055/s-2005-865234; Art ID: U06005ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
KHSO4-Mediated Condensation Reactions of tert-Butanesulfinamide with Aldehydes
1335
Table 1 Solvent Optimization for the Preparation of Aldimine 1a
Mediated by KHSO4
Table 2 Preparation of Aldimine 1 Mediated by KHSO4 in Toluenea
a
Entry
1
1
R
Catalyst
KHSO4
KHSO4
KHSO4
Cs2CO3
KHSO4
KHSO4
KHSO4
KHSO4
KHSO4
KHSO4
CuSO4
Yieldb
Entry
Solvent
CH2Cl2
CHCl3
Yieldb
61
Time (h)
24
1a
1b
1c
1c
1d
1e
1f
Ph
91
1
2
2
4-ClPh
87
56
24
3
4-MeOPh
4-MeOPh
4-Me2NPh
3,4-(MeO)2Ph
4-NO2Ph
(E)-PhCH=CH-
(Me)2CH=CH-e
2-Furyl
2-Furyl
2-Furyl
2-Pyridyl
3-Pyridyl
3-Pyridyl
3-Pyridyl
4-Pyridyl
PhCH2-
Pre
80
3
THF
75
24
4
<555
87
4
EtOH
70
24
5
5
MeCN
70
24
6
82
6
Benzene
(i-Pr)2O
Toluene
Toluenec
Toluened
Toluenee
78
24
7
92
7
82
24
8
1g
1h
1i
91
8
81
24
9
93
9
86
24
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
84
10
11
91
24
1i
404
824
95
65
24
1i
Ti(OEt)4
KHSO4
KHSO4
CuSO4
a Conditions: 25 °C, benzaldehyde (1.1 equiv), KHSO4 (2 equiv).
b Isolated yields.
1j
c Conditions: 45 °C.
d Conditions: 45 °C, benzaldehyde (2 equiv).
e Conditions: 80 °C, benzaldehyde (2 equiv).
1k
1k
1k
1l
88
trace4
quant.4
93
Ti(OEt)4
KHSO4
KHSO4
KHSO4
KHSO4
KHSO4
KHSO4
KHSO4
Ti(OEt)4
Cs2CO3
Yb(OTf)3
CuSO4
to act as an effective catalyst resulting in excellent yields
(Table 2, entries 8 and 9); this is almost as effective as
Yb(OTf)3.6 While CuSO4 mediated the condensation of 2-
furylaldehyde in low yield (Table 2, entry 11), and was in-
effective for the condensation of 3-pyridylaldehyde, the
poor yields resulted from complex formation between
CuSO4 and 3-pyridylaldehyde (entry 15).4 However, we
were pleased to discover that KHSO4-mediated the con-
densation reactions of 2-furylaldehyde, 2-pyridylalde-
hyde, 3-pyridylaldehyde, and 4-pyridylaldehyde in high
yields (Table 2, entries 10, 12–14, and 17).
1m
1n
1o
1p
1q
1r
1r
1r
1r
1r
1s
1t
60
80
Octyl
82
Ph(CH2)2-
2-Prc
86
80
t-Bu
81
t-Bu
824
595
526
trace4
86
Also it was gratifying to see that KHSO4 catalyzed the
condensation reaction of phenylacetaldehyde to give the
desired aldimine 1m in 60% yield without formation of
the enamine product (Table 2, entry 18).9 For aliphatic al-
dehydes, condensation reactions gave the corresponding
aldimines 1n–r in good to high yields (Table 2, entries
19–23). Even the extremely hindered pivaldehyde under-
went KHSO4-catalyzed condensation reaction to afford 1r
in 81% yield (Table 2, entry 23), which was almost as ef-
fective as Ti(OEt)4, and in fact was superior to CuSO4,
Cs2CO3, and Yb(OTf)3 (Table 2, entries 23–27). For vol-
atile aliphatic aldehydes such as butylaldehyde and iso-
butylaldehyde, 5 equivalents of aldehydes were essential
to the success of the reaction. The condensation of 2-
phthalimidoacetaldehyde with 3 gave aldimine 1s in 86%
yield (Table 2, entry 28). Unfortunately, when we tested
one ketone, acetophenone, it failed to react with 3 even
under our optimized conditions (Table 2, entry 29).
t-Bu
t-Bu
t-Bu
2-Phthalimidomethyl KHSO4
Acetophenone KHSO4
0
a Conditions: 45 °C, aldehyde (2 equiv), KHSO4 (2 equiv), toluene.
b Isolated yields.
c Conditions: aldehyde (5 equiv), sealed tube.
In light of the effectiveness of KHSO4 in the condensation
reaction, it is reasonable to believe that KHSO4 acts as
both a protic acid and a dehydrating agent. The acidity of
KHSO4 in toluene is not strong enough to cause the
resulting tert-butanesulfinyl aldimines 1 to undergo race-
mization and to scissor out the tert-butanesulfinyl group
from the condensation product.8
Synlett 2005, No. 8, 1334–1336 © Thieme Stuttgart · New York

1336
Z. Huang et al.
LETTER
(2) For the preparation of optically pure tert-butanesulfinamide
see: (a) Han, Zh.-X.; Krishnamurthy, D.; Grover, P.; Fang,
Q. K.; Senanayake, Ch. H. J. Am. Chem. Soc. 2002, 124,
7880. (b) Weix, D. J.; Ellman, J. A. Org. Lett. 2003, 5, 1317.
(c) Qin, Y.; Wang, C.-H.; Huang, Zh.-Y.; Xiao, X.; Jiang,
Y.-Zh. J. Org. Chem. 2004, 69, 8533.
(3) Branchaud, B. P. J. Org. Chem. 1983, 48, 3531.
(4) (a) Liu, G.-Ch.; Cogan, D. A.; Owens, T. D.; Tang, T. P.;
Ellman, J. A. J. Org. Chem. 1999, 64, 1278. (b) Davis, F.
A.; Zhang, Y.; Andemichael, Y.; Fang, T.; Fanelli, D. L.;
Zhang, H. J. Org. Chem. 1999, 64, 1403.
In summary, we have described a highly efficient method
for the preparation of optically pure tert-butanesulfinyl
aldimines 1 by using KHSO4 as a catalyst. KHSO4 is
applicable to the condensation reactions of a variety of
aldehydes, including electron deficient and electron rich
(hetero)aromatic aldehydes, and aliphatic aldehydes. The
current method offers several advantages including mild
reaction condition, cheap reagent, high yield of product,
as well as simple experimental procedure, which makes it
a useful and practical method for the syntheses of opti-
cally pure tert-butanesulfinyl aldimines.
(5) Higashibayashi, S.; Tohmiya, H.; Mori, T.; Hashimoto, K.;
Nakata, M. Synlett 2004, 457.
(6) Jiang, Zh.-Y.; Chan, W. H.; Lee, A. W. M. J. Org. Chem.
2005, 70, 1081.
(7) Ke, B.-W.; Qin, Y.; He, Q.-F.; Huang, Zh.-Y.; Wang, F.-P.
Tetrahedron Lett. 2005, 46, 1751.
Acknowledgment
Financial support from the Ministry of Education (NCET, RFDP,
EYTP), the Excellent Youth Foundation of Sichuan Province (No.
04ZQ026-011), Sichuan University (No. 2004CF07 and
2005CF01), and the National Natural Science Foundation of China
(No. 20372048) are gratefully acknowledged.
(8) General procedure: (S)-tert-Butanesulfinamide (1 mmol)
was stirred with benzaldehyde (2 mmol) in toluene (10 mL)
in the presence of KHSO4 (2 equiv) for 24 h at 45 °C. KHSO4
was then removed by filtration. The filtrate was concentrated
to dryness. The residue was purified by flash chromato-
graphy to afford (S)-tert-butanesulfinyl aldimine (1a) as a
colorless liquid. [a]D20 +105 (c 2.19, CHCl3, Lit.5,10
[a]D20 +104, CHCl3). 1H NMR and 13C NMR spectra were
identical to that reported in the literature.5,10 The ee of
synthesized aldimine 1, determined by HPLC analysis
(Daicel Chiralcel OD column), was over 99%.4,5
(9) 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.
(10) Ruano, J. L. G.; Fernandez, I.; del Catalina, M. P.; Cruz, A.
A. Tetrahedron: Asymmetry 1996, 7, 3407.
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Synlett 2005, No. 8, 1334–1336 © Thieme Stuttgart · New York