Elimination of benzotriazolyl group in N-(α -benzotriazol-1-ylalkyl)amides and N-(α -benzotriazol-1-ylalkyl)sulfonamides: Their self-coupling and cross-coupling reactions with carbonyl compounds

Article abstract of DOI:10.1016/j.tet.2003.08.039

The elimination of benzotriazolyl group from N-(α -benzotriazol-1-ylalkyl)amides and N-(α -benzotriazol-1-ylalkyl)sulfonamides are readily realized with samarium diiodide as a reducing agent. The resulting intermediates undergo a dimerization or cross-coupling reaction with carbonyl compounds, thus affording the corresponding dimers or α-hydroxyalkylated sulfonamides in moderate yields.

Full text of DOI:10.1016/j.tet.2003.08.039

Tetrahedron 59 (2003) 8257–8263
Elimination of benzotriazolyl group in
N-(a-benzotriazol-1-ylalkyl)amides and
N-(a-benzotriazol-1-ylalkyl)sulfonamides: their self-coupling
and cross-coupling reactions with carbonyl compounds
Xiaoxia Wang,a Yongjun Liua and Yongmin Zhanga,b
,
*
aDepartment of Chemistry, Zhejiang University (Campus Xixi), Hangzhou 310028, People’s Republic of China
bState Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, People’s Republic of China
Received 31 March 2003; revised 30 July 2003; accepted 4 August 2003
Abstract—The elimination of benzotriazolyl group from N-(a-benzotriazol-1-ylalkyl)amides and N-(a-benzotriazol-1-ylalkyl)sulfon-
amides are readily realized with samarium diiodide as a reducing agent. The resulting intermediates undergo a dimerization or cross-coupling
reaction with carbonyl compounds, thus affording the corresponding dimers or a-hydroxyalkylated sulfonamides in moderate yields.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
functionalized compounds, which are otherwise inaccess-
ible by conventional routes.
Benzotriazole is a very useful synthetic auxiliary1 and its
application in organic chemistry has been extensively
investigated. One of the most important aspects of
benzotriazole chemistry is its elimination at the appropriate
stage.1e Several methods have been exploited for the
removal of the benzotriazole group and reduction is often
indispensable. The single-electron reducing agent SmI2 is
well known for its subtle reductivity and has been widely
used in reductive coupling reactions.2 It has been reported
that SmI2 is capable of eliminating the benzotriazole group
in several cases.3 For example, SmI2 can remove the
benzotriazolyl moiety from a-benzotriazolyl ketones to
afford the corresponding ketones3a and from N-acylbenzo-
triazoles to give a-diketones.3b Also, SmI2 causes the
smoot0h elimination of benzotriazoyl radical (Btz) from
N-[(N ,N0-dialkylamino)alkyl]benzotriazoles and thus
affords the tertiary vicinal diamines.3c Furthermore, SmI2
can eliminate the Btz unit from appropriately designed
benzotriazole adducts with an activated double bond to
produce an a-amino radical, which undergoes intramole-
cular addition to the double bond to afford N-cycloalkyl-
amines.3d Therefore, it would be interesting to see whether
further applications of SmI2 chemistry on benzotrizole
derivatives can be developed to bring about various
The fact that N-[(N0,N0-dialkylamino)alkyl]benzotriazoles
are reactive towards SmI2 and the structural similarity of
3c
N-(a-benzotriazol-1-ylalkyl)amides (obtainable by the
union0 of an amide, an aldehyde, and benzotriazole4) to
N-[(N ,N0-dialkylamino)alkyl]benzotriazoles (the adducts
obtained from an amine, an aldehyde, and benzotriazole5)
make it reasonable to postulate that the benzotriazole group
in N-(a-benzotriazol-1-ylalkyl)amides may be susceptible
to SmI2 reduction.
2. Results and discussion
2.1. SmI2-promoted self-coupling of N-(a-benzotriazol-
1-ylalkyl)amides and N-(a-benzotriazol-1-
ylalkyl)sulfonamides
Just as anticipated, as shown in Scheme 1, the reductive
dimerization of N-(a-benzotriazol-1-ylalkyl)amides
occurred in the presence of SmI2 to afford 2 in moderate
to good yields.
As can be seen in Table 1, when R2 is a phenyl group, both
N-(a-benzotriazol-1-ylalkyl)amides derived from aromatic
aldehydes and aliphatic aldehydes can afford smoothly the
corresponding dimers (entries 1–5), which were reported
to be formed from the irradiation of the difficult-to-obtain
Keywords: samarium diiodide; reductive coupling; N-(a-benzotriazol-1-
ylalkyl)amides; N-(a-benzotriazol-1-ylalkyl)sulfonamides.
*
Corresponding author; e-mail: yminzhang@mail.hz.zj.cn
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.08.039

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X. Wang et al. / Tetrahedron 59 (2003) 8257–8263
Scheme 1.
Table 1. SmI2-promoted self-coupling of N-(a-benzotriazol-1-ylalkyl)amides
Entry
R1
R2
Product
Yield of 2 (%)
meso:dla of 2
Yield of 3 (%)
1
2
3
4
5
6
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
CH3
2a
2b
2c
2d
2e
2f
65
62
70
68
76
–
67:33
75:25
96:4
65:35
100:0
–
28
22
21
21
17
92
4-MeOC6H4
n-Pr
i-Pr
i-Bu
C6H5
a
1
The ratio was determined by 400 MHz H NMR spectral data.
Scheme 2.
N-acylimines.6 Aside from products 2, the simple debenzo-
triazolation products 3 were isolated as by-products. It
should be pointed out that when R2 is a methyl, the simple
reduction product 3 becomes the only product (entry 6).
(Scheme 2 and Table 2, entry 1). Since the solubility of
substrate 4a in THF is poor, we added solid 4a instead, and
surprising, the yield of 5a was increased appreciably
(Table 2, entry 2). However, for N-(a-benzotriazol-1-
ylalkyl)sulfonamides derived from aliphatic aldehydes,
only products 6 were obtained in nearly quantitative yields
(Table 2, entries 4 and 5). The interpretation may be that the
carbon radical resulting from the cleavage of C–Bt bond
abstracts a hydrogen from THF8a more quickly than it
dimerizes; or that the radical is further reduced to the
carbanion which abstracts a proton from THF8b affording
product 6 and failing to give the corresponding dimers 5.
In light of the above outcome, it seemed worthwhile to have
an investigation on N-(a-benzotriazol-1-ylalkyl)sulfon-
amides7 (compounds 4), which are easily formed from
sulfonamides, aldehydes and benzotriazole. At the outset,
compound 4a was added in the form of a saturated THF
solution to the SmI2-THF solution. It was found that the
simple reduction product 6a was the major product while
the coupling product 5a was obtained in a 30% yield
2.2. SmI2-promoted cross-coupling of N-(a-benzo-
triazol-1-ylalkyl)sulfonamides with carbonyl compounds
Table 2. SmI2 promoted self-coupling of N-(a-benzotriazol-1-ylalkyl)sul-
fonamides
Intermolecular cross-coupling of carbonyl compounds with
imines is an important way for the preparation of b-amino
alcohols.9 The reductive coupling reaction of oximes with
Entry
R3
Product Yield of 5 meso:dla of 5 Yield of 6
(%)
(%)
carbonyl compounds affording b-alkoxyamino alcohols can
or by electroreduction.10b
1
2
3
4
5
C6H5
C6H5
4-MeC6H4
n-Pr
i-Pr
5a
5a
5b
5c
5d
30b
65c
60
0
.99:1
.99:1
.99:1
–
62
27
22
96
94
10a
be realized either by SmI2
SmI2-promoted cross-coupling reaction between N-sulfonyl-
imines and aldehydes with a ferrocene structure can give
b-sulfonamido alcohols11 in an enantioselective as well as
diastereoselective manner. The protocols mentioned above
for the synthesis of b-amino alcohols or their derivatives all
involve the cross-coupling between CvN bonds and CvO
0
–
a
1
The ratio was determined by 400 MHz H NMR spectral data.
A saturated solution of 4a in THF was added to SmI2 in THF.
Solid 4a was added to SmI2 in THF.
b
c

X. Wang et al. / Tetrahedron 59 (2003) 8257–8263
8259
Scheme 3.
Scheme 4.
bonds. Among other methods for the construction of
b-amino alcohol derivatives, lithiation of the C atom
adjacent to the nitrogen in amine derivatives and subsequent
nucleophilic attack to the carbonyl compounds is well
documented.12 Very recently, SmI2-mediated cross-
coupling reaction between a-heteroatom-substituted amides
and carbonyl compounds offers a conceptually new strategy
for the construction of b-acylamido alcohols (a-hydro-
xyalkylation reaction of amides). For example, in the
presence of SmI2, a-sulfur-substituted aromatic lactams can
undergo tandem desulfurization and reductive coupling
reactions with carbonyl compounds to afford the a-hydroxy-
alkylated lactams in satisfactory yields.13 Furthermore, the
SmI2 promoted a-hydroxyalkylation reaction of amides is
applied in the preparation of peptide libraries.14a
aldehydes and ketones were subjected to the cross-coupling
reaction with substrates 4a or 4b at the optimized
conditions, and reasonable to good yields of products 7
were obtained (Scheme 4). Compound 4c derived from
aliphatic aldehydes, however, did not afford any cross-
coupling product and only the simple reduction product 6
was obtained (Table 3, entry 13).
According to the literature,11,14 a a-sulfonamido carbanion
mechanism is strongly favored in this cross-coupling
reaction, though in the absence of the carbonyl compounds
under the SmI2-THF conditions self-coupling of 4 likely
involve a radical mechanism.
The threo:erythro selectivities, for the present reaction are
shown in Table 3. The major products have larger coupling
constants between CH–O and CH–N than that of the minor
products, and the major products were assigned to be threo-
based on literature precedents.15 Though an in-depth
mechanistic investigation of the cross-coupling reaction
was not pursued, a tentative explanation of the prefer-
ence of the threo- to the erythro-products is illustrated
in Scheme 5.
With our successful SmI2-promoted debenzotriazolation
protocol in hand, we investigated the cross-coupling
reaction between N-(a-benzotriazol-1-ylalkyl)amides and
carbonyl compounds to explore the a-hydroxyalkylation of
amides.
Disappointingly, when 1a and iso-valeraldehyde were
tested, the expected a-hydroxyalkylated amides could not
be obtained and only in high yields was obtained the simple
reduction compound (Scheme 3). Further experiment was
carried out to find out if the cross-coupling reaction between
4 and aldehydes could occur. It was gratifying to see
that when a suspension of 1 mmol of 4a dissolved in 10 mL
THF was added slowly to a 20 mL THF solution of
2.2 equiv. of SmI2 and 1 mmol of iso-butyraldehyde, a
diastereoisomeric mixture of the a-hydroxyalkylated
sulfonamides 7a in 56% yield could be obtained. Also
isolated from the reaction mixture was the simple reduction
product 6 in 35% yield. Optimization of the reaction
conditions led to the observation that excess amount of
aldehydes could increase the yield of product 7a from 56 to
73%, which was satisfactory considering the simplicity of
the reaction conditions.
Since lanthanides are oxophilic,16 transition states T1 and
T2 are likely involved. However, the sterically less
cumbersome T2 would be more favorable as can be seen
in Scheme 5. As for aldehydes, a more than 80:20
threo:erythro ratio of products 7 can always be obtained;
as for the ketones, when R4 and R5 are comparable in
bulkiness the selectivity vanishes (threo:erythro<1:1,
entries 4–6). On the other hand, when one of the alkyl
groups in the ketone is substantially larger than the other,
the threo-selectivity re-emerges (entries 7, 11).
In conclusion, the benzotriazole group in N-(a-benzotriazol-
1-ylalkyl)amides or N-(a-benzotriazol-1-ylalkyl)sulfon-
amides can be eliminated by using SmI2 as a reducing
reagent. Subsequent self-coupling reaction affords the corre-
sponding dimers in good yields. Besides, the cross-coupling
reaction between N-(a-benzotriazol-1-ylalkyl)sulfonamides
To explore the generality of this reaction, a series of

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X. Wang et al. / Tetrahedron 59 (2003) 8257–8263
Table 3. SmI2-promoted stereoselective cross-coupling of N-(a-benzotriazol-1-ylalkyl)sulfonamides with carbonyl compounds
Entry
R3
R4
R5
Product
threo:erythroa
Yield (%)b of 7
Yield (%) of 6
1
2
3
4
5
6
7
8
C6H5 (4a)
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
4-CH3C6H4 (4b)
4-CH3C6H4
4-CH3C6H4
(CH3)2CH (4c)
H
H
CH3
CH3
CH3
CH3
CH3
–(CH2)4–
–(CH2)5–
CH3
CH3
H
–(CH2)4–
(CH3)2CH
(CH3)2CHCH2
CH3
7a
7b
7c
7d
7e
7f
7g
7h
7i
83:17
90:10
–
50:50
53:47
53:47
72:28
–
73
71
78
71
68
69
65
65
62
79
59
71
0
18
22
16
22
26
22
32
31
34
14
33
25
94
CH3CH2
CH3(CH2)2
CH3(CH2)3
CH3(CH2)4
9
–
–
10
11
12
13
CH3
(CH3)2CH
(CH3)2CH
7j
7k
7l
87:13
80:20
–
7m
a
1
The diastereoselectivity was determined by 400 MHz H NMR spectral data.
b
One mmol of substrate 4 was treated with 2 equiv. of the corresponding carbonyl compounds and 2.2 equiv. of SmI2. Isolated yields were based on substrates
4.
and carbonyl compounds offers a synthetically useful method
for the realization of a-hydroxyalkylation of sulfonamides.
before use. Substrates 14 and 47 were prepared according
to literature procedures.
3.2. SmI2-promoted self-coupling of N-(a-benzotriazol-
1-ylalkyl)amides and N-(a-benzotriazol-1-
ylalkyl)sulfonamides
3. Experimental
3.1. General
Under nitrogen atmosphere, 1 mmol of N-(a-benzotria-
zol-1-ylalkyl)amides (1) dissolved in dry THF (5 mL)
was added at room temperature to 2.2 mmol of SmI2
dissolved in THF (20 mL). The resulting solution turned
yellow in 20 min. Dilute hydrochloric acid (2 M, 5 mL)
was added and the resulting mixture extracted with
diethyl ether (3£20 mL). The combined organic layer
was washed with brine, dried over anhydrous sodium
sulfate, and concentrated under reduced pressure. The
residue was separated by preparative TLC on silica gel
with ethyl acetate and cyclohexane (1:2) as eluent to
afford the self-coupling products. For N-(a-benzotriazol-
1-ylalkyl)sulfonamides (4), the operation was similar to
that described above, except that solid N-(a-benzotriazol-1-
ylalkyl)sulfonamides (4) was added to the SmI2-THF
solution.
Tetrahydrofuran was distilled from sodium-benzophenone
and acetonitrile was distilled in the presence of phosphorus
pentoxide immediately prior to use. All reactions were
conducted under a nitrogen atmosphere. Melting points are
1
uncorrected. H NMR spectra were recorded on a Bruker
AC-400 instrument using CDCl3 or d6-DMSO as solvent
and TMS as internal standard. Chemical shifts (d) are
reported in ppm and coupling constants J are given in Hz. IR
spectra were recorded using KBr disks with a Bruker
Vector-22 infrared spectrometer. Mass spectra were
recorded on a HP 5989B MS spectrometer. Elemental
analyses were performed on an EA-1110 instrument.
Metallic samarium and other reagents were purchased
from commercial sources, without further purification
Scheme 5.

X. Wang et al. / Tetrahedron 59 (2003) 8257–8263
8261
3.3. SmI2-promoted cross-coupling of N-(a-benzo-
triazol-1-ylalkyl)sulfonamides with carbonyl compounds
(100). C22H28N2O2. Calcd C, 74.97; H, 8.01; N, 7.95. Found
C, 74.90; H, 8.07; N, 7.90%.
Under nitrogen atmosphere, 1 mmol of N-(a-benzotriazol-
1-ylalkyl)sulfonamides (4) dissolved in dry THF (10 mL)
was added at room temperature to a mixture of 2 mmol of
carbonyl compound and 2.2 mmol of SmI2 dissolved in THF
(20 mL). The characteristic blue color of SmI2 faded
gradually with the addition of compound 4 in about
30 min. Dilute hydrochloric acid (2 M, 5 mL) was added
and the resulting mixture extracted with diethyl ether
(3£20 mL). The combined organic layer was washed with
brine, dried over anhydrous sodium sulfate, and concen-
trated under reduced pressure. The residue was separated by
preparative TLC on silica gel with ethyl acetate and
cyclohexane (1:2) as eluent to afford the a-hydroxyalkyl-
ated sulfonamides.
3.3.5. Compound 2e. The title compound was obtained as
meso. IR (KBr) nmax: 3339 (NH), 3062, 2955, 2922, 2870,
1636, 1579, 1535 cm21. 1H NMR (400 MHz, d6-DMSO), d
8.18 (2H, br, NH), 7.84–7.88 (4H, m, ArH), 7.44–7.52 (6H,
m), 4.20 (2H, m), 1.53–1.57 (4H, m), 1.28–1.36 (2H, m),
0.65–0.71 (12H, m). m/z (%): 381 (Mþþ1, 0.57), 191
(32.24), 190 (17.01), 148 (28.65), 105 (100). C24H32N2O2.
Calcd C, 75.75; H, 8.48; N, 7.36. Found C, 75.79; H, 8.54;
N, 7.32%.
3.3.6. Compound 5a. The title compound was obtained as
meso. IR (KBr) nmax: 3316 (NH), 3031, 1599, 1456,
1
1327 cm21. H NMR (400 MHz, d6-DMSO), d 8.14 (2H,
d, J¼9.2 Hz, NH), 7.19 (4H, d, J¼8.0 Hz, ArH), 6.84–6.98
(14H, m), 4.51–4.53 (2H, m), 2.22 (6H, s). m/z (%): 260
(Mþ/2, 90.15), 155 (56.24), 106 (47.61), 91 (100).
C28H28N2O4S2. Calcd C, 64.59; H, 5.42; N, 5.38. Found
C, 64.68; H, 5.40; N, 5.31%.
3.3.1. Compound 2a. The title compound was obtained as
meso, white solid; mp .3008C (decomposition, lit.6 3528C).
IR (KBr) nmax: 3360 (NH), 3061, 3033, 1635, 1578,
1
1524 cm21. H NMR (400 MHz, d6-DMSO): d 8.80 (2H,
br, NH), 7.17–7.70 (20H, m, ArH), 5.67–5.69 (2H, m). dl,
3.3.7. Compound 5b. The title compound was obtained as
meso. IR (KBr) nmax: 3314 (NH), 3031, 2923, 1598, 1449,
white solid; mp 292–2958C (lit.6 2978C). IR (KBr) nmax
:
1
1
3318 (NH), 3061, 3031, 1635, 1578, 1533 cm21. H NMR
(400 MHz, CDCl3): d 7.77 (4H, d, J¼8.4 Hz), 7.38–7.49
(8H, m, ArH), 7.20–7.26 (10H, m, ArH), 5.59–5.61 (2H,
m). m/z (%): 421 (Mþþ1, 0.26), 210 (34.48), 105 (100).
C28H24N2O2. Calcd C, 79.98; H, 5.75; N, 6.66. Found C,
79.89; H, 5.74; N, 6.62%.
1322 cm21, meso: H NMR (400 MHz, CDCl3), d 7.49–
7.53 (4H, m, ArH), 7.09 (4H, d, J¼8.4 Hz, ArH), 6.78 (4H,
d, J¼8.4 Hz, ArH), 6.57–6.62 (4H, m, ArH), 5.67 (2H, br),
4.50–4.51 (2H, m), 2.36 (6H, s), 2.20 (6H, s). m/z (%): 549
(Mþþ1, 0.13), 274 (Mþ/2, 70.64), 155 (34.22), 120 (67.12),
91 (100). C30H32N2O4S2. Calcd C, 65.67; H, 5.88; N, 5.11.
Found C, 65.62; H, 5.94; N, 5.13%.
3.3.2. Compound 2b. The title compound was obtained as a
meso and dl mixture, white solid. IR (KBr) nmax: 3332 (NH),
3.3.8. Compound 7a. The title compound was obtained as
an inseparable diastereoisomeric mixture, white solid. IR
(KBr) nmax: 3475 (OH), 3280 (NH), 2962, 2873, 1599,
1455, 1324, 1159 cm21. Major: 1H NMR (400 MHz,
CDCl3): d 7.49–7.53 (2H, m, ArH), 7.14–7.19 (3H, m,
ArH), 7.02–7.10 (4H, m, ArH), 5.43 (1H, d, J¼7.2 Hz,
NH), 4.48 (1H, dd, J¼4.8, 7.6 Hz, CHNH), 3.37–4.00 (1H,
m), 2.35 (3H, s, CH3), 1.88 (1H, br, OH), 1.66–1.87 (1H,
m), 0.88–1.01 (6H, m). m/z (%): 260 (Mþ273, 33.53), 178
(6.95), 155 (24.86), 106 (100), 91 (53.55). Anal. C18H23-
NO3S. Calcd C, 64.84; H, 6.95; N, 4.20. Found C, 64.92; H,
7.11; N, 4.17%.
3061, 2954, 2836, 1633, 1579, 1516 cm21 1H NMR
.
(400 MHz, d6-DMSO), meso: d 8.71 (2H, br, NH), 7.36–
7.61 (14H, m, ArH), 6.85 (4H, d, J¼8.4 Hz), 5.59–5.61
(2H, m), 3.68 (6H, s). dl: d 8.94 (2H, br, NH), 7.73 (4H, d,
J¼8.0 Hz, ArH), 7.36–7.61 (6H, m), 7.28 (4H, d,
J¼8.4 Hz), 6.79 (4H, d, J¼8.8 Hz), 5.55–5.57 (2H, m),
3.68 (6H, s). m/z (%): 240 (Mþ/2, 37.55), 105 (100).
C30H28N2O4. Calcd C, 74.98; H, 5.87; N, 5.83. Found C,
74.91; H, 5.89; N, 5.78%.
3.3.3. Compound 2c. The title compound was obtained as a
meso and dl mixture, white solid. IR (KBr) nmax: 3336 (NH),
2957, 2871, 1634, 1579, 1534 cm21, meso: 1H NMR
(400 MHz, d6-DMSO), d 8.06 (2H, br, NH), 7.81–7.83
(4H, m, ArH), 7.45–7.52 (6H, m), 4.20–4.22 (2H, m),
1.49–1.52 (4H, m), 1.30–1.37 (4H, m), 0.86–0.88 (6H, m).
m/z (%): 353 (Mþþ1, 0.24), 176 (10.26), 177 (24.10), 148
(7.29), 105 (100). C22H28N2O2. Calcd C, 74.97; H, 8.01; N,
7.95. Found C, 74.90; H, 8.10; N, 7.88%.
3.3.9. Compound 7b. The title compound was obtained as
an inseparable diastereoisomeric mixture, white solid. IR
(KBr) nmax: 3498 (OH), 3309 (NH), 2951, 2866, 1599,
1455, 1321, 1159 cm21. Major: 1H NMR (400 MHz,
CDCl3): d 7.52–7.54 (2H, m, ArH), 7.03–7.22 (7H, m,
ArH), 5.44 (1H, d, J¼8.0 Hz, NH), 4.29 (1H, dd, J¼4.0,
8.0 Hz, CHNH), 3.92–3.98 (1H, m), 2.35 (3H, s, CH3),
1.63–1.71 (1H, m), 1.53 (1H, br), 1.06–1.13 (1H, m), 0.95–
1.02 (1H, m), 0.79–0.87 (6H, m). m/z (%): 330 (Mþ217,
0.21), 260 (20.93), 155 (17.19), 106 (100), 91 (53.45). Anal.
C19H25NO3S. Calcd C, 65.68; H, 7.25; N, 4.03. Found C,
65.59; H, 7.28; N, 4.01%.
3.3.4. Compound 2d. The title compound was obtained as a
meso and dl mixture, white solid. IR (KBr) nmax: 3317 (NH),
1
3064, 2960, 1636, 1579, 1534 cm21. H NMR (400 MHz,
CDCl3), meso: d 7.69–7.72 (4H, m, ArH), 7.44–7.58 (2H,
m, ArH), 7.36–7.40 (4H, m), 6.64 (2H, d, br, J¼7.2 Hz),
4.16–4.19 (2H, m), 2.10–2.17 (2H, m), 1.04–1.08 (12H, t,
J¼7.2 Hz). dl: d 7.83–7.86 (4H, m, ArH), 7.44–7.58 (6H,
m, ArH), 6.32 (2H, d, br, J¼6.8 Hz), 4.29–4.31 (2H, m),
2.06–2.08 (2H, m), 1.01–1.04 (12H, m). m/z (%): 353
(Mþþ1, 0.39), 176 (22.39), 177 (39.01), 162 (13.36), 105
3.3.10. Compound 7c. The title compound was obtained as
white solid; mp 162–1658C. IR (KBr) nmax: 3532 (OH),
3286 (NH), 3046, 2977, 2932, 1600, 1497, 1456,
.
1420 cm21 1H NMR (400 MHz, CDCl3): d 7.43–7.46
(2H, m, ArH), 7.09–7.17 (3H, m, ArH), 7.00–7.03 (4H, m,

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X. Wang et al. / Tetrahedron 59 (2003) 8257–8263
ArH), 5.50 (1H, d, J¼8.4 Hz, NH), 4.17 (1H, d, J¼8.8 Hz,
CHNH), 2.31 (3H, s, CH3), 1.62 (1H, br), 1.35 (3H, s), 1.03
(3H, s). m/z (%): 320 (Mþþ1, 1.04), 302 (35.62), 260 (2.99),
106 (100), 91 (18.25). Anal. C17H21NO3S. Calcd C, 63.92;
H, 6.63; N, 4.38. Found C, 64.01; H, 6.59; N, 4.35%.
CDCl3), major isomer: d 7.39–7.43 (2H, m, ArH), 7.08–
7.16 (3H, m, ArH), 6.98–7.02 (4H, m, ArH), 5.40–5.45
(1H, m, NH), 4.21 (1H, d, J¼8.8 Hz, CHNH), 2.30 (3H, s,
CH3), 1.45 (1H, s, OH), 1.33 (3H, s), 1.09–1.36 (8H, m),
0.84 (3H, t, J¼7.6 Hz). Minor isomer: d 7.39–7.43 (2H, m,
ArH), 7.08–7.16 (3H, m, ArH), 6.98–7.02 (4H, m, ArH),
5.40–5.45 (1H, m, NH), 4.21 (1H, d, J¼8.8 Hz, CHNH),
2.31 (3H, s, CH3), 1.50 (1H, s, OH), 1.20–1.24 (3H, m),
1.09–1.36 (8H, m), 0.92 (3H, s). m/z (%): 358 (Mþ217,
0.78), 260 (2.10), 155 (5.40), 115 (48.13), 106 (100), 91
(33.21). Anal. C21H29NO3S. Calcd C, 67.17; H, 7.78; N,
3.73. Found C, 67.11; H, 7.83; N, 3.69%.
3.3.11. Compound 7d. The title compound was obtained as
an inseparable diastereoisomeric mixture, white solid. IR
(KBr) nmax: 3521 (OH), 3290 (NH), 3065, 2971, 2939,
1597, 1497, 1456, 1418, 1320 cm21. Major isomer: d 7.41
(2H, d, J¼8.0 Hz, ArH), 7.06–7.13 (3H, m, ArH), 6.97–
7.02 (4H, m, ArH), 5.39–5.42 (1H, m, NH), 4.24 (1H, d,
J¼8.4 Hz, CHNH), 2.30 (3H, s, CH3), 1.62–1.76 (2H, m), d
1.49 (1H, s, OH), 0.92 (3H, s, COHCH3), 0.97 (3H, t,
J¼7.6 Hz, CH3CH2). Minor isomer: d 7.41 (2H, d,
J¼8.0 Hz, ArH), 7.06–7.13 (3H, m, ArH), 6.97–7.02
(4H, m, ArH), 5.39–5.42 (1H, m, NH), 4.22 (1H, d,
J¼8.8 Hz, CHNH), 2.30 (3H, s, CH3), 1.42 (1H, s, OH),
1.33 (3H, s, COHCH3), 1.20–1.26 (2H, m), 0.87 (3H, t,
J¼8.0 Hz, CH3CH2). m/z (%): 316 (Mþ217, 0.70), 260
(2.71), 155 (6.25), 106 (100), 91 (33.18), 73 (74.05). Anal.
C18H23NO3S. Calcd C, 64.84; H, 6.95; N, 4.20. Found C,
64.92; H, 6.91; N, 4.17%.
3.3.15. Compound 7h. The title compound was obtained as
white solid; mp 148–1528C. IR (KBr) nmax: 3526 (OH),
1
3288 (NH), 2961, 1599, 1454, 1422, 1322, 1159 cm21. H
NMR (400 MHz, CDCl3): d 7.44 (2H, d, J¼8.4 Hz, ArH),
7.00–7.16 (7H, m, ArH), 5.63–5.58 (1H, br), 4.29 (1H, d,
J¼8.8 Hz, CHNH), 2.31 (3H, s, CH3), 1.59–1.86 (7H, m),
1.38 (1H, s, OH), 1.05–1.14 (1H, m). m/z (%): 328
(Mþ217, 1.72), 260 (1.90), 155 (4.43), 106 (100), 91
(28.36), 85 (54.75). Anal. C19H23NO3S. Calcd C, 66.06; H,
6.71; N, 4.05. Found C, 66.14; H, 6.76; N, 4.01%.
3.3.12. Compound 7e. The title compound was obtained as
an inseparable diastereoisomeric mixture, white solid. IR
(KBr) nmax: 3499 (OH), 3276 (NH), 3034, 2959, 2872,
3.3.16. Compound 7i. The title compound was obtained as
white solid; mp 142–1458C. IR (KBr) nmax: 3509 (OH),
3293 (NH), 3062, 2931, 1598, 1454, 1422, 1320,
1
1
1599, 1497, 1457, 1423, 1327 cm21. H NMR (400 MHz,
1152 cm21. H NMR (400 MHz, CDCl3): d 7.41 (2H, d,
d6-DMSO), major isomer: d 7.77 (1H, d, J¼9.6 Hz, NH),
7.38 (2H, d, J¼8.4 Hz), 7.01–7.12 (7H, m, ArH), 4.24 (1H,
s, OH), 4.07 (1H, d, J¼9.6 Hz, CHNH), 2.24 (3H, s, CH3),
1.19–1.33 (4H, m), 0.80 (3H, s), 0.78 (3H, t, J¼7.2 Hz).
Minor isomer: d 7.87 (1H, d, J¼10 Hz, NH), 7.37 (2H, d,
J¼8.0 Hz), 7.01–7.12 (7H, m, ArH), 4.20 (1H, s, OH), 4.08
(1H, d, J¼10 Hz, CHNH), 2.24 (3H, s, CH3), 1.19–1.33
(4H, m), 0.97 (3H, s), 0.73 (3H, t, J¼7.6 Hz). m/z (%): 330
(Mþ217, 0.72), 260 (2.26), 155 (6.25), 106 (100), 91
(35.36), 87 (62.01). Anal. C19H25NO3S. Calcd C, 65.68; H,
7.25; N, 4.03. Found C, 65.76; H, 7.29; N, 4.07%.
J¼8.4 Hz, ArH), 7.08–7.14 (3H, m, ArH). 6.98–7.02 (4H,
m, ArH), 5.48 (1H, d, J¼8.8 Hz, NH), 4.23 (1H, d,
J¼9.6 Hz, CHNH), 2.30 (3H, s, CH3), 1.92–1.96 (1H, br,
OH), 1.53–1.58 (4H, m), 1.40–1.47 (3H, m), 1.19–1.26
(2H, m), 1.06–1.09 (1H, m). m/z (%): 342 (Mþ217, 0.55),
260 (1.10), 155 (3.41), 106 (100), 99 (54.23). Anal.
C20H25NO3S. Calcd C, 66.82; H, 7.01; N, 3.90. Found C,
66.90; H, 7.10; N, 3.83%.
3.3.17. Compound 7j. The title compound was obtained as
white solid; mp 153–1568C. IR (KBr) nmax: 3549 (OH),
3270 (NH), 3046, 2976, 2925, 1599, 1497, 1441, 1420,
1324, 1161 cm21. 1H NMR (400 MHz, CDCl3): d 7.44 (2H,
d, J¼7.6 Hz, ArH), 7.03 (2H, d, J¼8.0 Hz, ArH), 6.87–6.94
(4H, m, ArH), 5.38–5.46 (1H, br, NH), 4.13 (1H, d,
J¼8.8 Hz, CHNH), 2.33 (3H, s, CH3), 2.27 (3H, s, CH3),
1.64 (1H, br), 1.33 (3H, s), 1.04 (3H, s). m/z (%): 316
(Mþ217, 0.48), 274 (8.81), 155 (11.30), 120 (100), 91
(57.15). Anal. C18H23NO3S. Calcd C, 64.84; H, 6.95; N,
4.20. Found C, 64.79; H, 6.91; N, 4.17%.
3.3.13. Compound 7f. The title compound was obtained as
an inseparable diastereoisomeric mixture, white solid. IR
(KBr) nmax: 3565, 3475 (OH), 3275 (NH), 3065, 2954,
.
2871, 1599, 1497, 1457, 1431, 1379 cm21 1H NMR
(400 MHz, CDCl3), major isomer: d 7.40–7.43 (2H, dd,
J¼8.0, 8.4 Hz, ArH), 7.08–7.15 (3H, m, ArH), 6.98–7.02
(4H, m, ArH), 5.39–5.42 (1H, m, NH), 4.21 (1H, d,
J¼9.6 Hz, CHNH), 2.30 (3H, s, CH3), 1.46 (1H, s, OH),
1.26–1.33 (2H, m), 1.14–1.19 (4H, m), 1.34 (3H, s), 0.82
(3H, t, J¼7.6 Hz). Minor isomer: d 7.40–7.43 (2H, dd,
J¼8.0, 8.4 Hz, ArH), 7.08–7.15 (3H, m, ArH), 6.98–7.02
(4H, m, ArH), 5.39–5.42 (1H, m, NH), 4.21 (1H, d,
J¼9.6 Hz, CHNH), 2.31 (3H, s, CH3), 1.58–1.66 (2H, m),
1.50 (1H, s, OH), 0.92 (3H, s), 1.26–1.33 (4H, m), 0.90–
0.94 (3H, m). m/z (%): 344 (Mþ217, 2.35), 260 (1.72), 155
(4.02), 106 (100), 101 (48.35), 91 (24.67). Anal. C20H27-
NO3S. Calcd C, 66.45; H, 7.53; N, 3.87. Found C, 66.52; H,
7.57; N, 3.84%.
3.3.18. Compound 7k. The title compound was obtained as
an inseparable diastereoisomeric mixture, white solid. IR
(KBr) nmax: 3499 (OH), 3278 (NH), 3039, 2981, 1598,
1
1497, 1448, 1425, 1320, 1153 cm21. H NMR (400 MHz,
CDCl3), major isomer: d 7.36 (2H, d, J¼8.0 Hz, ArH), 6.96
(2H, d, J¼7.6 Hz), 6.84–6.91 (4H, m, ArH), 5.36–5.41
(1H, br), 4.39 (1H, d, J¼9.6 Hz, CHNH), 2.31 (3H, s, CH3),
2.26 (3H, s, CH3), 1.41 (1H, s, OH), 0.96–0.99 (6H, m),
0.84–0.87 (1H, m, (CH3)2CH), 0.75 (3H, s). Minor isomer:
d 7.50 (2H, d, J¼8.4 Hz, ArH), 7.11 (2H, d, J¼8.0 Hz),
6.84–6.91 (4H, m, ArH), 5.22–5.24 (1H, br), 4.53 (1H,
d, J¼8.4 Hz, CHNH), 2.37 (3H, s, CH3), 2.29 (3H, s,
CH3), 1.42 (1H, s, OH), 1.28 (3H, s), 0.96–0.99 (6H, m),
0.89–0.94 (1H, m, (CH3)2CH). m/z (%): 274 (Mþ287,
3.3.14. Compound 7g. The title compound was obtained as
an inseparable diastereoisomeric mixture, white solid. IR
(KBr) nmax: 3562, 3416 (OH), 3257 (NH), 2949, 2868,
1
1599, 1497, 1459, 1388, 1322 cm21. H NMR (400 MHz,

X. Wang et al. / Tetrahedron 59 (2003) 8257–8263
8263
Tetrahedron Lett. 2002, 43, 5431–5433. (c) Aurrecoechea,
J. M.; Fernandez-Acebes, A. Tetrahedron Lett. 1992, 33,
4763–4766. (d) Fernandez-Acebes, A.; Aurrecoechea, J. M.
Tetrahedron Lett. 1993, 34, 549–552.
3.87), 155 (6.17), 120 (100), 91 (40.56), 87 (58.23).
C20H27NO3S. Calcd C, 66.45; H, 7.53; N, 3.87. Found C,
66.51; H, 7.60; N, 3.82%.
3.3.19. Compound 7l. The title compound was obtained as
an inseparable diastereoisomeric mixture, white solid. IR
(KBr) nmax: 3491 (OH), 3280 (NH), 2961, 2873, 1598,
4. (a) Katritzky, A. R.; Drewniak, M. J. Chem. Soc., Perkin
Trans. 1 1988, 2339–2344. (b) Katritzky, A. R.; Drewniak,
M.; Lue, P. J. Org. Chem. 1988, 53, 5854–5856.
5. Katritzky, A. R.; Rachwal, S.; Hitchings, G. J. Tetrahedron
1991, 47, 2683–2732.
1444, 1321, 1159 cm21 1H NMR (400 MHz, CDCl3),
.
major isomer: d 7.51 (2H, d, J¼8.4 Hz, ArH), 7.09 (2H, d,
J¼7.6 Hz, ArH). 6.90–7.00 (4H, m, ArH), 5.47–5.54 (1H,
m, NH), 4.41 (1H, dd, J¼5.2, 7.6 Hz, CHNH), 3.38 (1H, dd,
J¼5.2, 11.2 Hz, CHOH), 2.36 (3H, s, CH3), 2.28 (3H, s,
CH3), 1.97–2.0 (1H, br, OH), 1.61–1.69 (1H, m, CH),
0.88–0.93 (6H, m, 2£CH3). Minor isomer: d 7.51 (2H, d,
J¼8.4 Hz, ArH), 7.09 (2H, d, J¼7.6 Hz, ArH). 6.90–7.00
(4H, m, ArH), 5.47–5.54 (1H, m, NH), 4.43 (1H, d,
J¼4.4 Hz, CHNH), 3.46–3.51 (1H, m, CHOH), 2.36 (3H, s,
CH3), 2.28 (3H, s, CH3), 2.02–2.04 (1H, br, OH), 1.61–
1.69 (1H, m, CH), 0.88–0.93 (6H, m, 2£CH3). m/z (%): 274
(Mþ217–56, 32.09), 192 (7.55), 155 (25.01), 121 (10.45),
120 (100). Anal. C19H25NO3S. Calcd C, 65.68; H, 7.25; N,
4.03. Found C, 65.71; H, 7.29; N, 3.96%.
6. (a) Chiacchio, U.; Corsaro, A.; Compagnini, A.; Purreuo, G.
J. Chem. Soc., Perkin Trans. 1 1983, 671–674. (b) The meso-
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chloric acid in the after treatment then was filtered off and
washed repeatedly by acetone; the dl-form was obtained by
usual work-up (see Section 3.2). While the meso- and dl-form
of other products 2 could not be separated this way.
7. Katritzky, A. R.; Oniciu, D. C.; Ghiviriga, I. Synth. Commun.
1997, 27, 907–922.
8. (a) Katritzky, A. R.; Qi, M.; Feng, D.; Nichols, D. A. J. Org.
Chem. 1997, 62, 4121–4124. (b) Broka, C. A.; Shen, T. J. Am.
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Acknowledgements
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We are grateful to the National Natural Science Foundation
of China (Project No. 20072033) and the Specialized
Research Fund for the Doctoral Program of Higher
Education.
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