Stereoselective synthesis and stereochemistry of r-2-alkoxycarbonyl-c-3-o- substituted phenyl-1,4-thiazane 1,1-dioxides

Article abstract of DOI:10.1139/v05-020

r-2-Alkoxycarbonyl-c-3-aryl-1,4-thiazane 1,1-dioxides were obtained as the stereoselective product, when the aldehyde used was o-substituted benzaldehyde while the p-substituted benzaldehydes gave a trans product. The relative configuration of the adjacen

Full text of DOI:10.1139/v05-020

202
Stereoselective synthesis and stereochemistry of
r-2-alkoxycarbonyl-c-3-o-substituted phenyl-1,4-
thiazane 1,1-dioxides
N. Bhavani, S. Perumal, and R. Banureka
Abstract: r-2-Alkoxycarbonyl-c-3-aryl-1,4-thiazane 1,1-dioxides were obtained as the stereoselective product, when the
aldehyde used was o-substituted benzaldehyde while the p-substituted benzaldehydes gave a trans product. The relative
3
configuration of the adjacent alkoxycarbonyl and aryl groups was assigned from the vicinal coupling constant, J =
10.6 Hz in the trans isomer and 3.2 Hz in the cis isomer, and from the multiplicity pattern, i.e., a doublet for the H-2
proton of the trans isomer and a triplet for the H-2 proton of the cis isomer. The unusual, large long-range coupling
(4J = 2.8 Hz) because of the “W” arrangement between H-2e and H-6e across the ring type was very useful for con-
1
firming the cis configuration and chair conformation of the isomer. The various H and 13C NMR assignments were
1
1
made with the help of H–1H COSY, H–13C COSY, HMBC, and NOESY spectral analyses.
1
1
1
Key words: H and 13C NMR, H–1H COSY, H–13C COSY, HMBC, NOESY, stereoselectivity, 1,4-thiazane.
Résumé : Les 1,1-dioxydes de r-2-alkoxycarbonyl-c-3-aryl-1,4-thiazane sont obtenus comme produit stéréosélectif
lorsque l’aldéhyde utilisé est un benzaldéhyde ortho substitué alors que les benzaldéhydes substitués en para conduisent
au produit trans. Les configurations relatives des groupes alkoxycarbonyle et aryle adjacents ont été attribuées sur la
3
base de la constante de couplage vicinale, J = 10,6 Hz dans l’isomère trans et 3,2 Hz dans l’isomère cis, et du patron
de multiplicité, c’est-à-dire la présence d’un doublet pour le proton H-2 de l’isomère trans et d’un triplet pour le pro-
ton H-2 de l’isomère cis. La constante de couplage à longue distance relativement importante (4J = 2,8 Hz) causée par
l’arrangement en « W » des protons H-2e et H-6e à travers ce type de cycle a été très utile pour confirmer la configu-
1
ration cis et la conformation chaise de l’isomère. Les diverses attributions des spectres RMN du H et du 13C ont été
1
1
faites sur la base d’analyses spectrales H–1H COSY, H–13C COSY, HMBC et NEOSY.
1
1
1
Mots clés : H et 13C RMN, H–1H COSY, H–13C COSY, HMBC, NEOSY, stéréosélectivité, 1,4-thiazane.
[Traduit par la Rédaction] Bhavani et al. 208
Introduction
tive starting material, and there too after several (more than
10 steps) tedious procedures. There has been no report on
the synthesis of 2,3-disubstituted-1,4-thiazane 1,1-dioxides
where the two substituents are different and in less stable cis
configuration. Here, we report an one-pot synthesis of cis-2-
alkoxycarbonyl-3-aryl-1,4-thiazane 1,1-dioxides, where the
position of a substituent in the aryl ring controls the stereo-
chemistry of the product.
For a 2,3-disubstituted 1,4-thiazane (in the rigid chair form),
two configurational isomers, cis and trans, are possible.
Generally, the thermal reaction will lead to the thermody-
namically more stable trans isomer with the preferred
diequatorial orientation of the substituents. The cis isomer
with one axial substituent and one equatorial substitutent
will be the less stable, kinetic-controlled product. In the
present work, the trans isomer was obtained with benzal-
dehyde and p-substituted benzaldehydes, but the cis isomer
was the product with o-substituted benzaldehydes.
Stereochemistry is an intrinsic universal feature of organic
compounds and influences virtually all pharmacodynamic,
pharmacokinetic, and biotransformation processes (1). Drug
molecules having the proper absolute configuration only re-
act with the receptor sites in the human body (2). Hence, the
stereoselectivity (3) gains importance in organic synthesis.
Thiazanes are widely used in new drug development (4, 5).
Thiazane derivatives stimulate calcium uptake (6) used as
antitumour, antiviral (7), bactericidal, parasiticidal (8), anti-
tuberculotic (9), and cardiovascular (10) agents, and they are
also used as local anesthetics (11).
So far 3,5-disubstituted (12), 2,3,5-trisubstituted (13, 14),
and 2,3,5,6-tetrasubstituted (15, 16) 1,4-thiazanes have been
reported. Eliel and co-workers (17) reported the synthesis of
cis-2,3-diphenyl-1,4-thiazane 1,1-dioxide from optically ac-
Received 5 July 2004. Published on the NRC Research Press
Web site at http://canjchem.nrc.ca on 9 March 2005.
Results and discussion
N. Bhavani and R. Banureka.1 Department of Chemistry,
Annamalai University, Annamalainagar – 608 002, India.
S. Perumal. School of Chemistry, Madurai Kamaraj
Universit, Madurai, India.
Synthesis of 2-alkoxycarbonyl-3-aryl-1,4-thiazane 1,1-dioxides
(Scheme 1) has been carried out by the condensation of
dialkyl ethane – 1,2-disulphonylacetate (18) with 1 mol of
araldehyde and ammonium acetate. Formation of a six-
1Corresponding author (banurekar@yahoo.co.in).
Can. J. Chem. 83: 202–208 (2005)
doi: 10.1139/V05-020
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Bhavani et al.
203
Scheme 1.
1
Spectrum 1. H NMR spectrum of 6.
membered 1,4-thiazane ring was confirmed by micro-
analysis, IR, and mass spectra. Their stereochemistry was
studied through NMR spectra.
The H NMR chemical shift values with multiplicity pat-
terns and coupling constants, along with their assignments
are given in Table 1.
The diaxial coupling constant (10.6 Hz) between the H-2
and H-3 protons for the compounds (1–3) gives evidence for
the trans (17) configuration with the preferred diequatorial
orientation of the two substituents for the p-substituted phenyl
compounds.
tons, it is inferred that there is a change in configuration
from e, e to a, e. For the cis configuration of the substituents
with an a, e conformation, there are two possibilities, i.e.,
aryl group equatorial and ethoxycarbonyl group axial or aryl
group axial and ethoxycarbonyl group equatorial. The
benzylic proton signal appears as a doublet (3Ja,e = 3.2 Hz)
so it has only one coupling partner. But the triplet (Spectrum
1) for the H-2 proton indicates that it has one more coupling
partner, and that should be necessarily a long-range coupling
partner (19). Long-range coupling is possible only with a
“W” arrangement (20), and hence, the H-2 proton must be
equatorial and ester group axial; consequently, the aryl
1
1
group should be equatorial. In the H–1H COSY (21) spec-
Stereochemistry of o-substituted phenyl compounds (6
and 7)
The H-2 and H-3 protons do not appear as two simple
doublets with diaxial coupling constants. From the small
coupling (17) constant (Table 1) between H-2 and H-3 pro-
trum (Spectrum 2), there is a cross peak (A) between the H-
2e triplet and the doublet of the quartet signal at 2.96 ppm
(i.e., H-6e), and this is an added evidence for the long-range
coupling. The large cross peak (B) is due to the coupling be-
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204
Table 1. H NMR spectral data of 2-alkoxycarbonyl-3-aryl-1,4–thiazane 1,1-dioxides (1–3, 6, 7).a
Can. J. Chem. Vol. 83, 2005
1
Compound
NH
H-6a
H-6e
H-5a
H-5e
H-2b
H-3c
1
1.88 (s) 3.22 (m, 13.7,
10.3, 3.8)
2.05 (s) 3.12 (m)
2.05 (s) 3.22 (m)
2.39 (s) 3.56 (td,
13.4 12.5, 2.2)
3.15 (m,
13.7, 3.0)
3.12 (m)
3.22 (m)
2.96 (dq,
3.47d (m)
3.47d (m)
4.06 (d, 10.6) 4.46 (d, 10.6)
2
3
6
3.40d (m)
3.48d (m)
3.40d (m)
3.48d (m)
4.04 (d, 10.6) 4.38 (d, 10.6)
4.09 (d, 10.6) 4.48 (d, 10.6)
3.42 (td, 14.1 12.5, 3.68 (m, 14.1, 2.2) 4.32 (t, 3.0)e
2.2)
4.38 (d, 3.2)
13.4, 2.4)
7
2.32 (s) 3.58 (ddd,13.3,
12.1, 3.8)
2.99 (dq,
13.3 2.4)
3.44 (ddd, 14.1,
12.1, 2.4)
3.68 (m, 14.1, 3.8) 4.26 (t, 3.0)
4.98 (d, 3.2)
aNMR could not be recorded for compounds 4 and 5 because of their low solubility in CDCl3 and DMSO-d6.
bH-2 is axial for 1–3 and equatorial for 6 and 7.
cH-3 is axial for 1–3, 6, and 7.
dOverlapped signals correspond to 2H.
e4
3
J
for H-2 is calculated as the total width (6 Hz) – Ja, e for H-3a (3.2 Hz) = 2.8 Hz.
e, e
1
Spectrum 2. H–1H COSY spectrum of 6.
tween ester methylene and methyl protons. The cross peak
(C) (between H-2e and H-3a) and a group of cross peaks
(D) (between H-6e and H-5a, H-6a, H-5e) are obvious since
they are coupling partners.
If the aryl group were to be axial, there would be steric
interaction (from the Drieding model) between the o-
substituent in the aryl group and the axial S=O bond of the
sulphonyl group (Fig. 1).
13C NMR assignments are given in Table 2. The carbon
signals, especially for the aromatic and ipso carbons, are as-
signed only with the help of the HMBC (21) spectrum
(Spectrum 3). For example, between the two high frequency
© 2005 NRC Canada

Bhavani et al.
205
Spectrum 3. HMBC spectrum of 6.
Table 2. 13C NMR chemical shift values (ppm) of the ring car-
Fig. 1. Steric interaction between the o-OCH3 group and the ax-
ial S=O group.
bons of 2-alkoxycarbonyl-3-aryl-1,4-thiazane 1,1-dioxides (1–3,
6, 7).a
Compound
C-2
C-3
C-5
C-6
1
2
3
6
7
72.65
72.58
72.44
67.04
66.72
62.78
62.42
62.67
56.39
58.56
43.71
43.62
43.58
43.90
43.92
52.89
52.77
52.73
48.32
48.35
aNMR could not be recorded for compounds 4 and 5 because of their
low solubility in CDCl3 and DMSO-d6.
signals, 155.41 and 165.67 ppm, the former is assigned to
the methoxy group bearing the ipso carbon (C-2′) since it
gives multiple bond correlations with aromatic protons and
methoxy methyl protons, and the latter is assigned to the
carbonyl carbon since it gives multiple bond correlations
with H-3a, H-2e, and ester methylene protons.
The orientation of the NH proton, whether axial or equa-
torial, is derived only from the NOE (21) spectrum (Spec-
trum 4). The NH proton gives a NOE with the H-6′ proton
(A) and a strong NOE with the H-5a proton (B); the latter
excludes the axial orientation of the NH proton and there is
no NOE cross peak between the NH proton and the methoxy
methyl protons. The various NOE cross peaks confirm the
equatorial orientation of the NH proton and the perpendicu-
lar orientation of the o-methoxyphenyl ring to the plane of
the thiazane ring (Fig. 2). The absence of NOE between the
NH and ethoxycarbonyl methyl and methylene protons
(which are relatively in the 1,3-diaxial position, if N-H is
axial) excludes the possibility of an equilibrium between ax-
ial NH and equatorial NH.
Thus, the axial orientation of the ester group at the C-2
position, the equatorial and perpendicular orientation of the
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206
Can. J. Chem. Vol. 83, 2005
Spectrum 4. NOESY spectrum of 6.
Fig. 2. Relative configuration and conformation of compound 6.
Fig. 3. ORTEP diagram of 6.
o-substituted phenyl group at the C-3 position, and the chair
conformation of the thiazane ring are derived from NMR
spectra and confirmed by single crystal X-ray diffraction
study. The ORTEP diagram is given in Fig. 3.
Conclusion
o-Substituted benzaldehydes give r-2a-alkoxycarbonyl-c-
3-o-substituted phenyl-1,4-thiazane 1,1-dioxides when
treated with dialkyl ethane – 1,2–disulphonylacetate and am-
monium acetate as the stereoselective cis product. On the
other hand, benzaldehyde and p-substituted benzaldehydes
© 2005 NRC Canada

Bhavani et al.
207
1
give stereoselectively the trans product. The cis configura-
tion with the axial ethoxycarbonyl group and equatorial aryl
group is a consequence of the steric hindrance between the
o-substituent in the phenyl ring and the ethoxycarbonyl
group if it were in an equatorial orientation.
1290 (asy. SO2), 1125 (sym. SO2). H NMR (ppm): 0.99
(3H, t, CH3), 2.05 (1H, br.s, NH), 2.29 (3H, s, tolyl), 3.12
(2H, m, H-6a, H-6e), 3.40 (2H, m, H-5a, H-5e), 3.99 (2H, q,
3
CH2), 4.04 (1H, d, Ja,a = 10.6 Hz, H-2a), 4.38 (1H, d,
3Ja,a = 10.6 Hz, H-3a), 7.10 (2H, d, aromatic), 7.23 (2H, d,
aromatic). 13C NMR (ppm): 13.66 (CH3), 21.03 (tolyl),
43.62 (C-5), 52.77 (C-6), 62.08 (CH2), 62.42 (C-3), 72.58
(C-2), 125.49–138.62 (aromatic), 161.71 (C=O). Anal.
calcd. for C14H19NO4S: C 56.56, H 6.40, N 4.71; found: C
56.43, H 6.46, N 4.63.
Experimental
Melting points are uncorrected. Microanalytical data were
obtained from IISc, Bangalore-12, India. IR spectra were re-
corded on a JASCO-IR-700 IR spectrophotometer as potas-
sium bromide discs of the sample. Mass spectra were
obtained from RSIC, IIT, Chennai, India.
r-2e-Methoxycarbonyl-t-3-phenyl-1,4-thiazane 1,1-
dioxide (3)
NMR spectra were recorded at 27 °C on a Bruker AMX
400 instrument operating at 400 MHz at a concentration of
20 mg/mL in CDCl3 for 1H NMR and 100 MHz at a concen-
tration of 40 mg/mL in CDCl3 for 13C NMR, and chemical
shifts were referenced internally to TMS in all cases.
The experimental parameters for the 1H–1H COSY spectra
were: number of scans 16, number of data points 1 K, relax-
ation delay 1 s, acquisition time 0.1348 s, and spectral width
r-2e-Methoxycarbonyl-t-3-phenyl-1,4-thiazane 1,1-dioxide (3)
was obtained following the procedure of compound 1. Yield:
45%; mp 144–146 °C. IR (cm–1), 3425 (NH), 1715 (C=0),
1
1295 (asy. SO2), 1130 (sym. SO2). H NMR (ppm): 2.05
(1H, s, NH), 3.22 (2H, m, H-6a, H-6e), 3.48 (2H, m, H-5a,
3
H-5e), 3.59 (3H, s, CH3), 4.09 (1H, d, Ja,a = 10.6 Hz,
3
H-2a), 4.48 (1H, d, Ja,a = 10.6 Hz, H-3a), 7.31 (5H, m,
aromatic). 13C NMR (ppm): 43.58 (C-5), 52.73 (C-6), 52.92
(CH3), 62.67 (C-3), 72.44 (C-2), 127.48–128.83 (aromatic),
138.07 (ipso), 162.28 (C=O). Anal. calcd. for C12H15NO4S:
C 53.53, H 5.58, N 5.20; found: C 53.38, H 5.62, N 5.14.
1
3817 Hz. The H–13C COSY spectra were obtained using
the following parameters: number of scans 64, number of
data points 2 K, acquisition time 0.666 s, relaxation delay
1 s, and spectral width 9981 Hz in F1 and 15 576 Hz in F2.
r-2e-Ethoxycarbonyl-t-3-(p-methoxyphenyl)-1,4–thiazane
1,1-dioxide (4)
Crystallogrpahic data (22)
Compound 6 forms monoclinic crystals, a = 25.706 Å (5),
b = 9.7180 Å (19), c = 12.245 Å (2), β = 93.44(3)°, Z = 8,
space group C2/c. The structure was solved from 3132 ob-
served reflections (Mo Kα radiation), and refined to R =
0.093 and Rw = 0.100.
Diethylethane-1,2-disulphonyl acetate (0.05 mol), p-
methoxybenzaldehyde (0.05 mol), and ammonium acetate
(0.06 mol) in ethanol (100 mL) was refluxed for 15 h. The
excess solvent was removed by distillation and the residue
was poured into water. It solidified after 15 days. The solid
was filtered, washed with water, then with ether, dried, and
recrystallized from an ethanol–acetone mixture. Yield: 25%;
mp 165–167 °C. IR (cm–1): 3450 (NH), 1735 (C=O), 1290
(asy. SO2), 1115 (sym. SO2). Anal. calcd. for C14H19NO5S:
C 53.67, H 6.07, N 4.47; found: C 53.60, H 6.03, N 4.38.
Very low solubility in CDCl3.
Compounds
r-2e-Ethoxycarbonyl-t-3-phenyl-1,4-thiazane 1,1-dioxide
(1)
A mixture of diethyl ethane – 1,2-disulphonylacetate
(0.05 mol) (18), benzaldehyde (0.05 mol), and ammonium
acetate (0.06 mol) in ethanol (100 mL) was heated under re-
flux for 6 h. The excess of solvent was removed by distilla-
tion and the mixture was kept overnight. The separated solid
was filtered, washed with water, dried and recrystallized
from ethanol. Yield: 55%; mp 164 to 165 °C. IR (cm–1):
3400 (NH), 1722 (C=O), 1292 (asy. SO2), 1126 (sym. SO2).
1H NMR (ppm): 1.00 (3H, t, CH3), 1.88 (1H, br.s, NH), 3.19
(2H, m, H-6a, H-6e), 3.47 (2H, m, H-5a, H-5e), 4.01 (2H, q,
r-2e-Ethoxycarbonyl-t-3-(p-chlorophenyl)-1,4-thiazane
1,1-dioxide (5)
r-2e-Ethoxycarbonyl-t-3-(p-chlorophenyl)-1,4-thiazane 1,1-
dioxide (5) was obtained following the procedure of com-
pound 4. Yield: 30%; mp 178–180 °C. IR (cm–1): 3420
(NH), 1687 (C=O), 1290 (asy. SO2), 1120 (sym. SO2). Anal.
calcd. for C13H16NO4SCl: C 49.21, H 5.05, N 4.42; found: C
49.24, H 5.02, N 4.38. Very low solubility in CDCl3.
3
3
CH2), 4.06 (1H, d, Ja,a = 10.6 Hz, H-2a), 4.46 (1H, d, Ja,a
=
10.6 Hz, H-3a), 7.32–7.38 (5H, m, aromatic). 13C NMR
(ppm): 13.69 (CH3), 43.71 (C-5), 52.89 (C-6), 62.20 (CH2),
62.78 (C-3), 72.65 (C-2), 127.71–128.92 (aromatic carbon),
and 138.05 (ipso carbon). MS (m/z): 283, 238, 211, 196,
191, 172, 146, 133, 131, 130, 119, 118, 105, 104. Anal.
calcd. for C13H17NO4S: C 55.12, H 6.01, N 4.94; found: C
55.45, H 6.10, N 4.81.
r-2a-Ethoxycarbonyl-c-3-(o-methoxyphenyl)-1,4-thiazane
1,1-dioxide (6)
r-2a-Ethoxycarbonyl-c-3-(o-methoxyphenyl)-1,4-thiazane
1,1-dioxide (6) was obtained following the procedure of
compound 4; reaction time 20 h. Yield: 20%; mp 143–
145 °C. IR (cm–1): 3475 (NH), 1740 (C=O), 1295 (asy.
1
SO2), 1114 (sym. SO2). H NMR (ppm): 0.86 (3H, s, CH3),
2.39 (1H, br.s, NH), 2.96 (1H, dt, J = 13.4, 2.2 Hz, H-6e),
3.42 (1H, td, J = 14.1, 12.5, 2.2 Hz, H-5a), 3.56 (1H, td, J =
13.4, 12.5, 2.2 Hz, H-6a), 3.68 (1H, m, J = 14.1, 2.2 Hz, H-
5e), 3.87 (3H, s, methoxy), 3.90 (2H, Dq, CH2), 4.32 (1H, t,
J = 3.2, 2.8 Hz, H-2e), 4.91 (1H, d, J = 3.2 Hz, H-3a), 7.07
(4H, m, aromatic). 13C NMR (ppm): 13.44 (CH3), 43.90 (C-
r-2e-Ethoxycarbonyl-t-3-p-tolyl-l,4-thiazane 1,1-dioxide
(2)
r-2e-Ethoxycarbonyl-t-3-p-tolyl-l,4-thiazane 1,1-dioxide (2)
was obtained following the procedure of compound 1. Yield:
50%; mp 145 to 146 °C. IR (cm–1): 3420 (NH), 1724 (C=0),
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Can. J. Chem. Vol. 83, 2005
7. I.A. Shehata, H.I. Elsubbagh, A.M. Abdelal, M.A. Elsherbeny,
and A.A. Alobaide. Med. Chem. Res. 6, 148 (1996).
8. A.J. Boulton and A. Mckillop. Comprehensive hetrocyclic
chemistry. 1st ed. Vol. 3. Pergmon, Oxford. 1984. p. 1038.
9. L. Bukowski. Pharmazie, 56, 23 (2001).
5), 48.32 (C-6), 55.31 (methoxy), 56.39 (C-3), 61.57 (CH2),
67.04 (C-2), 110.28 (C-3′), 120.51 (C-5′), 125.37 (C-6′),
125.57 (C-1′), 129.03 (C-4′), 155.41 (C-2′), 165.67 (C=O).
Anal. calcd. for C14H19NO5S: C 53.67, H 6.07, N 4.47;
found: C 53.58, H 5.59, N 4.38.
10. T. Yamamoto, M. Hori, I. Watanabe, K. Harada, S. Ikeda, and
H. Ohtaka. Chem. Pharm. Bull. 48, 843 (2000).
11. V. Paul, D. Rene, and R. Paul. Bull. Soc. Chim. Fr. 1252
(1962).
r-2a-Ethoxycarbonyl-c-3-(o-chlorophenyl)-1,4-thiazane
1,1-dioxide (7)
12. V. Baliah and T. Rangarajan. J. Chem. Soc. 3069 (1954).
13. D. Bhaskar Reddy, S. Reddy, N. Subba Reddy, and M.V.
Ramana Reddy. Indian J. Chem. 30B, 529 (1991).
14. D. Bhaskar Reddy, S. Reddy, N. Subba Reddy, and M.V.
Ramana Reddy. Indian J. Chem. 34B, 816 (1995).
15. S. Selvaraj, A. Dhanabalan, A. Mercypushpalatha, and N.
Arumugam. Phosphorus Sulphur Silicon, 63, 295 (1991).
16. S. Selvaraj, A. Dhanabalan, and N. Arumugam. Indian J.
Chem. 33B, 67 (1994).
r-2a-Ethoxycarbonyl-c-3-(o-chlorophenyl)-1,4-thiazane 1,1-
dioxide (7) was obtained following the procedure of com-
pound 4; reaction time 20 h. Yield: 20%; mp 134–136 °C.
IR (cm–1): 3410 (NH) 1682 (C=0), 1303 (asy. SO2), 1115
(sym. SO2). Anal. calcd. for C13H16NO4SCl: C 49.21, H
5.05, N 4.42; found: C 49.13, H 5.09, N 4.36.
17. J.L. Garcia Ruano, M.C. Martinez, J.H. Rodriguez, E.M.
Olefirowicz, and E.L. Eliel. J. Org. Chem. 57, 4215 (1992).
18. V. Baliah and G. Prema. Indian J. Chem. 9, 1310 (1971).
19. Atta-ur-Rahman. Nuclear magnetic resonance. Basic princi-
ples. Springer, New York. 1986. p. 86.
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© 2005 NRC Canada