An efficient multicomponent stereoselective synthesis of 1,2,4-trisubstituted 1,3-thiazetidines

Article abstract of DOI:10.1016/j.tetlet.2011.05.098

The first one-pot three-component coupling reaction of O,O-diethyl hydrogen phosphorodithioate, aldehydes, and aldimines affording 1,2,4-trisubstituted 1,3-thiazetidines is reported. The product is obtained in moderate to high yields (45-94%) and has exce

Full text of DOI:10.1016/j.tetlet.2011.05.098

Tetrahedron Letters 52 (2011) 3933–3936
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An efficient multicomponent stereoselective synthesis
of 1,2,4-trisubstituted 1,3-thiazetidines
⇑
Ankita Rai, Lal Dhar S. Yadav
Green Synthesis Lab, Department of Chemistry, University of Allahabad, Allahabad 211 002, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The first one-pot three-component coupling reaction of O,O-diethyl hydrogen phosphorodithioate, alde-
hydes, and aldimines affording 1,2,4-trisubstituted 1,3-thiazetidines is reported. The product is obtained
in moderate to high yields (45–94%) and has excellent diastereoselectivity (90–96%) in favour of the cis
isomer. Shorter reaction times, ambient temperature, operational simplicity, and high yields are the sali-
ent features of the present procedure.
Received 25 March 2011
Revised 18 May 2011
Accepted 22 May 2011
Available online 30 May 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
O,O-Diethyl hydrogen phosphorodithioate
Aldehydes
Aldimines
Stereoselective synthesis
1,3-Thiazetidines
Multicomponent synthesis
In times where premium is put on speed, diversity, and effi-
ciency in modern drug discovery processes,1,2 multicomponent
reaction (MCR) strategies offer significant advantages over conven-
tional linear-type syntheses.3–6 Various 1,3-thiazetidine deriva-
tives are useful as broad spectrum antibacterial agents,7a,b
commercial soil pesticides,7c and intermediates in the synthesis
of thiazine sulfones,7d thiazolidines,7e triazoles, and triazines.7f
Although 1,3-thiazetidines are pharmaceutically, agrochemically,
and chemically relevant moieties,7 limited efforts have been made
for their synthesis. The construction of 1,3-thiazetidine ring system
reported in the literature mainly includes photochemical rear-
rangement of 1,3-thiazines and their derivatives,8 addition of
aqueous methylamine saturated with hydrogen sulfide to forma-
lin,9 and cycloaddition of bis(trifluoromethy1)thioketene with
Schiff bases,10 isocyanates with carbodiimides,11 and ethylene
thiourea with aromatic aldehydes.12 However, all of these reac-
tions suffer from one or more disadvantages, such as expensive re-
agents, long reaction times, low yields, tedious work-up, and low
selectivity. In continuation of our interest in developing new
one-pot stereoselective cyclisation processes,13–15 especially
involving sulfur- and phosphorus-based leaving groups,16–20 we
report herein a conceptually new and convenient route to 1,2,4-
trisubstituted 1,3-thiazetidines as outlined in Scheme 1.
O,O-diethyl hydrogen phosphorodithioate 1 with sodium hydride
followed by aldimines 2 and aldehydes 3 to afford the target com-
pounds 1,3-thiazetidines 4 in 45–94% yields (Scheme 1).21 For
comparison purpose, different solvents were tested in the present
synthetic protocol and THF was found to be the best solvent
amongst THF, benzene, and CH3CN, in terms of yield and stereose-
lectivity. In order to investigate the scope of the substrate for gen-
eral validity of the present investigation, several aldimines 2 and
aldehydes 3 were used employing the present reaction conditions
(Table 1). Isolation and purification by column chromatography
afforded hitherto unreported target compounds 4 in 45–94% yields.
The yield and diastereoselectivity were found to be consistently
S
P
S
P
NaH
-H2
EtO
EtO
EtO
EtO
S
Na
SH
1
5
Ts
N
S
R1
R2
2
R1
R2
N
After preliminary experimentation, it was found that the envis-
aged three-component synthesis was successful on treatment of
O
4
3
Ts
yield 45-94%
cis selectivity 90-96%
rt, THF, 4.5-6 h
⇑
Corresponding author. Tel.: +91 532 2500652; fax: +91 532 2460533.
E-mail address: ldsyadav@hotmail.com (L.D.S. Yadav).
Scheme 1. One-pot synthesis of 1,2,4-trisubstituted 1,3-thiazetidines 4.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.05.098

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A. Rai L.D.S Yadav / Tetrahedron Letters 52 (2011) 3933–3936
Table 1
One-pot synthesis of functionalised 1,3-thiazetidines 4 from diethyl hydrogen phosphorodithioate 1, aldimines 2 and aldehydes 3a
S
S
P
NaH, THF
rt, 5-6.5 h
Ts
R1
R2
R2
EtO
EtO
N
O
R1
SH
N
Ts
1
3
2
4
Entry
R1
R2
Timeb (h)
Product 4
Yieldc,d (%)
Cis/transe (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
4-ClC6H4
2-ClC6H4
4-CH3OC6H4
2-CH3OC6H4
4-ClC6H4
Ph
Ph
Ph
Ph
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
2-ClC6H4
2-ClC6H4
2-ClC6H4
2-ClC6H4
Ph
6
5
5
6
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
88
89
87
88
94
93
89
90
94
91
89
90
85
80
91
45
95:5f
97:3
95:5
96:4
98:2
97:3
95:5
95:5
97:3
96:4
95:5
96:4
95:5
96:4
95:5
95:5
4.5
4.5
5.5
5
4.5
4.5
5
5.5
6
6
2-ClC6H4
4-CH3OC6H4
2-CH3OC6H4
4-ClC6H4
2-ClC6H4
4-CH3OC6H4
2-CH3OC6H4
4-CH3C6H4
Ph
4-ClC6H4
n-Propyl
4-CH3C6H4
CCl3
Ph
4.5
6
a
b
c
d
e
f
For experimental procedure, see Ref. 21.
Stirring time at room temperature.
Yield of isolated and purified product 4.
All compounds gave C, H and N analyses within 0.38% and satisfactory spectral (IR, 1H NMR, 13C NMR and EIMS) data.
As determined by 1H NMR spectroscopy of the crude isolates.
Cis/trans (%) after purification was 97:3.
S
EtO
S
R1
Ts
R1
S
P
P
OEt
OEt
EtO
O
H
N
S
Ts
N
O
R2
7
R2
R2
S
P
O
anti intermediate
major
EtO
EtO
3
Favoured transition state
S
N
Ts
unfavourable syn interaction
6
R1
S
EtO
EtO
S
R1
Ts
R1
S
P
P
OEt
OEt
R2
O
N
S
Ts
R2
N
O
7′
H
syn intermediate
minor
Disfavoured transition state
Figure 1. Transition state model for cis selectivity.
good (Table 1), the highest yield of the isolated and purified prod-
uct 4 was 94% and the best diastereoselectivity was 96% as deter-
mined by 1H NMR spectroscopy of the crude isolate in the case of
4e (Table 1, entry 5). However, the present procedure with other
carbonyl compounds, such as butanal, cyclohexanecarboxalde-
hyde, and acetophenone, does not give satisfactory results presum-
ably because of the basic reaction conditions (yields of the
corresponding products 4: 21–28%). Both electron donating and
electron withdrawing substituents in aldimines 2 as well as in
aldehydes 3 are compatible to afford the corresponding products
4. It was also realised that not only aromatic aldehydes but also
an aliphatic non-enolizable aldehyde, for example, trichloroacetal-
dehyde works well in the present synthesis (Table 1, entry 15). It
may be mentioned here that other groups like Boc and Cbz can also
be used for activating nitrogen of the imine, but they are far less
efficient than the tosyl group in terms of the yield of 1,3-
thiazetidines 4. It was also observed that an aldimine derived from
an enolizable aldehyde afforded considerably lower yield of 4 (Ta-
ble 1, entry 16). This is probably due to an easy -deprotonation of
a
the tautomerizable imine leading to several side reactions.
The formation of 1,3-thiazetidines 4 is highly diastereoselective
in favour of the cis isomer. Presumably, the factors that control dia-
stereoselectivity are the preference for placing substituents equa-
torially in six-membered transition states and the avoidance of
syn interaction, respectively, as depicted in Fig. 1. The unfavoured
syn transition state experiences steric interaction, thus the reaction
proceeds through the more favourable transition state to form the
anti configured intermediate 7, stereoselectively leads to product 4
through 8 and 9, successively with a high cis stereoselectivity via
an SN2 reaction involving an inversion of configuration of the rela-
tive stereocentre in 9 (Scheme 2).
The relative stereochemistry of 1,3-thiazetidines 4 was also
established by NOE observations (Fig. 2). The strong NOE at 2-H
upon irradiation of 4-H indicates that 2-H and 4-H are located on

A. Rai L.D.S Yadav / Tetrahedron Letters 52 (2011) 3933–3936
3935
R2
Ts
S
P
S
P
O
S
P
N
R1
EtO
EtO
NaH
-H2
EtO
EtO
EtO
EtO
3
2
S
N
S
Na
SH
Ts
R1
S
6
5
1
S
S
R1
Ts
EtO
S
R1
Ts
EtO
EtO
S
R1
Ts
EtO
S
P
P
P
EtO
EtO
O
N
O
N
O
N
R2
R2
R2
9
8
7
S
S
R2
OEt
R1
R2
O
P
Ts
OEt
N
S
N
R1
Ts
4
4
Scheme 2. A plausible mechanism for the formation of 1,3-thiazetidines 4.
References and notes
12.3%
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H
H
R2
Ts
S
N
R1
Figure 2. NOE observation.
the same face of the molecule, that is, 1,3-thiazetidines 4 have 3,5-
cis configuration (Fig. 2). The reactions were clean and all the syn-
thesised products were characterised by their 1H NMR, 13C NMR, IR
and mass spectroscopic data.
8. Nigel, K. C.; Gareth, M. D.; Peter, B. H.; David, L.; Richard, W.; Mc, C.; Douglas,
W. Y. J. Chem. Soc., Perkin Trans. 1 1992, 621–626.
A plausible mechanism for the formation of 1,3-thiazetidines is
depicted in Scheme 2. The treatment of O,O-diethyl hydrogen
phosphorodithioate 1 with sodium hydride in THF at 60 °C gener-
ates sulfur anion 5 in situ which nucleophilically attacks at the
aldimine carbon atom to give a nitrogen anion 6. The anion 6 at-
tacks aldehyde 3, and the alkoxide ion 7 thus formed undergoes
intramolecular cyclisation to afford the desired product 4 as de-
picted in Scheme 2. The high affinity of phosphorus to oxygen is
the main driving force for the present heterocyclisation reaction
(7?4, Scheme 2). Compounds 4 have potential to serve as interme-
diates of other compounds owing to their easy detosylation and
opening of the 1,3-thiazetidine ring. Investigations on this subject
are in our future plans and the results will be published elsewhere.
In summary, we have developed a convenient one-pot route for
the synthesis of 1,3-thiazetidines in high yields and excellent diaste-
reoselectivity. The synthesis utilises readily and widely available
starting materials and is performed under ambient conditions. Thus,
the present operationally simple and efficient methodology would
be a practical alternative to the existing procedures for the synthesis
of this kind of fine chemicals.
9. Le Fèvre, C. G.; Le Fèvre, R. J. W. J. Chem. Soc. 1932, 1142–1148.
10. Raasch, M. S. J. Org. Chem. 1978, 43, 2500–2508.
11. Yokayama, M.; Monma, H. Tetrahedron 1980, 21, 293–296.
12. Ulrich, H.; Tucker, B.; Sayigh, A. A. R. J. Am. Chem. Soc. 1972, 94, 3484–3487.
13. Rai, A.; Singh, A. K.; Singh, S.; Yadav, L. D. S. Synlett 2011, 335–340.
14. Rai, A.; Singh, A. K.; Singh, P.; Yadav, L. D. S. Tetrahedron Lett. 2011, 52, 1354–
1358.
15. Rai, A.; Yadav, L. D. S. Tetrahedron Lett. 2010, 51, 4045–4049.
16. Yadav, L. D. S.; Kapoor, R.; Garima Synlett 2009, 1055–1058.
17. Yadav, L. D. S.; Kapoor, R. Synthesis 2002, 1502–1504.
18. Yadav, L. D. S.; Vaish, A. J. Chem. Res., Synop. 1993, 508–509.
19. Yadav, L. D. S.; Sharma, S. Synthesis 1993, 864–866.
20. Ueno, Y.; Yadav, L. D. S.; Okawara, M. Synthesis 1981, 547–548.
21. General procedure for the synthesis of 1,2,4-trisubstituted 1,3-thiazetidines 4: To a
solution of O,O-diethyl hydrogen phosphorodithioate 1 (5 mmol) in dry THF
(5 mL) was added dropwise a suspension of NaH (5 mmol) in dry THF (10 mL)
with stirring at rt. After the addition was complete, and evolution of hydrogen
gas (effervescence) had ceased, the reaction mixture was stirred at 60 °C for
30 min. Next, after cooling to rt, a solution of aldimine 2 (5 mmol) in dry THF
(5 mL) was added, and the reaction mixture was stirred at rt for 1 h followed by
the addition of aldehyde 3 (5 mmol) and stirring at rt for 3.5–5 h (Table 1).
After completion of the reaction as indicated by TLC, 10% HCl (1 mL) was added
and the mixture was stirred well. Then water (20 mL) was added and the
mixture was extracted with CH2Cl2 (3 Â 5 mL). The combined organic layer
was dried over anhydrous magnesium sulfate and concentrated under reduced
pressure to yield the crude product which was purified by silica gel column
chromatography (hexane–EtOAc; 95:5) to give the corresponding thiazetidines
4. The structure of the products was confirmed by their elemental and spectral
analyses.
Acknowledgements
Physical data of representative compounds. Compound 4a: White solid, yield
89%, mp 92–94 °C. IR (KBr) 3082, 2965, 2892, 2813, 2132, 1604, 1495, 1451,
We sincerely thank SAIF, Punjab University, Chandigarh, for
providing microanalyses and spectra. A.R. is grateful to the CSIR,
New Delhi, for the award of a Research Associateship (CSIR File
No. 09/001/(0327)/2010/EMR-I).
753, 706 cmÀ1 1H NMR (400 MHz; CDCl3) d: 2.46 (s, 3H, CH3), 4.90 (s, 1H, 4-H),
.
4.92 (s, 1H, 2-H), 7.32 (d, 2H, J = 8.2 Hz, Ts), 7.61–7.72 (m, 5H, Ph), 7.64–7.69
(m, 2H, 4-ClPh), 7.74 (d, 2H, J = 8.3 Hz, Ts), 8.12–8.16(m, 2H, 4-ClPh). 13C NMR
(100 MHz, CDCl3) d: 24.3, 57.4, 58.9, 126.1, 127.2, 128.4, 129.5, 130.7, 131.6,

3936
A. Rai L.D.S Yadav / Tetrahedron Letters 52 (2011) 3933–3936
132.4, 133.2, 134.8, 136.3, 138.9, 141.6. EIMS (m/z) 415 (M+). Anal. Calcd for
21H18ClNO2S2: C, 60.64; H, 4.36; N, 3.37. Found: C, 61.01; H, 4.15; N, 3.07.
Compound 4e: White solid, yield 94%, mp 94–96 °C. IR (KBr) 3081, 2969, 2890,
2810, 2135, 1605, 1497, 1450, 756, 702 cmÀ1 1H NMR (400 MHz; CDCl3) d:
Ts), 7.65–7.69 (m, 2H, 4-ClPh), 7.67–7.70 (m, 2H, 2-ClPh), 7.76 (d, 2H, J = 8.4 Hz,
C
Ts), 8.10–8.15 (m, 2H, 2-ClPh), 8.12–8.16 (m, 2H, 4-ClPh). 13C NMR (100 MHz,
CDCl3) d: 24.3, 48.1, 57.4, 102.9, 125.8, 126.9, 127.9, 129.0, 129.9, 130.8, 132.2,
133.5, 134.6, 135.9, 136.5, 137.3, 141.2. EIMS (m/z) 449 (M+). Anal. Calcd for
.
2.44 (s, 3H, CH3), 4.94 (s, 2H, 2-H, 4-H), 7.34 (d, 2H, J = 8.2 Hz, Ts), 7.62–7.70
(m, 4H, 4-ClPh), 7.76 (d, 2H, J = 8.1 Hz, Ts), 8.14–8.19(m, 4H, 4-ClPh). 13C NMR
(100 MHz, CDCl3) d: 24.6, 57.1, 58.4, 126.4, 127.3, 128.3, 129.2, 130.2, 131.1,
132.5, 133.7, 135.7, 136.9, 138.0, 141.8. EIMS (m/z) 449 (M+). Anal. Calcd for
C21H17Cl2NO2S2: C, 56.00; H, 3.80; N, 3.11. Found: C, 55.68; H, 3.53; N,
3.49.Compound 4i: White solid, yield 91%, mp 91–93 °C. IR (KBr) 3084, 2969,
C
21H17Cl2NO2S2: C, 56.00; H, 3.80; N, 3.11. Found: C, 56.29; H, 3.50; N, 2.82.
Compound 4o: White solid, yield 91%, mp 84–87 °C. IR (KBr) 3081, 2969, 2890,
2813, 2134, 1605, 1497, 1450, 757, 702 cmÀ1 1H NMR (400 MHz; CDCl3) d:
.
2.46 (s, 3H, CH3), 4.81 (s, 1H, 4-H), 4.95 (s, 1H, 2-H), 7.37 (d, 2H, J = 8.2 Hz, Ts),
7.62–7.69 (m, 2H, 4-ClPh), 7.75 (d, 2H, J = 8.3 Hz, Ts), 8.10–8.17 (m, 2H, 4-ClPh).
13C NMR (100 MHz, CDCl3) d: 24.9, 56.4, 71.1, 101.5, 126.9, 128.4, 129.5, 130.8,
132.6, 136.5, 137.9, 142.4. EIMS (m/z) 415 (M+). Anal. Calcd for
2894, 2814, 2134, 1601, 1492, 1452, 754, 706 cmÀ1 1H NMR (400 MHz; CDCl3)
.
d: 2.41 (s, 3H, CH3), 4.94 (s, 1H, 4-H), 4.97 (s, 1H, 2-H), 7.31 (d, 2H, J = 8.3 Hz,
C16H13Cl4NO2S2: C, 42.03; H, 2.87; N, 3.06. Found: C, 41.81; H, 3.16; N, 3.26.