Catalyst-free regio- and stereospecific synthesis of β-sulfonamido dithiocarbamates: Efficient ring-opening reactions of N-tosyl aziridines by dialkyldithiocarbamates

Article abstract of DOI:10.1002/chem.201100817

Lord of the ring-opening! A metal-free strategy involving ring-opening of aziridines by the sodium salt of dialkyldithiocarbamate has been employed to give a variety of β-sulfonamido dithiocarbamates. The in situ generation of dialkyldithiocarbamates prov

Full text of DOI:10.1002/chem.201100817

DOI: 10.1002/chem.201100817
Catalyst-Free Regio- and Stereospecific Synthesis of b-Sulfonamido
Dithiocarbamates: Efficient Ring-Opening Reactions of N-Tosyl Aziridines
by Dialkyldithiocarbamates
Kaliyamoorthy Alagiri and Kandikere Ramaiah Prabhu*[a]
Functionalized dithiocarbamates are of great interest be-
cause of their potential applications in pharmaceuticals and
agrochemicals.[1–4] Functionalization of the carbamate
moiety offers an attractive method for the generation of
compounds containing sulfur and nitrogen, which have wide
applications and utility in solid-phase organic synthesis,[5]
vulcanization,[6] and polymerization.[7] They are well exploit-
ed as protective groups in peptide synthesis,[8a] in addition to
being used as ligands to stabilize transition metals in a wide
range of oxidation states.[8b] Due to their strong metal bind-
ing capability, they also can act as inhibitors of enzymes and
have a profound effect on biological systems. As a result, di-
thiocarbamate derivatives are used in medicinal chemistry
for the treatment of cancer.[8c,d] Additionally, dithiocarba-
mates serve as the precursors for substituted thiazole deriva-
tives, which are potential anti-HIV agents, antibacterial
agents, and phosphodiesterase 10 inhibitors.[9,10] Interesting-
ly, in most of the reactions that achieve such compounds,
thiocarbamates are treated with halides in the presence of a
dithiocarbamate derivatives have involved the following: a
one-pot Michael addition of alkyl dithiocarbamates to chal-
cones,[20a] reaction of dithiocarbamate with alcohols under
Mitsunobu conditions,[20b] coupling sodium dialkyldithiocar-
bamate with aryl iodide in the presence of copper iodide as
the catalyst,[20c] and ring-opening of epoxides using alkyl di-
thiocarbamates in an ionic liquid medium.[20d] Although nu-
cleophilic ring-opening of aziridines have been known for
over three decades, there are only few reports on the nucle-
ophilic ring-opening of aziridines by thiols and other thio-
derivatives.[12a,13a,21] Therefore, we envisioned that ring-open-
ing of aziridine using sodium dialkyl dithiocarbamate would
be a useful addition for the synthesis of functionalized di-
thiocarbamates. In continuation of our research program to
develop environmentally benign methods,[22] herein we
report a novel, efficient, and catalyst-free synthesis of b-sul-
fonamido dithiocarbamates through ring-opening of various
N-tosyl aziridines.
Preliminary experiments of the ring-opening reaction of
N-tosylaziridine 1a by sodium diethyldithiocarbamate
(DEDTC) using toluene as the solvent at ambient tempera-
ture did not give the expected product, even after a pro-
longed reaction time (48 h; Table 1, entry 1). Nevertheless,
the same reaction heated at reflux resulted in a ring-opening
of the aziridine to give the (S)-alkylthiocarbamate 2a in ex-
cellent yield (80%, 24 h; Table 1, entry 2). However, the
same reaction in water did not give the expected product,
[10]
À
metal catalyst to form C S bonds.
Hence, the develop-
ment of new synthetic routes to accomplish functionalized
dithiocarbamates has been an attractive field of research for
organic chemists for the past few decades.[11]
Interestingly, aziridines are versatile building blocks for
the synthesis of biologically important compounds.[12] The
ring-opening reaction of aziridines and their importance has
been reviewed by Hu,[13] Lu,[14] and others.[14b] The ring-
opening of meso-aziridines in an asymmetric fashion has
been well exploited by Schnieder[15] and Kagan.[16] The reac-
tivity of aziridines towards ring-opening reactions is attribut-
ed to their extremely strained ring structure, which enables
them to act as carbon electrophiles.[17,18]The classical meth-
ods of synthesizing N-alkyl or N-aryl dithiocarbamate deriv-
atives involves the reaction of amines with expensive and
toxic reagents, such as thiophosgene and/or an isothiocya-
nate.[19] Recent examples of synthesizing N-alkyl- or N-aryl-
Table 1. Optimization of the reaction conditions.
Entry
Solvent
T
[8C]
t
Yield
[%][a]
[h]
1
2
3
4
5
6
7
8
9
toluene
toluene
H2O
RT
110
RT
100
RT
78
50
RT
80
48
24
120
48
96
24
67
96
12
–
80
–
[a] K. Alagiri, Dr. K. R. Prabhu
Department of Organic Chemistry
Indian Institute of Science
H2O
–
EtOH
EtOH
EtOH
CH3CN
CH3CN
95
95
95
95
97
Bangalore, Karnataka (India)
Fax : (+91)80-23600529
E-mail: prabhu@orgchem.iisc.erenet.in
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201100817.
[a] Yields of isolated products. Ts=tosyl.
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Chem. Eur. J. 2011, 17, 6922 – 6925

COMMUNICATION
either at room temperature or at reflux conditions (Table 1,
entries 3 and 4). Furthermore, ring-opening reactions of N-
tosyl aziridine proceeded well in solvents such as EtOH or
CH3CN and afforded the corresponding ring-opened prod-
uct in excellent yields (Table 1, entries 5–9). As shown in
Table 1, the reactions at ambient temperature required a
longer time (Table 1, entries 5 and 8), whereas the reactions
at elevated temperature were faster (Table 1, entries 6, 7,
and 9). Finally, we found that treatment of 1a (1 equiv) with
sodium DEDTC (1.05 equiv) in CH3CN heated to reflux are
the ideal conditions for this reaction, which gave the product
2a in excellent yield (97%,
yields (Table 2, entries 4–7). Aziridines 1e and 1 f reacted
well with DEDTC to give the corresponding products 2e
and 2 f in almost quantitative yields (Table 2, entries 8 and
9). However, aziridine derived from cyclooctene 1g required
a longer time to give the product 2g in moderate yield (3
days, 65%; Table 2, entry 5). Although, most of the reac-
tions of aziridines with DEDTC and DMDTC were regio-
specific (Table 2, entries 1–10), the reactions of 2-phenyl-1-
tosylaziridine (1h) with DEDTC or DMDTC was different
and gave a mixture of regioisomers (Table 2, entries 11 and
12).
12 h; Table 1, entry 9).
Table 2. Ring-opening of tosyl aziridine by sodium DEDTC[a] and DMDTC.[b]
After optimizing the condi-
tions, we examined the general-
ity of the reaction by using a
variety of N-tosylaziridines and
dialkyldithiocarbamates
Entry
Substrate
t
Product
Yield
[%][c]
(Table 2). The reactions of dif-
ferent cyclic and open-chain N-
tosyl
aziridines
proceeded
1
2
3
1a
1a
1b
12 h
1 h
2a: R3 =Et
3a: R3 =Me
2b
97
97
88
smoothly under the optimized
conditions with high regio- and
stereoselectivity. We believe
that the attack of the dialkyldi-
thiocarbamate ion at the less
hindered side of the aziridine
ring is responsible for the for-
mation of the product in a ste-
reospecific fashion. To general-
ize the application of the ring-
opening reaction by dialkylthio-
carbamate we used sodium salts
of DEDTC and sodium dime-
thyldithiocarbamate
0.5 h
4
5
6
7
8
1c
1c
1d
1d
1e
1 h
2c: R3 =Et
3c: R3 =Me
2d: R3 =Et
3d: R3 =Me
2e
97
99
97
98
99
30 min
10 min
10 min
12 h
(DMDTC). As shown in
Table 2, 2-isopropyl-3-methyl-1-
tosylaziridine (1a) reacted well
with DEDTC or DMDTC to
produce the corresponding
ring-opened products 2a and
3a in excellent yields (Table 2,
entries 1 and 2). The reaction of
(2-methyl-1-tosylaziridin-2-yl)-
methanol 1b with DEDTC also
proceeded well to give the cor-
responding ring-opened product
2b in excellent yield. Similarly,
aziridines that are part of cyclic
structures such as cyclopentyl-
and cyclohexyl N-tosyl aziri-
dines (1c and 1d, respectively)
underwent smooth ring-opening
reaction with DEDTC or
DMDTC to afford the corre-
sponding trans-b-sulfonamido
9
1 f
1g
0.5 h
2 f
2g
99
65
10
3 days
11
1h
1 h
2h: R3 =Et
99[d]
3h: R3 =Et
12
1h
10 min
4h, 5h: R3 =Me
99[e]
[a] DEDTC=Diethyldithiocarbamate. [b] DMDTC=Dimethyldithiocarbamate. [c] Yields of isolated products.
dithiocarbamates in excellent [d] Isolated as a mixture of regioisomers: 2h/3h; 2:1. [e] Isolated as a mixture of regioisomers: 4h/5h; 3:1.
Chem. Eur. J. 2011, 17, 6922 – 6925
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K. Ramaiah Prabhu and K. Alagiri
Since dialkyldithiocarbamates are obtained by the reac-
tion of N,N-dialkylamine with CS2 in the presence of a base,
we thought that it would be ideal to generate the dialkyldi-
thiocarbamate in situ by reacting CS2 and the corresponding
N,N-dialkylamine, then further treat the reaction mixture
(without isolation) with aziridine. Therefore, we generated
dithiocarbamate anion in situ by reacting CS2 with N,N-di-
ethylamine at 08C for 2 h and the reaction mixture was then
treated with aziridine 1c and refluxed until completion of
the reaction (1 h). As expected, the ring-opened product 2c
was isolated in almost quantitative yield (Scheme 1).
tion of 2-phenyl-1-tosylaziridine (1h) resulted in the forma-
tion of mixture of regioisomers; isomers 2h and 3h were
isolated in 2:1 ratios (99%; Table 3, entry 5).
However, the mechanism of this reaction is still not clear.
Based on the literature precedence, we believe that the thio-
carbamate anion is attacking aziridine at the less hindered
side to generate the trans isomer.[12a] We speculate that both
the nucleophilicity of sulfur and activation by the tosyl
group on the aziridine ring facilitates the ring-opening.
In conclusion, we have developed an efficient protocol for
the synthesis of b-sulfonamido dithiocarbamates by using a
ring-opening strategy of aziridnes by thiocarbamates. This
strategy provides an elegant method for synthesizing a wide
range of b-sulfonamido dithiocarbamates by using inexpen-
sive and readily available starting materials. In addition, a
one-pot method has been developed for a facile ring-open-
ing of aziridines by using in situ generated dialkyldithiocar-
bamate. These methods avoid toxic catalysts and, in most
cases, give nearly quantitative yields without any byproducts.
This methodology could potentially prove useful for the syn-
thesis of medicinally active and other commercial dithio-
carbamate derivatives. Further exploitation of this method-
ology and mechanism are currently underway in our labora-
tories.
Scheme 1. One-pot reaction.
The one-pot reaction of dialkyldithiocarbamate (gener-
ated in situ) with aziridine to produce b-sulfonamido dithio-
carbamates is further illustrated in Table 3 with several ex-
amples. This approach appears to be general, because the in
situ generated DEDTC or DMDTC reacted with aziridines
1a and 1d to afford corresponding ring-opened products in
excellent yields (Table 3, entries 1–4) As expected, the reac-
Experimental Section
Typical experimental procedure: A mixture of well-stirred aziridine de-
rived from cyclopentene (1c, 119 mg, 0.5 mmol) and sodium diethyldi-
thiocarbamate (119 mg, 0.527 mmol) in CH3CN (1 mL) was heated at
reflux until the completion of reaction (1 h, monitored by TLC). The re-
action mixture was concentrated under vacuum and the resultant crude
mixture was purified by column chromatography on silica gel (EtOAc/
Hexane; 1:10) to give the corresponding b-sulfonamido dithiocarbamate
2c as a white solid in 97% yield.
Table 3. Ring-opening of tosyl aziridine by in situ generated DEDTC
and DMDTC.
Typical experimental procedure (in situ method): Carbon disulfide
(0.06 mL, 1 mmol) was added to a well-stirred mixture of aziridine de-
rived from cyclohexene (1d, 125 mg, 0.5 mmol) and diethyl amine
(0.067 mL, 0.65 mmol) in CH3CN (1 mL) at 08C and the mixture was
stirred at same temperature for 2 h and then heated at 808C for 1 h. The
reaction mixture was concentrated under vacuum and the resultant crude
mixture was purified by column chromatography on silica gel (EtOAc/
Hexane; 1:5) to give the corresponding b-sulfonamido dithiocarbamate
2d as yellow-white solid in 98% yield.
Entry Substrate
t
Product
Yield
[%][a]
[h]
1
2
1a 15
2a: R3 =Et
98
1a
3
3a: R3 =Me 97
2d: R3 =Et 98
3d: R3 =Me 98
3
4
1d 2.5
1d 2.5
99[b]
Acknowledgements
5
1h
3
2h
We are grateful to Indian Institute of Science, CSIR, New-Delhi (No. 01-
AHCTUNGERTG(NNUN 2415)/10/EMR-II) and Ray Chemicals for financial support. Dr. A. R.
Ramesha for useful discussion and Prof. Sosale Chandrasekhar and
Anjan Roy for encouragement. K.A. thanks CSIR, New-Delhi for a re-
search fellowship.
3h
Keywords: aziridines · dithiocarbamates · regioselectivity ·
ring-opening · synthetic methods
[a] Yields of isolated products. [b] Isolated as a mixture of regioisomers:
2h/3h; 2:1.
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Chem. Eur. J. 2011, 17, 6922 – 6925

Efficient Ring-Opening Reactions of N-Tosyl Aziridines
COMMUNICATION
[12] a) D. Tanner, Angew. Chem. 1994, 106, 625; Angew. Chem. Int. Ed.
Engl. 1994, 33, 599; b) T. Ibuka, Chem. Soc. Rev. 1998, 27, 145;
c) C. M. Rayner, Synlett 1997, 11; i) W. McCoull, F. A. Davis, Synthe-
sis 2000, 1347; e) J. B. Sweeney, Chem. Soc. Rev. 2002, 31, 247.
[13] X. E. Hu, Tetrahedron 2004, 60, 2701.
[14] a) P. Lu, Tetrahedron 2010, 66, 2549; b) J. E. Baldwin, R. M. Adling-
ton, I. A. OꢁNeil, C. Schofield, A. C. Spivey, J. B. Sweeney, J. Chem.
Soc. Chem. Commun. 1989, 1852.
[1] M. J. Earle, S. P. Katdare, K. R. Seddon, Org. Lett. 2004, 6, 707.
[2] a) B. C. Ranu, S. Banerjee, Org. Lett. 2005, 7, 3049; b) B. C. Ranu,
R. Jana, S. Sowmiah, J. Org. Chem. 2007, 72, 3152.
[3] L. Ronconi, C. Marzano, P. Zanello, M. Corsini, G. Miolo, C. Macca,
A. Trevisan, D. Fregona, J. Med. Chem. 2006, 49, 1648.
[4] M. Dꢁhooghe, N. De Kimpe, Tetrahedron 2006, 62, 513, and referen-
ces therein.
[5] a) P. Morf, F. Raimondi, H.-G. Nothofer, B. Schnyder, A. Yasuda,
J. M. Wessels, T. A. Jung, Langmuir 2006, 22, 658; b) A. McClain,
Y.-L. Hsieh, J. Appl. Polym. Sci. 2004, 92, 218; c) A. D. Dunn, W.-D.
Rudorf, Carbon Disulphide in Organic Chemistry, Ellis Horwood,
Chichester, 1989, p. 226.
[15] a) C. Schneider, Angew. Chem. 2009, 121, 2116; Angew. Chem. Int.
Ed. 2009, 48, 2082; b) S. Peruncheralathan, H. Teller, C. Schneide r
Angew. Chem. 2009, 121, 4943; Angew. Chem. Int. Ed. 2009, 48,
4849; Angew. Chem. Int. Ed. 2009, 48, 4849, and references cited
therein.
[6] a) P. J. Nieuwenhuizen, A. W. Ehlers, J. G. Haasnoot, S. R. Janse, J.
Reedijk, E. J. Baerends, J. Am. Chem. Soc. 1999, 121, 163; b) G. D.
Thorn, R. A. Ludwig, The Dithiocarbamates and Related Com-
pounds, Elsevier, Amsterdam, 1962; c) H. R. Nice, Org. React. 1962,
12, 57.
[7] a) M. R. Wood, D. J. Duncalf, S. P. Rannard, S. Perrier, Org. Lett.
2006, 8, 553, and references therein; b) D. Crich, L. Quintero, Chem.
Rev. 1989, 89, 1413; c) D. H. R. Barton, Tetrahedron 1992, 48, 2529;
d) S. Z. Zard, Angew. Chem. 1997, 109, 724; Angew. Chem. Int. Ed.
Engl. 1997, 36, 672.
[16] a) C. Girard, H. Kagan, Angew. Chem. 1998, 110, 3088; Angew.
Chem. Int. Ed. 1998, 37, 2922; b) T. Satyanarayana, S. Abraham,
H. B. Kagan, Angew. Chem. 2009, 121, 464; Angew. Chem. Int. Ed.
2009, 48, 456, and references therein.
[17] a) A. K. Yudin, Aziridines and Epoxides in Organic Synthesis,
Wiley-VCH, Weinheim, 2006; b) D. M. Hodgson, M. J. Fleming, S. J.
Stanway, Org. Lett. 2005, 7, 3295, and references therein.
[18] a) Y. Fukuta, T. Mita, N. Fukuda, M. Kanai, M. Shibasaki, J. Am.
Chem. Soc. 2006, 128, 6312; b) P. Li, E. M. Forbeck, C. D. Evans,
M. M. Joullie, Org. Lett. 2006, 8, 5105.
[8] a) T. W. Greene, P. G. M. Wuts, Protecting Groups in Organic Syn-
thesis, 3rd ed., Wiley Interscience, New York, 1999, p. 484; b) G. Ho-
garth, Prog. Inorg. Chem. 2005, 53, 7; c) W. Walter, K.-D. Bode,
Angew. Chem. 1967, 79, 285; Angew. Chem. Int. Ed. Engl. 1967, 6,
281; d) G. H. Elgemeie, S. H. Sayed, Synthesis 2001, 1747.
[9] S. Massari, D. Daelemans, M. L. Barreca, A. Knezevich, S. Sabatini,
V. Cecchetti, A. Marcello, C. Pannecouque, O. Tabarrini, J. Med.
Chem. 2010, 53, 641.
[19] a) H. Tilles, J. Am. Chem. Soc. 1959, 81, 714; b) W. Chin-Hsien, Syn-
thesis 1981, 622; c) H. Sugiyama, J. Synth. Org. Chem. Jpn. 1980, 38,
555.
[20] a) N. Azizi, F. Aryanasab, M. R. Saidi, Org. Lett. 2006, 8, 5275; b) D.
Chaturvedi, S. Ray, Tetrahedron Lett. 2006, 47, 1307; c) Y. Liu, W.
Bao, Tetrahedron Lett. 2007, 48, 4785; d) B. C. Ranu, A. Saha, S.
Banerjee, Eur. J. Org. Chem. 2008, 519.
[21] a) D. Sureshkumar, S. M. Koutha, S. Chandrasekaran, J. Am. Chem.
Soc. 2005, 127, 12760; b) H Stamm, J. Prakt. Chem. 1999, 341, 319.
[22] a) M. Maddani, K. R. Prabhu, J. Org. Chem. 2010, 75, 2327; b) M.
Maddani, K. R. Prabhu, Tetrahedron Lett. 2007, 48, 7151.
[10] D. Ma, X. Lu, L. Shi, H. Zhang, Y. Jiang, X. Liu, Angew. Chem.
2011, 123, 1150; Angew. Chem. Int. Ed. 2011, 50, 1118, and referen-
ces therein.
[11] a) T. F. Wood, J. H. Gardner, J. Am. Chem. Soc. 1941, 63, 2741;
b) A. Goel, S. J. Mazur, R. J. Fattah, T. L. Hartman, J. A. Turpin, M.
Huang, W. G. Rice, E. Appella, J. K. Inman, Bioorg. Med. Chem.
Lett. 2002, 12, 767.
Received: March 17, 2011
Published online: May 6, 2011
Chem. Eur. J. 2011, 17, 6922 – 6925
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6925