Tributylphosphine-catalyzed cycloaddition of aziridines with carbon disulfide and isothiocyanate

Article abstract of DOI:10.1021/jo801703h

(Chemical Equation Presented) Aziridines underwent cyclization reaction with carbon disulfide and isothiocyanate in the presence of organophosphine to afford thiazolidinone derivatives in good to high yields. The mechanistic study revealed that organophosphine serves as a catalyst in the reaction.

Full text of DOI:10.1021/jo801703h

TABLE 1. Reaction of Aziridine 1a with CS2 in the Presence of
Organophosphinea
Tributylphosphine-Catalyzed Cycloaddition of
Aziridines with Carbon Disulfide and
Isothiocyanate
entry
solvent
catalyst
yield (%)b
1
2
3
4
5
6
7
8
THF
toluene
CCl4
PPh3
PPh3
PPh3
PPh3
PPh3
PCy3
PBu3
none
20
trace
81
83
78
Jing-Yu Wu, Zhi-Bin Luo, Li-Xin Dai, and Xue-Long Hou*
EtOH
State Key Laboratory of Organometallic Chemistry,
Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Road,
Shanghai 200032, P. R. China
t-BuOH
t-BuOH
t-BuOH
t-BuOH
92
78
c
PBu3
a Molar ratio of 1a:CS2:organophosphine ) 1:6.6:0.1, run in 2 mL of
solvent. b Isolated yield, the structure was determined by 1H NMR. c 50
mol % of PBu3 was used.
xlhou@mail.sioc.ac.cn
ReceiVed July 31, 2008
epoxides with heterocumulenes, such as carbon disulfide and
isothiocyanate, to form heterocycles.3 However, a relatively
limited number of reports on the reaction of aziridines with
heterocumulenes have appeared.4 Most of the reactions pro-
ceeded in the presence of a metal catalyst,4b-d and few of them
used organo-molecules as the catalyst. During the studies on
the transformation of aziridines,5 we found that organophos-
phines played a role as a trigger to initiate the ring-opening
reaction of aziridines6a-c as well as the transformation of
aziridines to conjugated dienes.6d Upon the basis of these results,
further investigations on the reaction of aziridines using
organophosphine were carried out. In this paper, we disclose
the organophosphine-catalyzed reaction of aziridines with carbon
disulfide and isothiocyanate to produce 1,3-thiazolidine deriva-
tives, which are commonly used as potential intermediates in
pharmaceutical chemistry and organic synthesis.7 Furthermore,
a plausible mechanism is proposed.
At the beginning, the reaction of aziridine 1a with CS2 in
the presence of Bu3P was studied (eq 1). The solvent has great
impact on the reaction (Table 1). No product was obtained when
the reaction was carried out in THF using triphenylphosphine
as a catalyst (entry 1). 1,3-Thiazolidine 2a was afforded in 20%
yield when the reaction was carried out in toluene (entry 2),
while only a trace of the desired product was isolated with CCl4
Aziridines underwent cyclization reaction with carbon di-
sulfide and isothiocyanate in the presence of organophosphine
to afford thiazolidinone derivatives in good to high yields.
The mechanistic study revealed that organophosphine serves
as a catalyst in the reaction.
Aziridines are versatile intermediates for the synthesis of
biologically important compounds due to their ability to function
as carbon electrophiles.1,2 Many transformations of activated
and unactivated aziridines have well been documented, and the
ring-opening reactions are among the most studied ones. On
the other hand, there are many reports on the reaction of
(3) For examples: (a) Baba, A.; Seki, K.; Matsuda, H. J. Heterocycl. Chem.
1990, 27, 1925. (b) Nozaki, K.; Nakano, K.; Hiyama, T. J. Am. Chem. Soc.
1999, 121, 11008. (c) Peng, J. J.; Deng, Y. Q. New J. Chem. 2001, 25, 639. (d)
Paddock, R. L.; Nguyen, S. T. J. Am. Chem. Soc. 2001, 123, 11498. (e) Calo,
V.; Nacci, A.; Monopoli, A.; Fanizzi, A. Org. Lett. 2002, 4, 2561. (f) Shen,
Y. M.; Duan, W. L.; Shi, M. J. Org. Chem. 2003, 68, 1559. (g) Lu, X. B.;
Liang, B.; Zhang, Y. J.; Tian, Y. Z.; Wang, Y. M.; Bai, C. X.; Wang, H.; Zhang,
R. J. Am. Chem. Soc. 2004, 126, 3732.
(4) (a) Clapp, L. B.; Watjen, J. W. J. Am. Chem. Soc. 1953, 75, 1490. (b)
Nomura, R.; Nakano, T.; Nishio, Y.; Ogawa, S.; Ninagawa, A.; Matsuda, H.
Chem. Ber. 1989, 122, 2407. (c) Baeg, J. O.; Bensimon, C.; Alper, H. J. Am.
Chem. Soc. 1995, 117, 4700. (d) McCormick, B. J.; Kaplan, R. I.; Stormer, B. P.
Can. J. Chem. 1971, 49, 699. (e) Tascedda, P.; Dunach, E. Chem. Commun.
2000, 6, 449. (f) Hancock, M. T.; Pinhas, A. R. Tetrahedron Lett. 2003, 44,
5457. (g) Sudo, A.; Morioka, Y.; Koizumi, E.; Sanda, F.; Endo, T. Tetrahedron
Lett. 2003, 44, 7889.
(5) (a) Hou, X. L.; Wu, J.; Fan, R. H.; Ding, C. H.; Luo, Z. B.; Dai, L. X.
Synlett 2006, 2, 181. (b) Ding, C. H.; Dai, L. X.; Hou, X. L. Tetrahedron 2005,
61, 9586. (c) Luo, Z. B.; Hou, X. L.; Dai, L. X. Tetrahedron: Asymmetry 2007,
18, 443. (d) Luo, Z. B.; Wu, J. Y.; Hou, X. L.; Dai, L. X. Org. Biomol. Chem.
2007, 5, 3427.
(6) (a) Fan, R. H.; Hou, X. L.; Dai, L. X. J. Org. Chem. 2002, 67, 5295. (b)
Fan, R. H.; Hou, X. L. J. Org. Chem. 2003, 68, 726. (c) Fan, R. H.; Hou, X. L.
Tetrahedron Lett. 2003, 44, 4411. (d) Fan, R. H.; Hou, X. L.; Dai, L. X. J. Org.
Chem. 2004, 69, 689.
(1) For some reviews of reactions of aziridines, see: (a) Tanner, D. Angew.
Chem., Int. Ed. Engl. 1994, 33, 599. (b) Stamm, H. J. Prakt. Chem. 1999, 341,
319. (c) Hu, X. E. Tetrahedron 2004, 60, 2701. (d) Yudin, A. K., Ed. Aziridines
and Epoxides in Organic Synthesis; Wiley-VCH: Weinheim, 2006.
(2) Some examples of the reaction of aziridines, see: (a) Jacques, B.; Josette,
C. R.; Roger, V. Synthesis 1992, 288. (b) Bellos, K.; Stamm, H. J. Org. Chem.
1995, 60, 5661. (c) Antolini, L.; Bucciarelli, M.; Caselli, E.; Davoli, P.; Forni,
A.; Moretti, I.; Prati, F.; Torre, G. J. Org. Chem. 1997, 62, 8784. (d) Maligres,
P. E.; See, M. M.; Askin, D.; Reider, P. J. Tetrahedron Lett. 1997, 38, 5253. (e)
Wipf, P.; Uto, Y. Tetrahedron Lett. 1999, 40, 5165. (f) Bae, J. H.; Shin, S. H.;
Park, C. S.; Lee, W. K. Tetrahedron 1999, 55, 10041. (g) Katagiri, T.; Takahashi,
M.; Fujiwara, Y.; Ihara, H.; Uneyama, K. J. Org. Chem. 1999, 64, 7323. (h)
Mu¨ller, P.; Nury, P. Org. Lett. 1999, 1, 439. (i) Yadav, J. S.; Reddy, B. V. S.;
Premalatha, K. AdV. Synth. Catal. 2003, 345, 948. (j) Hedley, S. J.; Moran, W. J.;
Price, D. A.; Harrity, J. P. A. J. Org. Chem. 2003, 68, 4286. (k) Hancock, M. T.;
Pinhas, A. R. Synthesis 2004, 2347. (l) Hodgson, D. M.; Fleming, M. J.; Stanway,
S. J. Org. Lett. 2005, 7, 3295. (m) Fukuta, Y.; Mita, T.; Fukuda, N.; Kanai, M.;
Shibasaki, M. J. Am. Chem. Soc. 2006, 128, 6312. (n) Sun, X.; Ye, S.; Wu, J.
Eur. J. Org. Chem. 2006, 4787. (o) Li, P.; Forbeck, E. M.; Evans, C. D.; Joullie,
M. M. Org. Lett. 2006, 8, 5105. (p) Savoia, D.; Alvaro, G.; Di Fabio, R.;
Gualandi, A. J. Org. Chem. 2007, 72, 3859. (q) Yang, X.; Yudin, A. K. Synlett
2007, 2912.
10.1021/jo801703h CCC: $40.75
Published on Web 10/23/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 9137–9139 9137

TABLE 2. Cycloaddition of CS2 with Aziridines Catalyzed by
Bu3Pa
showed that Bu3P was still the best catalyst, while a trace of
product was afforded if Ph3P was used. In addition, CH3CN
was the choice among common solvents tested, including THF,
DMF, BuOH, and CHCl3. Under the conditions described in
eq 3, the scope of aziridines was investigated (Table 3).
entry
aziridine
R1, R2, R3
product
yield %b
t
1
2
3
4
5
6
7
8
9
10
1a
1b
1c
1d
1e
1f
1g
1h
1i
-(CH2)4-, H
-(CH2)3-, H
-(CH2)5-, H
-(CH2)6-, H
n-C4H9, H, H
n-C6H13, H, H
n-C16H33, H, H
Bn, H, H
2a
2b
2c
2d
2e
2f
92
tracec
41
-
98
90
83
93
91
98
2g
2h
2i
n-C3H7, H, CH3
Ph, H, H
1j
2j:2j’ ) 1:1d
Good yields were obtained from the reaction of aziridine 1a
and 1m derived from cyclohexene and cyclohexadiene, respec-
tively, with phenyl isothiocyanate (entries 1 and 11), while 3b
was obtained in 16% yield with the same reason as that in the
reaction with CS2 (entry 2). Aziridine 1c derived from cyclo-
heptene gave the product in 47% yield (entry 3), while no
product was obtained when aziridine 1d derived from cy-
clooctene was used (entry 4). Substrates 1j and 1k derived from
styrene and internal aliphatic alkene, respectively, afforded the
corresponding heterocycles in good yields (entries 8 and 9),
while 1e-g derived from terminal alkenes gave moderate yields
(entries 5-7). The reaction of other disubstituted aziridines 1l
and 1n provided the products in lower yields (entries 10 and
12). A moderate yield of product 3p was afforded when butyl
isothiocyanate was used (entry 14), but a lower yield of 3o was
obtained when naphthyl isothiocyanate was the reagent (entry
13). The reactions have the same regiochemistry as that with
CS2 (vide supra).
a Reaction conditions: aziridine (0.25 mmol), CS2 (0.1 mL, 1.65 mmol),
and Bu3P (6.25 µL, 0.025 mmol). b Isolated yield based upon aziridine.
d
c Indicated by TLC. Products ratio was determined by H NMR.
1
as the solvent (entry 3). The yield of 2a increased dramatically
to 81% and 83% when EtOH and t-BuOH were the solvent,
respectively (entries 4 and 5). The influence of organophosphines
on the reaction was also investigated. The yield of 2a was 92%
when Bu3P was used (entry 7), while 78% and 83% yield of
the product was obtained using Cy3P and PPh3 as the catalyst,
respectively (entries 6 and 5). An increase of the amount of
organophosphine did not improve the yield of product (entry 8
vs entry 7). The trans-structure of product 2a was determined
by the coupling constant of the two bridgehead hydrogens (J
) 11.7 Hz) and confirmed further by the X-ray analysis (see
Supporting Information).
The thiol group plays a vital role in the function of a large
number of biopolymers. The active sites of enzymes, subunit
interactions, and certain membrane functions may also involve
mercapto groups. For this reason, numerous attempts have been
made to develop highly specific thiol group reagents. To
demonstrate the utility of the current reactions, we found that
the treatment of compound 2a with LiAlH4 overnight at room
temperature afforded ꢀ-thio amine 5 in nearly quantitative yield
(eq 4).
Under the optimized reaction conditions, the scope of the
reaction was examined (eq 2, Table 2). Excellent yields were
obtained from the reactions of aziridine 1a derived from
cyclohexene and 1e-j derived from acyclic alkenes (entries 1
and 5-10). However, no product was obtained from aziridine
1b derived from cyclopentene (entry 2) because of the high
strain energy of trans-stereochemistry of the product. For the
reaction of 1c derived from cycloheptene, only 41% yield of
the desired product was afforded (entry 3) likely due to the steric
hindrance of the substrate. Only the products formed by the
attack of the S-atom of CS2 at the terminal carbon were detected
This organophosphine-catalyzed reaction of heterocumulenes
can also be extended to that with epoxides, providing corre-
sponding heterocycles in good yields (eq 5). However, oligo-
merization of phenyl isocyanate was observed in the reaction
of aziridine 1a with it.
1
by H NMR from the reaction of monoalkyl-substituted aziri-
dines 1e-h and gem-disubstituted aziridine 1i (entries 5-8 and
9). For the phenyl-substituted aziridine 1j, the terminal- and
benzylic-attacked products were formed in a ratio of 1:1 (entry
10) caused by the interference of the electronic and steric effect.
The regioselectivity of the reaction is in accordance with that
of aziridines with other nucleophiles reported in the literature.1,2
To understand the role of organophosphine in this reaction,
the study of 31P NMR was performed. As we reported before,
the mixture of aziridine 1a and Bu3P in benzene at 25 °C in a
molar ratio of 1:1 gave a signal at δ 31.07 ppm from the 31P
NMR spectrum.6a No product was detected when CS2 was added
to the above solution and after the resulting mixture was refluxed
To extend the scope of this organophosphine-catalyzed
cyclization reaction, the reaction of aziridines with isothiocy-
anates was tested (eq 3). Optimization of the reaction conditions
9138 J. Org. Chem. Vol. 73, No. 22, 2008

TABLE 3. Cycloaddition of Isothiocyanate with Aziridines
Catalyzed by Bu3Pa
SCHEME 1. Plausible Mechanism of the P-Catalyzed
Reaction of Aziridine 1 with CS2
entry
aziridine
R1, R2
product
yield %b
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1j
1k
1l
1m
1n
1a
1a
-(CH2)4-
-(CH2)3-
-(CH2)5-
-(CH2)6-
n-C4H9, H
n-C6H13, H
n-C16H33, H
Ph, H
n-C5H11, CH3
Ph, CO2Me
-CH2CHdCHCH2-
Ph, Me
3a
3b
3c
3d
3e
3f
78
16
47
-
39
53
56
78
62
27
77
38
23
55
3g
3j:3j ) 5:2c
9
3k + 3k’
10
11
12
13
14
3l
3m
3n
-(CH2)4-
-(CH2)4-
3od
3pe
a Reaction conditions: aziridine (0.5 mmol), isothiocyanate (1 mmol),
and Bu3P (6.25 µL, 0.05 mmol). b Isolated yield based upon aziridine.
c Product ratio was determined by 1H NMR. d 1-Naphthyl isothiocyanate
was used. e Butyl isothiocyanate was used.
for 24 h. On the other hand, when CS2 and Bu3P were mixed
in benzene in a ratio of 1:1, a signal at δ 15.35 ppm from the
31P NMR spectrum appeared, indicating the formation of a
zwitterion.8 Product 2a was afforded when aziridine 1a was
added and refluxed for 12 h, while the signals at 15.76 and
-30.90 ppm were detected from the 31P NMR spectrum, which
showed the reproduction of Bu3P.
From these clues, a plausible reaction mechanism is proposed
(Scheme 1). Phosphine attacks CS2 to form zwitterion Int-A,8
which reacts with aziridine 1 to give ring-opened intermediate
Int-B. Ring closure of this intermediate affords product 3 and
reproduces Bu3P to complete the catalytic cycle. This mecha-
nism differs from that of organophosphine-mediated ring-
opening reaction of aziridines with nucleophiles,6a in which
organophosphine just serves as a trigger to initiate the reaction.
In summary, we have developed an efficient organophos-
phine-catalyzed ring-opening reaction of carbon disulfide and
isothiocyanates with aziridines as well as with epoxides, which
provides a simple and convenient way to the synthesis of
thiazolidinone derivatives. The mechanistic study reveals that
the organophosphine serves as catalyst in the reaction.9 Further
investigations on the asymmetric version of the reaction as well
as the further applications of this organophosphine-catalyzed
reaction of heterocumulene in organic synthesis are in progress.
Experimental Section
Representative Procedure for the Phosphine-Catalyzed Reac-
tion of Aziridine 1a with Phenyl Isothiocyanate. In a Schlenk
tube equipped with condenser, Bu3P (6.25 µL, 0.025 mmol) was
added to a stirring mixture of aziridine 1a (62.75 mg, 0.25 mmol),
phenyl isothiocyanate (60 µL, 0.5 mmol), and anhydrous acetonitrile
(2 mL) under argon at rt. Then the mixture was heated to reflux
for 24 h until the substrate disappeared and monitored by TLC.
After that, the mixture was concentrated under reduced pressure,
and the residue was purified by flash chromatography on silica gel
using PE/EtOAc (10:1) as eluent to give 3a as solid, 75.3 mg, 78%
yield. 1H NMR (300 MHz, CDCl3) δ: 1.35-1.57 (m, 3H),
1.68-1.86 (m, 2H), 1.93-2.03 (m, 2H), 2.45 (s, 3H), 3.13-3.26
(m, 2H), 3.62 (td, J ) 3.3 Hz, 11.1 Hz, 1H), 6.55 (d, J ) 7.8 Hz,
2H), 7.04 (t, J ) 7.2 Hz, 1H), 7.12 (m, 2H), 7.31 (d, J ) 8.1 Hz,
2H), 7.90 (d, J ) 8.4 Hz, 2H). 13C NMR (300 MHz, CDCl3) δ:
21.7 (Ar-CH3), 24.4 (CH2), 25.3 (CH2), 29.4 (CH2), 32.7 (CH2),
49.1 (S-CH), 70.6 (N-CH), 120.5 (Ar-C), 124.3 (Ar-C), 128.9
(Ar-C), 129.0 (Ar-C), 129.1 (Ar-C), 135.2 (Ar-C), 144.5
(Ar-C), 150.0 (Ar-C), 154.8 (NdC). IR: 1641, 1594, 1359, 1174,
1087. Anal. Calcd for C20H22N2O2S2: C, 62.15; H, 5.74; N, 7.25.
Found: C, 61.98; H, 5.76; N, 7.19.
Acknowledgment. Financially supported by the Major Basic
Research Development Program (2006CB806100), National
Natural Science Foundation of China (20532050, 20672130),
Chinese Academy of Sciences, and Science and Technology
Commission of Shanghai Municipality.
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Supporting Information Available: Full experimental pro-
cedures, characterization data, copies of 1H and 13C NMR
spectra of products, and X-ray analysis data of compounds 2a
and 3a (cif file). This material is available free of charge via
the Internet at http://pubs.acs.org.
(9) For review of organophosphine as catalyst in the reactions: Methot, J. L.;
Roush, W. R. AdV. Synth. Catal. 2004, 346, 1035.
JO801703H
J. Org. Chem. Vol. 73, No. 22, 2008 9139