Copper-catalyzed synthesis of N-fused heterocycles through regioselective 1,2-aminothiolation of 1,1-dibromoalkenes

Article abstract of DOI:10.1021/ol101563f

The first aminothiolation of 1,1-dibromoalkene is described using an inexpensive copper/N,N-dimethylethylenediamine catalyst. The method provides a powerful means of using easily available 1,1-dihaloalkenes as precursors to fused heterocycles.

Full text of DOI:10.1021/ol101563f

ORGANIC
LETTERS
2010
Vol. 12, No. 16
3704-3707
Copper-Catalyzed Synthesis of N-Fused
Heterocycles through Regioselective
1,2-Aminothiolation of 1,1-Dibromoalkenes
Hui Xu, Yin Zhang, Jianqiang Huang, and Wanzhi Chen*
Department of Chemistry, Zhejiang UniVersity, Xixi Campus,
Hangzhou 310028, Peoples Republic of China
chenwzz@zju.edu.cn
Received July 7, 2010
ABSTRACT
The first aminothiolation of 1,1-dibromoalkene is described using an inexpensive copper/N,N-dimethylethylenediamine catalyst. The method
provides a powerful means of using easily available 1,1-dihaloalkenes as precursors to fused heterocycles.
Transition-metal-catalyzed hydroelementation of unsaturated
organic compounds represents an atom-economic protocol
for the construction of C-heteroatom bonds.1-3 Catalytic
Ullmann-type C-heteroatom coupling is an alternative
powerful tool for synthesis of heteroatom-containing com-
pounds.4-6 Both approaches have found wide application
in material science and pharmaceutical chemistry. We
envisioned that 1,2-aminothiolation of unsaturated halides
would yield compounds with N and S nucleophiles at the
1,2- positions (Scheme 1). Sequential nucleophilic substitu-
tion and H-X (X ) S, N) addition would simultaneously
result in the formation of C-S and C-N bonds. Here we
report a concise and practical preparation of imidazol[2,1-b]-
thiazole and related N-fused heterocyles based on a novel
copper-catalyzed 1,2-aminothiolation of 1,1-dihaloalkenes.
The starting materials are easily available from aldehydes,
and the resulting N-fused heterocyles have shown promising
(1) For recent reviews on hydroelementation of unsaturated compounds,
see: (a) Mu¨ller, T. E.; Hultzsch, K. C.; Yus, M.; Foubelo, F.; Tada, M.
Chem. ReV. 2008, 108, 3795. (b) Alonso, F.; Beletskaya, I. P.; Yus, M.
Chem. ReV. 2004, 104, 3079
.
(4) For recent reviews on C-heteroatom coupling, see: (a) Monnier,
F.; Taillefer, M. Angew. Chem., Int. Ed. 2009, 48, 6954. (b) Hartwig, J. F.
Acc. Chem. Res. 2008, 41, 1534. (c) Hartwig, J. F. Nature 2008, 455, 314.
(5) A few examples of C-N coupling: (a) Chen, W.; Zhao, Q.; Xu,
M.; Lin, G. Org. Lett. 2010, 12, 1072. (b) Fors, B. P.; Davis, N. R.;
Buchwald, S. L. J. Am. Chem. Soc. 2009, 131, 5766. (c) Thansandote, P.;
Raemy, M.; Rudolph, A.; Lautens, M. Org. Lett. 2007, 9, 5255. (d) Kabir,
M. S.; Lorenz, M.; Namjoshi, O. A.; Cook, J. M. Org. Lett. 2010, 12, 464.
(6) A few examples of C-S coupling: (a) Murru, S.; Ghosh, H.; Sahoo,
S. K.; Patel, B. K. Org. Lett. 2009, 11, 4254. (b) Ferna´ndez-Rodríguez,
M. A.; Hartwig, J. F. J. Org. Chem. 2009, 74, 1663. (c) Sperotto, E.; van
Klink, G. P. M.; de Vries, J. G.; van Koten, G. J. Org. Chem. 2008, 73,
5625. (d) Zhang, Y.; Ngeow, K. C.; Ying, J. Y. Org. Lett. 2007, 9, 3495.
(2) Recent examples of hydroamination: (a) Rizk, T.; Bilodeau, E. J.-
F.; Beauchemin, A. M. Angew. Chem., Int. Ed. 2009, 48, 8325. (b) Han, J.;
Xu, B.; Hammond, G. B. J. Am. Chem. Soc. 2010, 132, 916. (c) Iska,
V. B. R.; Verdolino, V.; Wiest, O.; Helquist, P. J. Org. Chem. 2010, 75,
1325. (d) Enomoto, T.; Girard, A.-L.; Yasui, Y.; Takemoto, Y. J. Org.
Chem. 2009, 74, 9158. (e) Duan, H.; Sengupta, S.; Petersen, J. L.;
Akhmedov, N. G.; Shi, X. J. Am. Chem. Soc. 2009, 131, 12100
.
(3) For recent examples of hydrothiolation, see: (a) Cao, C.; Fraser, L. R.;
Love, J. A. J. Am. Chem. Soc. 2005, 127, 17614. (b) Ogawa, A.; Ikeda, T.;
Kimura, K.; Hirao, T. J. Am. Chem. Soc. 1999, 121, 5108. (c) Yang, J.;
Sabarre, A.; Fraser, L. R.; Patrick, B. O.; Love, J. A. J. Org. Chem. 2009,
74, 182. (d) Sabarre, A.; Love, J. A. Org. Lett. 2008, 10, 3941
.
10.1021/ol101563f  2010 American Chemical Society
Published on Web 07/29/2010

reactions of thiols are less explored. To our delight, the
aminothiolation reaction took place smoothly using Cu salts
as catalysts, leading to the desired cyclization product. CuI
is more suitable than other copper salts, and DMEDA is the
best ligand. As shown in Table 1, the aminothiolation of 1
has a significant dependence on the nature of the bases.
Inorganic bases such as K3PO4 and Cs2CO3 and organic bases
DBU and Bu4NF are efficient. The organic bases gave better
yields of octylbenzoimidazo[2,1-b]thiazole, whereas inor-
ganic bases required higher temperature and gave lower
conversions. The results showed that the regioselectivity is
not sensitive to the copper sources, bases, and temperature.
Under the optimized conditions, a total yield of 2- and
3-octylimidazo[2,1-b]thiazole was obtained in ca. 7:1 ratio.
The scope of the copper-catalyzed aminothiolation was
examined by reacting 1a with different aromatic 1,1-
dibromoalkenes with various substituents and aliphatic 1,1-
dibromoalkenes of different chains. As shown in Table 2,
under the optimized conditions (10 mol % of CuI, 15 mol
% of DMEDA, and 2-5 equiv of Bu4NF), the aminothiola-
tion of 2 and 1a appeared to be quite general with respect to
the substituents. Thus, aromatic olefins bearing electron-
donating and -withdrawing groups and heteroaromatic olefins
were smoothly aminothiolated to give N-fused heterocycles
3a-j in good to very high yields (entries 1-10). The isomers
4a-j were not obtained. Electron-deficient substrates gave
better yields. Aromatic halides are tolerated, and no amina-
tion or thiolation was observed, so that this offers additional
opportunity for further functionalization. The olefins bearing
heteroaryl groups could also be aminothiolated to afford
cyclization products in good yields. Unlike aromatic alkenes,
the linear aliphatic olefins underwent aminothiolation to
furnish isomers 4k-n as the major products. However, bulky
2o yielded a mixture of 3o and 4o in a 3:1 ratio (entries 16).
It should be noted that in the absence of CuI, the reaction of
aliphatic olefin 2k yielded only 5k in addition to the desired
cyclization product (entry 12).8 In addition, under the same
reaction conditions, both aromatic and aliphatic alkynyl
bromides could be aminothiolated in comparable yields and
regioselectivities (entries 17-19).
Scheme 1. Aminothiolation of 1,1-Dibromoalkene
biological activities as inhibitors of neurodegenerative dis-
orders and antitumor drugs.7
Initially, the aminothiolation of 1,1-dibromodecene and
2-mercaptobenzoimidazole (1a) was selected as a model
system to optimize the reaction conditions; the results are
summarized in Table 1. It was found that the choices of metal
Table 1. Optimization of Copper-Catalyzed Aminothiolation of
1,1-Dibromodecenea
yield (%)
entry
catalyst
solvent base ligandb t (°C) (3/4 ratio)
1
DMF
Cs2CO3
110
75
2
dioxane DBU
toluene DBU
3
75
4
CuI
DMF
Cs2CO3 DMEDA 110
43 (1/6)
5
CuI
toluene CsCO3 DMEDA 110
6
CuI
DMF
DMF
Cs2CO3 DMEDA
Cs2CO3 DMEDA
rt
50
65
65
65
7
CuI
19 (1/4)
27 (1/4)
70 (1/7)
81 (1/7)
80 (1/7)
8
CuI
dioxane K3PO3 DMEDA
9
CuI
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DBU
DMEDA
10
11
12
13
14
15
15
16
17
18
19
20
21
CuI
TBAF DMEDA
CuI
TBAF DMEDA 110
Et3N DMEDA 110
K3PO3 DMEDA 110
CuI
Cu2O
Cu2O
Cu2O
37 (1/7)
80 (1/7)
74 (1/7)
47 (1/6)
78 (1/7)
76 (1/7)
trace
TBAF DMEDA
65
65
110
65
65
110
110
110
DBU
DMEDA
CuSO4·5H2O DMF
CuSO4·5H2O DMF
CuSO4·5H2O DMF
K3PO3 phen
TBAF DMEDA
DBU
DMEDA
NiCl2
DMF
DMF
DMF
DMF
Cs2CO3 dmdi
Cs2CO3 dppf
Cs2CO3 PPh3
Pd(AcO)2
Pd(dba)2
FeCl3
trace
trace
Cs2CO3 DMEDA 110
trace
a Reactions were carried out using 2-mercaptobenzimidazole (1 mmol),
1,1-dibromodecene (1.2 mmol), base (5 mmol), catalyst (0.1 mmol), ligand
(0.15 mmol), and solvent (3 mL), 24 h, under N2. b DMEDA ) N,N′-
dimethylethanediamine; phen )1,10-phenanthroline; dppf )1,1′-bis(dipheny-
phosphino)ferrocene; dmdi )1,1′-dimethyl-3,3′- methylenedi- imidazolium
dibromide.
The methodology was also applied to the aminothiolation
of unsubstituted and substituted 2-mercaptoimidazole, peri-
midine, and pyrimidine derivatives with aromatic and
aliphatic dibromoalkenes (Table 3). Good yields of the
expected N-fused heterocycles, 10-phenylthiazolo[3,2-a]peri-
midine, 3-phenyl-5H-thiazolo[3,2-a]pyrimidin-5-one, and
imidazothiazine derivatives were obtained in most cases.
However, the cyclization of 1c with 2k did not occur under
catalysts, bases, and solvents are critical to the reaction. In
the absence of a metal catalyst, the cyclization reaction did
not procceed no matter what inorganic and organic bases
were used. When Bu4NF was used as the base, the dehy-
drohalogenation of 1,1-dibromodecene and subsequent hy-
drothiolation of 1-bromoalkyne was observed, giving (Z)-
2-(1-bromooct-1-en-2-ylthio)-1H-benzo[d]imidazole as the
major product. Pd, Fe, and Ni salts together with various N-
and P-donors were found ineffective using Cs2CO3 or DBU
(1,8-diazabicyclo[5.4.0] undec-7-ene) as bases in either polar
or nonpolar solvents, and these reactions yielded complicated
mixtures. Sulfur compounds are often considered to be
poisons to transition metal catalysts, and thus the catalytic
(7) (a) Andreani, A.; Granaiola, M.; Leoni, A.; Locatelli, A.; Morigi,
R.; Rambaldi, M.; Garaliene, V.; Welsh, W.; Arora, S.; Farruggia, G.;
Masotti, L. J. Med. Chem. 2005, 48, 5604. (b) Venkatesan, A. M.; Gu, Y.;
Santos, O. D.; Abe, T.; Agarwal, A.; Yang, Y.; Petersen, P. J.; Weiss, W. J.;
Mansour, T. S.; Nukaga, M.; Hujer, A. M.; Bonomo, R. A.; Knox, J. R.
J. Med. Chem. 2004, 47, 6556. (c) Pietrancosta, N.; Moumen, A.; Dono,
R.; Lingor, P.; Planchamp, V.; Lamballe, F.; Bähr, M.; Kraus, J.-L.; Maina,
F. J. Med. Chem. 2006, 49, 3645. (d) Andreani, A.; Burnelli, S.; Granaiola,
M.; Leoni, A.; Locatelli, A.; Morigi, R.; Rambaldi, M.; Varoli, L.; Calonghi,
N.; Cappadone, C.; Farruggia, G.; Zini, M.; Stefanelli, C.; Masotti, L.; Radin,
N. S.; Shoemaker, R. H. J. Med. Chem. 2008, 51, 809.
(8) The structures of compounds 5k and 3z were confirmed by X-ray
single crystal diffraction analysis. See Supporting Information.
Org. Lett., Vol. 12, No. 16, 2010
3705

Table 2. Copper-Catalyzed Regioselective Aminothiolationa
a 1a (1.0 mmol) and 2 (1.2 mmol) for 24 h. b Isolated yields and 3 and 4 ratio in bracket. c No copper was used.
the conditions described above but gave the hydrothiolated
product 5c as the sole isolated product. When a stronger base
(DBU) was used, the expected 4t could be obtained in a
moderate yield. 2-Thioxo-2,3-dihydropyrimidin-4(1H)-ones
1e and 1f also reacted with dibromoalkenes, giving the
corresponding cyclization. In the case of aliphatic alkene,
the regioselectivity is low. Finally, (1H-benzo[d]imidazol-
2-yl)methanethiol (1g) reacted with 2a, yielding 8H-benz-
imidazo[2,1-c][1,4]thiazine 3z.8
alkene takes place via a copper-catalyzed C-S coupling
of 1-bromoalkyne to alkynyl thioether 6 and subsequent
intramolecular hydroamination (5-endo-dig cyclization) of
6.10,11 In the case of an aliphatic alkene, the nucleophilic
N-alkynylation would occur, leading to ynamide 5 through
copper-catalyzed C(sp)-N coupling of 1-bromoalkyne and
subsequent formation of a thiazole ring via a 5-endo-dig
hydrothiolation giving the final product 4 (Scheme 2).12
(10) Ochiai, M.; Tada, N. Chem.Commun. 2005, 5083.
Most probably the reaction involves 1-bromoalkyne in situ
generated from dehydrohalogenation of 1,1-dibromoal-
kenes.9 We propose that the aminothiolation of aromatic
(11) A few examples of 5-endo-dig cyclizations: (a) Staben, S. T.;
Kennedy-Smith, J. J.; Toste, F. D. Angew. Chem., Int. Ed. 2004, 43, 5350.
(b) Yao, P.-Y.; Zhang, Y.; Hsung, R. P.; Zhao, K. Org. Lett. 2008, 10,
4275. (c) Sniady, A.; Durham, A.; Morreale, M. S.; Wheeler, K. A.;
Dembinski, R. Org. Lett. 2007, 9, 1175. (d) Kim, I.; Kim, K.; Choi, J. J.
Org. Chem. 2009, 74, 8492. (e) Arimitsu, S.; Hammond, G. B. J. Org.
Chem. 2007, 72, 8559. (f) Yin, Y.; Ma, W.; Chai, Z.; Zhao, G. J. Org.
Chem. 2007, 72, 5731. (g) Fustero, S.; Ferna´ndez, B.; Bello, P.; del Pozo,
C.; Arimitsu, S.; Hammond, G. B. Org. Lett. 2007, 9, 4251.
(9) Base-promoted dehydrohalogenation of dihaloalkenes: (a) Okutani,
M.; Mori, Y. J. Org. Chem. 2009, 74, 442. (b) Söederberg, B. C. G.;
Gorugantula, S. P.; Howerton, C. R.; Petersen, J. L.; Dantale, S. W.
Tetrahedron 2009, 65, 7357.
3706
Org. Lett., Vol. 12, No. 16, 2010

Table 3. Aminothiolation of Various Thiolsa
Scheme 2. Possible Pathways for Aminothiolation
In conclusion, we have developed a novel copper-
catalyzed aminothiolation of 1,1-dibromoalkenes by using
a catalytic amount of CuI in combination with DMEDA.
The procedure is economical and experimentally simple
for the facile preparation of fused heterocyclic compounds
having two different heteroatoms from easily available
1,1-dibromoalkenes. The scope and limitations of the
reaction itself and the synthetic application of the products
obtained are now under investigation.
Acknowledgment. The project is supported by NSFC
(20872129 and J0830413) and the Fundamental Research
Funds for the Central Universities (2009QNA3004).
Supporting Information Available: Experimental pro-
cedures, spectroscopic data, crystallographic data of 3z and
5k in CIF format. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL101563F
(12) For copper-catalyzed C(sp)-N coupling of 1-bromoalkyne, see:
(a) DeKorver, K. A.; Li, H.; Lohse, A. G.; Hayashi, R.; Lu, Z.; Zhang, Y.;
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Freyer, M. W.; Kerwin, S. M. J. Org. Chem. 2008, 73, 6462. (e) Fukudome,
Y.; Naito, H.; Hata, T.; Urabe, H. J. Am. Chem. Soc. 2008, 130, 1820. (f)
Dooleweerdt, K.; Birkedal, H.; Ruhland, T.; Skrydstrup, T. J. Org. Chem.
2008, 73, 9447. (g) Hamada, T.; Ye, X.; Stahl, S. S. J. Am. Chem. Soc.
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a The reaction conditions are the same as denoted in Table 1. b DBU
(1,8-Diazabicyclo[5.4.0]undec-7-ene) was used as the base.
Although 6-endo-dig cyclization is also favored,13 the yield
is relatively low (Table 2, entry 11).
(13) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734.
Org. Lett., Vol. 12, No. 16, 2010
3707