Regioselective bromocyclization of unsaturated N-tosylcarbamates promoted by N, N-dibromosulfonamides

Article abstract of DOI:10.1055/s-0034-1378314

Simple and highly regioselective bromo-N-cyclization and bromo-O-cyclization reactions of unsaturated N-tosylcarbamates have been developed. The use of N,N-dibromosulfonamides as brominating reagents plays an important role in these electrophilic cyclizat

Full text of DOI:10.1055/s-0034-1378314

LETTER
▌1921
lRetteergioselective Bromocyclization of Unsaturated N-Tosylcarbamates Promoted
by N,N-Dibromosulfonamides
Regioselective Bromocyclization
Guo-Tao Fan, Ming-Hui Sun, Ge Gao, Jie Chen,* Ling Zhou*
Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, Department of Chemistry & Materials
Science, Northwest University, Xi’an 710069, P. R. of China
Fax +86(29)88303915; E-mail: chmchenj@nwu.edu.cn; E-mail: zhoul@nwu.edu.cn
Received: 02.04.2014; Accepted after revision: 12.05.2014
3a, in 27% and 42% yields, respectively (Table 1, entry
Abstract: Simple and highly regioselective bromo-N-cyclization
1). We then examined the effects of stoichiometric
and bromo-O-cyclization reactions of unsaturated N-tosylcarba-
amounts of various bases (entries 2–6). The regioselectiv-
ity was improved slightly by using potassium carbonate or
mates have been developed. The use of N,N-dibromosulfonamides
as brominating reagents plays an important role in these electrophil-
ic cyclization reactions. This method is useful in organic synthesis. sodium carbonate as the base (entries 2 and 3, respective-
ly),8,11 but when potassium tert-butoxide or triethylamine
was used, oxazolidinone 2a was obtained as the sole prod-
The desired products can be smoothly transformed into aziridines or
epoxides.
Key words: alkenes, amides, cyclizations, electrophilic additions,
regioselectivity
uct in low yield (entries 4 and 6).
The structures of oxazolidinone 2a and dioxolanimine 3a
were unambiguously confirmed by NMR spectroscopy
and X-ray crystal studies (Figure 1).10
Electrophilic intramolecular halocyclizations of olefins
are valuable synthetic transformations.1 Various sub-
strates, including unsaturated carboxylic acids, alcohols,
amines, amides, and carbamates, have been widely used
in syntheses of halogenated cyclic compounds.2 Whereas
halolactonization, haloetherification, and haloaminocycli-
zation are efficient reactions,1,3 halocyclizations of unsat-
urated substrates having ambident nucleophilic groups,
such as amides or carbamates, can give mixtures of N- and
O-cyclization products.4 Generally, the O-selective prod-
ucts are obtained in preference to the N-selective prod-
ucts,5 various methods have been developed to achieve
regioselective halo-N-cyclization reactions, such as en-
hancement of the acidity of NH groups by the introduction
of an electron-withdrawing group on the nitrogen atom4d,6
conversion of the amide group into an imidate such as an
N,O-disilyl imidate or thioimidate,7 or the use of a strong
base.6b,8 However, under such conditions, the bromocycli-
zation of the ambident substrate 2-phenylprop-2-en-1-yl
tosylcarbamate (1a) resulted in low regioselectivities or
yields (see below). Here, we describe an efficient, regio-
selective bromo-N- and -O-cyclization reactions of unsat-
urated N-tosylcarbamates by using N,N-dibromo-
sulfonamides as brominating reagents.
Figure 1 X-ray crystal structures of oxazolidinone 2a (left) and di-
oxolanimine 3a (right)
Electrophilic bromocyclizations catalyzed by Lewis or
Brønsted acids or bases are well developed,1,3 whereas
catalytic regioselective bromocyclizations of ambident
nucleophiles are less well understood.12 We therefore at-
tempted to optimize this cyclization by using various cat-
alysts. Our preliminary results showed that the
regioselectivity of bromo-O-cyclization could be im-
proved by using a Lewis base (Table 1, entry 7), a Lewis
acid (entries 9 and 10), or a Brønsted acid (entries 12–14)
as a catalyst. However, a catalytic amount of 1,4-diazabi-
cyclo[2.2.2]octane or scandium(III) triflate had less effect
on the regioselectivity (entries 8 and 11).
We also examined the effects of various bromine sources
(Table 1, entries 15–19) and, to our delight, we obtained
the dioxolanimine 3a as a single isomer in 89% yield
when N,N-dibromo-4-nitrobenzenesulfonamide was used
in the absence of a catalyst (entry 19). Moreover, the oxa-
zolidinone 2a was obtained exclusively in 88% yield
when N,N-dibromo-4-toluenesulfonamide was used as
brominating source in tetrahydrofuran containing a stoi-
chiometric amount of potassium tert-butoxide (entry 21).
As active reagents, N,N-dibromo sulfonamides can be
used as bromine sources,13,14 as amine sources,15 as sourc-
es of both bromine and amine,16 as oxidation reagents,17 or
as catalysts.18 To the best of our knowledge, an improve-
ment in the regioselectivity of bromocyclization reactions
We began our investigation by using tosylcarbamate 1a as
the substrate (Table 1).9 After treatment of tosylcarbamate
1a with N-bromosuccinimide in dichloromethane at 25 °C
for four hours, thin-layer chromatography revealed the
presence of two new spots with markedly different polar-
ities. Column chromatography resulted in the isolation of
the bromo-N-cyclization product, the oxazolidinone 2a,
and the bromo-O-cyclization product, the dioxolanimine
SYNLETT 2014, 25, 1921–1925
Advanced online publication: 01.07.2014
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1
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3
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DOI: 10.1055/s-0034-1378314; Art ID: st-2014-w0278-l
© Georg Thieme Verlag Stuttgart · New York

1922
G.-T. Fan et al.
LETTER
stituents also gave high regioselectivities and good yields
under the standard conditions (entries 8 and 11), whereas,
substrates with 4-methoxyphenyl, 4-tolyl, or 3-methoxy-
phenyl substituents gave high regioselectivities and good
yields when sodium carbonate was used as the base (en-
tries 5–6 and 9). A substrate with an alkyl substituent also
gave a good regioselectivity and yield (entry 13), as did a
homoallylic tosylcarbamate (entry 14) and a trisubstituted
alkene (entry 15).
Table 1 Bromocyclization of 2-Phenylprop-2-en-1-yl Tosylcarba-
mate (1a)a
Br
Br
Ts
N
conditions
O
NTs
O
NHTs
O
+
Ph
Ph
O
Ph
O
O
1a
2a
3a
Entry Br source Reagent or
catalyst (equiv)
Solvent Yieldb
Yieldb
(%) of 2a (%) of 3a
Next, we examined the scope of the bromo-O-cycliza-
tion.20 In general, the desired products were obtained with
excellent regioselectivity and in good yields (Table 2).
For aromatic substituted tosylcarbamates, this reaction
worked well with both electron-deficient and electron-
rich aryl substituents (entries 2–12), showing that the
electronic character of the aromatic substituent has less ef-
fect on the regioselective bromo-O-cyclization reaction.
1
2
NBS
–
CH2Cl2 27
42
35
37
NBS
K2CO3 (1.1)
MeCN
42
45
29
3
NBS
Na2CO3 (1.1) MeCN
c
4
NBS
t-BuOK (1.1) THF
–
5
NBS
DBU (1.1)
Et3N (1.1)
Ph3PS (0.1)
CH2Cl2 32
35
c
6
NBS
CH2Cl2 14
–
Note that N,N-dibromo sulfonamides play a crucial role in
the regioselective cyclization reactions. Although the
mechanism has not yet been clarified, the high regioselec-
tivity of bromo-N-cyclization might result from the great-
er activity of N,N-dibromo-4-toluenesulfonamide as a
brominating reagent.14 A similar result was observed
when 1,3-dibromo-5,5-dimethylhydantoin, a more active
brominating reagent than N-bromosuccinimide, was used
as a bromine source, and a high yield of a oxazolidinone
2a was exclusively obtained in the presence of potassium
tert-butoxide (Table 1, entry 20).
c
7
NBS
CH2Cl2
–
65
60
11
14
26
43
49
57
54
57
63
41
89
8
NBS
DABCO (0.1) CH2Cl2 27
c
9
NBS
Cu(OTf)2 (0.1) CH2Cl2
Y(OTf)3 (0.1) CH2Cl2
–
–
c
10
11
12
13
14
15
16
17
18
19
20
21
NBS
NBS
Sc(OTf)3 (0.1) CH2Cl2 36
c
NBS
TFA (0.1)
CH2Cl2
–
–
c
NBS
HCO2H (0.1) CH2Cl2
NBS
AcOH (0.1)
CH2Cl2 23
CH2Cl2 5
For the regioselective bromo-O-cyclization, we suspected
that N,N-dibromo-4-nitrobenzenesulfonamide not only
acts as an active brominating reagent, but that the result-
ing N-bromo-4-nitrobenzenesulfonamide byproduct cata-
lyzes the reaction as a Brønsted acid.21 To test this
hypothesis, we treated tosylcarbamate 1a with N-bromo-
succinimide and a catalytic amount of 4-nitrobenzenesul-
fonamide and, indeed, both the regioselectivity and the
yield were clearly improved (Scheme 1).
NBPd
NBAe
DBDMHf
TsNBr2
–
–
–
–
–
CH2Cl2 36
CH2Cl2 28
CH2Cl2 56
g
c
NsNBr2
CH2Cl2
–
DBDMHf t-BuOK (1.1) THF
TsNBr2 t-BuOK (1.1) THF
54
88
–
c
Br source (equiv), catalyst (equiv)
c
–
1a
2a
3a
+
a Reaction conditions: 1a (0.20 mmol), Br source (0.22 mmol), cata-
lyst (0.02 mmol) or base reagent (0.22 mmol), solvent (3.0 mL), 25
°C, 4 h.
6%
8%
0
48%
73%
71%
80%
NsNH2 (0.2)
NsNH2 (0.5)
NBS (1.2)
NBS (1.2)
NsNBr2 (0.5)
NsNBr2 (0.5)
0
NsNH2 (0.5)
b Isolated yield.
c The desired product was not isolated by column chromatography.
d NBP = N-bromophthalimide.
Ns = 4-O2NC6H4
Scheme 1 Bromocyclization of tosylcarbamate 1a in the presence of
N-bromosuccinimide and 4-nitrobenzenesulfonamide
e NBA = N-bromoacetamide
f DBDMH = 1,3-dibromo-5,5-dimethylhydantoin.
g NsNBr2 = 4-O2NC6H4SO2NBr2.
On the other hand, N-bromo-4-nitrobenzenesulfonamide
might also act as a source of activated halogen. To test this
hypothesis, we conducted the cyclization of tosylcarba-
mate 1a in the presence of 0.5 equivalents of N,N-dibro-
in the presence of N,N-dibromo sulfonamides has never
previously been reported.
Having identified the optimal conditions,19 we examined mo-4-nitrobenzenesulfonamide, and we obtained
the reactions of other substrates (Table 2). With electron- dioxolanimine 3a exclusively in 71% yield, suggesting
deficient aryl-substituted unsaturated tosylcarbamates, that both the bromine atoms in N,N-dibromo-4-nitroben-
the bromo-N-cyclization reactions proceeded smoothly zenesulfonamide were used. Interestingly, when a catalyt-
with high regioselectivities and good yields (entries 2–4, ic amount of 4-nitrobenzenesulfonamide was added to the
7, and 10). Substrates with electron-rich 3- or 2-tolyl sub- same mixture, the yield of the desired product 3a was
Synlett 2014, 25, 1921–1925
© Georg Thieme Verlag Stuttgart · New York

LETTER
Regioselective Bromocyclization
1923
slightly improved (Scheme 1). It appears that 4-nitroben- To demonstrate the synthetic utility of our method, we
zenesulfonamide might also act as a Brønsted acid cata- smoothly transformed the oxazolidinone 2a and the diox-
lyst to promote the reaction. Furthermore, improvements olanimine 3a into the aziridine 4a and the epoxide 5a, re-
in the regioselectivity of bromo-O-cyclization catalyzed spectively (Scheme 2); these products are useful building
by Brønsted acids were observed previously (entries 12– blocks in organic synthesis and medicinal chemistry.22 In-
14). In these reactions, it is possible that a hydrogen bond terestingly, the desired aziridine and epoxide were ob-
is formed between the bromine source and the N-bromo- tained with good overall yields from the single starting
4-nitrobenzenesulfonamide or other Brønsted acid. Addi- material 1a after bromocyclization and reaction with po-
tionally, when N-bromosuccinimide was activated by a tassium carbonate in methanol.
catalytic amount of a Lewis acid or base, the regioselec-
In summary, we have developed a general and efficient re-
tivity of the bromo-O-cyclization was improved (Table 1).
gioselective bromocyclization of unsaturated tosylcarba-
These observations suggest that the regioselectivity of
mates by using N,N-dibromosulfonamides as bromine
sources. A wide range of oxazolidinone and dioxolan-
imine derivatives can be synthesized regioselectively. The
bromo-O-cyclization should be improved by the use of a
more active bromine source.
Table 2 Regioselective Bromocyclization of Unsaturated Tosylcarbamatesa
Br
Br
Ts
N
O
NTs
O
NHTs
O
B
A
R
R
O
R
O
O
2a–n
1a–n
3a–n
Entry
Substrate
R
Product
Yieldb (%)
Product
Yieldb (%)
E/Zc
1
2
1a
1b
1c
1d
1e
1f
Ph
2a
2b
2c
88
88
77
65
83
74
73
82
59
85
71
65
81
3a
3b
3c
3d
3e
3f
89
73
64
68
80
65
66
86
71
67
73
63
51
E only
10:1
4-FC6H4
4-ClC6H4
4-BrC6H4
4-MeOC6H4
4-Tol
3
10:1
4
2d
2ed
2fd
2g
2h
2id
2j
10:1
5
9:1
6
E only
11:1
7
1g
1h
1i
3-ClC6H4
3-Tol
3g
3h
3i
8
15:1
9
3-MeOC6H4
3,5-Cl2C6H3
2-Tol
10:1
10
11
12
13
1j
3j
16:1
1k
1l
2k
2l
3k
3l
E only
E only
E only
2-Naphthyl
Me
1m
2m
3m
O
O
NTs
O
Br
Br
O
O
O
TsN
14
15
79
87
77
56
10:1
O
O
NHTs
NHTs
1n
2nd
3n
Br
Br
NTs
O
E only
O
NTs
O
O
1o
2od
3o
a Reaction conditions: A: 1 (0.20 mmol), TsNBr2 (0.22 mmol), t-BuOK (0.22 mmol), THF (3.0 mL), 25 °C, 4 h. B: 1 (0.20 mmol), 4-O2NC6H4SO2NBr2
(0.22 mmol), CH2Cl2 (3.0 mL), 25 °C, 1 h.
b Isolated yield.
c The ratio was determined by 1H NMR analysis.
d Na2CO3 (0.22 mmol) was used instead of t-BuOK.
e Toluene (3.0 mL) was used instead of CH2Cl2.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 1921–1925

1924
G.-T. Fan et al.
LETTER
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1a
NTs
OH
O
K2CO3, MeOH
K2CO3, MeOH
25 °C, 1 h, 85%
Ph
2a
3a
Ph
25 °C, 1 h, 88%
OH
4a
5a
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Scheme 2 Synthesis of the aziridine 4a and the epoxide 5a
resulting products can be readily converted into syntheti-
cally useful building blocks. Further research on reactions
with N,N-dibromosulfonamides as reagents is underway.
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Acknowledgment
We thank the National Natural Science Foundation of China (NS-
FC-21203148, 21302151), the Science and Technology Department
of Shaanxi Province (2013JQ2012), the Education Department of
Shaanxi Province (2013JK0644), the New Teachers’ Fund for Doc-
tor Stations (20126101120010), the Scientific Research Foundation
for Returned Overseas Chinese Scholars of the Ministry of Educa-
tion, and Northwest University for financial support.
Gouverneur, V. Chem. Eur. J. 2012, 18, 13126.
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Supporting Information for this article is available online
at
http://www.thieme-connect.com/products/ejournals/journal/
10.1055/s-00000083.SunpfgIpi
m
o
nr
i
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Synlett 2014, 25, 1921–1925
© Georg Thieme Verlag Stuttgart · New York

LETTER
carbamates, see: Liu, N.; Werness, J. B.; Guzei, I. A.; Tang,
Regioselective Bromocyclization
1925
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chromatography (silica gel, PE–EtOAc) to give a white
solid; yield: 72.2 mg (88%); mp 148–149 °C; IR (KBr):
1777, 1595, 1160, 811, 756, 618, 584 cm–1; 1H NMR (400
MHz, CDCl3): δ = 7.38–7.32 (m, 7 H), 7.11 (d, J = 8.2 Hz, 2
H), 4.65 (d, J = 9.2 Hz, 1 H), 4.50 (s, 2 H), 4.49 (d, J = 9.2
Hz, 1 H), 2.38 (s, 3 H); 13C NMR (100 MHz, CDCl3): δ =
152.0, 145.4, 137.5, 134.2, 129.4, 129.1, 128.9, 126.5,
124.3, 75.9, 67.7, 36.9, 21.6; HRMS (ESI): m/z [M + Na]+
calcd for C17H16BrNO4SNa: 431.9876; found: 431.9887.
(20) N-[4-(Bromomethyl)-4-phenyl-1,3-dioxolan-2-ylidene]-
4-toluenesulfonamide (3a); Typical Procedure
(14) (a) Suketaka, I.; Toshi, O. Bull. Chem. Soc. Jpn. 1967, 40,
418. (b) Phukan, P.; Chakraborty, P.; Kataki, D. J. Org.
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(e) Saikia, I.; Rajbongshi, K. K.; Phukan, P. Tetrahedron
Lett. 2012, 53, 758. (f) Ghorbani-Vaghei, R.; Shahbazi, H.;
Veisi, H. Tetrahedron Lett. 2012, 53, 2325. (g) Borah, A. J.;
Phukan, P. Tetrahedron Lett. 2012, 53, 3035.
(15) (a) Saikia, I.; Kashyap, B.; Phukan, P. Chem. Commun.
2011, 47, 2967. (b) Borah, A. J.; Phukan, P. Chem. Commun.
2012, 48, 5491. (c) Nagamachi, T.; Takeda, Y.; Nakayama,
K.; Minakata, S. Chem. Eur. J. 2012, 18, 12035.
(16) (a) Kharasch, M. S.; Priestley, H. M. J. Am. Chem. Soc.
1939, 61, 3425. (b) Urno, Y.; Takemura, S.; Ozawa, K.;
Komatsu, S. J. Med. Chem. 1968, 11, 1269. (c) Shen, R.;
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5698.
4-O2NC6H4SO2NBr2 (79.2 mg, 0.22 mmol) was added in
one portion to a stirred solution of N-tosylcarbamate 1a
(0.20 mmol) in anhydrous CH2Cl2 (3.0 mL). The mixture
was stirred at r.t. for 1 h and then the reaction was quenched
with sat. aq Na2SO3 (2.0 mL) and H2O (2.0 mL). The
mixture was extracted with CH2Cl2 (3 × 5.0 mL) and the
extracts were combined, washed with brine (10.0 mL), dried
(Na2SO4), filtered, and concentrated in vacuo. The residue
was purified by flash column chromatography (silica gel,
PE–EtOAc) to give a white solid; yield: 73.0 mg (89%); mp
125–126 °C; IR (KBr): 3126, 1778, 1160, 1093, 756, 584
cm–1; 1H NMR (400 MHz, CDCl3): δ = 7.90 (d, J = 7.8 Hz,
2 H), 7.44–7.43 (m, 3 H), 7.32–7.28 (m, 4 H), 5.04 (d, J =
8.4 Hz, 1 H), 4.77 (d, J = 8.4 Hz, 1 H), 3.73 (d, J = 12.0 Hz,
1 H), 3.70 (d, J = 12.0 Hz, 1 H), 2.42 (s, 3 H); 13C NMR (100
MHz, CDCl3): δ = 158.5, 143.5, 138.1, 136.5, 129.8, 129.34,
129.25, 127.3 124.3, 88.2, 75.7, 37.3, 21.5; HRMS (ESI):
m/z [M + Na]+ calcd for C17H16BrNO4SNa: 431.9876; found:
431.9881.
(17) (a) Zolfigol, M. A.; Ghorbani-Vaghei, R.; Mallakpour, S.;
Chehardoli, G.; Choghamarani, A. G.; Yazdi, A. H.
Synthesis 2006, 1631. (b) Saika, I.; Chakraborty, P.; Phukan,
P. ARKIVOC 2009, (xiii), 281.
(18) Khazaei, A.; Rostami, A.; Tanbakouchian, Z.; Zinati, Z.
Catal. Commun. 2006, 7, 214.
(19) 4-(Bromomethyl)-4-phenyl-3-tosyl-1,3-oxazolidin-2-one
(2a); Typical Procedure
(21) (a) Catino, A. J.; Nichols, J. M.; Forslund, R. E.; Doyle,
M. P. Org. Lett. 2005, 7, 2787. (b) Chen, Z.-G.; Wei, J.-F.;
Wang, M.-Z.; Zhou, L.-Y.; Zhang, C.-J.; Shi, X.-Y. Adv.
Synth. Catal. 2009, 351, 2358. (c) Zhou, L.; Tan, C.-K.;
Jiang, X.; Chen, F.; Yeung, Y.-Y. J. Am. Chem. Soc. 2010,
132, 15474.
TsNBr2 (72.4 mg, 0.22 mmol) was added in one portion to
a stirred solution of N-tosylcarbamate 1a (0.20 mmol) and
t-BuOK (24.7 mg, 0.22 mmol) in anhydrous THF (3.0 mL)
under N2. The mixture was stirred at r.t. for 4 h then the
reaction was quenched with sat. aq Na2SO3 (2.0 mL) and
H2O (2.0 mL). The mixture was extracted with EtOAc (3 ×
5.0 mL) and the extracts were combined, washed with brine
(22) Aziridines and Epoxides in Organic Synthesis; Yudin, A. K.,
Ed.; Wiley-VCH: Weinheim, 2006.
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