NBS-promoted rearrangement of 1,1-diarylmethylenecyclopentane

Article abstract of DOI:10.1002/jccs.201190135

The 1-aroyl-1-aryl-2-bromocyclopentanes 3a, 3b, 3c and 3d (Ar = C ₆H₅, 2-FC₆H₄, 3-FC₆H ₄, 4-FC₆H₄) were prepared from N-bromosuccinimide (NBS)-promoted rearrangement o

Full text of DOI:10.1002/jccs.201190135

Journal of the Chinese Chemical Society, 2011, 58, 853-856
853
Communication
NBS-Promoted Rearrangement of 1,1-Diarylmethylenecyclopentane
Meng-Yang Chang* and Chung-Han Lin
Department of Medicinal and Applied Chemistry, Kaohsiung Medical University,
Kaohsiung 807, Taiwan, R.O.C.
Received June 15, 2011; Accepted August 19, 2011; Published Online August 30, 2011
The 1-aroyl-1-aryl-2-bromocyclopentanes 3a, 3b, 3c and 3d (Ar = C6H5, 2-FC6H4, 3-FC6H4, 4-FC6H4)
were prepared from N-bromosuccinimide (NBS)-promoted rearrangement of 1,1-diarylmethylenecyclo-
pentane 2. The possible mechanism was proposed. Two 1-phenyl-cyclopentane carbamides 5a and 5b
with the anti-influenza effect were also accomplished from compound 3a.
Keywords: 1,1-Diarylmethylenecyclopentane; N-Bromosuccinimide; Rearrangement.
INTRODUCTION
RESULTS AND DISCUSSION
Cyclopentanecarboxylic acid (1) was chosen as the
starting materials for the NBS-mediated rearrangement re-
action, as shown in Table 1. Initially, skeleton 2 was pro-
vided by the Grignard addition of acid with 4.0 equivalents
of arylmagnesium bromide (1.0 M in tetrahydrofuran, Ar =
a, C6H5; b, 2-FC6H4; c, 3-FC6H4; d, 4-FC6H4; e, 4-CH3C6H4;
f, 4-CH3OC6H4) at reflux for 10 h, followed by boron tri-
fluoride etherate (BF3-OEt2)-mediated dehydration of the
resulting tertiary alcohol in dichloromethane at rt for 1 h.4
Compounds 2a~2f were isolated in 27~78% total yields of
N-Bromosuccinimide (NBS) serves as an important
and useful synthetic reagent in a variety of reactions.1-2
NBS is a source of free-radical or positive bromine, used
primarily in the bromination of organic substrates. A major
use is in the bromination of allylic or benzylic positions
(Wohl-Ziegler reaction) in the substrate. Other potential
uses are para-bromination of phenol,2a Biginelli reaction,2b
Hunsdiecker reaction,2c oxidative deprotection of ether,2d
conversion of alcohols to bromides,2e E/Z isomerization,2f
formation of heterocycles,2g and oxidation of reactive sub-
strates.2h Recently, we have developed a facile NBS-medi-
ated rearrangement reaction of 1,1-diarylmethylenecyclo-
hexane under mild and base-free bromination condition.3
This study showed that an efficient synthetic approach for
preparing the skeleton of 1-aroyl-1-arylcyclohexane by
NBS. In this article, NBS-mediated rearrangement reaction
of 1,1-diarylmethylenecyclopentane was further investi-
gated (Scheme I).
Table 1. Synthesis of 1-aroyl-1-aryl-2-bromocyclopentanes 3[a]
O
Ar
Ar
Br
Ar
Ar
CO2H
3a~3f
1) ArMgBr, THF, reflux
2) BF -OEt , DCM, rt
(27~78% of two-steps)
NBS (2.1 equiv)
+
MeOH, reflux
45~60 min
3
2
OCH3
Br
O
1
2a~2f
H3CO
3g
Ar = a, C H ; b, 2-FC H ; c, 3-FC H ; d, 4-FC H ; e, 4-CH C H ; f, 4-CH OC H
6 4
6
5
6
4
6
4
6
4
3
6
4
3
Scheme I NBS-mediated rearrangement reaction
Entry
Ar group
2 / Yield (%)
3 / Yield (%)
Ar
Ar
Ar
Ar
NBS
1
2
3
4
5
6
C6H5
2a / 78
2b / 27
2c / 55
2d / 68
2e / 41
2f / 50
3a / 66
3b / ~ 10
3c / 31
3d / 52
3e / trace
O
2-FC6H4
3-FC6H4
4-FC6H4
4-CH3C6H4
4-CH3OC6H4
(ref. 3a)
O
Ar
Ar
Ar
NBS
Ar
3f / trace; 3g / 45%
Br
(this work)
[a] The products are > 95% pure as judged by 1H-NMR analysis.
* Corresponding author. Tel: +886-7-3121101 ext 2220; Fax: +886-7-3125339; E-mail: mychang@kmu.edu.tw

854 J. Chin. Chem. Soc., Vol. 58, No. 7, 2011
Chang and Lin
two steps. The structure of compound 2d was determined
using single-crystal X-ray analysis (Fig. 1).5
pound 2a with N-chlorosuccinimide (NCS) failed, perhaps
due to an insufficient reactivity.
Furthermore, treatment of skeleton 2 with NBS (2.1
equiv) in methanol at reflux for 45~60 min was converted
into skeleton 3. The compounds 3a, 3b, 3c and 3d were iso-
lated in 66%, ~10%, 31% and 52% yield, respectively.6 The
structure of compound 3a was determined using single-
crystal X-ray analysis (Fig. 2).5 The total procedure was
monitored by TLC until the skeleton 2 was consumed.
To investigate the optimal reaction condition, com-
pound 2a was chosen as the starting material in the synthe-
sis of skeleton 3. We found that the reasonable reaction
time and reaction temperature are the important issues.
When the reaction time increased to 90 min at reflux, the
yield of compound 3a was obtained in only 37% yield. In
the other way, when the reaction was carried out at rt for 10
h, we found that the provided products included 22% of
starting material 2a and 27% of compound 3a. But, treat-
ment of compound 2a with an excess amount of NBS (3.1
equiv.) in methanol, major complex product was obtained.
Attempts to examine the rearrangement reaction of com-
The possible explanation for the interesting transfor-
mation from compound 2a to 3a could be that NBS-medi-
ated rearrangement was induced by involvement of bro-
monium ion on the exo-olefinic position of cyclopentane
skeleton (Scheme II). The initial event may be considered
to be the formation of bromonium ion via the equilibrium
between intermediate I and II. Hydrogen abstraction of in-
termediate II provided intermediate III. Then, treatment of
intermediate III with the second equivalent of NBS gave
intermediate IV with another bromonium ion. Next, inter-
mediate V was formed by an 1,2-aryl group sigmatropic
shift of intermediate IV from the back-side face. By the in-
troduction of methanol on the tertiary carbocation, inter-
mediate VI might be generated. Further, compound 3a was
yielded via the methanolysis of intermediate VI.
Scheme II The possible mechanism of compound 2a
Ph
Ph
Ph
Ph
Ph
Br
Br
Ph
NBS
Br
NBS
2a
H
I
II
III
Me
Ph
O
Br
Br
Ph
Ph
Ph
Ph
Ph
MeOH
Br
Br
Br
3a
IV
V
VI
Treatment of compound 2b (Ar = 2-FC6H4, for entry
2) with NBS was generated compound 3b in low yield (~
10%) under the above-mentioned condition. After chang-
ing the reaction temperature, time and equivalents of NBS,
product 3b could be only provided in a trace amount. Prob-
ably, the rearranged procedure was affected by the fluoro
atom on the 2-position of phenyl group. In the preparation
of compounds 3c (Ar = 3-FC6H4, for entry 3) and 3d (Ar =
4-FC6H4, for entry 4), the above reaction condition could
provide 31% and 52% yields. For NBS-mediated rear-
rangement reaction of compound 2e with 4-methylphenyl
group (Ar = 4-CH3C6H4, for entry 5), the complex product
mixture was observed. This result showed that NBS might
promote the in situ benzylic bromination to occur at the po-
sition of 4-methyl group. When compound 2f was reacted
with NBS (Ar = 4-CH3OC6H4, for entry 6), a trace amount
of compound 3f was isolated. Especially, compound 3g
was afforded in 45% yield. In comparison with the elec-
Fig. 1. X-Ray structure of compound 2d.
Fig. 2. X-Ray structure of compound 3a.

NBS-Promoted Rearrangement of 1,1-Diarylmethylenecyclopentane
J. Chin. Chem. Soc., Vol. 58, No. 7, 2011 855
tron-withdrawing fluoro group and electron-donating meth-
oxy group, it was believed that 4-methoxyphenyl group
should provide a stabilizing factor for the formation of in-
termediate I with a tertiary benzylic carbocation. Further,
compound 3g could be formed via addition of benzylic
carbocation with methanol, oxygen lone-pair promoted
1,2-aryl shift and ortho-bromination by the second equiva-
lent of NBS. The exhibited results were similar to the re-
ported phenomena.3 Based on the results, we found that the
similar products (1-aroyl-1-arylcyclopentane and 1-aroyl-
1-arylcyclohexane) could be obtained from the NBS-medi-
ated rearrangement reaction of 1,1-diarylmethylenecyclo-
pentane and 1,1-diarylmethylenecyclohexane with the
electron-donating methoxy functional group. Although the
synthetic application is limited, this presented rearrange-
ment method is novel.
While poring over recent literature,7 we found that 1-
phenylcycloalkane carbamide, containing the similar struc-
ture to 1-arylcyclopentyl group, exhibited high activity
against influenza viruses. With the idea in mind, the simple
synthesis of 1-phenyl-cyclopentane carbamides 5a and 5b
was further achieved from compound 3a via a two-step
procedure. One step is the azobisisobutyronitrile (AIBN)-
mediated radical debromonination of compound 3a with
tri-n-butyltin hydride. The other step is the regioselective
Baeyer-Villiger reaction of the corresponding compound 4
with m-chloroperoxybenzoic acid (MCPBA) under the ba-
sic reflux condition and followed by the nucleophilic addi-
tion of the resulting phenyl ester with piperidine (for com-
pound 5a) and morpholine (for compound 5b) in reflux
(Scheme III). Two compounds, 5a and 5b, with the biologi-
cal activities were isolated in 76% and 69% yield, respec-
tively, in one-pot reactions.8
ACKNOWLEDGEMENTS
The authors would like to thank the National Science
Council of the Republic of China for its financial support
(NSC 99-2113-M-037-006-MY3). The project is also sup-
ported by a grant from the Kaohsiung Medical Research
Foundation (KMU-Q100004).
REFERENCES
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2003, 59, 6489. (g) Collins, M. R.; Huang, Q.; Ornelas, M.
A.; Scales, S. A. Tetrahedron Lett. 2010, 51, 3528. (h) Mul-
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3. (a) Chang, M.-Y.; Lee, M.-F.; Lin, C.-H.; Lee, N.-C. Tetrahe-
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4. Jiang, M.; Shi, M. Org. Lett. 2008, 10, 2239.
5. CCDC 829110 (2d) and CCDC 784043 (3a) contain the sup-
plementary crystallographic data for this paper. This data
can be obtained free of charge via www.ccdc.cam.ac.uk/
conts/retrieving.html (or from the CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: 44-1223-336033; e-mail: de-
posit@ccdc.cam.ac.uk).
6. A representative synthetic transformation of skeleton 3 from
2 is as follows: NBS (374 mg, 2.1 mmol) was added to a solu-
tion of skeleton 2 (1.0 mmol) in MeOH (10 mL) at rt. The re-
action mixture was stirred at reflux for 45~50 min. Saturated
NaHCO3(aq) (2 mL) was added to the reaction mixture and the
solvent was concentrated. The residue was extracted with
EtOAc (3 ´ 20 mL). The combined organic layers were
washed with brine, dried, filtered and evaporated to afford
crude product. Purification on silica gel (hexanes/EtOAc =
10/1~6/1) afforded skeleton 3. For compound 3a: M.p. =
121-122 oC; HRMS (ESI, M++1) calcd for C18H18BrO
329.0541, found 329.0542; 1H NMR (400 MHz): d 7.61-7.58
(m, 2H), 7.46-7.43 (m, 2H), 7.40-7.34 (m, 3H), 7.30-7.24
(m, 3H), 5.10 (d, J = 5.2 Hz, 1H), 2.86 (ddd, J = 9.2, 10.0,
Scheme III Synthesis of compounds 4a and 4b
O
O
Ph
MCPBA, K CO
2
Bu SnH, AIBN
3
Ph
3
Ph
N
3a
X
DCM, reflux, then
piperidine (for 5a) or
morpholine (for 5b)
(78%)
4
5a, X = CH2 (76%)
5b, X = O (69%)
In summary, we have successfully presented a conve-
nient synthetic methodology for producing the 1-aroyl-1-
aryl-2-bromocyclopentanes from the NBS-mediated reac-
tion of 1,1-diarylmethylenecyclopentane. Synthesis of two
1-phenyl-cyclopentane carbamides with the anti-influenza
effect is also accomplished.

856 J. Chin. Chem. Soc., Vol. 58, No. 7, 2011
Chang and Lin
13.6 Hz, 1H), 2.56-2.33 (m, 3H), 2.13-2.02 (m, 1H), 1.77-
1.63 (m, 1H); 13C NMR (100 MHz): d 198.96, 139.67,
137.76, 131.72, 129.18 (2x), 128.77 (2x), 128.03 (2x),
127.56, 126.39 (2x), 69.12, 58.60, 35.63, 34.05, 20.46. Sin-
gle-crystal X-ray diagram: crystal of compound 3a was
grown by slow diffusion of EtOAc into a solution of com-
pound 3a in DCM to yield colorless prism. The compound
crystallizes in the monoclinic crystal system, space group P
1 21/n 1, a = 9.5922(11) Å, b = 15.0043(17) Å, c =
11.0273(12) Å, V = 1256.6(3) Å3, Z = 4, dcalcd = 1.432 g/cm3,
F(000) = 672, 2q range 2.35~26.39o, R indices (all data) R1
= 0.0811, wR2 = 0.1313. For compound 3b: Oil; HRMS
(ESI, M++1) calcd for C18H16BrF2O 365.0353, found
365.0358; 1H NMR (400 MHz): d 7.36-7.28 (m, 2H), 7.22 (s,
1H), 7.19 (s, 1H), 7.13-7.10 (m, 2H), 7.00-6.99 (m, 2H), 5.06
(dt, J = 1.6, 5.6 Hz, 1H), 2.91-2.83 (m, 1H), 2.60-2.50 (m,
1H), 2.45-2.34 (m, 2H), 2.17-2.09 (m, 1H), 1.86-1.77 (m,
1H); 13C NMR (100 MHz): d 197.33, 163.96 (d, J = 240.6
Hz), 161.50 (d, J = 241.3 Hz), 143.55 (d, J = 5.7 Hz), 140.33
(d, J = 5.3 Hz), 131.99, 130.67, 128.69, 126.73, 120.22,
118.69, 114.35, 112.13, 60.23, 58.32, 36.02, 33.91, 20.28.
For compound 3c: Oil; HRMS (ESI, M++1) calcd for
C18H16BrF2O 365.0353, found 365.0355; 1H NMR (400
MHz): d 7.36-6.99 (m, 8H), 5.02 (d, J = 5.2 Hz, 1H), 2.84
(ddd, J = 8.8, 10.0, 13.6 Hz, 1H), 2.57-2.47 (m, 1H),
2.42-2.31 (m, 2H), 2.13-2.04 (m, 1H), 1.76-1.63 (m, 1H); 13C
NMR (100 MHz): d 197.10, 163.20 (d, J = 246.3 Hz), 162.26
(d, J = 245.5 Hz), 142.12 (d, J = 6.0 Hz), 139.40 (d, J = 6.1
Hz), 130.89 (d, J = 7.6 Hz), 129.80 (d, J = 8.3 Hz), 124.38 (d,
J = 3.1 Hz), 122.05 (d, J = 3.1 Hz), 119.05 (d, J = 21.9 Hz),
115.70 (d, J = 22.7 Hz), 114.89 (d, J = 21.2 Hz), 113.68 (d, J
= 22.7 Hz), 63.98, 57.41, 35.71, 34.40, 20.40. For compound
3d: Oil; HRMS (ESI, M++1) calcd for C18H16BrF2O 365.0353,
found 365.0355; 1H NMR (400 MHz): d 7.64-7.59 (m, 2H),
7.40-7.35 (m, 2H), 7.09-7.03 (m, 2H), 6.98-6.92 (m, 2H),
5.10 (dt, J = 1.2, 5.2 Hz, 1H), 2.85 (ddd, J = 8.8, 10.0, 13.6
Hz, 1H), 2.55-2.45 (m, 1H), 2.42-2.30 (m, 2H), 2.13-2.02
(m, 1H), 1.75-1.64 (m, 1H); 13C NMR (100 MHz): d 197.22,
164.59 (d, J = 272.1 Hz), 162.09 (d, J = 266.8 Hz), 135.44 (d,
J = 3.8 Hz), 133.66 (d, J = 3.0 Hz), 131.46, 131.37, 128.11,
128.04, 116.36, 116.15, 115.38, 115.16, 68.44, 57.88, 35.58,
34.41, 20.44.
7. Tang, G.; Qiu, Z.; Lin, X.; Li, W.; Zhu, L.; Li, S.; Li, H.;
Wang, L.; Chen, L.; Wu, J. Z.; Yang, W. Bioorg. Med. Chem.
Lett. 2010, 20, 3507.
o
8. For compound 5a: M.p. = 57-58 C; HRMS (ESI, M++1)
1
calcd for C17H24NO 258.1858, found 258.1860; H NMR
(400 MHz): d 7.31-7.27 (m, 2H), 7.22-7.16 (m, 3H), 3.56 (br
s, 2H), 2.99 (br s, 2H), 2.45-2.39 (m, 2H), 2.04-1.95 (m, 2H),
1.78-1.66 (m, 6H), 151-1.45 (m, 2H), 0.99 (br s, 2H); 13C
NMR (100 MHz): d 174.35, 145.95, 128.54 (2x), 125.94,
125.11 (2x), 58.55, 47.23, 43.86, 38.43 (2x), 25.23 (3x),
24.45 (2x). For compound 5b: M.p. = 71-72 oC; HRMS (ESI,
1
M++1) calcd for C16H22NO2 260.1651, found 260.1652; H
NMR (400 MHz): d 7.33-7.29 (m, 2H), 7.22-7.18 (m, 3H),
3.60 (br s, 4H), 3.10 (br s, 4H), 2.45-2.38 (m 2H), 2.04-1.95
(m, 2H), 1.77-1.69 (m, 4H); 13C NMR (100 MHz): d 174.75,
145.46, 128.77 (2x), 126.31, 125.03 (2x), 66.69, 65.86,
58.33, 46.94, 43.27, 38.33 (2x), 25.28 (2x).