Acetoxylation and hydroxylation of diarylmethylenecycloalkanes via radical approach

Article abstract of DOI:10.1021/jo9027209

Diarylmethylenecycloalkanes were acetoxylated under the radical reaction conditions with PhI(OAc)₂, I₂, and TsNH₂. Moreover, upon treating the products from the reactions of methylenecyclobutanes with N-bromosuccinimide (N

Full text of DOI:10.1021/jo9027209

pubs.acs.org/joc
Acetoxylation and Hydroxylation of Diarylmethylenecycloalkanes via
Radical Approach
Min Jiang, Yin Wei,* and Min Shi*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
mshi@mail.sioc.ac.cn
Received December 25, 2009
Diarylmethylenecycloalkanes were acetoxylated under the radical reaction conditions with PhI-
(OAc)2, I2, and TsNH2. Moreover, upon treating the products from the reactions of methylene-
cyclobutanes with N-bromosuccinimide (NBS) through silica gel column chromatography, the
corresponding substituted methylenecyclobutanols were obtained in moderate to good yields. The
plausible mechanisms have been proposed on the basis of the control experiments.
Introduction
stereoselectivity, regioselectivity, and site selectivities. Re-
cently transition metal-catalyzed functionalization of allylic
C-H bonds has been well developed and widely used in
organic synthesis.2,3 In these processes, transition metal
complexes of rhodium, ruthenium, manganese, silver, cop-
per, palladium, cobalt, and iron as catalysts are essential.4
Meanwhile, the transition metal-free intermolecular acetoxy-
lation and amination methods for saturated C-H bonds,
which are more environmentally benign processes,5 have also
been developed and have attracted much attention. During
our ongoing investigation on the chemical reactivity of highly
strained small rings, we found that it is necessary to find a
simple and direct method to functionalize the allylic C-H
bond of methylenecycloalkanes. Moreover, we also found
that methylenecycloalkanes having a four-, five-, or six-
membered ring such as methylenecyclobutanes (MCBs) and
methylenecyclopentanes as well as methylenecyclohexanes, a
The functionalization of an allylic C-H bond in an olefinis
of fundamental importance in organic synthesis due to the
broad synthetic potential of these alkene derivatives includ-
ing enantioenriched ones obtained for the preparation of
complex molecules.1 The practical utility of such reactions for
complex molecule synthesis is governed by their ability to
operate with predictable and high levels of chemoselectivity,
*To whom correspondence should be addressed. Fax: 86-21-64166128.
(1) (a) Trost, B. M. J. Org. Chem. 2004, 69, 5813–5837. (b) Trost, B. M.;
Crawley, M. L. Chem. Rev. 2003, 103, 2921–2944.
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7785–7811. (b) Koser, G. F. Top. Curr. Chem. 2003, 224, 137–172.
(c) Dauban, P.; Dodd, R. H. Synlett 2003, 1571–1586. (d) Davies,
H. M. L.; Long, M. S. Angew. Chem., Int. Ed. 2005, 44, 3518–3520.
(e) Davies, H. M. L. Angew. Chem., Int. Ed. 2006, 45, 6422–6425.
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2528 J. Org. Chem. 2010, 75, 2528–2533
Published on Web 03/24/2010
DOI: 10.1021/jo9027209
r
2010 American Chemical Society

Jiang et al.
JOCArticle
TABLE 1. Optimization of the Reaction Conditions for the Acetoxylation of MCB 1a
entrya
RNH2
TsNH2
TsNH2
TsNH2
TsNH2
TsNH2
TsNH2
TsNH2
TsNH2
PhSONH2
TsNHNH2
PhCH2NH2
BocNH2
TsNH2
TsNH2
TsNH2
TsNH2
TsNH2
1/PhI(OAc)2/RNH2/I2
solvent
temp (°C)
yield (%)b of 2a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
1.0/2.5/1.0/1.0
1.0/2.5/0/1.0
1.0/1.5/1.0/0
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
60
60
60
60
60
60
60
58
0
0
27
54
63
72
0
NR
NR
NR
trace
65
NR
32
78
0
1.0/1.0/1.0/0.3
1.0/1.0/0.3/0.3
1.0/1.5/0.3/0.3
1.0/2.0/0.3/0.3
1.0/2.0/0.3/0.3
1.0/1.5/1.5/1.5
1.0/1.5/1.5/1.5
1.0/1.5/1.5/1.5
1.0/1.5/1.5/1.5
1.0/2.0/0.3/0.3
1.0/2.0/0.3/0.3
1.0/2.0/0.3/0.3
1.0/2.0/0.3/0.3
1.0/2.0/0.3/0.3 (NBS)
1.0/2.0/0.3/0.3 (NCS)
1.0/2.0/0.3/0.3 (NIS)
rtc
60c
60c
60c
60c
60
CH3CN
THF
toluene
DCE, toluene (1:1)
DCE
60c
60c
60
60
60
TsNH2
TsNH2
DCE
DCE
complex
trace
60
aReaction conditions: 1a (0.2 mmol), PhI(OAc)2 (1.0-2.5 mmol), RNH2 (0-1.5 mmol), I2 (0-1.5 mmol), and solvent (2.0 mL) were employed; the
reactions were carried out at various temperatures within 10 min. Iodine was added into the reaction mixtures two times (at the first minute and the fifth
minute). bIsolated yields. cThe reaction time is 2 h.
class of moderately strained alkenes, have been seldom used
as substrates in organic synthesis. For example, as for MCBs,
it has been only known that they could be easily oxidized to
the corresponding cyclopentanone or cyclobutylmethanone
derivatives in good yields under mild reaction conditions.6a-f
Previously, we reported that the reactions of MCBs with acyl
chlorides produced the corresponding substituted cyclopen-
tene derivatives in moderate to high yields via ring enlarge-
ment in the presence of aluminum chloride under mild
conditions.6g Herein, we wish to report the interesting
acetoxylation and hydroxylation methods of diarylmethyl-
enecycloalkanes via the free radical reaction processes.
higher yield of 2a (Table 1, entries 6 and 7). However, upon
decreasing the temperature to room temperature (20 °C), the
product 2a was not obtained (Table 1, entry 8). If TsNH2 was
replaced by other amines such as PhSONH2, TsNHNH2, or
PhCH2NH2, no reactions occurred (Table 1, entries 9-11)
and only a trace amount of acetoxylation product was
acquired if BocNH2 was employed. Further examination
of solvent effects revealed that in acetonitrile (CH3CN),
tetrahydrofuran (THF), and toluene, 2a was obtained in
65%, 0%, and 32% yield at 60 °C, respectively (Table 1,
entries 13-15). It was observed that using toluene as solvent
led to the formation of 2a in 32% yield in a very clean
reaction within 2 h and the abundant substrate 1a was
recovered after workup. The highest yield was achieved
(78%, Table 1, entry 16) with the mixed solvents of DCE
and toluene (1:1). When I2 was changed to NBS, NCS, or
NIS, almost no desired product was obtained (Table 1, entries
17-19). Thus, the ratio of 1.0/2.0/0.3/0.3 for 1a/PhI(OAc)2/
TsNH2/I2 is the best one for this reaction to give 2a in good yield
at 60 °C, employing DCE and toluene as mixed solvents.
Under these optimal reaction conditions, we next carried
out the reactions of a variety of diarylmethylenecycloalkanes
1 including diarylmethylenecyclobutanes (n = 1), diaryl-
methylenecyclopentanes (n=2), and diarylmethylenecyclo-
hexanes (n=3) with iodobenzene diacetate in the presence
of TsNH2 and iodine to examine the scope and limitations.
We found that the corresponding products 2 were obtained
in moderate to good yields within 10 min in spite of 1 (n = 1,
2, 3) bearing electron-rich, electron-neutral, and electron-
poor substituents on the benzene rings (Table 2). For aryl-
substituted MCBs 1b-d (n=1) having an electron-poor sub-
stituent at the para-position of the benzene ring, the corre-
sponding products 2b-d were obtained in 69-76% yields
(Table 2, entries 1-3). However, for MCBs 1e and 1f having
an electron-rich substituent at the ortho-, meta-, and para-
positions of the benzene ring, the corresponding products 2e
Results and Discussion
The reaction of MCB 1a with iodobenzene diacetate,
amine, and iodine was initially investigated for seeking the
optimal reaction conditions. The results are summarized in
Table 1. As shown in Table 1, it was found that using
PhI(OAc)2 (2.5 equiv), TsNH2 (1.0 equiv), and I2 (1.0 equiv)
to react with 1a afforded acetoxylation product 2a in 58%
yield at 60 °C in 1,2-dichloroethane (DCE) within 10 min
(Table 1, entry 1). Prolongation of reaction time led to the
low yield. If the reactions were carried out in the absence of
TsNH2 or I2, no product 2a was obtained (Table 1, entries
2 and 3). Varying the ratio of 1a/PhI(OAc)2/TsNH2/I2 to 1.0/
1.0/1.0/0.3 or 1.0/1.0/0.3/0.3 provided 2a in 27% and 54%
yield, respectively (Table 1, entries 4 and 5). Thus we found
that the lesser amount of TsNH2 gave the better result.
Increasing the amount of PhI(OAc)2 to 2.0 equiv led to the
(6) (a) Graham, S. H.; William, A. J. S. J. Chem. Soc. 1959, 4066–4072.
(b) Farcasiu, D.; Schleyer, P. v. R.; Ledlie, D. J. Org. Chem. 1973, 38, 3455–
3459. (c) Graham, S. H.; William, A. J. S. J. Chem. Soc. C 1966, 655–660.
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5528. (e) Shen, Y. M.; Wang, B.; Shi, Y. Angew. Chem., Int. Ed. 2006, 45,
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9604. (g) Jiang, M.; Shi, M. Org. Lett. 2008, 10, 2239–2242.
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TABLE 2. Scope and Limitations of the Acetoxylation Reaction of
Diarylmethylenecycloalkanes 1
SCHEME 1. The Reaction of MCB 1a with PhI(OAc)2 or
PhI(O2CtBu)2, TsNH2, and I2
As a proposed mechanism for the PhI(OAc)2/I2-mediated
amination reactions by Fan’s group,8 a plausible reaction has
been shown in the Supporting Information (Scheme SI-1).
On the other hand, N-bromosuccinimide (NBS) is exten-
sively used in allylic and benzylic brominations9 which have
been generally described as a free radical chain reaction
involving succinimidyl radical.10 Allylic bromination, as a
common synthetic method for introducing a substituent in
the organic compound, has resulted in a steadily growing
interest in organic chemistry and has proved to be a powerful
synthetic tool with numerous applications in organic chem-
istry and pharmaceutical chemistry.11 Bergman’s group
recently also reported that cyclopropyl methyl ketone can
be transformed into methylenecyclobutane through halogena-
tion along with the acetoxylation of 2-bromo-1-methylene-
cyclobutane.12 Moreover, the hydroxylation at the “allylic
position” of an olefin is also essential in organic synthesis.
However, hydroxylation of the allylic position is mainly carried
out by the action of oxygen. It is necessary to find other facile
synthetic methods to achieve the hydroxylation at the “allylic
position” of an olefin without oxygen.
aReaction conditions: 1 (0.2 mmol), PhI(OAc)2 (0.2 mmol), TsNH2
(0.06 mmol), I2 (0.06 mmol) in mixed solvent [DCE (1.0 mL) and toluene
(1.0 mL)]; the reactions were carried out at various temperatures within
10 min. Iodine was added two times (at the first minute andthe fifth
minute). bIsolated yields. cThe ratios of cis and trans isomers were
determined by 1H NMR spectroscopic data.
We next investigated the allylic bromination reactions of
MCBs using NBS as free radical reagent. Surprisingly we
found that the desired bromination products were readily
converted into the corresponding methylenencyclobutanol
in moderate to good yields during purification of the bromi-
nation products through silica gel column chromatography.
Subsequent examinations with diphenylmethylenecyclo-
butane 1a as the substrate to react with N-bromosuccinimide
(NBS) (1.0-2.0 equiv) in carbon tetrachloride (CCl4) were
aimed at determining the optimal conditions and the results
are summarized in Table 3. The reaction of 1a with NBS
(1a/NBS = 1/1.5) was carried out at 70 °C for 10 h and then
the solvent was removed under reduced pressure and
the residue was purified by Huang Hai silica gel column
chromatography (SiO2 with 300-400 mesh). It was found
that 2-(diphenylmethylene)cyclobutanol 4a was obtained in
70% yield (Table 3, entry 1). Increasing the amounts of NBS
to 2.0 equiv, the reaction became disordered, affording
and 2f were obtained in 74% and 71% yield, respectively
(Table 2, entries 4 and 5). Using methylenecyclopentanes
1g-i (n = 2) and the methylenecyclohexanes 1j-k (n = 3) as
the substrates afforded the corresponding products 2g-k in
76-86% yields under the standard conditions (Table 2,
entries 6-10). Unfortunately, when using aliphatic substi-
tuted MCB 1l as the substrate, the reaction yielded unknown
complex mixtures without the desired product 2l, suggesting
that an aromatic group is required in this transformation
(Table 2, entry 11). When compound 1m was used as sub-
strate, the expected product 2m was isolated in 45% yield
(Table 2, entry 12). Furthermore, using methylenecyclo-
proane 1n as substrate provided complex product mixtures,
indicating that a higher yield of the desired product could be
obtained for these methylenecycloalkanes having a four-,
five-, or six-membered ring (Table 2, entry 13).
The amination of MCB 1a was also carried out with use of
a large excess of TsNH2 (1a/PhI(OAc)2/TsNH2/I2 = 1.0/1.0/
3.0/1.0) under the standard conditions, but affording the
corresponding product 3 in trace and 2a in 25% yield. With
use of PhI(OOCtBu)27 instead of PhI(OAc)2, the correspond-
ing amination product 3 was isolated in 49% yield when the
ratio of 1a/PhI(OOCtBu)2/TsNH2/I2 was also changed to
1.0/1.0/3.0/1.0 (Scheme 1).
(9) (a) Horner, L.; Winkelmann, E. H. Angew. Chem. 1979, 18, 349–352.
(b) Thaler, W. A. Methods Free-Radical Chem. 1969, 2, 121. (c) Bovonsombat,
P.; McNelis, E. Synthesis 1993, 237–241. (d) Filler, R. Chem. Rev. 1963, 63,
21–43. (e) Djerassi, C. Chem. Rev. 1948, 43, 271–317.
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Jr.; McCoy, L. L. J. Am. Chem. Soc. 1959, 81, 4863–4873.
(11) (a) Fan, C. A.; Tu, Y. Q.; Song, Z. l.; Zhang, E.; Shi, L.; Wang, M.;
Wang, B. M. Org. Lett. 2004, 6, 4691–4694. (b) Koizumi, Y.; Kobayashi, H.;
Wakimoto, T.; Furuta, T.; Fukuyama, T.; Kan, T. J. Am. Chem. Soc. 2008,
130, 16854–16855. (c) Miyashita, K.; Sakai, T.; Imanishi, T. Org. Lett. 2003,
5, 2683–2686.
(7) Fiori, K. W.; Bois, J. D. J. Am. Chem. Soc. 2007, 129, 562–568.
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1940.
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Jiang et al.
JOCArticle
TABLE 3. Optimization of the Reaction Conditions
TABLE 4. Scope and Limitations of the Reactions of MCBs with NBS
yield
(%)b
of 4a
1a/
entrya halogen halogen additive solvent
temp
(°C)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
Br2
NCS
NIS
I2
NBS
NBS
NBS
NBS
1/1.5
1/2
1/1
CCl4
CCl4
CCl4
CCl4
CCl4
CCl4
CCl4
70
70
70
rt
70
complexd
42
NR
1/1.5
1/1.5
1/1.5
1/1.5
1/1.5
1/1.5
1/1.5
1/1.5
1/1.5
1/1.5
1/1.5
1/1.5
1/1.5
70
70
70
70
70
70
70
70
70
70
70
70
65e
21
30
NR
25
NR
trace
complexd
trace
complexd
36
AIBNc
BPOc
TEMPOc CCl4
CCl4
CCl4
CCl4
CCl4
CH3CN
DMF
toluene
DCE
trace
aReaction conditions: 1 (0.2 mmol), NBS (0.4 or 0.9 mmol), CCl4
(2.0 mL); the reactions were carried out at 70 °C. Then, the solvent was
removed under reduced pressure and the residue was purified by silica
gel column chromatography to give the corresponding products 4 in
moderate to good yields. bIsolated yields. cThe ratios could not be
aReaction conditions: 1a (0.2 mmol), halogen (x mmol), solvent
(2.0 mL); the reactions were carried out at various temperatures. Then,
the solvent was removed under reduced pressure and the residue was
purified by silica gel column chromatography. Isolated yields. Addi-
tive (0.02 mmol). dThe reactions were complex during the bromide steps.
eThe residue was purified by neutral aluminum oxide column chromato-
graphy (Al2O3).
b
c
d
determined by NMR spectroscopic data. The ratios were determined
by 1H NMR spectra.
has been unambiguously determined and its CIF data are
presented in the Supporting Information (Figure SI-1).13
With these optimal conditions in hand, we next carried out
the reactions of a variety of MCBs 1 with NBS to examine the
scope and limitations and the results of these experiments are
shown in Table 4. It can be seen from Table 4, as for
symmetrical MCBs 1b and 1o bearing electron-poor substit-
uents on the benzene ring, the corresponding products 4b
and 4e were obtained in 71% and 71% yield, respectively,
after purification with silica gel column chromatography
(Table 4, entries 1 and 4). In the case of unsymmetrical MCBs
1c and 1d, 4c and 4d were obtained in 73% and 74% yield,
respectively, as isomeric mixtures (Table 4, entries 2 and 3).
The isomeric ratios of 4c and 4d were determined after they
were transformed to the compounds 2c and 2d by acetyl
chloride in the presence of triethylamine (1.2 equiv) and
DMAP (0.1 equiv) because the isomeric ratios of 2c and 2d
complex product mixtures (Table 3, entry 2). Reducing the
amounts of NBS to 1.0 equiv, the yield of 4a was only 42%
(Table 3, entry 3). Thus, the best ratio of 1a:NBS was 1:1.5.
The reaction did not take place at room temperature (20 °C)
within 10 h (Table 3, entry 4). Product 4a could also be
obtained in 65% yield after purification with neutral alumi-
num oxide column chromatography (Al2O3) (Table 3,
entry 5). Adding 2,2-azobisisobutyronitrile (AIBN) or ben-
zoyl peroxide (BPO) as the radical initiator produced 4a in
21% and 30% yield, respectively (Table 3, entries 6 and 7). In
the presence of a radical inhibitor such as 2,2,6,6-tetra-
methyl-1-piperidinyloxy (TEMPO), no reaction occurred,
rendering likely the intervention of a radical pathway
(Table 3, entry 8). With Br2 instead of NBS, 4a was obtained
in 25% yield under identical conditions (Table 3, entry 9).
When N-chlorosuccinimide (NCS), N-iodosuccinimide (NIS),
or I2 was used to replace NBS in the reaction with MCB 1a,
either no reaction was observed or a trace amount of 4a and
complex mixtures were obtained (Table 3, entries 10-12).
The examination of the solvent effects revealed that CCl4 was
the best one for this transformation. Using toluene as the
solvent afforded 4a in 36% yield under the standard condi-
tions. However, in acetonitrile or 1,2-dichloroethane (DCE),
4a was formed in a trace amount, and in N,N-dimethylfor-
mamide (DMF), the reaction became disordered, affording
complex product mixtures with many unidentified bypro-
ducts (Table 3, entries 13-16). Therefore, the best conditions
are to carry out the reaction in CCl4 at 70 °C with 1.0 equiv of
1a and 1.5 equiv of NBS as the starting materials.
1
could be determined by H NMR spectroscopic data (see
Scheme SI-3 in the Supporting Information).
As for MCBs 1p, 1e, 1f, and 1q bearing electron-rich
substituents on the benzene ring, we found that a portion
of starting materials 1 were recoverd under the standard
conditions. Increasing the employed amount of NBS to 3.0
equiv afforded the corresponding products 4f-i in 79-84%
yields within 3 h after purification by silica gel column
(13) The crystal data of 5 have been deposited with the Cambridge Crystal-
lographic Data Centre; deposition no. 687450. These data can be obtained free
of charge from the Cambridge Crystallographic Data Centre, 12 Union Rd.,
Cambridge CB2 1EZ, UK or via www.ccdc.cam.ac.uk/conts/retrieving.html.
Empirical formula, C24H19NO4; formula weight, 385.40; crystal color/habit,
colorless/prismatic; crystal dimensions, 0.432 ꢀ 0.411 ꢀ 0.128 mm3; crystal
To confirm the structure of product 4a, we further trans-
ferred 4a to the corresponding ester product 5 with 4-nitro-
benzoic acid as a colorless solid (see Scheme SI-2 in the
Supporting Information). The X-ray crystal structure of 5
˚
system, monoclinic; lattice type, primitive; lattice parameters, a = 18.083(2) A,
o
˚
˚
b = 13.6403(15) A, c = 7.8790(9) A, R = 90°, β = 97.809(2) , γ = 90°, V =
1925.4(4)A ; space group, P2(1)/c; Z = 4; Dcalc = 1.330 g/cm3; F000 = 808;
3
˚
diffractometer, Rigaku AFC7R; residuals, R/Rw 0.0664/0.1729.
J. Org. Chem. Vol. 75, No. 8, 2010 2531

Jiang et al.
JOCArticle
SCHEME 2. Reaction of 1 (0.2 mmol) with NBS (0.3 mmol) and
Then Separation of Products by Silica Gel Column Chromato-
graphy
SCHEME 3. Control Experiments
SCHEME 4. A Proposed Reaction Mechanism
chromatography (Table 4, entries 5-8). Unfortunately, as
for aliphatic MCBs 1r and 1s, complex reaction products
were formed without the expected products 4j and 4k under
the standard conditions (Table 4, entries 9 and 10). Further-
more, employing MCB 1m with an aromatic substitute (R1)
and a methyl group (R2) as the substrate gave the corre-
sponding cyclobutanol 4l in 54% yield (Table 4, entry 11).
However, for MCB 1t in which R1 is an aromatic group and
R2 is a proton, the reaction became disordered and a complex
product mixture was formed (Table 4, entry 12). The product
structures of 4b-i and 4l were determined by NMR spectro-
scopic data, mass, HRMS, and microanalyses (see the Sup-
porting Information).
Under these optimal conditions, we further investigated
the reaction of 2-methyl-1,1-diphenylpropene 1m and diphe-
nylmethylenecycloalkanes 1n, 1g, and 1j with NBS. It was
found that these reactions did not give the hydroxylation
products (Scheme 2). In the case of 1m, the corresponding
dibrominated compound 6a, derived from a radical reaction
pathway, was obtained in 54% yield. Using diphenylmethylene-
cyclopropane 6b as the substrate afforded the ring-opening
product 6b in 42% yield along with the recovery of the
starting materials.14 But by using diphenylmethylenecyclo-
pentane 1g and diphenylmethylenecyclohexane 1j as the
substrates under the standard conditions, the reactions
became disordered, forming the complex product mixtures.
Thus, the cyclobutane ring plays an important role in this
transformation.
solution, we found that 6 could be transformed to 4a within
2 min (Scheme 3).
To confirm the mechanism of this reaction, we performed
deuterium-labeling studies using deuterated silica gel to
purify the product.16 Under the standard reaction condi-
tions, the cyclobutanol 4a-d with deuterated hydroxyl group
(OD) was separated in 79% yield on the basis of the
1
corresponding H NMR spectroscopic data (see Figure SI-
2 in the Supporting Information).
On the basis of the above experimental results, it is clear
that the transformation of brominated compound 7 to 4a can
take place easily in silica gel, neutral aluminum oxide, and
aqueous potassium hydroxide solution, suggesting that the
hydroxylation of 7 by water could be assisted by silica gel and
neutral aluminum oxide due to its particular structure. The
detailed mechanistic investigation is underway on the basis
of DFT calculation.
A plausible mechanism for the formation of cyclobutanols
4 is outlined in Scheme 4 based on the above deuterium
labeling and control experiments. We proposed that the
reaction proceeded through the Wohl-Ziegler reaction
pathway.17 The bromine radical Br and succinimidyl radical
E are first produced by thermal cleavage of NBS.18 The
radical E abstracts a proton from the allylic position of MCB
1 to give radical C and succinimide. The radical C abstracts
the bromo atom from NBS to afford the brominated product
We found that if using the deactivated silica gel column
chromatography to purify the product after reaction,15 the
brominated product 7 was obtained in 81% yield rather than
4a (Scheme 3). Adding silica gel into the brominated product
7 in a 1H NMR tube, we found that the cyclobutanol 4a was
produced after 10 min on the basis of 1H NMR spectroscopic
data shown in Figure SI-2 (Supporting Information). By
stirring product 6 with 2.0 equiv of aqueous hydrochloric
acid solution (0.1 M) in CCl4 at 70 °C, no reaction occurred
(Scheme 3). However, with use of aqueous potassium hydro-
xide solution (0.1 M) instead of aqueous hydrochloric acid
(16) The silica gel was stirred in deuterium oxide (D2O) for 48 h, then it
was dried for 10 h at 120 °C.
(17) Wohl, A. Ber. Dtsch. Chem. Ges. 1919, 52, 51.
(18) For eamples for similar bromination reaction, see: (a) Kim, S. S.;
Choi, S. Y.; Kang, C. H. J. Am. Chem. Soc. 1985, 107, 4234–4237. (b) Heasley,
V. L.; Louie, T. J.; Luttrull, D. K.; Millar, M. D. J. Org. Chem. 1988, 53, 2199–
2204. (c) Buckles, R. E.; Johnson, R. C. J. Org. Chem. 1957, 22, 55–59.
(14) (a) Shao, L. X.; Zhao, L. J.; Shi, M. Eur. J. Org. Chem. 2004, 23,
4894–4900. (b) Zhou, H. W.; Huang, X.; Chen, W. L. Synlett 2003, 13, 2080–
2082.
(15) The silica gel was stirred in petroleum ether with 5% NEt3 for 24 h,
then it was dried for 2 h at 120 °C.
2532 J. Org. Chem. Vol. 75, No. 8, 2010

Jiang et al.
JOCArticle
F (R1 = R2 = Ph, product F = product 7). Purification of F
with the silica gel column chromatography produces the
cyclobutanol 4 through hydroxylation.
This is a very simple and convenient synthetic approach
to obtain the methylenecyclobutanol compounds from
methylenecyclobutanes without using other reagents except
NBS under mild reaction conditions, although it is only
limited to diarylmethylenecyclobutanes (both R1 and R2 =
aromatic rings).
(22-24 °C) to give the corresponding products 2 in moderate to
good yields.
Preparation of the Products 4. Under ambient atmosphere,
methylenecybutanes 1 (MCBs) (0.2 mmol) and NBS (0.3 mmol)
were added into a Schlenk tube. The reaction mixture was stirred
at 70 °C in CCl4 until the reaction was complete. Then, the
solvent was removed under reduced pressure and the residue was
purified by 32 g of 300-400 mesh silica gel column chromato-
graphy with ethyl acetate and petroleum ether (1:10) at room
temperature (22-24 °C) to give the corresponding products 4 in
moderate to good yields.
Conclusions
2-(Diphenylmethylene)cyclobutyl acetate (2a): olorless oil; IR
(CH2Cl2) ν3055, 2951, 1737, 1599, 1370, 1072, 1033, 939, 769, 700,
633 cm-1; 1H NMR(400 MHz, CDCl3, TMS) δ 1.72 (3H, s, CH3),
2.09-2.16 (1H, m, CH2), 2.46-2.53 (1H, m, CH2), 2.70 (1H, ddd,
J = 16.0, 8.0, 8.0 Hz, CH2), 2.94-3.01 (1H, m, CH2), 5.90-5.94
(1H, m, CH), 7.17-7.33 (10H, m, ArH); 13C NMR (100 MHz,
CDCl3, TMS) δ 20.7, 26.2, 27.1, 71.5, 126.8, 126.9, 127.8, 128.1,
128.5, 129.2, 137.1, 137.7, 139.2, 139.8, 169.9; MS (EI) m/z (%)
278 (40.88) [Mþ], 236 (81.19), 218 (100.00), 203 (23.54), 178
(27.35), 129 (32.60), 115 (40.75), 91 (83.09); HRMS (EI) calcd
for C19H18O2 (Mþ) requires 278.1307, found 278.1303.
2-(Diphenylmethylene)cyclobutanol (4a): colorless oil; IR
(CH2Cl2) ν 3549, 3022, 2854, 1727, 1607, 1510, 1446, 1118,
1042, 820, 723 cm-1; 1H NMR (400 MHz, CDCl3, TMS) δ 1.66
(1H, br s, OH), 1.99-2.08 (1H, m, CH2), 2.37-2.45 (1H, m,
CH2), 2.62 (1H, ddd, J = 18.0, 9.0, 9.0 Hz, CH2), 2.87-2.98
(1H, m, CH2), 5.03-5.08 (1H, m, CH), 7.19-7.37 (10H, m,
ArH); 13C NMR (100 MHz, CDCl3, TMS) δ 25.2, 28.7, 71.5,
128.5, 128.6, 129.8, 130.5, 132.8, 133.1, 133.4, 137.6, 138.2,
144.3; MS (EI) m/z (%) 236 (61.86) [Mþ], 218 (81.84), 208
(63.99), 178 (46.28), 159 (45.66), 115 (47.65), 91 (100.00), 77
(33.86); HRMS (EI) calcd for C17H16O (Mþ) requires 236.1201,
found 236.1202.
In summary, we have developed fairly efficient acetoxy-
lation and hydroxylation reactions of diarylmethylenecyclo-
alkanes with PhI(OAc)2, I2, TsNH2, and NBS respectively
upon heating through radical process to produce the corres-
ponding products in moderate to good yields under mild
conditions. In the case of methylenecyclobutanes, an unex-
pected transformation of methylenecyclobutanes to methylene-
cyclobutanols via bromination with N-bromosuccinimide and
silica gel purification was discovered through a Wohl-Ziegler
reaction pathway. These functionalized cyclo-compounds are a
useful structural motif in the synthesis of many natural products
and bioactive compounds.19 Plausible mechanisms have been
proposed. Clarification of the reaction mechanism and further
application of this transformation are in progress.
Experimental Section
These olefin starting materials are not commercially available
and they have been prepared according to previous literature.20
General Procedure for the Reactions. Preparation of the Pro-
ducts 2. Under ambient atmosphere, diarylmethylenecycloalkanes
1 (0.2mmol) and PhI(OAc)2 (0.3mmol), TsNH2 (0.06 mmol), and
I2 (0.03 mmol) were added into a Schlenk tube. The reaction
mixture was stirred at 60 °C in DCE. After 5 min another sample
of I2 (0.03 mmol) was added into the reaction mixtures. The
reaction was completed after 10 min. The solvent was removed
under reduced pressure and the residue was purified by the
300-400 mesh silica gel column chromatography with ethyl
acetate and petroleum ether (1:30) under room temperature
Acknowledgment. We thank the Shanghai Municipal
Committee of Science and Technology (06XD14005,
08dj1400100-2), National Basic Research Program of China
(973)-2009CB825300, and the National Natural Science
Foundation of China for financial support (20472096,
20872162, 20672127, 20821002, and 20732008) and Mr. Jie
Sun for performing X-ray diffraction.
(19) (a) Cereghetti, M.; Wehrli, H.; Schaffner, K.; Jeger, O. Helv. Chim.
Acta 1960, 43, 354–366. (b) Buchschacher, P.; Cereghetti, M.; Wehrli, H.;
Schaffner, K.; Jeger, O. Helv. Chim. Acta 1959, 42, 2122–2138. (c) Catherine,
H.; Gaelle, B.; Jean, S. J. Am. Chem. Soc. 2008, 130, 5046–5047.
(20) (a) Jiang, M.; Shi, M. Tetrahedron 2009, 65, 798–801. (b) Jiang, M.;
Liu, L.-P.; Shi, M. Tetrahedron 2007, 63, 9599–9604. (c) Jiang, M.; Shi, M.
Org. Lett. 2008, 10, 2239–2242. (d) Jiang, M.; Shi, M. Tetrahedron 2008, 64,
10140–10147.
Supporting Information Available: Spectroscopic data
(1H, 13C spectroscopic data), HRMS of the compounds shown
in the tables, the X-ray crystal structure of compound 7, along
with the detailed description of experimental procedures.
This material is available free of charge via the Internet at
http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 8, 2010 2533