Regiocontrolled halohydroxylations of bicyclic vinylidenecyclopropanes: A versatile strategy for the construction of diverse highly functionalized carbocyclic scaffolds

Article abstract of DOI:10.1002/chem.201002141

Highly regioselective halohydroxylations of bicyclic vinylidenecyclopropanes that lead to four types of products 2, 3, 4, and 6 were developed. The halohydroxylation reaction occurs at room temperature to give rise to ring-keeping products vinylbicyclo[(n+2).1.0]alkanols 2 in 55-90% yields with excellent regio- and diastereoselectivity; the reaction of bicyclic vinylidenecyclopropanes with 2.0a equiv of N-bromosuccinimide (NBS) at 100°C affords alkylidenebicyclo[(n+2).2.0]alkanones 3 in 48-75% yields by means of further proximal cleavage of the cyclopropane ring. The structures of both types of compounds 2 and 3 have been elucidated by X-ray crystal diffraction. An interesting sequential reaction that consists of a couple electrophilic addition and elimination reactions was developed when the reaction of bicyclic vinylidenecyclopropanes with N-halosuccinimide (NXS; 3.0a equiv) was performed under the specified conditions to furnish a variety of divinyl ketones 4 by means of proximal cleavage of the cyclopropane ring. In addition, vinylidenecyclopropanes that bore one aryl group at the cyclopropyl ring reacted with NBS or I₂ at room temperature, thereby producing the corresponding divinyl ketones 4 in moderate to good yields with excellent E selectivity. Unexpectedly, 2-vinylic cyclohex-2-enols 6 were generated through a very different distal C-C bond cleavage of the cyclopropane due to the significant ring-size effect. Possible mechanisms are proposed on the basis of the obtained intermediates. Tuning regioselectivity: From a starting material of bicyclic vinylidenecyclopropanes 1, it is possible to assemble four types of useful functionalized carbocyclic scaffolds (bicyclic products 2 and 3, divinyl ketones 4, and cyclohex-2-enols 5) in a highly selective and efficient manner, as a function of electrophiles, temperature, stoichiometry and the ring-size effects (see scheme).

Full text of DOI:10.1002/chem.201002141

FULL PAPER
DOI: 10.1002/chem.201002141
Regiocontrolled Halohydroxylations of Bicyclic Vinylidenecyclopropanes:
A Versatile Strategy for the Construction of Diverse Highly Functionalized
Carbocyclic Scaffolds
[a]
Chenliang Su, Jian Cao, Xin Huang, Luling Wu,* and Xian Huang†
Abstract: Highly regioselective halohy-
droxylations of bicyclic vinylidenecy-
clopropanes that lead to four types of
products 2, 3, 4, and 6 were developed.
The halohydroxylation reaction occurs
at room temperature to give rise to
ring-keeping products vinylbicyclo-
of both types of compounds 2 and 3
have been elucidated by X-ray crystal
diffraction. An interesting sequential
reaction that consists of a couple elec-
trophilic addition and elimination reac-
tions was developed when the reaction
of bicyclic vinylidenecyclopropanes
mal cleavage of the cyclopropane ring.
In addition, vinylidenecyclopropanes
that bore one aryl group at the cyclo-
propyl ring reacted with NBS or I2 at
room temperature, thereby producing
the corresponding divinyl ketones 4 in
moderate to good yields with excellent
E selectivity. Unexpectedly, 2-vinylic
[(n+2).1.0]alkanols 2 in 55–90% yields
with
N-halosuccinimide
(NXS;
with excellent regio- and diastereose-
lectivity; the reaction of bicyclic vinyli-
denecyclopropanes with 2.0 equiv of N-
bromosuccinimide (NBS) at 1008C af-
3.0 equiv) was performed under the
specified conditions to furnish a variety
of divinyl ketones 4 by means of proxi-
cyclohex-2-enols
6
were generated
À
through a very different distal C C
bond cleavage of the cyclopropane due
to the significant ring-size effect. Possi-
ble mechanisms are proposed on the
basis of the obtained intermediates.
fords
alkylidenebicyclo
ACHTUNGTREN[NUNG (n+2).2.0]-
Keywords: allenes · carbocycles ·
reaction mechanisms · regioselectiv-
ity · small-ring systems
alkanones
3
in 48–75% yields by
means of further proximal cleavage of
the cyclopropane ring. The structures
Introduction
synthesis due to the presence of the cumulated C=C bonds
adjacent to the highly strained cyclopropyl ring, and yet
they are thermally stable.[2] An attractive but often trouble-
some feature of vinylidenecyclopropanes is their multiple re-
action “points” that may lead to the formation of a variety
of different products through various reaction pathways: re-
gioselective addition to a cumulated C=C bond[3] and two
types of ring openings of the cyclopropane (i.e., the proxi-
mal cleavage[4] and the distal cleavage).[5] In addition, for
unsymmetrical vinylidenecyclopropanes, there is an addi-
tional issue of regio- and stereoselectivity. Thus, the control
of regio- and stereoselectivity in reactions that involve vinyl-
idenecyclopropanes is an attractive research topic in organic
chemistry.
Halohydroxylations of C=C double bond are powerful
methods for introducing the halogen and hydroxyl group
into substrates by a single step.[6] During the past decade,
the halohydroxylations of allenes[7] and cyclopropane deriva-
tives[8] with defined regio- and stereoselectivity have been
investigated in detail. However, reports on the halohydroxy-
lation of vinylidenecyclopropanes are limited,[8e,f] probably
due to the fact that their multiple reaction pathways are a
The development of novel reactions with high selectivity for
the construction of potentially useful compounds is a hot re-
search topic in organic synthesis. Recently, we have wit-
nessed robust growth in the development of efficient strat-
egies that convert easily accessible starting materials to com-
plex target molecules with high regio- and stereoselectivity.
Vinylidenecyclopropanes[1] show unique reactivity in organic
[a] Dr. C. Su, J. Cao, Prof. X. Huang, Prof. L. Wu, Prof. X. Huang
Department of Chemistry, Zhejiang University (Campus Xixi)
Hangzhou 310028 (P.R. China)
Fax : (+86)571-88807077
E-mail: Wululing@zju.edu.cn
[†] Professor Huang passed away on March 6, 2010. He had been fully in
charge of this project. At this moment, Professor Luling Wu is help-
ing to finish all the projects with assistance from Professor Shengming
Ma.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201002141.
Chem. Eur. J. 2011, 17, 1579 – 1585
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1579

Table 1. Optimization of the reaction conditions for the bromohydroxyla-
tion of 1a.
tremendous challenge to make this methodology synthetical-
ly attractive unless the regio- and stereoselectivity could be
controlled in a highly efficient manner. In the context of our
recent studies on the regio- and stereoselective chemistry of
vinylidenecyclopropanes, we have developed several novel
reactions of vinylidenecyclopropanes by means of controlla-
ble pathways to result in a diversity-oriented synthesis of
different potentially useful compounds.[9] Stimulated by
these interesting results, we turned our effort toward the
highly selective halohydroxylations of vinylidenecyclopro-
panes. The reactivity of vinylidenecyclopropanes is unex-
pected in some respects. Herein, we report our detailed
study on the highly regioselective halohydroxylations of vi-
nylidenecyclopropanes that lead to a variety of vinylbicyclo-
NBS
T
DMSO/H2O
t
Yield of
Yield of
A
[8C]
[h]
2a [%]
3a [%]
1
2
3
4
5
6
7
8
2.0
2.0
2.0
2.0
1.3
1.3
1.5
2.0
2.0
2.0
RT
RT
RT
RT
RT
40
40
70
100
120
4:1
10:1
40:1
80:1
80:1
80:1
80:1
80:1
80:1
80:1
48
48
48
48
48
16
10
20
16
12
41[a]
53[b]
78
87
75
85
90
51
trace
–
–
–
–
–
–
–
–
18
75
64
ACHTUNGTRENNUNG
9
10
ACHTUNGTRENNUNG
nylic cyclohex-2-enols 6 in a highly selective manner as a
function of the employed electrophiles, temperature, stoichi-
ometry, and the substituent effects. The defined structural
features of these bicyclic products not only often occur in
natural products and biologically active compounds,[10] but
also have been used as useful synthetic intermediates for the
synthesis of other carbocyclic systems.[11] In addition, these
unsymmetrical divinyl ketones are valuable building blocks
for organic synthesis, which have been utilized in a wide
range of reactions to prepare various ring systems,[12] includ-
ing acid-catalyzed Nazarov cyclization that leads to cyclo-
pentenones.[13]
[a] 52% of 1a was recovered. [b] 43% of 1a was recovered.
Results and Discussion
The bromohydroxylation of vinylidenecyclopropane 1a with
N-bromosuccinimide (NBS; 2.0 equiv) was initially per-
formed in aqueous DMSO (DMSO/H2O=4:1) at room tem-
perature for 48 h, thereby affording the ring-keeping prod-
uct 7-(1-bromo-2,2-diphenylvinyl)bicycloACTHNUTRGNE[NUG 4.1.0]heptan-7-ol
Figure 1. ORTEP representation of 3a’.
(2a) in 41% yield with an excellent diastereoselectivity;
however, 52% of vinylidenecyclopropane 1a was recovered
(Table 1, entry 1). A screening of the ratio of the mixed sol-
vent (DMSO/H2O) showed that the amount of water in the
system had significant effect on the yield of 2a. When the
reaction was carried out in aqueous DMSO (DMSO/H2O=
80:1), the yield of product 2a was efficiently improved to
87% (Table 1, entries 2–4). Although decreasing the amount
of NBS led to a reduced yield, our further testing revealed
that by using 1.5 equiv of NBS in aqueous DMSO (DMSO/
H2O=80:1) at 408C, an excellent yield of the product 2a
was observed (entries 5–7). To our surprise, the bromohy-
droxylation of vinylidenecyclopropane 1a with 2.0 equiv of
NBS at 708C afforded 2a in 51% yield together with an in-
teresting product, 6-bromo-8-(diphenylmethylene)-bicyclo-
(entry 9). However, the reaction at 1208C afforded 3a in
lower yield (entry 10).
Having established the optimized conditions for the syn-
thesis of polysubstituted bicycloACTHNUGTRNEUNG[4.1.0]heptan-7-ol 2a, we set
out to explore the scope of this reaction. As shown in
Table 2, the reaction of bicyclic vinylidenecyclopropanes
1a–d with variation in ring size (n=2, 3, 4, 8) proceeded
smoothly, and gave
a
variety of multisubstituted
vinylbicyclo[(n+2).1.0]alkanols 2a–d in good to high yields
AHCTUNGTRENNUNG
with an excellent diastereoselectivity (Table 2, entries 1–4).
Bicyclic vinylidenecyclopropanes 1 that bore a methyl group
or chloro moiety on the aromatic rings (R1) were accommo-
dated (entries 5 and 6). On the other hand, reaction of 1a,b
and 1e with N-iodosuccinimide (NIS) under similar condi-
tions afforded the corresponding iodohydroxylation adducts
2g–i in lower yields (entries 7–9). All of the products were
characterized by spectroscopic methods, and 2e was further
confirmed by its X-ray crystallographic study (Figure 2).
ACHTUNGTRENNUNG[4.2.0]octan-7-one (3a) in 18% yield (entry 8). The structure
of 3a was confirmed by X-ray crystallographic analysis of its
(2,4-dinitrophenyl)hydrazine derivative 3a’ (Figure 1). The
yield of product 3a with a four-membered ring was im-
proved to 75% when the reaction was conducted at 1008C
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Bicyclic Vinylidenecyclopropanes
FULL PAPER
Table 2. Synthesis of multisubstituted vinylbicyclo
G
Table 3. Synthesis of alkylidenebicycloACTHNGUTERNNUG
[(n+2).2.0]alkanones 3.[a]
Entry
1
NXS
t [h]
T [8C]
Yield of 2 [%]
Entry
1
t [h]
Yield of 3 [%]
R1
n
R1
n
1
2
3
4
5
6
7
8
9
H
H
H
2 (1a)
3 (1b)
4 (1c)
8 (1d)
2 (1e)
2 (1 f)
2 (1a)
3 (1b)
2 (1e)
NBS
NBS
NBS
NBS
NBS
NBS
NIS
10
14
12
10
14
12
24
15
20
40
40
40
40
40
90 (2a)
81 (2b)
84 (2c)
71 (2d)
87 (2e)
74 (2 f)
62 (2g)
59 (2h)
55 (2i)
1
2
3
4
5
H
Me
H
Me
H
2 (1a)
2 (1 f)
3 (1b)
3 (1h)
4 (1c)
20
8
48
30
10
75 (3a)
58 (3b)
55 (3c)
48 (3d)
H
Cl
Me
H
H
Cl
[b]
–
40
[a] The reaction was carried out using 1 (1.0 equiv) and NBS (2.0 equiv)
in DMSO/H2O (80:1). [b] The reaction was complicated.
RT
RT
RT
NIS
NIS
[a] The reaction was carried out using 1 (1.0 equiv) and NBS (1.5 equiv)
or NIS (1.2 equiv) in DMSO/H2O (80:1).
vinylidenecyclopropanes were subjected to optimal reaction
conditions,
the
desired
alkylidenebicycloACTHUGNETRNNU[G (n+2).2.0]-
alkanones 3a–d were formed in moderate to good yields
(Table 3, entries 1–4). However, when cyclooctane-fused
vinylidenecyclopropane 1c was reacted with NBS under the
same conditions, no desired product was obtained, and the
reaction was complicated (entry 5).
It was surprising but also quite exciting to observe a dif-
ferent reaction pattern when 2.0 equiv of NIS was used as
the electrophile. The substituted methylene-6-iodobicyclo-
AHCTUNGTREG[NNNU 4.2.0]octan-7-one 3e was only formed in a trace amount,
whereas an unsymmetrical divinyl ketone 4a was harvested
in 21% yield (Scheme 2).
Figure 2. ORTEP representation of 2e.
Scheme 2.
Further investigation showed that the bromohydroxyla-
tion of unsymmetrical substrate 1g afforded 2j as a mixture
of E/Z isomers (1:1) in 82% yield as expected (Scheme 1).
We next turned our attention to the highly selective syn-
We then tried to optimize the reaction conditions to get a
useful synthesis of these versatile building blocks. After
treatment of bicyclic vinylidenecyclopropane 1a with
3.0 equiv of NIS in aqueous DMSO (DMSO/H2O=80:1) at
room temperature for 3 h, the resulting mixture was
warmed to 858C for another 1 h with stirring. Then Et3N
(5.0 equiv) was added, and the
thesis of a variety of alkylidenebicycloACTHNUTRGNEUNG[(n+2).2.0]alkanones
3. The typical results summarized in Table 3 show that ring
size had a significant effect on the outcome of this reaction.
When a series of six- to seven-membered cycloalkane-fused
mixture was stirred at 858C for
10 h. With a general workup, di-
vinyl ketone 4a could be ob-
tained in 66% yield (Table 4,
entry 1). To further explore the
scope of this transformation, a
variety of vinylidenecyclopro-
panes 1 were examined and the
results are listed in Table 4. Bi-
Scheme 1. Bromohydroxylation of unsymmetrical substrate 1g.
cyclic vinylidenecyclopropane
Chem. Eur. J. 2011, 17, 1579 – 1585
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1581

L. Wu et al.
Table 4. Synthesis of various unsymmetrical divinyl ketones 4.
Scheme 3.
Entry
1
X+
[equiv]
t
Yield of
4 [%]
Ar
R1
(CH2)4 (1a)
(CH2)4 (1 f)
(CH2)5 (1h)
(CH2)6 (1c)
(CH2)6 (1c)
R2
G
[h]
1
2
3
4
Ph
p-MeC6H4
p-MeC6H4
T
NIS (3.0) 3/1/10[a] 66 (4a)
ACHTUNGTRENNUNG
NIS (3.0) 3/1/10[a] 58 (4b)
N
NIS (3.0)
NIS (3.0)
7[b] 60 (4c)
6[b] 52 (4d)
Ph
Ph
ACHTUNGTRENNUNG
5
T
NBS/NIS 12/10[c] 46 (4e)
6
7
8
9
10
11
Ph
p-MeC6H4
Ph
Ph
Ph
H (1i) I2 (2.2)
H (1j) I2 (2.2)
48[d] 65 ((E)-4 f)
30[d] 71 ((E)-4g)
48[d] 55 ((E)-4h)
72[d] 60 ((E)-4i)
96[e] 47 ((E)-4j)
96[e] 62 ((E)-4k)
p-MeC6H4 H (1k) I2 (2.2)
p-ClC6H4 H (1l) I2 (2.2)
Ph
Ph
Ph
Ph
H (1i) NBS (5.0)
p-ClC6H4 H (1l) NBS (5.0)
[a] The reaction was carried out using 1.0 equiv of 1 with 3.0 equiv of
NIS at room temperature in aqueous DMSO (DMSO/H2O=80:1). After
being stirred for 3 h, the reaction mixture was heated to 858C for another
1 h with stirring. Then 5.0 equiv of Et3N were added, and the mixture
was stirred at 858C for another 10 h. [b] The reaction was carried out
using 1 (1.0 equiv) and NIS (3.0 equiv) in aqueous DMSO (DMSO/
H2O=80:1) at room temperature. [c] The reaction was carried out using
1 (1.0 equiv) and NBS (1.5 equiv) in aqueous DMSO (DMSO/H2O=
80:1) at room temperature for 12 h, and then NIS (1.5 equiv) was added.
The resulting mixture was stirred for another 10 h. [d] The reaction was
carried out using 1 (1.0 equiv) and I2 (2.2 equiv) in DMSO (analytical
grade) at room temperature. [e] The reaction was carried out using 1
(1.0 equiv) and NBS (3.0 equiv) in DMSO (analytical grade) at room
temperature. After being stirred for 48 h, another 2.0 equiv of NBS were
added and the mixture was stirred for another 48 h.
Figure 3. ORTEP representation of 5a.
the presence of Et3N smoothly furnished 4a in a good yield
(Scheme 4).
1 f (Ar=4-MeC6H4) also readily participated in the reaction
and gave 58% yield of the corresponding divinyl ketone
compound 4b (entry 2). Two substrates 1h and 1c were em-
ployed to examine the ring-size effect of the bicyclic group,
and the desired products 4c and 4d were obtained in accept-
able yields even at room temperature (entries 3 and 4).
After treatment of 1c with 1.5 equiv of NBS at room tem-
perature for 12 h, 1.5 equiv of NIS was added for another
10 h with stirring to furnish the bromo-substituted divinyl
ketone 4e in 46% yield (entry 5). Furthermore, vinylidene-
cyclopropanes 1i–l that bore one aryl group at the cyclo-
propyl ring were also investigated, thereby affording the cor-
responding divinyl ketones 4 f–k in 47–71% yields with an
excellent E selectivity (entries 6–11).
To shed light on the reaction mechanism, attempts to iso-
late the intermediates were made. Initially, the relationship
between the ring-keeping products 2 and ring-expansion
products 3 was revealed by the fact that treatment of
vinylbicycloACHTUNGTRENNUNG[(n+2).1.0]alkanol 2a with NBS in DMSO/H2O
(80:1) at 1008C successfully delivered the corresponding
product 3a in 82% yield (Scheme 3).
Scheme 4.
On the basis of the obtained intermediates, a plausible re-
action mechanism is proposed in Scheme 5. It begins with
an electrophilic interaction of X+ with the electron-rich C=
C bond adjacent to the cyclopropane, thereby forming a
three-membered cyclic halonium ion intermediate A, which
is selectively attacked by H2O from the less sterically hin-
dered side to produce the ring-keeping halohydroxylation
products 2 with excellent diastereoselectivity. With NBS at
1008C, the addition of bromonium ion to the double bond
induces a ring enlargement to give the dibromocyclobuta-
none C. Then a known rearrangement occurs with bromine
atom migration mediated by HBr to afford D,[14] which un-
dergoes an elimination reaction to furnish the ultimate prod-
uct 3a (Scheme 5, path a). However, in the presence of I+, a
different electrophilic ring-opening of 2g occurs with high
stereoselectivity to give the intermediate product 5a, which
is finally transformed to divinyl ketone 4a through an elimi-
nation of HI (Scheme 5, path b).
To our delight, intermediate 5a could also be obtained in
68% yield from the electrophilic ring-opening reaction of
Interestingly, when the reaction was extended to five-
membered ring-fused vinylidenecyclopropane 1m, an unex-
pected product 2-(1-bromo-2,2-diphenylvinyl)cyclohex-2-
enol (6a) was obtained in 58% yield by means of a very dif-
vinylbicycloACHTUNGTRENNUNG
[(n+2).1.0]alkanol 2g with I+. The structure of
5a was determined by the X-ray diffraction study (Figure 3).
In addition, treatment of 5a at the specified temperature in
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Chem. Eur. J. 2011, 17, 1579 – 1585

Bicyclic Vinylidenecyclopropanes
FULL PAPER
tuning the regioselectivity of
the reaction. As a matter of
fact, when using tetrahydrofur-
an-fused
vinylidenecyclopro-
pane 1p as the substrate, 5,6-di-
hydro-2H-pyran-2-ol derivative
6 f was obtained in 62% yield
with an excellent regioselectivi-
ty (Scheme 7).
The mechanism for the for-
mation of ring-expansion prod-
ucts 6 through distal cleavage
of the cyclopropane is proposed
in Scheme 8. First, X+ reacts
with the electron-rich internal
C=C bond adjacent to the cy-
clopropane to produce a three-
membered cyclic halonium ion
intermediate E, which under-
goes a ring-opening process to
Scheme 5. Tentative mechanism for the selective synthesis of products 2, 3, and 4.
À
ferent distal C C bond cleav-
age of the cyclopropane ring
due to the significant ring-size
effect (Table 5, entry 1). Conse-
quently, we examined the scope
of the reaction for the synthesis
of various 2-vinylic cyclohex-2-
enols 6. In one case, the bromo-
hydroxylations of cyclopentane-
fused vinylidenecyclopropane
Scheme 6. Bromohydroxylation of unsymmetrical substrate 1o.
1n proceeded to afford the product 6b smoothly in 69%
yield (entry 2). In other cases, iodohydroxylations of 1m,n
proceeded faster to give the corresponding adducts 6c,d in
52–60% yields (entries 3 and 4).
Scheme 7. Regioselective bromohydroxylation of vinylidenecyclopropane
1p.
For unsymmetrical substrate 1o, the reaction afforded 6e
as a mixture of 1:1 E/Z isomers in 62% yield (Scheme 6).
We reasoned that the presence of functional groups on
the cyclopropane moiety may facilitate the selective cleav-
À
age of C C bonds of the cyclopropane, thus delicately
afford the six-membered ring cationic intermediate F, proba-
bly due to the strained nature of the bicycloACTHNURTGNEU[GN 3.1.0]hexane
cationic intermediate. Then the cationic cyclic allylic inter-
mediate F was subsequently attacked by H2O to give 6. It
should be noted that the bromohydroxylation reaction of
Table 5. Synthesis of 2-vinylic cyclohex-2-enols 6.[a]
Entry
R1 (1)
NXS
t [h]
Yield of 6 [%]
1
2
3
4
H (1m)
Me (1n)
1m
NBS
NBS
NIS
NIS
24
24
4
58 (6a)
69 (6b)[b]
52 (6c)
60 (6d)
1n
4
[a] Unless otherwise specified, the reaction was carried out using 1
(1.0 equiv) and NXS (1.3 equiv) in DMSO/H2O (80:1). [b] 1.6 equiv of
NBS were added.
Scheme 8. Tentative mechanism for the formation of ring-expansion
products 6.
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1583

L. Wu et al.
with water (5 mL) and extracted with EtOAc (3ꢁ5 mL). The combined
organic layers were washed with a saturated aqueous solution of Na2S2O3
and dried over anhydrous Na2SO4. Filtration, evaporation, and column
chromatography on silica gel (eluent: petroleum ether/ethyl acetate 50:1)
afforded 4a (83 mg, 66%). 1H NMR (400 MHz, CDCl3, 258C, TMS): d=
7.29–7.43 (m, 5H), 7.16–7.23 (m, 3H), 7.02–7.07 (m, 2H), 6.85–6.90 (m,
1H), 1.95–2.08 (m, 4H), 1.31–1.42 ppm (m, 4H); 13C NMR (100 MHz,
CDCl3, 258C, TMS): d=21.3, 21.6, 23.2, 26.2, 97.2, 128.1, 128.2, 128.3,
129.0, 129.1, 136.5, 140.3, 143.7, 144.1, 152.7, 195.5 ppm; IR (neat): n˜ =
2924, 2858, 1638, 1625, 1491, 1443, 1268, 753, 696 cmÀ1; MS (70 eV, EI):
m/z: 414 [M+]; HRMS (EI): m/z calcd for C21H19IO: 414.0481 [M+];
found: 414.0485.
substrate 1p demonstrates an alkoxy group effect, which
could be explained by its stabilization effect in the cationic
allylic intermediate.
Conclusion
In summary, we have presented here a comprehensive study
of the unique regiocontrolled halohydroxylation reaction of
vinylidenecyclopropanes that provides direct synthetic
access to a variety of bicyclic products, cyclohex-2-enols, and
divinyl ketones in controllable ways, which may open up a
new area for the control of selectivity in addition reactions
of vinylidenecyclopropanes. Possible mechanisms are pro-
posed on the basis of the obtained intermediates. Due to the
easily accessible starting materials, simple reaction proce-
dure, mild conditions, and the selective pathways, this reac-
tion should be an appealing strategy in organic synthesis.
Further studies on the synthetic application are currently
ongoing.
A typical procedure for the synthesis of compound 6a: Vinylidenecyclo-
propane 1m (70 mg, 0.271 mmol), DMSO/H2O (80:1, 3 mL), and NBS
(62 mg, 0.348 mmol) were added sequentially to a reaction tube. Then
the mixture was stirred at room temperature. After the reaction was
complete as monitored by TLC, the resulting mixture was quenched with
water (5 mL). The mixture was extracted with EtOAc (3ꢁ5 mL). The
combined organic layers were dried over anhydrous Na2SO4. Filtration,
evaporation, and column chromatography on silica gel (eluent: petrole-
um ether/ethyl acetate 10:1) afforded 6a (56 mg, 58%). 1H NMR
(400 MHz, CDCl3, 258C, TMS): d=7.23–7.38 (m, 7H), 7.12–7.23 (m,
3H), 5.74 (t, J=3.8 Hz, 1H), 4.54 (t, J=5.6 Hz, 1H), 2.09 (s, 1H), 1.76–
1.94 (m, 3H), 1.58–1.76 (m, 2H), 1.45–1.58 ppm (m, 1H); 13C NMR
(100 MHz, CDCl3, 258C, TMS): d=18.4, 25.8, 30.8, 65.9, 123.5, 126.9,
127.3, 127.7, 128.0, 129.5, 129.7, 134.3, 139.9, 141.5, 143.1, 143.6 ppm; IR
(neat): n˜ =3415, 2930, 1491, 1443, 1030, 912, 760, 742 cmÀ1; MS (70 eV,
EI): m/z: 354 [M+]; HRMS (EI): m/z calcd for C20H19BrO: 354.0619 [M+
]; found: 354.0626.
Experimental Section
X-ray crystal data for 2e: C21H19BrCl2O; Mr =438.17; crystal system:
monoclinic; space group: P21/n; final R indices (I>2s(I)): R1=0.0326,
A typical procedure for the synthesis of compound 2a: Vinylidenecyclo-
propane 1a (82 mg, 0.301 mmol) and DMSO/H2O (80:1, 3 mL) were
added sequentially to a reaction tube. Then NBS (81 mg, 0.455 mmol)
was added and the mixture was stirred at 408C. After the reaction was
complete as monitored by TLC, the resulting mixture was quenched with
water (5 mL). The mixture was extracted with EtOAc (3ꢁ5 mL). The
combined organic layers were dried over anhydrous Na2SO4. Filtration,
evaporation, and column chromatography on silica gel (eluent: petrole-
um ether/ethyl acetate 10:1) afforded 2a (100 mg, 90%). 1H NMR
(400 MHz, CDCl3, 258C, TMS): d=7.48 (d, J=7.2 Hz, 2H), 7.20–7.42
(m, 8H), 3.17 (s, 1H), 1.77–2.00 (m, 2H), 0.88–1.54 (m, 7H), 0.06–
0.28 ppm (m, 1H); 13C NMR (100 MHz, CDCl3, 258C, TMS): d=19.2,
19.4, 21.2, 26.6, 29.0, 64.3, 126.9, 127.7, 127.8, 128.1, 128.2, 129.5, 130.3,
140.4, 143.9, 147.3 ppm; IR (neat): n˜ =3364, 2925, 2854, 1491, 1446, 1075,
999, 760 cmÀ1; MS (70 eV, EI): m/z: 368 [M+]; HRMS (EI): m/z: calcd
for C21H21BrO: 368.0776 [M+]; found: 368.0770.
wR2=0.0657;
10.0629(3), b=12.6575(3), c=15.2116(5) ꢂ; a=90.00, b=102.082(3), g=
90.008; V=1894.60(10) ꢂ3, T=293(2) K, Z=4; F
(000)=888; reflections
collected/unique: 7978/3868 (R(int)=0.0219); number of observations
R indices (all data): R1=0.0573, wR2=0.0682; a=
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
(I>2s(I)): 2514; parameters: 226.
X-ray crystal data for 3a’: C27H27BrN4O4; Mr =551.44; crystal system:
monoclinic; space group: P21/c; final R indices (I>2s(I)): R1=0.0444,
wR2=0.1024;
11.9391(10),
R
indices (all data): R1=0.0783, wR2=0.1103; a=
b=13.8894(11), c=16.1459(13) ꢂ; a=90.00, b=
(000)=
(int)=0.0425); number
110.4020(10), g=90.008; V=2509.5(4) ꢂ3, T=293(2) K, Z=4; F
ACHTUNGTRENNUNG
1136; reflections collected/unique: 13939/5178 (R
of observations (I>2s(I)): 3026; parameters: 338.
ACHTUNGTRENNUNG
X-ray crystal data for 5a: C21H20I2O; Mr =542.17; crystal system: triclinic;
¯
space group: P1; final R indices (I>2s(I)): R1=0.0274, wR2=0.0559; R
indices (all data): R1=0.0433, wR2=0.0591; a=9.4896(6), b=9.7121(5),
c=11.4236(6) ꢂ; a=72.322(5), b=78.215(5), g=85.356(5)8; V=
A typical procedure for the synthesis of compound 3a: Vinylidenecyclo-
propane 1a (94 mg, 0.346 mmol), DMSO/H2O (80:1, 3 mL), and NBS
(123 mg, 0.691 mmol) were added sequentially to a reaction tube. Then
the resulting mixture was stirred at 1008C. After the reaction was com-
plete as monitored by TLC, the resulting mixture was quenched with
water (5 mL). The mixture was extracted with EtOAc (3ꢁ5 mL). The
combined organic layers were dried over anhydrous Na2SO4. Filtration,
evaporation, and column chromatography on silica gel (eluent: petrole-
um ether/ethyl acetate 50:1) afforded 3a (95 mg, 75%). 1H NMR
(400 MHz, CDCl3, 258C, TMS): d=7.33–7.43 (m, 8H), 7.26–7.31 (m,
2H), 3.65 (t, J=6.2 Hz, 1H), 2.20–2.28 (m, 1H), 2.06–2.16 (m, 1H), 1.65–
1.75 (m, 2H), 1.50–1.62 (m, 1H), 1.36–1.46 (m, 2H), 1.20–1.31 ppm (m,
1H); 13C NMR (100 MHz, CDCl3, 258C, TMS): d=17.9, 19.6, 22.4, 30.5,
47.7, 66.7, 128.1, 128.3, 128.4, 129.2, 129.5, 129.8, 137.5, 138.5, 141.9,
148.8, 193.5 ppm; IR (neat): n˜ =2934, 1736, 1694, 1599, 1444, 1260,
734 cmÀ1; MS (70 eV, EI): m/z: 366 [M+]; HRMS (EI): m/z: calcd for
C21H19BrO: 366.0619 [M+]; found: 366.0614.
981.78(9) ꢂ3, T=293(2) K, Z=2;
FACHTUNGTRENNUNG
unique: 7332/3590 (RACHTUNGTRENNUNG
2716; parameters: 217.
CCDC-785607 (2e), 785608 (3a’), and 785609 (5a) contain the supple-
mentary crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Acknowledgements
A typical procedure for the synthesis of compound 4a: Vinylidenecyclo-
propane 1a (82 mg, 0.301 mmol), DMSO/H2O (80:1, 3 mL), and NIS
(203 mg, 0.902 mmol) were added sequentially to a reaction tube. After
being stirred for 3 h, the reaction mixture was heated to 858C and stirred
for another 1 h. Then Et3N (5.0 equiv) was added, and the mixture was
stirred at 858C for another 10 h. The resulting mixture was quenched
We are grateful to the National Natural Science Foundation of China
(project nos. 20732005 and 20872127), the National Basic Research Pro-
gram of China (973 Program, 2009CB825300), CAS Academician Foun-
dation of Zhejiang Province and the Fundamental Research funds for the
Central Universities for financial support.
1584
www.chemeurj.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 1579 – 1585

Bicyclic Vinylidenecyclopropanes
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Received: July 27, 2010
Published online: December 16, 2010
Chem. Eur. J. 2011, 17, 1579 – 1585
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1585