Halohydroxylation of alkylidenecyclopropanes using N-halosuccinimide (NXS) as the halogen source: an efficient synthesis of halocyclopropylmethanol and 3-halobut-3-en-1-ol derivatives

Article abstract of DOI:10.1016/j.tetlet.2009.07.146

A variety of halocyclopropyl-methanol and 3-halo-but-3-en-1-ol derivatives were prepared in moderate to excellent yields via the simple halohydroxylation reaction of alkylidenecyclopropanes with convenient and mild sources of electrophilic halogen NXS (X

Full text of DOI:10.1016/j.tetlet.2009.07.146

Tetrahedron Letters 50 (2009) 5754–5756
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Tetrahedron Letters
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Halohydroxylation of alkylidenecyclopropanes using N-halosuccinimide
(NXS) as the halogen source: an efficient synthesis of halocyclopropylmethanol
and 3-halobut-3-en-1-ol derivatives
a
Yewei Yang a, Chenliang Su a, Xian Huang a,b, , QingYang Liu
*
a Department of Chemistry, Zhejiang University (Xixi Campus), Hangzhou 310028, People’s Republic of China
b State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
A variety of halocyclopropyl-methanol and 3-halo-but-3-en-1-ol derivatives were prepared in moderate
to excellent yields via the simple halohydroxylation reaction of alkylidenecyclopropanes with convenient
and mild sources of electrophilic halogen NXS (X = I, Br, Cl, F) and H2O. A plausible mechanism for the
halohydroxylation has been proposed.
Received 7 May 2009
Revised 24 July 2009
Accepted 30 July 2009
Available online 3 August 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Difunctional olefins and cyclopropanes are ubiquitous and
essential structural constituents as they are widespread, ranging
from many biologically active compounds to useful building blocks
in organic molecules.1 During the last decade, a variety of novel
methods have been developed to synthesize difunctional olefins
and cyclopropanes.2 Among these reactions, halohydroxylation of
the C@C double bond is an efficient access to the synthesis of b-hal-
ogen-substituted alcohols, introducing halogen and hydroxyl
groups into substrates by a single step.3
Alkylidenecyclopropanes (ACPs) are highly strained but readily
available molecules that have served as useful building blocks in
organic synthesis.1g–h,4 So far, increasing attention has been paid
to the transition metal-catalyzed reactions of unsubstituted meth-
ylenecyclopropanes, which have been employed for the construc-
tion of complex organic molecules.5–7 Recently, we have
investigated a novel iodohydroxylation of ACPs 1 with iodine and
water that gave iodine-substituted allylic alcohols or iodine-
substituted cyclopropylic alcohols.3j In order to enlarge its
applications and overcome some inherent limitations such as
inconvenience in using and environmental toxicity, we wished to
explore the use of N-halosuccinimides, NXS (i.e., NFS, NCS, NBS
and NIS) as more convenient, mild, and variable sources of electro-
philic halogen,8 providing more efficient and green method for the
synthesis of various halogen-substituted allylic alcohols and halo-
gen-substituted cyclopropylic alcohols which are potentially very
useful synthetic intermediates (Scheme 1).
yield. With this result in hand, various ACPs 1 were examined with
N-halosuccinimide (NXS) under the identified conditions. The re-
sults are summarized in Table 1. When aryl-substituted ACPs 1 re-
acted with NBS and NIS, the corresponding products 2 were
obtained smoothly in good yields (Table 1, entries 1–4).10 For
alkyl-substituted substrate 1g, the corresponding product was ob-
tained only in 31% yield (Table 1, entry 10). Moreover, for NCS, the
reactions proceeded very slowly and the corresponding products
2e–f were obtained in moderate yields (Table 1, entries 5–6). Even
when the weaker electrophile NFS was employed, the expected
products were obtained in moderate yields as well (Table 1, entries
7–9). It should be noted that fluorinated organic compounds are of
current interest owing to the rapidly increasing number of exam-
ples of these compounds with attractive and useful biological
activity.9 Herein we provided a facile approach for the synthesis
of these interesting fluorinated compounds.
Furthermore, we have also explored halohydroxylation of alky-
lidenecyclopropanes with N-halosuccinimides (NXS) as sources of
electrophilic halogen to give the ring-opening 3-halo-but-3-en-
1-ol derivatives.11 In the presence of 2.0 equiv of NBS in DMSO/
H2O, 1a was consumed after 24 h at 100 °C to afford 3a as a major
product in 93% yield (Table 2, entry 1). We next examined the reac-
tion of various ACPs 1 with N-halosuccinimides (NXS) under iden-
tical conditions. As indicated in Table 2, a wide variety of ACPs 1
reacted with NBS and NIS in DMSO/H2O, giving the expected prod-
ucts efficiently (Table 2, entries 1–8). However, when the weaker
electrophiles NCS and NFS were employed as the sources of elec-
trophilic halogen, the desired products were not observed (Table
2, entries 9–10).
The reaction of ACP 1a with 2.0 equiv of N-bromosuccinimide
(NBS) was initially performed in aqueous acetone at room temper-
ature for 3 h, giving the (1-bromocyclopropyl) methanol 2a in 91%
A possible mechanistic pathway for the formation of 2–3 is
shown in Scheme 2.3a First, electrophilic addition of X+ to the C-1
position of the double bond provides the cyclopropylcarbinyl
* Corresponding author. Tel./fax: +86 571 88807077.
E-mail address: huangx@mail.hz.zj.cn (X. Huang).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.07.146

Y. Yang et al. / Tetrahedron Letters 50 (2009) 5754–5756
5755
Table 1
Halohydroxylation of ACPs in aqueous acetonea
R1
R2
OH
R1
X
NXS (2.0 mmol)
acetone/H2O (4:1), rt
R2
1 (1.0 mmol)
2
Entry
ACP 1 (R1/R2)
NXS
Time (h)
Yield of 2b (%)
1
2
3
4
5
6
7
8
9
C6H5/C6H5(1a)
p-ClC6H4/p-ClC6H4(1b)
p-FC6H4/p-FC6H4(1c)
1b
1a
1b
1a
p-MeOC6H4/p-MeOC6H4(1e)
p-i-PrOC6H4/p-i-PrOC6H4(1f)
R1,R2 = CH2CH2CHPhCH2CH2(1g)
NBS
NBS
NBS
NIS
NCS
NCS
NFS
NFS
NFS
NIS
3
3
3
24
60
60
60
48
48
2
2a, 91
2b, 89
2c, 95
2d, 87
2e, 48
2f, 52
2g, 63
2h, 44
2i, 64
2j, 31
10
a
Unless otherwise specified, the reaction was carried out using 1 (1.0 mmol) and NXS (2.0 mmol) in aqueous acetone.
Isolated yields and the reaction time are determined by TLC on the basis of consumption of the starting materials 1.
b
Table 2
Halohydroxylation of ACPs in aqueous DMSOa
R1
R2
X
R1
NXS (2.0 mmol)
DMSO/H2O (4:1), 100 o
C
R2
HO
1 (1.0 mmol)
3
Entry
ACP 1 (R1/R2)
NXS
Time (h)
Yield of 3b (%)
1
2
3
4
5
6
7
8
9
1a
1b
1c
NBS
NBS
NBS
NBS
NBS
NBS
NIS
NIS
NCS
NFS
24
24
24
24
48
24
24
36
72
72
3a, 93
3b, 75
3c, 65
3d, 72
3e, 89
3f, 94
3g, 68
3h, 85
3i, —c
3k, —c
p-MeC6H4/p-MeC6H4(1g)
p-i-BuOC6H4/p-i-BuOC6H4(1h)
p-i-PrOC6H4/p-i-PrOC6H4(1i)
1b
1h
1a
1b
10
a
b
c
Unless otherwise specified, the reaction was carried out using 1 (1.0 mmol) and NXS (2.0 mmol) in DMSO/H2O.
Isolated yields.
No desired product was observed.
cation 4. Subsequently one molecule of water attacks the C-2 posi-
tion of 4, affording the product 2 (Scheme 2, path a). Apparently,
product 3 is also derived from the cation 4 (Scheme 2, path b). In
this case, strain release is more favorably accomplished by ring
opening of the intermediate and bond migration owning to the
higher temperature. Nucleophilic attack of the H2O produces the
ring-opened products 3.
R2
R1
X
a
R1
NXS, H2O
HO
X
R2
R1
b
HO
R2
NXS, X= I, Br, Cl, F.
In conclusion, we have developed a halohydroxylation of
methlenecyclopropanes using inexpensive and easily handled
Scheme 1. Halohydroxylation of ACPs 1.
R1
R2
R1
R2
X
X
X
Path a
Path b
OH
2
R1
R2
H2O
R1
R2
X
X+
1
2
R1
R2
H2O
R1
R2
X
4
1
HO
3
Scheme 2. A plausible mechanism for the halohydroxylation of ACPs 1.

5756
Y. Yang et al. / Tetrahedron Letters 50 (2009) 5754–5756
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N-halosuccinimide (NXS) as the halogen source, providing ready
access to a variety of halocyclopropyl-methanol and 3-halo-but-
3-en-1-ol derivatives. These convenient available products bearing
two functional groups –X and –OH may be converted to other
interesting and useful structural units in organic synthesis.12 In
addition, different solvents can lead to selective synthesis of di-
verse products, which have been the highlight of methylenecyclo-
propane chemistry. Further studies to expand the scope and
synthetic utility of the method are underway.
4. (a) Nakamura, I.; Yamamoto, Y. Adv. Synth. Catal. 2002, 344, 111.
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Camacho, D. H.; Nakamura, I.; Saito, S.; Yamamoto, Y. J. Org. Chem. 2001, 66, 270;
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10. Preparation of (1-halo-cyclopropyl)-diphenyl-methanol (2): To a solution of ACP
1a (1.0 mmol) in 8 mL of acetone was added 2 mL of H2O. Then NXS (2.0 mmol)
was subsequently added. The progress of the reaction was monitored by TLC,
and the mixture was stirred until the starting material disappeared. The
mixture was extracted with ether (25 mL Â 2) and dried over MgSO4.
Evaporation and column chromatography on silica gel afforded 2.
11. Preparation of 3-halo-4,4-diphenyl-but-3-en-1-ol (3): To a solution of ACP 1a
(1.0 mmol) in 8 mL of DMSO was added 2 mL of H2O. Then NXS (2.0 mmol) was
subsequently added. The reaction mixture was then heated to 100 °C for the
required time. The course of the reaction was monitored by TLC. The mixture
was extracted with ether (25 mL Â 2) and dried over MgSO4. Evaporation and
column chromatography on silica afforded 3.
Acknowledgments
We are grateful to the National Natural Science Foundation of
China (Project Nos. 20732005, 20872127 and J0830413) and CAS
Academician Foundation of Zhejiang Province for financial support.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.07.146.
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