Halohydroxylation of 1-cyclopropylallenes: An efficient and stereoselective method for the preparation of multisubstituted olefins

Article abstract of DOI:10.1021/jo801087d

(Chemical Equation Presented) The halohydroxylation of 1-cyclopropylallenes would generate two multisubstituted C=C double bonds and at the same time stereoselectively gives 5-halohexa-3,5-dien-1-ols in moderate to good yields. The latter could be transfo

Full text of DOI:10.1021/jo801087d

since the two functional groups, i.e., -X and -OH, could be
introduced into substrates at the same time. However, for allenes,
the regio- and stereoselectivity would be a formidable challenge
to make this methodology feasible. Previously, Ma has reported
that introducing a heteroatom such as sulfur or selenium adjacent
to allenes would be an effective solution and a series of
corresponding 2-halogen-substituted allylic alcohols could be
regio- and stereoselectively synthesized via the halohydroxy-
lation of the modified allenes.6 Encouraged by these works, we
are interested in the halohydroxylation of activated olefins.
Herein, we wish to report the halohydroxylations of allenes with
an adjacent cyclopropyl group introduced as the factor to control
the selectivity, which might provide a novel method for the
stereoselective synthesis of multisubstituted olefins.
Halohydroxylation of 1-Cyclopropylallenes: An
Efficient and Stereoselective Method for the
Preparation of Multisubstituted Olefins
Lei Yu,† Bo Meng,† and Xian Huang*,†,‡
Department of Chemistry, Zhejiang UniVersity (Xixi
Campus), Hangzhou 310028, People’s Republic of China,
and State Key Laboratory of Organometallic Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy
of Sciences, Shanghai 200032, People’s Republic of China
huangx@mail.hz.zj.cn
ReceiVed May 19, 2008
We initially examined the reaction of 1-phenyl-1-cyclo-
propylallene (1a) with I2 in CH2Cl2-H2O (5:1) at room
temperature under nitrogen atmosphere. After stirring for
0.5 h, the anticipated iodohydroxylation product 2a could
be isolated in very low yield while the iodine adduct 3a was
obtained in 56% yield as the major product (entry 1, Table
1). Further screening demonstrated that acetone-H2O should
be a better solvent (entry 3, Table 1). To enhance the yield
of 2a, we increased the ratio of water in solvent (entry 3-7,
Table 1). However, the byproduct 3a could not be totally
eliminated, even when the reaction was carried out overnight
(entry 6, Table 1). This was due to the existence of iodine
anions, which could react with the intermediate homoallylic
carbocation. Therefore, we tried to employ some other “I+”
donors, which did not contain iodine anion. When N-
iodosuccinimide (NIS) was employed as the “I+” donor, the
yield of iodohydroxylation product 2a was enhanced and the
byproduct 3a could be avoided (entry 8, Table 1).This
reaction was highly selective and only Z-isomer was obtained.
The configuration of 2a was established by the NOESY
spectrum studies (Scheme 1).
The halohydroxylation of 1-cyclopropylallenes would gener-
ate two multisubstituted CdC double bonds and at the same
time stereoselectively gives 5-halohexa-3,5-dien-1-ols in
moderate to good yields. The latter could be transformed
into the corresponding alkynyl-substituted conjugated dienes
through the further Sonogashira coupling.
Multisubstituted olefins are ubiquitous and essential structural
constituents in organic molecules. Due to the discovery of many
multisubstituted olefinic natural products and their broad ap-
plications,1 the stereospecific synthesis of multisubstituted
olefins has been one of the most challenging subjects in synthetic
organic chemistry for a long time. During the past decade, a
variety of novel methods have been developed to synthesize
multisubstituted olefins.2 1-Cyclopropylallenes,3 which contain
both a cyclopropyl group and an allene structural unit, are a
kind of high-activated small organic molecule. Our recent
research4 has found that the electrophilic addition to 1-cyclo-
propylallenes would provide a convenient and stereoselective
method for the synthesis of 2,6-disubstituted-1,3-hexadienes,
which contain at least one multisubstituted CdC double bond
in their molecules.
(2) Selected recent articles: (a) McKinley, N. F.; O’Shea, D. F. J. Org. Chem.
2006, 71, 9552. (b) Ma, S.-M.; Negishi, E. J. Org. Chem. 1997, 62, 784. (c)
Asao, N.; Yoshikawa, E.; Yamamoto, Y. J. Org. Chem. 1996, 61, 4874. (d)
Konno, T.; Daitoh, T.; Noiri, A.; Chae, J.; Ishihara, T.; Yamanaka, H. Org.
Lett. 2004, 6, 933. (e) Yamagami, T.; Shintani, R.; Shirakawa, E.; Hayashi, T.
Org. Lett. 2007, 9, 1045. (f) Shindo, M.; Matsumoto, K.; Mori, S.; Shishido, K.
J. Am. Chem. Soc. 2002, 124, 6840. (g) Yamago, S.; Fujita, K.; Miyoshi, M.;
Kotani, M.; Yoshida, J. Org. Lett. 2005, 7, 909. (h) Itami, K.; Ushiogi, Y.;
Nokami, T.; Ohashi, Y.; Yoshida, J. Org. Lett. 2004, 6, 3695. (i) Nishihara, Y.;
Miyasaka, M.; Okamoto, M.; Takahashi, H.; Inoue, E.; Tanemura, K.; Takagi,
K. J. Am. Chem. Soc. 2007, 129, 12634. (j) Itami, K.; Nokami, T.; Ishimura, Y.;
Misudo, K.; Kamei, T.; Yoshida, J. J. Am. Chem. Soc. 2001, 123, 11577.
(3) 1-Cyclopropylallenes could be conveniently prepared by the classical
reaction of cyclopropyl Grignard reagent with toluene-4-sulfonic acid prop-2-
ynyl ester catalyzed by copper(I) bromide. For details see: Brandsma, L.;
Verkruijsse, H. D. Synthesis of Acetylenes, Allenes and Cumlenes; Elsevier:
Amsterdam, The Netherlands, 1981.
Halohydroxylations of the CdC double bond are efficient
methods for the preparation of ꢀ-halogen substituted alcohols,5
(4) (a) Yu, L.; Meng, B.; Huang, X. Synlett 2007, 2919. (b) Yu, L.; Meng,
B.; Huang, X. Synlett 2008, 1331.
† Zhejiang University (Xixi Campus).
(5) (a) Cabanal-Duvillard, I.; Berrien, J.; Royer, J.; Husson, H. Tetrahedron
Lett. 1998, 39, 5181. (b) Rossen, K.; Reamer, R. A.; Volante, R. P.; Reider,
P. J. Tetrahedron Lett. 1996, 37, 6843. (c) Mevellec, L.; Evers, M.; Huet, F.
Tetrahedron 1996, 52, 15103. (d) Sawyer, D. T.; Hage, J. P.; Sobkowiak, A.
J. Am. Chem. Soc. 1995, 117, 106. (e) Fu, H.; Kondo, H.; Ichikawa, Y.; Look,
G. C.; Wong, C. J. Org. Chem. 1992, 57, 7265. (f) Lai, J.; Wang, F.; Guo, G.;
Dai, L. J. Org. Chem. 1993, 58, 6944. (g) Rodebaugh, R.; Fraser-Reid, B. J. Am.
Chem. Soc. 1994, 116, 3155. (h) Yamashita, M.; Iida, A.; Ikai, K.; Oshikawa,
T.; Hanaya, T.; Yamamoto, H. Chem. Lett. 1992, 407. (i) Kato, T.; Hirukawa,
T.; Namiki, K. Tetrahedron Lett. 1992, 33, 1475.
‡ Chinese Academy of Sciences.
(1) Selected examples: (a) Negishi, E.; Abramovitch, A. Tetrahedron Lett.
1977, 18, 411. (b) Onoda, T.; Shirai, R.; Koiso, Y.; Iwasaki, S. Tetrahedron
Lett. 1995, 36, 5765. (c) Ohta, S.; Uno, M.; Yoshimura, M.; Hiraga, Y.; Ikegami,
S. Tetrahedron Lett. 1996, 37, 2265. (d) Jordan, V. C. Nat. ReV. Drug DiscoVery
2003, 2, 205. (e) Robertson, D. W.; Katzenellenbogen, J. A. J. Org. Chem. 1982,
47, 2387. (f) Kido, J.; Shionoya, H.; Nagai, K. Appl. Phys. Lett. 1995, 67, 2281.
(g) Kim, J.-H.; Noh, S.; Kim, K.; Lim, S.-T.; Shin, D.-M. Synth. Met. 2001,
117, 227.
10.1021/jo801087d CCC: $40.75
Published on Web 07/29/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 6895–6898 6895

TABLE 1. Optimization of the Reaction Conditions of the
Iodohydroxylation of 1-Phenyl-1-cyclopropylallene (1a)a
TABLE 3. Iodohydroxylations of 1,3-Disubstituted-1-
cyclopropylallenes
yield of yield of
2a (%)c 3a (%)c
b
entry “ I+
”
solvent
time (h)
1
2
3
4
5
6
7
8
9
I2
I2
I2
I2
I2
I2
I2
NIS
NIS
CH2Cl2-H2O (5:1)
CHCl3-H2O (5:1)
acetone-H2O (5:1)
acetone-H2O (4:1)
acetone-H2O (3:1)
acetone-H2O (3:1)
acetone-H2O (2:1)
acetone-H2O (3:1)
CH3CN-H2O (3:1)
0.5
0.5
1
1
2
24
3
3
24
17
34
40
51
64
41
56
58
41
36
34
25
18
0
yield of 2 (%)b
a
entry
R1, R2
time (h)
(A/B/C/D)c
1
2
3
4
5
6
7
8
9
C6H5, p-BrC6H4 (1g)
o-CH3C6H4, p-BrC6H4 (1h)
m-CH3C6H4, p-BrC6H4 (1i)
p-CH3C6H4, p-BrC6H4 (1j)
p-ClC6H4, p-BrC6H4 (1k)
n-C4H9, p-BrC6H4 (1l)
C6H5, C6H5 (1m)
C6H5, p-CH3C6H4 (1n)
C6H5, p-ClC6H4 (1o)
C6H5, C2H5 (1p)
2
3
3
2
4
4
3
2
3
3
78 (86:7:5:2) (2j)
63 (99:0:1:0) (2k)
60 (99:0:1:0) (2l)
85 (83:10:7:0) (2m)
72 (82:11:7:0) (2n)
19 (42:16:32:10) (2o)
80 (78:11:10:1) (2p)
75 (86:6:6:2) (2q)
71 (91:0:9:0) (2r)
86 (56:44:0:0) (2s)
76
5
traced
0
a 0.3 mmol of 1a and 0.3 mmol of “I+” reagent and 2 mL of solvent
were employed. b The reaction was monitored by TLC (eluent:
petroleum ether). c Isolated yields. d Only unidentified complex mixtures
were obtained.
10
SCHEME 1. Configuration of Z-2a
a The reaction was monitored by TLC (eluent: petroleum ether).
b Isolated yields. c The ratio of the isomers was calculated from 1H
NMR spectrum.
SCHEME 2. Configurations of 3Z,5Z-2m, 2o, and 2s
TABLE 2. Halohydroxylations of 1-Cyclopropylallenes (1)
a
entry
R
X
time (h)
yield of 2 (%)b
76 (2a)
1
2
3
4
5
6
7
8
9
C6H5 (1a)
I
I
I
I
I
3
3
3
2
4
3
3
3
4
o-CH3C6H4 (1b)
m-CH3C6H4 (1c)
p-CH3C6H4 (1d)
p-ClC6H4 (1e)
Bn (1f)
C6H5 (1a)
m-CH3C6H4 (1c)
C6H5 (1a)
70 (2b)
75 (2c)
2 stereoselectively. It is obvious that if the distally substituted
substrate 1 were employed, the possible halohydroxylation
products 2 would contain two multisubstituted CdC double
bonds. The stereospecific synthesis of two multisubstituted
CdC double bonds at the same time is a much more
challenging subject. Hence, we tried to examine the iodohy-
droxylation of the distally substituted substrate 1.
Initially, we employed 1-phenyl-3-(p-bromophenyl)-1-
cyclopropylallene (1g) as substrate and the expected product
2j could be obtained in 78% yield smoothly (entry 1, Table
3). Further experimental results showed that when R1 and
R2 are both aryl groups, the selectivity of this reaction was
generally good and the 3Z,5 Z isomers were obtained as the
overwhelming major product in moderate to good yields
(entries 1-5 and 7-9, Table 3). When R1 ) n-C4H9, both
the yield of 2 and the reaction stereoselectivity clearly
declined (entry 6, Table 3). When R2 ) C2H5, the stereose-
lectivity on the 5-position CdC double bond declined and
both of the 3Z,5Z and 3Z,5E isomers were obtained (entry
10, Table 3). The configurations of the 3Z,5Z isomers of 2m,
2o, and 2s were established by the NOESY spectrum studies
(Scheme 2).
82 (2d)
67 (2e)
I
53 (2f) (Z/E ) 82:18)c
78 (2g)
Br
Br
Cl
65 (2h)
46 (2i)
a The reaction was monitored by TLC (eluent: petroleum ether).
b Isolated yields. c The ratio of Z/E was calculated from 1H NMR
spectrum.
We next examined the application scope of this reaction under
the optimized conditions. When R ) aryl groups, the iodohy-
droxylation reaction proceeded smoothly and the corresponding
Z-5-iodo-hexa-3,5-dien-1-ols (2) could be synthesized in moder-
ate to good yields (entries 1-5, Table 2). When R ) Bn, the
yield of 2f was obliviously decreased and the reaction
selectivity was a little poorer (entry 6, Table 2). Similarly,
NBS and NCS could also be employed as the halogen cation
donor to give the corresponding 5-bromo- or 5-chlorohexa-
3,5-dien-1-ols (entries 7-9, Table 2).
Accordingly, the halohydroxylation of 1-cyclopropylallenes
would create a multisubstituted CdC double bond in product
(6) (a) Ma, S.-M.; Hao, X.-S.; Huang, X. Chem. Commun. 2003, 1082. (b)
Ma, S.-M.; Hao, X.-S.; Huang, X. Org. Lett. 2003, 5, 1217. (c) Ma, S.-M.; Ren,
H.-J.; Wei, Q. J. Am. Chem. Soc. 2003, 125, 4817. (d) Ma, S.-M.; Wei, Q.;
Wang, H. Org. Lett. 2000, 2, 3893.
A possible mechanism of this reaction was shown in
Scheme 3. Electrophilic addition of halogen cation to 1 would
give the intermediate allylic carbon cation 4, which could
6896 J. Org. Chem. Vol. 73, No. 17, 2008

SCHEME 3. Possible Mechanism of the Halohydroxylation
Diels-Alder reactions and exploration of materials for
electronic and photonic applications,11 and in part because
of their existence in many chromophores as a substructure.12
Recently, the synthesis of alkynyl-substituted conjugated
dienes has been widely reported.13 Here, we developed a
novel and convenient method for the synthesis of these
analogues.
In conclusion, we reported the halohydroxylation of
1-cyclopropylallenes. The selectivity of this reaction was
good and two multisubstituted CdC double bonds could be
generated at the same time stereoselectively to give 5-halo-
hexa-3,5-dien-1-ols. Further Sonogashira coupling of 5-io-
dohexa-3,5-dien-1-ols would give the corresponding alkynyl-
substituted conjugated dienes in high yield. All of these
analogues are useful in organic synthesis.
TABLE 4. Sonogashira Coupling of 2
Experimental Section
GeneralProcedurefortheHalohydroxylationof1-Cyclopropy-
lallenes. In a Schlenk tube, 0.3 mmol of 1 was dissolved in 2
mL of acetone-H2O (3:1) under nitrogen atmosphere. Then, 0.3
mmol of NXS was added slowly. The mixture was stirred at
room temperature and the reaction was monitored by TLC
(eluent: petroleum ether). When the reaction terminated, the
solvent was evaporated under vacuum and the residue was
isolated by preparative TLC (eluent: petroleum:EtOAc 4:1) to
give the corresponding product 2. Compound 2a: Yellow oil.
IR (film): 3352, 2924, 2876, 1603, 1444, 1088, 1047, 907, 763,
697 cm-1. 1H NMR (400 MHz, CDCl3, TMS): δ 7.30-7.44 (m,
5H), 6.22 (s, 1H), 6.20 (s, 1H), 5.93 (t, J ) 7.6 Hz, 1H), 3.78
(t, J ) 6.8 Hz, 2H), 2.54-2.59 (m, 2H), 1.64 (s, 1H). 13C NMR
(100 MHz, CDCl3): δ 33.3, 61.7, 103.0, 125.3, 126.5, 127.9,
128.4, 130.6, 137.5, 146.1. MS (EI, 70 eV): m/z (%) 300 (10)
[M+], 173 (44), 141 (100). HRMS (EI): m/z calcd for C12H13OI
300.0011, found 300.0019.
General Procedure for the Sonogashira Coupling. Under
nitrogen atmosphere, 0.2 mmol of 2, 0.4 mmol of alkyne, 0.5
mL of DMSO, and 0.5 mL of newly distilled Et3N were added
to a Schlenk tube. Then, 0.02 mmol of Pd(PPh3)2Cl2 and 0.02
mmol of CuI were added. The mixture was stirred at 60 °C.
After 6 h, the reaction liquid was cooled to room temperature
and quenched with 5 mL of water. The mixture was extracted
with EtOAc (3 × 5 mL) and the combined organic layer was
washed two times with 5 mL of saturated NaCl solution. After
drying with MgSO4, the solvent was evaporated under vacuum
and the residue was purified with TLC (eluent: petroleum ether:
EtOAc 4:1) to give the corresponding product 5. Compound 5a:
Yellow oil. IR (film): 3384, 3057, 2926, 1724, 1598, 1490, 1443,
1099, 1047, 913, 875 cm-1. 1H NMR (400 MHz, CDCl3, TMS):
δ 7.26-7.49 (m, 10H), 5.99 (t, J ) 7.6 Hz, 1H), 5.91 (s, 1H),
5.47 (s, 1H), 3.80 (t, J ) 6.4 Hz, 2H), 2.66-2.71 (m, 2H), 1.60
(s, 1H). 13C NMR (100 MHz, CDCl3): δ 33.2, 62.4, 89.5, 89.6,
entry
R
yield of 5 (%)a
1
2
3
4
5
C6H5 (2a)
94(5a)
85(5b)
90(5c)
81(5d)
87(5e)
m-CH3C6H4 (2c)
p-CH3C6H4 (2d)
p-ClC6H4 (2e)
Bn (2f)
a Isolated yields.
be 4(A) and 4(B) in resonance.4 In 4(A), R2 was inclined to
be at the same side as X due to the steric hindrance factor
while in 4(B), R1 was inclined to be at the same side as the
hydrogen atom. These determined the configuration of the
3-position and 5-position CdC double bonds in product 2.7
Further reaction of 4(B) with water would give the final
product 2 in 3Z,5Z configuration as the overwhelming major
product (Scheme 3). When R1 ) alkyl group, the carbon
cation in 4(B) could not be well stabilized. Thus, the yield
of 2 declined (entry 6, Table 3). Meanwhile, when R1 or R2
were lower steric hindrance groups, the selectivity on the
3-position and 5-position CdC double bonds declined
respectively (entry 6, Table 2 and entries 6 and 10, Table
3).
Containing both a conjugated diene structural unit and a
homoallylic structural unit, 2 might be of potential value in
organic synthesis.8,9 Moreover, the Sonogashira coupling10
of 2 with alkyne could give alkynyl-substituted conjugated
dienes in good to excellent yields (Table 4).
Alkynyl-substituted conjugated dienes are very important
organic compounds, in part because of their applications in
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J. Org. Chem. Vol. 73, No. 17, 2008 6897

122.9, 126.1, 126.6, 126.9, 127.3, 128.1, 128.2 (d), 128.8, 131.5,
140.0, 142.0. MS (EI, 70 eV): m/z (%) 274 (90) [M+], 259 (66),
228 (100). HRMS (EI): m/z calcd for C20H18O 274.1358, found
274.1370.
Supporting Information Available: General experimental
procedures and spectroscopic data for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. This work was supported by the National
Natural Science Foundation of China (20672095, 20732005)
and Academic Foundation of Zhejiang Province.
JO801087D
6898 J. Org. Chem. Vol. 73, No. 17, 2008