Electrophilic addition to 1-cyclopropylallenes: A highly efficient and stereoselective method for the preparation of 6-substituted-1,3-hexadienes

Article abstract of DOI:10.1055/s-2008-1072631

Electrophilic additions to 1-cyclopropylallenes were investigated, providing an efficient and stereoselective method for the synthesis of 6-substituted-1,3-hexadienes. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1072631

LETTER
1331
Electrophilic Addition to 1-Cyclopropylallenes: A Highly Efficient and
Stereoselective Method for the Preparation of 6-Substituted-1,3-hexadienes
Preparation of
6
e
-Substitute
i
d-1,3-hexadie
Y
nes u,a Bo Meng,a Xian Huang*a,b
a
Department of Chemistry, Zhejiang University (Campus Xixi), Hangzhou 310028, P. R. of China
Fax +86(571)88807077; E-mail: huangx@zju.edu.cn
b
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai
200032, P. R. of China
Received 13 January 2008
E
R1
R2
E
Abstract: Electrophilic additions to 1-cyclopropylallenes were in-
vestigated, providing an efficient and stereoselective method for the
synthesis of 6-substituted-1,3-hexadienes.
R1
E
(1)
(2)
H2C
R1
R2
R2
1
4
5
Key words: cyclopropyl, allene, 1,3-hexadiene, electrophilic addi-
tion, stereoselective
E
E+
R
R
C
R
CH2
2
6
H2C
E
C
Methylenecyclopropanes 1 (MCP), which are highly
strained but readily accessible molecules, are of current
interest in synthetic organic chemistry. The relief of their
ring strain provides a potent thermodynamic driving
force, which facilitates the construction of complex and
interesting organic molecules under mild conditions. Re-
cently, the reactions and applications of MCP have been
widely investigated.1 Allenes 2 are also useful building
blocks in organic synthesis and have attracted much atten-
tion of chemists for a long period. Due to their higher re-
activity than noncumulated C–C double bonds, a variety
of reactions could take place to produce a series of inter-
esting products. During the last decade, allenes have
played very important roles in organic methodology stud-
ies.2
E
C
C
(3)
R
R
R
8
3
7
Scheme 1
C
CuBr
Et2O
MgBr
+
R
OTs
R
3
Scheme 2
cial structure of compound 3, we assumed that when an
electrophile E+ reacts with 3, the most probable interme-
diate would be 7. The structure of 7 was very similar to
that of the intermediate 4. Therefore, if the same b-scis-
sion of C–C bond in the cyclopropyl group takes place,
the corresponding 1,3-hexadiene cation 8 might be gener-
ated (Scheme 1, equation 3). Subsequent reactions of 8
could produce a compound that contains a conjugate diene
structural unit. Conjugate dienes are useful building
blocks in organic synthesis.6 Hence, the investigations on
the reactions of 1-cyclopropylallenes and their applica-
tions are of value.
Previous investigations on MCP have showed that when
an electrophile (E+) reacted with MCP, it first added to the
C=C bond to produce an intermediate carbocation 4. Be-
cause of the high strain of the cyclopropyl ring, C–C bond
cleavage of 4 takes place and gives the intermediate 5
(Scheme 1, equation 1),3 which can be transformed to ho-
moallylic compounds in the subsequent reactions. Simi-
larly, when E+ reacts with allenes, the central carbon of
allenes is attacked first to give intermediate 6 (Scheme 1,
equation 2),2c,4 which could be attacked by nucleophiles to
produce the corresponding allyl derivatives.
Recently, we reported the reaction of 1-cyclopropyl-al-
lenes with phenylselenyl bromide (Scheme 3).7 In that re-
action, the phenylselenyl cation first added to compound
3 to produce the intermediate 9. Due to the large steric
hindrance of phenylselenyl group, the cyclopropyl group
in 9 should be at the same side with the group R. Hence,
10 was obtained as E-isomer selectively in the subsequent
reaction. Herein, we wish to report additional findings on
the electrophilic additions to 1-cyclopropyl-allenes. As it
turned out, the reaction selectivity could be reversed when
electrophiles (E+) with less steric hindrance were em-
ployed.
1-Cyclopropylallenes 3, which contain both a cyclopropyl
group and an allene structural unit, could be conveniently
prepared by the classical reaction of cyclopropyl Grignard
reagent and toluene-4-sulfonic acid prop-2-ynyl ester cat-
alyzed by copper(I) bromide (Scheme 2).5 Due to the spe-
SYNLETT 2008, No. 9, pp 1331–1334
x
x.
x
x.
2
0
0
8
Advanced online publication: 07.05.2008
DOI: 10.1055/s-2008-1072631; Art ID: W00908ST
© Georg Thieme Verlag Stuttgart · New York

1332
L. Yu et al.
LETTER
Br –
Table 2 Synthesis of 2,6-Diiodo-1,3-hexadienes from 1-Cyclopro-
pylallenes
PhSe+
R
R
I
C
Br
CH2Cl2
N2, r.t.
C
H
I2
+
R
I
PhSe
SePh
R
R
3
9
10
3
11
Scheme 3
Entry
R
Yield of 11 (%)a
85 (Z) (11a)
Table 1 Reaction of 1-Phenyl-1-cyclopropylallene with Iodine un-
1
2
3
4
5
6
Ph (3a)
der Different Conditionsa
2-MeC6H4 (3b)
3-MeC6H4 (3c)
4-MeC6H4 (3d)
4-ClC6H4 (3e)
Bn (3f)
73 (Z) (11b)
I
solvent
r.t., N2
C
79 (Z) (11c)
+
I2
I
Ph
Ph
88 (Z) (11d)
3a
11a
70 (Z) (11e)
Entry
Solvent
Et2O
Time (min)b
Yield of 11a (%)c
65 (Z/E = 84:16) (11f)
1
2
3
4
5
6
1
5
72
66
78
60
85
81
a Isolated yields.
PE
responding 1-cyclopropylallenes.8 In most cases, the Z-
isomers were obtained as the only product (Table 2, en-
tries 1–5). When R = Bn, a small quantity of the E-isomer
was also observed from H NMR spectrum. This was
probably due to the lower steric hindrance of the Bn group
(Table 2, entry 6).
THF
1
Me2CO
CH2Cl2
CHCl3
30
1
1
1
a Reaction conditions: iodine (0.3 mmol) was dissolved in solvent (5
mL. The solution was dropped into 1a (0.3 mmol), which was dis-
solved in solvent (1 mL) at r.t. under nitrogen atmosphere.
b The reaction was monitored by TLC (eluent: PE).
c Isolated yields.
Interestingly, when the reaction was conducted in aqueous
acetone, iodohydroxylation product 12a was obtained in
64% yield as the major product (Scheme 4).9,10
Furthermore, we investigated electrophilic addition of H+
as electrophile to 1-cyclopropylallenes. When 1-phenyl-
1-cyclopropylallene 3a was heated in AcOH for two hours
in the presence of KI, the corresponding electrophilic ad-
dition product 3-phenyl-6-iodo-1,3-hexadiene (13a) was
obtained in 52% yield with poor stereoselectivity
(Table 3, entry 1). The stereoselectivity was enhanced
when KBr or NaCl was employed (Table 3, entries 2, 3).
However, when KF was employed, no HF adduct was
found (Table 3, entry 4). Meanwhile, the experimental re-
sults showed that the substituent position at the aryl ring
would strongly affect the stereoselectivity (Table 3, en-
tries 5–7).11
Initially, we examined the electrophilic addition of iodine
to 1-cyclopropyl allenes (Table 1). When an iodine solu-
tion in diethyl ether was dropped to 1-phenyl-1-cyclopro-
pylallene (3a), the reaction proceeded rapidly and the
color of iodine disappeared immediately. After stirring for
one extra minute, the product 2,6-diiodo-3-phenyl-1,3-
hexadiene (11a) was obtained in 72% yield. Further
screening demonstrated that CH2Cl2 was a better solvent
and in this case, the product yield could be enhanced to
85% (Table 1, entry 5). It was notable that in this reaction,
the selectivity was different from our previous investiga-
tions and only the Z-isomer was obtained. The configura-
tion of the product 11a was established by the NOESY
spectrum studies (Figure 1).
We also examined the Lewis acid assisted addition of
EtOH to 1-cyclopropylallenes. However, the stereoselec-
tivity of the reaction was poor. When 3a was heated in
EtOH at 60 °C under nitrogen atmosphere in the presence
of BF3·OEt2, the EtOH adduct 14a was obtained in 78%
yield while the ratio of E/Z was 63:37. Similarly, protonic
acid could also be employed in this reaction (Scheme 5).12
We next examined the application scope of this reaction
under the optimized conditions (Table 2) and a series of
2,6-diiodo-1,3-hexadienes were synthesized from the cor-
H
I
I
I
acetone–H2O
(3:1)
NOE
H
C
+
+
I2
I
I
HO
(Z)-11a
N2, r.t., 24 h
Ph
Ph
Ph
H
3a
11a
12a
64%
25%
NOE
Figure 1
Scheme 4
Synlett 2008, No. 9, 1331–1334 © Thieme Stuttgart · New York

LETTER
Preparation of 6-Substituted-1,3-hexadienes
1333
Table 3 Electrophilic Addition of HX to 1-Cyclopropylallenesa
Acknowledgment
This work was supported by the National Natural Science Founda-
tion of China (20332060, 20472072) and Academic Foundation of
Zhejiang Province.
AcOH
C
+ MX
+
X
X
N2, 80 °C
Ar
Ar
Ar
3
(E)-13
(Z)-13
References and Notes
Entry
Ar
MX
Time (h)b Yield of 13
(%, E/Z)c
(1) Selected reviews about MCP: (a) Brandi, A.; Goti, A. Chem.
Rev. 1998, 98, 589. (b) Brandi, A.; Cicchi, S.; Cordero, F.
M.; Goti, A. Chem. Rev. 2003, 103, 1213. (c) Nakamura, I.;
Yamamoto, Y. Adv. Synth. Catal. 2002, 344, 111.
1
2
3
4
5
6
7
Ph (3a)
Ph (3a)
Ph (3a)
Ph (3a)
KI
2
4
13a 52 (59:41)
13b 65 (87:13)
13c 75 (91:9)
0d
KBr
(2) Selected recent articles about allenes: (a) Zhou, C.; Li, J.;
Lv, B.; Fu, C.-L.; Ma, S.-M. Org. Lett. 2008, 10, 581.
(b) Deng, Y.-Q.; Yu, Y.-H.; Ma, S.-M. J. Org. Chem. 2008,
73, 585. (c) Zhou, C.; Ma, Z.-C.; Gu, Z.-H.; Fu, C.-L.; Ma,
S.-M. J. Org. Chem. 2008, 73, 772. (d) Jiang, X.-F.; Ma, S.-
M. Tetrahedron 2007, 63, 7589. (e) Lu, P.; Ma, S.-M. Org.
Lett. 2007, 9, 5319. (f) Lu, Z.; Chai, G.-B.; Ma, S.-M. J. Am.
Chem. Soc. 2007, 129, 14546. (g) Guo, H.; Ma, S.-M.
Synthesis 2007, 2731. (h) Ma, S.-M. Chem. Rev. 2005, 105,
2829. (i) For a monograph on the chemistry of allenes, see:
Krause, N.; Hashmi, A. S. K. Modern Allene Chemistry;
Wiley-VCH: Weinheim, 2004. (j) For a recent review on the
synthesis of allenes, see: Brummond, K. M.; DeForrest, J. E.
Synthesis 2007, 795.
(3) (a) Shi, M.; Xu, B. Org. Lett. 2002, 4, 2145. (b) Xu, B.; Shi,
M. Org. Lett. 2003, 5, 1415. (c) Liu, L.-P.; Shi, M. J. Org.
Chem. 2004, 69, 2805. (d) Siriwardana, A. I.; Nakamura, I.;
Yamamoto, I. Tetrahedron Lett. 2003, 44, 985. (e) Huang,
J.-W.; Shi, M. Tetrahedron 2004, 60, 2057. (f) Huang, X.;
Yu, L. Synlett 2005, 2953. (g) Yu, L.; Huang, X. Synlett
2007, 1371. (h) Chen, Y.; Shi, M. J. Org. Chem. 2004, 69,
426. (i) Huang, J.-W.; Shi, M. Tetrahedron Lett. 2003, 44,
9343. (j) Shao, L.-X.; Huang, J.-W.; Shi, M. Tetrahedron
2004, 60, 11895. (k) Zhou, H.-W.; Huang, X.; Chen, W.-L.
Synlett 2003, 2080.
NaCl
KF
4
24
6
2-MeC6H4 (3b) NaCl
3-MeC6H4 (3c) NaCl
4-MeC6H4 (3d) NaCl
13d 60 (68:32)
13e 67 (81:19)
13f 72 (97:3)
6
4
a Reaction conditions: 3 (0.3 mmol) and MX (0.6 mmol) were heated
in AcOH (1 mL) at 80 °C under a nitrogen atmosphere.
b The reaction was monitored by TLC (eluent: PE).
c Isolated yields.
d Only the cyclopropyl-ring-untouched AcOH adduct was observed.
conditions
C
+
EtOH
EtO
N2, 60 °C
Ph
Ph
3a
14a
conditions
a: BF3⋅OEt2, 5 h
78%, E/Z = 63:37
b: CF3SO3H, 2 h 71%, E/Z = 69:31
(4) Selected articles about this kind of reactions: (a) Mueller,
W. H.; Butler, P. E.; Griesbaum, K. J. Org. Chem. 1967, 32,
2651. (b) Okuyama, T.; Ohashi, K.; Izawa, K.; Fueno, T.
J. Org. Chem. 1974, 39, 2255. (c) Hagen, J. P.; Harris, J. J.;
Lakin, D. J. Org. Chem. 1987, 52, 782. (d) Yu, L.; Chen,
B.; Huang, X. Tetrahedron Lett. 2007, 48, 925.
Scheme 5
H
Cl
H
(5) For details, see: Brandsma, L.; Verkruijsse, H. D. Synthesis
of Acetylenes, Allenes and Cumulenes; Elsevier:
EtO
Amsterdam, 1981.
Ph
(6) Selected recent articles about conjugated dienes: (a) Zhou,
C.; Fu, C.-L.; Ma, S.-M. Tetrahedron 2007, 63, 7612.
(b) Shi, M.; Wang, B.-Y.; Huang, J.-W. J. Org. Chem. 2005,
70, 5606. (c) Wong, K.; Hung, Y. Tetrahedron Lett. 2003,
44, 8033. (d) Taylor, D. K.; Avery, T. D.; Greatrex, B. W.;
Tiekink, E. R. T.; Macreadie, I. G.; Macreadie, P. I.;
Humphries, A. D.; Kalkanidis, M.; Fox, E. N.; Klonis, N.;
Tilley, L. J. Med. Chem. 2004, 47, 1833.
Me
(E)-13f
(E)-14a
Figure 2
The configurations of 13f and 14a were also established
by NOESY spectroscopic studies (Figure 2).
(7) Yu, L.; Meng, B.; Huang, X. Synlett 2007, 2919.
(8) Preparation of (Z)-2,6-Diiodo-3-phenyl-1,3-hexadiene
(11a); Typical Procedure
In conclusion, we reported the electrophilic addition reac-
tions of electrophiles (E+) to 1-cyclopropylallenes. In
most cases, the stereoselectivity of the reaction was good.
Hence, it might provide a highly efficient and stereoselec-
tive method for the synthesis of 6-sustituted-1,3-hexa-
dienes. Compared with our previous investigations, we
have found that the stereoselectivity could be reversed
when electrophiles with lower steric hindrance were em-
ployed. Further investigations on 1-cyclopropylallenes
are being undertaken in our laboratory.
1-Phenyl-1-cyclopropylallene (3a, 0.3mmol) was first
dissolved in CH2Cl2 (1 mL). Under a nitrogen-atmosphere
protection, a solution of I2 (0.3 mmol) in CH2Cl2 (5 mL) was
slowly added. The reaction proceeded very rapidly and color
of I2 disappeared immediately. The reaction liquid was
stirred for an extra 1 min. Then, the solvent was evaporated
under vacuum and residue was separated by preparation
TLC (eluent: PE) to give 11a in 85% yield. The other 2,6-
diiodo-1,3-hexadienes were prepared in a similar way.
Synlett 2008, No. 9, 1331–1334 © Thieme Stuttgart · New York

1334
L. Yu et al.
LETTER
Selected Spectroscopic Data of 11a
dissolved in AcOH (1 mL). The mixture was stirred at 80 °C
for 4 h. Then, the solvent was evaporated under vacuum and
residue was separated by preparation TLC (eluent: PE) to
give 13c in 75% yield. The other 6-halo-1,3-hexadienes
could be prepared in the similar way.
IR (film): 3055, 3024, 2956, 2923, 1602, 1444, 1235, 1171,
1104, 908, 762, 696 cm–1. 1H NMR (400 MHz, CDCl3):
d = 7.25–7.45 (m, 5 H), 6.24 (s, 1 H), 6.21 (s, 1 H), 5.83 (t,
J = 7.2 Hz, 1 H), 3.26 (t, J = 7.2 Hz, 2 H), 2.86–2.91 (m, 2
H). 13C NMR (100 MHz, CDCl3): d = 3.6, 33.4, 102.6,
126.6, 127.4, 128.1, 128.5, 130.6, 137.4, 145.8. MS (EI, 70
eV): m/z (%) = 410 (13) [M+], 283 (100). HRMS (EI): m/z
calcd for C12H12I2: 409.9029; found: 409.9038.
Selected Spectroscopic Data of 13c
IR (film): 3057, 3024, 2959, 1492, 1444, 990, 919, 767, 702
cm–1. 1H NMR (400 MHz, CDCl3): d = 7.24–7.34 (m, 5 H),
6.77–6.82 (m, 1 H), 5.56 (t, J = 7.2 Hz, 1 H), 5.32 (d, J =
11.2 Hz, 1 H), 5.13 (d, J = 17.2 Hz, 1 H), 3.61 (t, J = 7.2 Hz,
2 H), 2.76–2.81 (m, 2 H). 13C NMR (100 MHz, CDCl3):
d = 31.4, 43.9, 118.9, 127.2, 128.0, 128.7, 129.4, 132.7,
140.9, 142.4. MS (EI, 70 eV): m/z (%) = 192 (32) [M+], 143
(80), 128 (100). HRMS (EI): m/z calcd for C12H13Cl:
192.0706; found: 192.0712.
(9) Spectroscopic Data of Compound 12a
IR (film): 3352, 2924, 2876, 1603, 1444, 1088, 1047, 907,
763, 697cm–1. 1H NMR (400 MHz, CDCl3): d = 7.26–7.44
(m, 5 H), 6.23 (s, 1 H), 6.21 (s, 1 H), 5.93 (t, J = 7.6 Hz, 1
H), 3.79 (t, J = 6.4 Hz, 2 H), 2.55–2.60 (m, 2 H), 1.60 (s, 1
H). 13C NMR (100 MHz, CDCl3): d = 33.4, 61.8, 103.1,
125.3, 126.5, 127.9, 128.4, 130.6, 137.6, 146.2. 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.
(10) For previous investigations on iodohydroxylation reactions
see: (a) Ma, S.-M.; Ren, H.-J.; Wei, Q. J. Am. Chem. Soc.
2003, 125, 4817. (b) Ma, S.-M.; Hao, X.-S.; Huang, X.
Chem. Commun. 2003, 1082. (c) Ma, S.-M.; Hao, X.-S.;
Huang, X. Org. Lett. 2003, 5, 1217. (d) Ma, S.-M.; Wei, Q.;
Wang, H.-M. Org. Lett. 2000, 2, 3893.
(12) Spectroscopic Data of Compound 14a
E-Isomer: 1H NMR (400 MHz, CDCl3): d = 7.13–7.39 (m, 5
H), 6.83–6.90 (m, 1 H), 5.59 (t, J = 7.2 Hz, 1 H), 5.28 (d, J =
11.2 Hz, 1 H), 5.10 (d, J = 17.2 Hz, 1 H), 3.50–3.59 (m, 4 H),
2.59–2.65 (m, 2 H), 1.24 (t, J = 7.2 Hz, 3 H).
Z-Isomer: 1H NMR (400 MHz, CDCl3): d = 7.13–7.39 (m, 5
H), 6.54–6.61 (m, 1 H), 5.77 (t, J = 7.6 Hz, 1 H), 5.01 (d,
J = 10.8 Hz, 1 H), 4.70 (d, J = 17.2 Hz, 1 H), 3.36–3.45 (m,
4 H), 2.21–2.26 (m, 2 H), 1.16 (t, J = 7.2 Hz, 3 H).
Mixture of Z- and E-isomers: IR (film): 2974, 2863, 1491,
1443, 1377, 1112, 911, 768, 703 cm–1. MS (EI, 70 eV): m/z
(%) = 202 (10) [M+], 201 (17), 156 (96), 129 (100). HRMS
(EI): m/z calcd for C14H18O: 202.1358; found: 202.1356.
(11) Preparation of (E)-3-Phenyl-6-chloro-1,3-hexadiene
(13c); Typical Procedure
Under a nitrogen-atmosphere protection, 1-phenyl-1-
cyclopropylallene (3a, 0.3 mmol) and NaCl (0.6 mmol) were
Synlett 2008, No. 9, 1331–1334 © Thieme Stuttgart · New York

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