Carbon-carbon bond formation via the electrophilic addition of carbocations to allenes

Article abstract of DOI:10.1021/ol3006985

A novel electrophilic addition of aryl-substituted allenes and carbocations forming a carbon-carbon bond is described. Stereodefined allylic halides and indenes were furnished with excellent regio- and stereoselectivity depending on the structure of allenes.

Full text of DOI:10.1021/ol3006985

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
CarbonꢀCarbon Bond Formation via the
Electrophilic Addition of Carbocations to
Allenes
Bo Meng and Shengming Ma*
Laboratory of Molecular Recognition and Synthesis, Department of Chemistry,
Zhejiang University, Hangzhou 310027, Zhejiang, People’s Republic of China
masm@sioc.ac.cn
Received March 20, 2012
ABSTRACT
A novel electrophilic addition of aryl-substituted allenes and carbocations forming a carbonꢀcarbon bond is described. Stereodefined allylic
halides and indenes were furnished with excellent regio- and stereoselectivity depending on the structure of allenes.
Electrophilic addition reactions of allenes have become
increasingly attractive in organic synthesis as two func-
tionalities may be introduced within one synthetic opera-
Scheme 1
tion in high regio- and stereoselectivity.1,2 In our previous
reports, a variety of functional groups, such as sulfide,
selenide, sulfoxide, sulfone, phosphine oxide, carboxylate,
and butenolide, etc., have been introduced into allenes to
control the regio- and stereochemistry (Scheme 1).3 In
these reactions, the electrophilic moiety (I, Br, Cl, F, PhSe,
PhS, etc.) is added to the central carbon atom of the allene
moiety, and in most of these reactions, the hydroxyl group
acts as the nucleophile due to the presence of evena trace of
toluene with ZnI2.4 Interestingly (1Z,4E)-(1,3,5-triphenyl)-
water in the solvent. We envisioned that a carbocation may
2-(iodomethyl)penta-1,4-diene Z,E-3a was formed in 46%
yield, indicating that the iodine anion was acting as the
nucleophile.5 However, the stereochemistry is opposite
from our previous reports on such chlorinations,5 as
determined by an NOE study of 3c (Figure 1). In addition,
it should be noted that the reaction with Selectfluor and
NBS afforded the 2-halo-2-propenol as the only or major
product,6 indicating the influence of the electrophile on the
also act as the electrophile in such transformations to form
a CꢀC bond directly. In this paper, we wish to report the
realization of such a concept with the observation that the
halogen anion and aromatic substituents participated in
the reaction as the nucleophiles to afford stereodefined
allylic halides or indenes (Scheme 1).
Initially, we began by trying to react propa-1,2-dienyl-
benzene 1a with a 1,3-diphenyl allyl cation generated
from the treatment of 1,3-diphenylprop-2-en-1-ol 2a in
(4) (a) Yao, L.-F.; Shi, M. Eur. J. Org. Chem. 2009, 4971. (b) Yao,
L.-F.; Shi, M. Org. Lett. 2007, 9, 5187.
(5) (a) Chen, G.; Fu, C.; Ma, S. Tetrahedron 2006, 62, 4444. (b) He,
G.; Guo, H.; Qian, R.; Guo, Y.; Fu, C.; Ma, S. Tetrahedron 2009, 65,
4877. (c) He, G.; Yu, Y.; Fu, C.; Ma, S. Eur. J. Org. Chem. 2010, 101.
(1) For a review, see: Ma, S. Ionic AdditiontoAllenes. InModern Allene
Chemistry; Krause, N., Hashmi, A. S. K., Eds.; Wiley-VCH: Weinheim,
Germany, 2004.
(2) Ma, S. Pure Appl. Chem. 2007, 79, 261.
€
(6) (a) Zhou, C.; Li., J.; Lu, B.; Fu, C; Ma, S. Org. Lett. 2008, 10, 581.
(3) Ma, S. Acc. Chem. Res. 2009, 42, 1679.
(b) Kong, W.; Guo, B.; Fu, C.; Ma, S. Eur. J. Org. Chem. 2011, 2278.
r
10.1021/ol3006985
XXXX American Chemical Society

reactivity of the in situ formed allylic intermediate.
Efforts were then made to optimize the reaction conditions
(Table 1). Of the solvents screened, CH2Cl2 was the better
choice to afford 3a in 66% yield (Table 1, entry 5). The
yield of 3a was further improved to 73% when the reaction
was carried out at 0 °C (Table 1, entry 8). However, the
reaction at ꢀ40 °C gave 3a only in 54% yield (Table 1,
entry 9).
Table 2. Reaction of Arylpropa-1,2-dienes 1 and 1,3-Diarylprop-
2-en-1-ol 2 for the Synthesis of 1,4-Pentadiene Derivatives 3a
Table 1. Optimization of Conditions for the ZnI2-Mediated
Electrophilic Carbochlorination of 1,3-Diphenylprop-2-en-1-ol
2a with Propa-1,2-dienylbenzene 1aa
1
2
time
(h)b
yield of
3 (%)c
entry
R1
R2
X
1
2
3
4
5
6
7
H (1a)
1a
H (2a)
2a
I
15
15
20
13
19
40
6
60 (3a)
40 (3b)
36 (3c)
53 (3d)
33 (3e)
50 (3f)
53 (3g)
Br
Cl
I
1a
2a
Me (1b)
1b
2a
time
(h)b
yield of
2a
Cl
I
entry
solvent
Toluene
temp
rt
3a (%)c
Cl (1c)
1a
2a
Cl (2b)
I
1
2
3
4
5
6
7
8
9
26
48
21
18
9
46
EtOAc
rt
rt
rt
rt
rt
rt
0 o
NR
trace
0
a The reactions were carried out using 1.0 equiv of 1, 1.0 equiv of 2,
and 1.0 equiv of ZnX2 in CH2Cl2 under a nitrogen atmosphere at 0 °C.
b The reaction was monitored by TLC. c Isolated yields.
THF
MeCN
CH2Cl2
CHCl3
66
12
16
15
48
62
of 1,4-pentadiene product 3i, indene product 4a was ob-
served in 88% yield (Table 3, entry 1). It should be noted
that indenes are important core structures in organic
chemistry, which serve as building blocks for ligands in
metallocene-based olefin polymeriztion catalysts,8 func-
tional materials,9 and bioactive pharmaceutical com-
pounds.10 This indicates that the formed allylic cationic
intermediate may undergo a FriedelꢀCraft-type reaction
with one of the two phenyl rings, indicating the dramatic
influence of the initial electrophile on the reactivity of the
formed intermediate via the intermolecular addition with
the allenes.3,6 Then we focused on optimizing the condi-
tions (Table 3). Besides ZnCl2, ZnI2 was also tested in this
reaction to yield 4a in a lower yield (76% vs 88%, compare
Table 3, entries 2 and 1). When the reaction was conducted
at rt, the yield of 4a was improved to 97% (Table 3, entry 3).
The reaction under reflux did not give better results (Table 3,
entry 4); other solvents were tested with CH2Cl2 being most
suitable (Table 3, entries 5ꢀ10). When the amount of ZnCl2
was reduced to 0.5 equiv, the yield of 4a dropped to 80%
(Table 3, entry 11).
ClCH2CH2Cl
CH2Cl2
CH2Cl2
14
C
73
54
ꢀ40 °C
a The reactions were conducted using 0.2 mmol of 1a, 0.2 mmol of 2a,
and 0.2 mmol of ZnI2 in 2 mL of solvent under a nitrogen atmosphere in
a Schlenk tube. b The reaction was monitored by TLC. c Determined by
1H NMR of crude product.
Figure 1. NOE study of 3c, 4e, and 6f.
By utilizing different ZnX2, different halogen atoms
(I, Br, Cl) could be smoothly introduced into correspond-
ing 3aꢀc in 36ꢀ60% yields (Table 2, entries 1ꢀ3). Reac-
tions employing other aryl-substituted propadienes 1b and
1c were also carried out successfully to furnish 3dꢀf in
33ꢀ53% yield (Table 2, entries 4ꢀ6). 1,3-Diarylallyl alco-
hol 2b could also be utilized to construct allylic iodides 3g
in 53% yield, respectively (Table 2, entry 7). It should be
noted that such stereodefined allylic halides are not easy to
make and ZnI2 provided the highest yields.7
With these optimized reaction conditions (Table 3,
entry 3), the scope of the ZnCl2-mediated reaction of
€
(8) Alt, H. G.; Koppl, A. Chem. Rev. 2000, 100, 1205.
(9) (a) Barbera, J.; Rakitin, O. A.; Ros, M. B.; Torroba, T. Angew.
Chem., Int. Ed. 1998, 37, 296. (b) Yang, J.; Lakshmikantham, M. V.;
Cava, M. P.; Lorcy, D.; Bethelot, J. R. J. Org. Chem. 2000, 65, 6739.
ꢀ
ꢀ
(10) (a) Guillon, J.; Dallemagne, P.; Leger, J. ꢀM.; Sopkova, J.;
Bovy, P. R.; Jarry, C.; Rault, S. Bioorg. Med. Chem. 2002, 10, 1043. (b)
Kolanos, R.; Siripurapu, U.; Pullagurla, M.; Riaz, M.; Setola, V.; Roth,
B. L.; Dukat, M.; Glennon, R. A. Bioorg. Med. Chem. Lett. 2005, 15,
1987. (c) Watanabe, N.; Nakagawa, H.; Ikeno, A.; Minato, H.;
Kohayakawa, C.; Tsuji, J. Bioorg. Med. Chem. Lett. 2003, 13, 4317.
Further exploration on the ZnCl2-promoted reaction of
1,1-diphenylpropa-1,2-diene 1d and 1,3-diphenylprop-2-
en-1-ol 2a surprisingly led to the observation that, instead
€
(d) Karaguni, I.-M.; Glusenkamp, K.-H.; Langerak, A.; Geisen, C.;
Ullrich, V.; Winde, G.; Moroy, T.; Muller, O. Bioorg. Med. Chem. Lett.
2002, 12, 709.
˚
€ €
€
(7) (a) Connell, R. D.; Helquist, P.; Akermark, B. J. Org. Chem. 1989,
54, 3359. (b) Yadav, V. K.; Babu, K. G. Tetrahedron 2003, 59, 9111.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 3. Optimization of Conditions for the Electrophilic Ad-
dition of 1,3-Diphenylprop-2-en-1-ol 2a with 1,1-Diphenyl-
propadiene 1da
Table 4. Reaction of Allenes 1 and 1,3-Diarylprop-2-en-1-ols 2
for the Synthesis of Indene Derivatives 4a
yield of
entry
solvent
CH2Cl2
temp
x
timeb
2 h
4a (%)c
1
2
R3
1
0 °C
0 °C
rt
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0.5
88
76
97
83
46
73
36
69
40
31
80
entry R1
R2
timeb
yield of 4 (%)c
2d
3
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
2 h 30 min
40 min
30 min
1
2
3
4
5
6
7
8
H
Ph (1d)
H (2a)
40 min
35 min
5 h 50 min 81,d 85e (4c)
89 (4a)
77 (4b)
4
reflux
rt
Me p-CH3C6H4 (1e) 2a
5
45 min
Cl p-ClC6H4 (1f)
Me p-ClC6H4 (1g)
2a
2a
6
ClCH2CH2Cl
toluene
THF
rt
1 h 20 min
3 h
1 h
90 (4d)
86 (4e)
61 (4f)
89 (4g)
7
rt
Me p-BrC6H4 (1h) 2a
1 h 5 min
25 min
45 min
8
rt
50 min
H
H
H
C2H5 (1i)
Ph (1d)
Ph (1d)
2a
9
EtOAc
rt
45 min
Cl (2b)
10
11
MeCN
rt
35 min
OMe (2c) 1 h 30 min 64 (4h)
CH2Cl2
rt
3 h 45 min
a Unless otherwise specified, the reactions were carried out using 1.0
a Unless otherwise specified, the reactions were conducted using 0.2
mmol of 1d, 0.2 mmol of 2a, and 0.2 mmol of ZnCl2 in 2 mL of solvent
under a nitrogen atmosphere in a Schlenk tube. b The reaction was
monitored by TLC. c Determined by 1H NMR of crude product. d The
reaction was conducted utilizing 1.0 equiv of ZnI2.
equiv of 1, 1.0 equiv of 2, and 1.0 equiv of ZnCl2 in CH2Cl2 under a
nitrogen atmosphere at rt. b The reaction was monitored by TLC.
c Isolated yields. d The reaction was conducted at rt for 5 h and 50 min.
e The reaction was conducted under reflux for 35 min.
different terminal arylallenes 1 and 1,3-diarylprop-2-en-
1-ols 2 was then studied. As demonstrated in Table 4,
symmetric 1,1-diarylallenes 1dꢀf afforded the correspond-
ing indene derivatives 4aꢀc in good to excellent yields
(Table 4, entries 1ꢀ3). To our delight, the reaction showed
excellent regioselectivity with nonsymmetric allenes 1g and
1h, which was established by the NOE study of 4e (Table 4,
entries 4 and 5; Figure 1): cyclization occurred on the
aryl ring bearing an electron-donating group exclusively,
furnishing 4d and 4e as the sole product in 90% and
86% yields, respectively. Allene 1i bearing an alkyl group
reacted smoothly to produce corresponding indene deri-
vative 4f in 61% yield (Table 4, entry 6). In addition, other
1,3-diarylallyl alcohols bearing a para-electron-withdraw-
ing or -donating group 2b and 2c were also examined to
give corresponding products 4g and 4h smoothly (Table 4,
entries 7 and 8).
Notably, the reaction utilizing nonsymmetric alcohol
2d also gave the product 4i exclusively in 69% yield
(Scheme 2). The regiochemistry of this reaction was estab-
lished by the NOE study of 4i. Interestingly, employment
of nonsymmetric alcohol 2e led to the same product 4i in
71% yield.
Furthermore, we observed that diaryl methols may also
be used as the source for the in situ generated carbocation.
After a series of trials, it was demonstrated that diphenyl-
methanol 5a afforded 2-diphenylmethyl-6-methyl-3-p-tolyl-
1H-indene 6a in high yield (Table 5, entry 1) when the
amounts of both 5a and ZnCl2 were raised to 2.0 equiv. The
scope of the electrophilic addition of allenes 1 and diaryl-
methanols 5 was then examined (Table 5). Substituted
Scheme 2
diarylmethanol 5b and 5c were smoothly utilized; 5c,
bearing a p-Cl group on the aryl ring, gave product with
a higher yield than 5b with a p-OMe group (96% vs 82%,
Table 5, enties 2 and 3). Nonsymmetric alcohol 5d was
applied smoothly to generate 6d in 87% yield (Table 5,
entry 4). Nonsymmetric diaryl allenes 1g and 1h were also
introduced successfully: corresponding products 6e and 6f
were furnished in 89% and 79% yields, showing excellent
regioselectivity with the cyclization occurring on the aryl
ring with an electron-donating group (Table 5, entries 5
and 6). The regiochemistry of this reaction was established
by the NOE study of 6f (Figure 1). Allene 1i bearing an
alkyl group was also successfully utilized to generate cor-
responding indene derivative 6g in 76% yield (Table 5,
entry 7). The reaction may be easily conducted on a scale
of 5 mmol of 1e (1.100 g) in a slightly higher yield (Table 5,
entry 8).
Org. Lett., Vol. XX, No. XX, XXXX
C

Table 5. Reaction of Allenes 1 and Diarylmethanols 5 for the
Synthesis of Indene Derivatives 6a
Scheme 3. A Proposed Mechanism
1
5
yield of
entry R1
R2
R4
H
R5
timeb
6 (%)c
1
Me p-CH3C6H4 (1e)
H (5a) 1 h
88 (6a)
2
1e
OMe OMe (5b) 1 h 30 min 82 (6b)
3
1e
Cl
H
Cl (5c) 1 h 35 min 96 (6c)
4
1e
Cl (5d) 40 min
87 (6d)
89 (6e)
79 (6f)
76 (6g)
84 (6b)
5
Me p-ClC6H4 (1g)
Me p-BrC6H4 (1h)
5d
45 min
1 h
6
5a
5a
5b
7
8d
H
C2H5 (1i)
45 min
2 h
1e
a The reactions were carried out using 1.0 equiv of 1, 2.0 equiv of 5,
and 2.0 equiv of ZnCl2 in CH2Cl2 under a nitrogen atmosphere at rt.
b The reaction was monitored by TLC. c Isolated yields. d The reaction
was conducted with a 5 mmol (1.100 g) scale of 1e.
For the first time, the sp3 carbocation adds directly to allenes
forming a carbonꢀcarbon bond with excellent regio- and
stereoselectivity, providing a novel and efficient strategy to
construct stereodefined allylic halides or substituted indene
derivatives depending on the nature of the allenylic substi-
tuents. Due to the potential of the products, easy availability
of the starting materials, and the high selectivity, this meth-
odology may be of high interest for organic and pharma-
ceutical chemists.
A rationale for this transformation is shown in
Scheme 3. Initially, carbocation A would be formed via
the interaction of ZnX2 with an alcohol.4 Electrophilic
addition of the in situ generated cations with allene 1 at the
central carbon atom from the opposite side of the R1-aryl
group generates the stereodefined allylic carbocation inter-
mediate B. Cationic intermediate B is captured by the
halogen anion to form allylic halide 3. In contrast, when
alkyl or aryl groups are introduced as the R2 group, a
concertedprocessofcationinteraction withthe moietyand
the FriedelꢀCrafts-type of attack of the electron-rich aryl
ring would afford intermediate C. Elimination of Hþ
forms the final product 4 or 6.
In conclusion, we have disclosed the highly regio- and
stereoselective electrophilic addition of carbocations with
aryl-substituted allenes. When monosubstituted allenes
are employed, the halogen anion acts as the nucleophile
and attacks the allenes to generate stereodefined allylic
halides. By utilization of 1,1-disubstituted allenes, a Friedelꢀ
Crafts cyclization reaction occurs to form indene derivatives.
Acknowledgment. Financial support from National Basic
Research Program of China (2011CB808700) is greatly ap-
preciated. We thank Mr. Xiaobing Zhang in this group for
reproducing the results presented in entry 5 of Table 2, entry 4
of Table 4, and entry 5 of Table 5.
Supporting Information Available. Typical procedure
and spectroscopic data. This material is available free of
charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX