Highly regioselective synthesis of trisubstituted allenes via lithiation of 1-Aryl-3-alkylpropadiene, subsequent transmetalation, and Pd-catalyzed negishi coupling reaction

Article abstract of DOI:10.1021/ol8001909

A novel methodology for the synthesis of trisubstituted allenes is reported. Lithiation of 1-aryl-3-alkylpropadienes and subsequent transmetalation with zinc bromide followed by Pd-catalyzed Negishi coupling reactions with halides afforded the corresponding trisubstituted allenes in a highly regioselective fashion with moderate to excellent yields. A plausible regioselective lithiation mechanism was proposed on the basis of deuterium labeling experiments.

Full text of DOI:10.1021/ol8001909

ORGANIC
LETTERS
2008
Vol. 10, No. 8
1521-1523
Highly Regioselective Synthesis of
Trisubstituted Allenes via Lithiation of
1-Aryl-3-alkylpropadiene, Subsequent
Transmetalation, and Pd-Catalyzed
Negishi Coupling Reaction
Jinbo Zhao,† Yu Liu,‡ and Shengming Ma*,†,‡
Shanghai Institutre of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Lu, Shanghai 200032, People’s Republic of China, and
Shanghai Key Laboratory of Green Chemistry and Chemical Process,
Department of Chemistry, East China Normal UniVersity,
3663 North Zhongshan Road, Shanghai 200062, People’s Republic of China
masm@mail.sioc.ac.cn
Received January 26, 2008
ABSTRACT
A novel methodology for the synthesis of trisubstituted allenes is reported. Lithiation of 1-aryl-3-alkylpropadienes and subsequent transmetalation
with zinc bromide followed by Pd-catalyzed Negishi coupling reactions with halides afforded the corresponding trisubstituted allenes in a
highly regioselective fashion with moderate to excellent yields. A plausible regioselective lithiation mechanism was proposed on the basis of
deuterium labeling experiments.
Selectivity control has always been a challenge in organic
synthesis.1 Traditionally, the transition-metal-catalyzed cross-
coupling reaction involving propargyl/1,2-allenyl species is
one of the most important tools in the synthesis of allenes.2
However, there is, in principle, a regioselectivity issue for
this transformation. The ratio of allene/alkyne in the products
usually depends on many factors including steric and
electronic properties of the transition metals, ligands, and
substrates, etc.3 The propargyl/1,2-allenyl metal species
usually exist in an equilibrium in the solution,4 which is the
intrinsic reason for the regioselectivity. Recently, during the
† Shanghai Institute of Organic Chemistry.
‡ East China Normal University.
(1) (a) Trost B. M., Fleming, I. Eds. ComprehensiVe Organic Synthesis:
SelectiVity, Strategy and Efficiency in Modern Organic Chemistry; Pergamon
Press: Oxford, 1991. (b) Ward, R. S., Ed. SelectiVity in Organic Synthesis;
John Wiley: Chichester, 1999.
(2) For a review, see: Stang, P.; Diederich, F. Eds Metal Catalyzed Cross
Coupling Reactions; VCH: Weinheim, 1998. For a handbook of the
reactivity of organozinc reagents in organic synthesis, see: Knochel, P.,
Jones, P., Eds. Organozinc Reagents: a Practical Approach; Oxford
University Press: New York, 1999. For a recent monograph on the
preparation and reactivity of propargyl/allenyl zinc species, see: Rappoport
Z., Marek, I., Eds. The Chemistry of Organozinc Compounds; John Wiley
& Sons: Haifa, 2006, Chapter 10. For reviews on the cross-coupling
reactions involving propargyl/1,2-allenyl metal species, see: Tsuji, J.;
Mandai, T. Angew. Chem., Int. Ed. Engl. 1995, 34, 2589. Ma, S. Eur. J.
Org. Chem. 2004, 1175 and references cited therein. For some early
references involving the cross coupling of propargyl/1,2-allenylpalladium
species with organozinc species, see: Ruitenburg, T.; Kleijn, H; Elservier,
C. J.; Vermeer, P. Tetrahedron Lett. 1981, 22, 1451. Elservier, C. J.;
Mooiweer, H. H.; Kleijn, H.; Vermeer, P. Tetrahedron Lett. 1984, 25, 5571.
(3) (a) Colas, Y.; Cazes, B.; Gore, J. Tetrahedron Lett. 1984, 25, 845.
(b) Tsuji, J.; Sujiura, T.; Yuhara, M.; Minami, I. J. Chem. Soc.,
Chem. Commun. 1986, 922. (c) Mandai, T.; Matsumoto, T.; Kawada,
M.; Tsuji, J. Tetrahedron Lett. 1993, 34, 2161. (d) Mandai, T.; Matsumoto,
T.; Tsujiguchi, Y.; Matsuoka, S.; Tsuji, J. J. Organomet. Chem. 1994,
473, 343. (e) Radinov, R.; Hutchings, S. D. Tetrahedron Lett.
1999, 40, 8955. (f) Ma, S.; Wang, G. Angew. Chem., Int. Ed.
2003, 42, 4215. (g) Ma, S.; Zhang, A. J. Org. Chem. 1998, 63, 9601. (h)
Ma, S.; Zhang, A. J. Org. Chem. 2000, 65, 2287. (i) Ma, S.; Zhang,
A. J. Org. Chem. 2002, 67, 2287. For some selected recent examples,
see: (j) Kjellgren, J.; Sunde´n, H.; Szabo´, K. J. J. Am. Chem. Soc.
2004, 126, 474. (k) Zimmermann, M.; Wibbeling, B.; Hoppe, D. Synthesis
2004, 765. (l) Hayashi, T.; Tokunaga, N.; Inoue, K. Org. Lett. 2004,
6, 305.
10.1021/ol8001909 CCC: $40.75
© 2008 American Chemical Society
Published on Web 03/26/2008

course of study on the cross coupling of propargyl/allenylzinc
species with aryl halides, we have observed a controlled 1,3-
lithium/hydrogen exchange and subsequent highly regiose-
lective synthesis of trisubstituted allenes starting from
lithiation of 1-phenyl-1-alkynes.5 In this paper, we wish to
report a highly regioselective synthesis of trisubstituted
allenes from lithiation of 1-phenyl-1,2-alkadienes,6 trans-
metalation, and the subsequent Negishi coupling with aryl
and alkenyl halides.
Table 2. Lithiation of 1-Aryl-1,2-alkadienes, Transmetalation,
and Subsequent Pd-Catalyzed Cross-Coupling Reaction with
Iodidesa
After some screening, it was quite interesting to observe
that the lithiation of 1-phenyl-1,2-octadiene with LDA
followed by transmetalation with ZnBr2 and Pd(PPh3)4-
catalyzed cross coupling with phenyl iodide afforded 1-phen-
yl-3-(4-cyanophenyl)octa-1,2-diene (3ad) highly regioselec-
tively (entry 1, Table 1).7 Based on this observation, we
1
yield of
entry
Ar
R1
R2
3b (%)
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
n-C5H11 (1a) p-MeO2CC6H4 (2a) 75 (3aa)
n-C5H11 (1a) p-BrC6H4 (2b)
n-C5H11(1a) p-FC6H4 (2c)
n-C5H11(1a) p-NCC6H4(2d)
n-C6H13 (1b) Ph(2e)
n-C6H13 (1b) p-MeOC6H4 (2f)
n-C6H13 (1b) p-MeO2CC6H4 (2a) 86 (3ba)
79 (3ab)
73 (3ac)
68 (3ad)
92 (3be)
79 (3bf)
Table 1. Effects of Base and Temperature on the Related
Reaction of 1a
n-C6H13 (1b) p-BrC6H4 (2b)
n-C6H13 (1b) m-MeC6H4 (2g)
n-C6H13 (1b) R-Naphthyl (2h)
84 (3bb)
82 (3bg)
57 (3bh)
10 Ph
11 Ph
n-C6H13 (1b) (E)-n-BuCHdCH2 56c (3bi)
(2i)
lithiation
temp (°C)
yield of
ratio of
12 Ph
13 Ph
n-C5H11 (1a) (E)-C6H4CHdCH2 71c (3aj)
entry
base (equiv)
3ada (%)
3ad/4adb
(2j)
n-C5H11 (1a) (E)-C6H13CHdCH2 68c (3ak)
(2k)
1
2
3
4
5
LDA (2.0)
LDA (1.5)
LDA (1.2)
LDA (2.0)
n-BuLi (2.0)
-78-24
-78-24
-78-24
-78c
84
71
25
67
88
>98:2
>99:1
>99:1
>99:1
96:4
14 p-MeOC6H4 n-C6H13 (1c) p-MeO2CC6H4 (2a) 78d (3ca)
15 p-MeOC6H4 n-C6H13 (1c) p-MeOC6H4 (2f)
16 p-MeC6H4 n-C6H13(1d) p-NCC6H4 (2d)
80 (3cf)
81e (3dd)
-78-24
a NMR yields using dibromomethane as the internal standard based on
iodide used. b Determined by the NMR analysis of crude products. c Both
lithiation and transmetalation were carried out at -78 °C, and then the
reaction mixture was warmed to room temperature.
a Unless otherwise noted, allene (0.5 mmol), LDA (1.0 mmol), ZnBr2
(2.0 mmol), Pd(PPh3)4 (0.020 mmol), and iodides (0.4 mmol) were used in
the reaction. b Isolated yields based on iodides used. c The cross-coupling
reaction was conducted at 0 °C overnight. d 0.3 mmol of iodide was used
with 22% of aryl iodide being recovered. e 0.2 mmol of iodide was used.
screened the reaction conditions (Table 1). It is apparent that
an excess amount of LDA is essential for the achievement
of high yields. Reducing the amount of LDA led to lower
yields but still high regioselectivities (entries 2 and 3, Table
1). Lithiation at -78 °C with 2 equiv of LDA gave similar
results. Using n-BuLi as the lithiation reagent, higher yield
was achieved, but the regioselectivity dropped to 96:4 (entry
5, Table 2). As a compromise between yield and selectivity,
entry 1 was chosen as the standard conditions for this
transformation.
in Table 2. A broad range of functionality on R2 is readily
compatible with the optimized reaction conditions due to the
mild nature of zinc reagents.8 Both electron-donating (entries
6, 9, and 15, Table 2) and electron-withdrawing (entries 1,
4, 7, 14, and 16, Table 2) group substituted aryl iodides gave
satisfactory yields. Steric effects of R2 do not seriously
influence the cross coupling since the cross coupling with
1-iodonaphthalene 2h afforded the corresponding allene 3bh
in 57% yield (entry 11, Table 2). The reaction with alkenyl
iodides 2i-k proceeded efficiently at 0 °C to afford the
corresponding vinylallenes 3bi, 3aj, and 3ak in moderate to
good yields (entries 11-13, Table 2). Electronic properties
on the substrates seem to have some effects on the conver-
sion, since for the reaction of 1-(4-methoxylphenyl)nona-1,
2-diene 1c, aryl iodide 2a could not be fully consumed (entry
14, Table 2). It is noteworthy that bromine or fluorine atoms
on the aryl iodide could be well tolerated (entries 2, 3 and
8, Table 2).
With the optimized reaction conditions in hand, the scope
of this reaction was examined, and the results are summarized
(4) (a) Li: Reich, H. J.; Holladay, J. E. Angew. Chem., Int. Ed. Engl.
1996, 35, 2365. (b) Zinc: see ref 3g,h. (c) In: Lee, P. H.; Kim, H.; Lee,
K.; Kim, M.; Noh, K.; Kim, H.; Seomoon, D. Angew. Chem., Int. Ed. 2005,
44, 1840. (d) Sn: Yu, C.-M.; Yoon, S.-K.; Baek, K.; Lee, J.-Y. Angew.
Chem., Int. Ed. 1998, 37, 2392. (e) Cr: Muller, T. J. J.; Ansorge, M.;
Polborn, K. Organometallics 1999, 18, 3690. (f) Pt and Pd: Baize, M. W.;
Blosser, P. W.; Plantevin, V.; Schimpff, D. G.; Gallucci, J. C.; Wojcicki,
A. Organometallics 1996, 15, 164.
(5) Ma, S.; He, Q. Angew. Chem., Int. Ed. 2004, 43, 988.
(6) For pioneering studies on the lithiation of simple allenes, see: (a)
Michelot, D.; Linstrumelle, G. J. Chem. Soc., Chem. Commun. 1975, 561.
(b) Clinet, J.-C.; Linstrumelle, G. Synthesis 1981, 875.
(7) The assignment of the regioselectivity was based on the distinct
coupling constant of the two different allenic hydrogens.
(8) Negishi, E.; Qian, M.; Zeng, F.; Anastasia, L.; Babinski, D. Org.
Lett. 2003, 5, 1597.
1522
Org. Lett., Vol. 10, No. 8, 2008

To have a clear understanding of the mechanism of this
process, 1-deuterated-1-phenylocta-1,2-diene 1a-d was syn-
thesized and subjected to the standard reaction conditions.
It was found that the deuterium incorporation in the product
3af-d dropped from >99% to 76% (run 1, Scheme 1). These
Besides the 1,3-lithium/hydrogen exchange mechanism
(path a), an alternative mechanism, which involves the
formation of alkyne derivative 5 and the subsequent isomer-
ization to allene 3 (path b), was proposed to account for
the deuterium loss under the conditions where LDA was used
as the base (Scheme 2). To test the viability of path b, alkyne
5a was prepared9 and treated with 2 equiv of n-BuZnBr in
THF at room temperature with no isomerization after 4 h.
Furthermore, when 5a was subjected to the propargyl/allenyl
zinc species generated from 1c, no reaction occurred with
5a being recovered in 90% yield (Scheme 3). Meanwhile, a
Scheme 1. Deuterium Labeling Experiments
Scheme 3
results imply that with LDA as the base a direct regioselec-
tive lithiation is the major pathway (76%) leading to the
1-phenyl-1,2-octadien-3-yllithium intermediate M1, while
about 24% of the allene was proposed to be lithiated at the
1-position to form the 1-phenyl-1,2-octadien-1-yl lithium
intermediate M2, which may undergo 1,3-lithium/hydrogen
exchange to form 1-phenyl-1,2-octadien-3-yl lithium inter-
mediate M1.5 Subsequent transmetalation and Pd-catalyzed
cross coupling afforded the final products (Scheme 2).
mixture was isolated and identified as the protonated mixture
of propargyl/1,2-allenyl zinc species. This observation
excludes the possibility of path b.
In conclusion, we have reported a facile highly regiose-
lective synthesis of trisubstituted allenes from the lithiation
of 1-aryl-3-alkylpropadienes, transmetalation, and subsequent
Pd-catalyzed Negishi coupling with aryl and alkenyl iodides.
Further studies in this area are currently underway in our
laboratory.
Scheme 2. Proposed Mechanism for the Lithiation of
1-Aryl-1,2-alkadienes and Subsequent Regioselective Synthesis
of Trisubstituted Allenes
Acknowledgment. Financial support from National Natu-
ral Science Foundation of China (20732005 and 20423001),
State Basic and Research Development Program (Grant No.
2006CB806105), and Shanghai Municipal Committee of
Science and Technology are gratefully appreciated. We thank
Mr. Ping Lu in our group for reproducing the results reported
in entry 1, Table 1, and entries 1, 7, and 13, Table 2.
Supporting Information Available: Detailed experi-
mental procedures and spectroscopic data for all compounds.
This information is available free of charge via the Internet
at http://pubs.acs.org.
However, if the substrate was lithiated with 1.5 equiv of
n-BuLi at -78 °C (run 2, Scheme 1) before transmetalation
and cross coupling, the deuteration ratio in the product could
be almost intact and the regioisomeric product observed in
entry 5 of Table 1 was not formed, indicating a highly
regioselective lithiation at the 3-position probably due to the
isotopic effect of the deuterium atom.
OL8001909
(9) Yasuda, M.; Saito, T.; Ueba, M.; Baba, A. Angew. Chem. Int. Ed.
2004, 43, 1414.
Org. Lett., Vol. 10, No. 8, 2008
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