Cyclopropylmethyl palladium species from carbene migratory insertion: New routes to 1,3-butadienes

Article abstract of DOI:10.1021/ol2034405

Cyclopropylmethyl palladium species can be accessed by Pd-catalyzed reaction of either cyclopropyl N-tosylhydrazone with halide or N-tosylhydrazone with cyclopropyl halide. In both approaches migratory insertion of Pd carbene is the key process. These transformations constitute new approaches toward 1,3-butadiene derivatives.

Full text of DOI:10.1021/ol2034405

ORGANIC
LETTERS
2012
Vol. 14, No. 3
922–925
Cyclopropylmethyl Palladium Species
from Carbene Migratory Insertion:
New Routes to 1,3-Butadienes
Lei Zhou,†,‡ Fei Ye,† Yan Zhang,† and Jianbo Wang*,†
Beijing National Laboratory of Molecular Sciences (BNLMS) and Key Laboratory of
Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of
Chemistry, Peking University, Beijing 100871, China, and School of Chemistry and
Chemical Engineering, Sun Yat-Sen University, Guangzhou 510275, China
wangjb@pku.edu.cn
Received December 24, 2011
ABSTRACT
Cyclopropylmethyl palladium species can be accessed by Pd-catalyzed reaction of either cyclopropyl N-tosylhydrazone with halide or N-
tosylhydrazone with cyclopropyl halide. In both approaches migratory insertion of Pd carbene is the key process. These transformations
constitute new approaches toward 1,3-butadiene derivatives.
Molecules bearing cyclopropyl groups are versatile
building blocks in organic synthesis.1 Their unique struc-
tural and electronic properties give rise to an array of very
interesting and characteristic transformations. Among
these small ring compounds, reactions of highly strained
methylenecyclopropanes (MCPs) with various reactants,
catalyzed by transition metals such as Pd,2 Ni,3 and Pt,4
have attracted much attention. One of the characteristic
reaction patterns of MCPs is the formation of cyclopro-
pylmethyl metal species, followed by cyclopropyl ring
opening through β-carbon elimination, which ultimately
leads to homoallylic compounds (Scheme 1). In general, the
cyclopropylmethyl metal species is generated upon the
addition of MꢀM0 or RꢀM intermediates to the double
bond of MCPs, and palladium is the most commonly used
transition metal for this transformation (path a, Scheme 1).1a,f,2
For an earlier example, de Meijere and co-workers have
demonstrated that Pd-catalyzed ring opening of MCPs
affording polyenes in a cascade reaction consisting of intra-
molecular Heck-type coupling.2f Suginome and co-workers
have developed transition-metal-catalyzed silaborative
CꢀC bond cleavage of MCPs.2c,d Palladium-catalyzed ring
† Peking University.
‡ Sun Yat-Sen University.
(1) For selected reviews, see: (a) Rubin, M.; Rubina, M.; Gevorgyan,
V. Chem. Rev. 2007, 107, 3117. (b) Brackmann, F.; de Meijere, A. Chem.
Rev. 2007, 107, 4493. (c) Patai, S. The Chemistry of the Cyclopropyl Group,
€
Part 2; John Wiley & Sons: New York, 1987; Vol. 1. (d) Salaun, J. Top. Curr.
Chem. 2000, 207, 1. (e) Doucet, H. Eur. J. Org. Chem. 2008, 2013. (f)
Nakamura, I.; Yamamoto, Y. Adv. Synth. Catal. 2002, 344, 111. (g)
Brandi, A.; Goti, A. Chem. Rev. 1998, 98, 589. (h) Nakamura, E.; Yamago,
S. Acc. Chem. Res. 2002, 35, 867. (i) Ma, S. Pure Appl. Chem. 2008, 80, 695.
(2) For recent Pd-catalyzed reactions of MCPs, see: (a) Jiang, M.;
Mei, Y.; Shi, M. Eur. J. Org. Chem. 2010, 3307. (b) Shao, L.; Li, J.;
Wang, B.; Shi, M. Eur. J. Org. Chem. 2010, 6448. (c) Ohmura, T.;
Taniguchi, H.; Suginome, M. Org. Lett. 2009, 11, 2880. (d) Ohmura, T.;
Taniguchi, H.; Kondo, Y.; Suginome, M. J. Am. Chem. Soc. 2007, 129,
3518. (e) Shi, M.; Liu, L.; Tang, J. J. Am. Chem. Soc. 2006, 128, 7430. (f)
Braese, S.; de Meijere, A. Angew. Chem., Int. Ed. 1995, 34, 2545.
(3) For recent Ni-catalyzed reactions of MCPs, see: (a) Yao, B.; Li, Y.;
Liang, Z.; Zhang, Y. Org. Lett. 2011, 12, 640. (b) Ohashi, M.; Taniguchi, T.;
Ogoshi, S. Organometallics 2010, 29, 2386. (c) Terao, J.; Tomita, M.; Singh,
S. P.; Kambe, N. Angew. Chem., Int. Ed. 2010, 49, 144. (d) Taniguchi, H.;
Ohmura, T.; Suginome, M. J. Am. Chem. Soc. 2009, 131, 11298.
(e) Shirakura, M.; Suginome, M. J. Am. Chem. Soc. 2009, 131, 5060.
(4) For representative references on Pt-catalyzed transformations of
MCPs, see: (a) Itazaki, M.; Nishihara, Y.; Osakada, K. J. Org. Chem.
2002, 67, 6889. (b) Suginome, M.; Ito, Y. J. Organomet. Chem. 2003, 680,
(5) (a) Siriwardana, A. I.; Kamada, M.; Nakamura, I.; Yamamoto,
Y. J. Org. Chem. 2005, 70, 5932. (b) Siriwardana, A. I.; Kathriarachchi,
K. K. A. D. S.; Nakamura, I.; Yamamoto, Y. Heterocycles 2005, 66, 333.
(c) Nakamura, I.; Itagaki, H.; Yamamoto, Y. J. Org. Chem. 1998, 63,
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r
10.1021/ol2034405
Published on Web 01/24/2012
2012 American Chemical Society

as nonstabilized diazo precursors in this type of Pd-cata-
lyzed cross-coupling reactions, pioneered by Barluenga
and co-workers,7b,c,8a has significantly expanded this
chemistry. As a continuation of our interest in the explora-
tion of Pd-carbene migratory insertion as a key process in
the development of new synthetic transformations, we
have conceived that the cyclopropylmethyl palladium
species may be accessed by the migratory insertion of
carbene. Herein we wish to report the Pd-catalyzed cross-
coupling of cyclopropyl N-tosylhydrazones with aryl ha-
lide, which leads to the 1,1-disubstituted 1,3-butadienes
via cyclopropylmethyl palladium species (Scheme 1, path b).
Moreover, we observed that the Pd-catalyzed coupling of
N-tosylhydrazones with bromocycylopropane led to the
formation of same palladium intermediate. This latter
reaction involves a migratory insertion of a carbenoid
ligand into the cyclopropyl-palladium bond (Scheme 1,
path c).
Scheme 1. Routes to the Cyclopropylmethyl Palladium Species
opening of MCPs with alcohols or amines as the nucleophile
have been reported by Yamamoto5 and Shi.6
Initially, the path b process was explored by the reaction
of iodobenzene and cyclopropyl N-tosylhydrazone 2a in
1,4-dioxane at 80 °C with various palladium catalysts
(Table 1). It was observed that Pd(II) complexes such as
Pd(OAc)2 and PdCl2(PPh3)2 were not effective, while Pd-
(PPh3)4 gave 10% of product 3a (Table 1, entries 1ꢀ3).
When Pd2(dba)3 was employed with P(2-furyl)3 as the
ligand, 1,3-diene product 3a was obtained in a slightly
higher yield (15%). Encouraged by this result, we then
decided to optimize the reaction conditions with Pd2(dba)3
and various phosphine ligands (Table 1, entries 5ꢀ8).We
were delighted to find that an 81% yield of the desired
product 3a could be obtained when the reaction was
carried out in the presence of 2.5 mol % of Pd2(dba)3
and 5 mol % of Xphos (Table 1, entry 8). The effect of
solvents was subsequently examined, and the reactions
were found to proceed more efficiently in polar solvents
(Table 1, entries 8ꢀ11), whereasa nonpolarsolvent such as
toluene was found to be unfavorable (Table 1, entry 12).
The reaction at 80 °C provided the optimal results; either
higher or lower temperatures resulted in diminished yields
(Table 1, entries 13 and 14).
In the previous studies, the regioselectivity of pallada-
tion across the CdC bond of MCPs is usually substrate-
dependent, which in some cases results in the formation of
isomeric products. This may limit the wide application of
this type of transformations. Thus, the methods for the
generation of cyclopropylmethyl metal species through
alternative approaches are highly desirable.
Recently, Pd-catalyzedcross-coupling reactionsofdiazo
compounds have been proven as an efficient method for
the formation of CdC double bonds.7 The characteristic
steps of these reactions are the formation of a Pd-carbene
complex and the subsequent migratory insertion of the
carbene. The carbenoid ligand can migrate intothe aryl-,8,9
benzyl-,10 vinyl-,11 allyl-,12 acyl-,13 alkynyl-,14 and allenyl-
palladium bonds.15 The application of N-tosylhydrazones
(6) Shi, M.; Chen, Y.; Xu, B. Org. Lett. 2003, 5, 1225.
(7) For recent reviews, see: (a) Zhang, Y.; Wang, J. Eur. J. Org.
ꢀ
Chem. 2011, 1015. (b) Barluenga, J.; Valdes, C. Angew. Chem., Int. Ed.
2011, 50, 7486. (c) Shao, Z.; Zhang, H. Chem. Soc. Rev. 2012DOI:
10.1039/C1CS15127D.
(8) (a) Barluenga, J.; Moriel, P.; Valdes, C.; Aznar, F. Angew. Chem.,
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Int. Ed. 2007, 46, 5587. (b) Barluenga, J.; Tomas-Gamasa, M.; Moriel,
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P.; Aznar, F.; Valdes, C. Chem.;Eur. J. 2008, 14, 4792. (c) Kudirka, R.;
Van Vranken, D. L. J. Org. Chem. 2008, 73, 3585. (d) Tsoi, Y.-T.; Zhou,
Z.; Chan, A. S. C.; Yu, W.-Y. Org. Lett. 2010, 12, 4506. (e) Barluenga, J.;
Florentino, L.; Aznar, F.; Valdes, C. Org. Lett. 2011, 13, 510. (f)
Barluenga, J.; Escribano, M.; Moriel, P.; Aznar, F.; Valdes, C.
With the acceptable conditionsin hand (Table1, entry8),
we next explored the scope of the reaction with a variety of
aryl halides and cyclopropyl N-tosylhydrazones (Table 2).
The reaction is general with respect to the structure of aryl
halides, and both iodides and bromides could be employed
as substrates with similar results (Table 2, entries 2 and 3).
Chloride was also effective, albeit providing the prod-
uct with a slightly diminished yield (Table 2, entry 3).
The reaction with ortho-, meta-, and para-substituted aryl
halides all proceeded efficiently (Table 2, entries 2ꢀ10).
2-Iodo naphthalene was also a suitable substrate for the
coupling, leading to the 1,3-butadiene 3i in good yield
(85%) (Table 2, entry 11). When 1,4-diiodobenzene was
used as a substrate, double cross-coupling occurs, afford-
ing the corresponding butadiene derivative 3j in 70% yield
(Table 2, entry 12). To further examine the scope of the
reaction, N-tosylhydrazone 2d and 2e were employed to
react with aryl halides, and they all gave the cross-coupling
products in good yields (Table 2, entries 13ꢀ16).
~
Chem.;Eur. J. 2009, 15, 13291. (g) Barluenga, J.; Quinones, N.; Cabal,
ꢀ
M.-P.; Aznar, F.; Valdes, C. Angew. Chem., Int. Ed. 2011, 50, 2350.
(9) (a) Peng, C.; Wang, Y.; Wang, J. J. Am. Chem. Soc. 2008, 130,
1566. (b) Zhao, X.; Jing, J.; Lu, K.; Zhang, Y.; Wang, J. Chem. Commun.
2010, 1724. (c) Zhou, L.; Ye, F.; Zhang, Y.; Wang, J. J. Am. Chem. Soc.
2010, 132, 13590. (d) Zhao, X.; Wu, G.; Yan, C.; Lu, K.; Li, H.; Zhang,
Y.; Wang, J. Org. Lett. 2010, 12, 5580.
(10) (a) Greenman, K. L.; Van Vranken, D. L. Tetrahedron 2005, 61,
6438. (b) Yu, W.-Y.; Tsoi, Y.-T.; Zhou, Z.; Chan, A. S. C. Org. Lett.
2009, 11, 469. (c) Xiao, Q.; Ma, J.; Yang, Y.; Zhang, Y.; Wang, J. Org.
Lett. 2009, 11, 4732.
(11) (a) Devine, S. K. J.; Van Vranken, D. L. Org. Lett. 2007, 9, 2047.
(b) Devine, S. K. J.; Van Vranken, D. L. Org. Lett. 2008, 10, 1909. (c)
Kudirka, R.; Devine, S. K. J.; Adams, C. S.; Van Vranken, D. L. Angew.
Chem., Int. Ed. 2009, 48, 3677.
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(13) Zhang, Z.; Liu, Y.; Gong, M.; Zhao, X.; Zhang, Y.; Wang, J.
Angew. Chem., Int. Ed. 2010, 49, 1139.
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Ed. 2011, 50, 3510.
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Org. Lett., Vol. 14, No. 3, 2012
923

Table 1. Palladium-Catalyzed Cross-Coupling of Iodobenzene
with N-Tosylhydrazone 2aa
Table 2. Palladium-Catalyzed Cross-Coupling of Aryl Halides
with Various N-Tosylhydrazonesa
t
yield
(%)b
entry
catalyst
L
solvent
(°C)
1
Pd(OAc)2
PPh3
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
MeCN
80
80
80
80
80
80
80
80
80
80
80
80
60
100
0
2
PdCI2(PPh3)2
Pd(PPh3)4
ꢀ
0
3
ꢀ
10
15
<10
20
37
81
51
40
33
<10
45
75
c
4
Pd2(dba)3
P(2-furyl)3
L1
5
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
6
L2
7
L3
8
Xphosd
Xphos
Xphos
Xphos
Xphos
Xphos
Xphos
9
10
11
12
13
14
DCE
DMF
toluene
dioxane
dioxane
a All of the reactions were carried out by using iodobenzene
(0.5mmol),2a (1 mmol), and tBuOLi (2 mmol) with 2.5 mol % of palladium
as the catalyst and 5 mol % of ligand in 5 mL of solvent for 16 h. b Yields
were determined by using GC/MS methods with n-dodecane as the
internal standard. c Pd2(dba)3 = tris(dibenzylideneacetone)dipalladium(0).
d Xphos = 2-dicyclohexylphosphino-20,40,60-triisopropylbiphenyl.
The stereochemical outcome of the reaction seems to be
directed by the steric bulkiness of the substituents. When
the steric hindrances are similar for both E and Z products,
the E/Z selectivity is poor (Table 2, entries 6ꢀ8 and 12).
However, when there are substituents at the ortho-position
of aryl halides, or Ar groups are much larger than the R
group, the Z-isomers are obtained as the major products.
The configuration of 3h is confirmed by its X-ray crystal
diffraction, and the configurationsofothermajor products
are assumed to be same as that of 3h.
To further expand the scope of the reaction, N-tosylhy-
drazone 4 was prepared and was subjected to the Pd-
catalyzed coupling with iodobenzene under the same reac-
tion conditions (Scheme 2). Interestingly, 1,4-diene 5 was
obtained as the major product instead of the expected 1,3-
diene 6. This result can be rationalized as follows. The
β-carbon elimination, which is driven by strain release,
requires syn-periplanar alignment of the CꢀPd bond with
the proximal CꢀC bond of the cyclopropyl ring, as depicted
in A. This leads to the exclusive formation of cis-(2-vinyl-
cyclohexyl)palladium species B. The intermediate B is un-
able to undergo syn-β-hydride elimination to form a
conjugate diene 6, thus producing 5 as the major product.
a All the reactions were carried out by using N-tosylhydrazone
(0.5 mmol), aryl halide (0.25 mmol), and t-BuOLi (3.5 equiv) in the
presence of Pd2(dba)3 (2.5 mol %) and Xphos (5 mol %) in 1,4-dioxane
(2 mL) at 80 °C for 12 h. b Isolated yields. c The ratio of E/Z selectivity was
determinedby the crude 1H NMR andGC MS. d The Z-configuration was
confirmed by X-ray diffraction.
The observation of a minor amount of 6 can be explained
by the double bond migration, which is likely the result of
hydropalladation/dehydropalladation processes promoted
by HPdX, which is often observed in Pd-catalyzed
reactions.16 Alternatively, 6 may be formed through the
conformational change of B.
Since we have previously reported the Pd-catalyzed
cross-coupling of benzyl halides with N-tosylhydrazone,10c
we next conceived that benzyl halide might also be em-
ployed in this typeof reaction. Weare delighted tofind that
(16) (a) Larhed, M.; Hallberg, A. In Handbook of Organopalladium
Chemistry for Organic Synthesis; Negishi, E.-i., Ed.; Wiley-Interscience:
New York, 2002; Chapter IV, p 2. (b) Gauthier, D.; Lindhardt, A. T.;
Olsen, E. P. K; Overgaard, J.; Skrydstrup, T. J. Am. Chem. Soc. 2010,
ꢀ
nez, C.; Alvarez, R.; Aurrecoechea, J. M. Org. Lett.
132, 7998. (c) Martı
´
2009, 11, 1083.
924
Org. Lett., Vol. 14, No. 3, 2012

zone 10f was employed to react with bromocyclopropane,
only the Z-isomer was isolated as the major product. This
result indicates that the stereochemical outcome of the reac-
tion is dominated by the steric bulkiness of the substituents.
Scheme 2. Cross-Coupling of Iodobenzene with 4
Table 3. Palladium-Catalyzed Cross-Coupling of Bromide 9
with N-Tosylhydrazones 10a
benzyl bromide is a suitable substrate for the cross-cou-
pling with cyclopropyl N-tosylhydrazone 2a, which furn-
ished the ring-opening product 7 in moderate yield (59%).
It is noteworthy that alkene 8 was also formed in a
considerable amount, which indicates that in the corre-
sponding cyclopropylmethyl palladium intermediate the
β-H elimination competes effectively with the ring opening
of the cyclopropane moiety.
product
yield
(%)b
entry
Ar
Ar0
3
E/Zc
1
2
3
4
5
6
Ph
Ph
3a
3o
3p
3q
3r
3s
ꢀ
40
45
28
45
36
32
p-MeC6H4
p-PhC6H4
Ph
p-MeC6H4
p-PhC6H4
ꢀ
ꢀ
p-PhC6H4
1:1
1:1
>10:1
Ph
3,4-diMeC6H3
1-naphthyl
Ph
a N-Tosylhydrazones (0.5 mmol), bromocyclopropane (1 mmol),
Cs2CO3 (4 equiv), [Pd(allyl)Cl]2 (2.5 mol %), Xphos (10 mol %),
CH3CN (5 mL), 80 °C, 4 h. b Isolated yield. c E/Z selectivity was
determined by 1H NMR of the crude product.
Asshown in Scheme 1, the cyclopropylmethyl palladium
intermediate can also be generated by migratory insertion
of a carbenoid ligand into a cyclopropyl-palladium bond
(pathc). To explore such a possibility, Pd-catalyzed reaction
of bromocyclopropane and diphenyl N-tosylhydrazone was
investigated. After extensive optimization experiments by
varying palladium catalysts, ligands and solvents, we found
that the expected 1,10-diphenyl-1,3-butadiene 3a could be
obtained in moderate yield as shown in Table 3 (entry 1).
The major byproduct is tetraphenylethylene, which is
derived from the homo coupling of an in situ generated
diazo substrate. Upon experimentation, it seems to us
that this obstacle is not easily overcome.
Thus, with [Pd(allyl)Cl]2 as the catalyst, Xphos as the
ligand, and Cs2CO3 as the base in MeCN at 80 °C, the
reaction provided the coupling product 3a in 40% yield.
Several other N-tosylhydrazones were also examined un-
der the same conditions, and they afforded the cross-
coupling products in low to moderate yields. In the cases
of coupling with N-tosylhydrazones 10d and 10e, the ratio of
E/Z isomers was almost 1:1. However, when N-tosylhydra-
In conclusion, we have developed two novel routes
toward the cyclopropylmethyl palladium species, which
ultimately lead to the formation of 1,3-butadiene deriva-
tives in moderate to good yields.17 Further studies on the
scope and synthetic application of these coupling reactions
are ongoing in our laboratory.
Acknowledgment. The project is supported by 973 Pro-
grams (Nos. 2009CB825300, 2012CB821600), NSFC, and
GSK R&D China Postdoctoral Science Foundation.
Supporting Information Available. Experimental proce-
dures, mechanism, X-ray structure of 3h, and characteriza-
tion data of all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
(17) For the details of the proposed reaction mechanism, see Sup-
porting Information.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 3, 2012
925