Palladium-catalyzed highly regioselective [3 + 2] cycloaddition reactions of alkylidenecyclopropa[b]naphthalenes with alkenes or alkynes: An efficient synthesis of 1(3)-alkylidene-2,3-dihydro-1H-benzo[f]indenes and 1-alkylidene-1H-benzo[f]indenes

Article abstract of DOI:10.1021/ol8023083

(Chemical Equation Presented) The first palladium-catalyzed highly regioselective [3 + 2] cycloaddition reactions of alkylidenecyclopropa[b] naphthalenes 1 with alkenes or alkynes is presented, providing an efficient method for the synthesis of 1(3)-alkyl

Full text of DOI:10.1021/ol8023083

ORGANIC
LETTERS
2008
Vol. 10, No. 24
5537-5540
Palladium-Catalyzed Highly Regioselec-
tive [3 + 2] Cycloaddition Reactions of
Alkylidenecyclopropa[b]naphthalenes
with Alkenes or Alkynes: An Efficient
Synthesis of 1(3)-Alkylidene-2,3-dihydro-
1H-benzo[f]indenes and 1-Alkylidene-1H-
benzo[f]indenes
Wanli Chen,† Jian Cao,‡ and Xian Huang*,‡,§
Department of Chemistry, Zhejiang UniVersity, Hangzhou 310028, P. R. China, Center
of Analysis & Measurement, Zhejiang UniVersity of Technology, Hangzhou 310014,
P. R. China, and State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, P. R. China
huangx@mail.hz.zj.cn
Received October 6, 2008
ABSTRACT
The first palladium-catalyzed highly regioselective [3 + 2] cycloaddition reactions of alkylidenecyclopropa[b]naphthalenes 1 with alkenes or
alkynes is presented, providing an efficient method for the synthesis of 1(3)-alkylidene-2,3-dihydro-1H-benzo[f]indenes or 1-alkylidene-1H-
benzo[f]indenes under mild conditions.
Naphthalenes fusing a cyclopentyl or cyclopentenyl ring are
of marked interest due to their applications as bioactive
compounds and synthetic intermediates in organic synthesis.1
However, there are only limited reports about their synthesis
with substituent groups due to a lack of sufficient construc-
tion of the annulated naphthalene ring at one time during
the five-membered ring closure reaction.2,3 Thus, there is a
need to develop a new method for the efficient synthesis of
these compounds with different substituent groups.
The transition-metal-catalyzed [3 + 2] cycloaddition
reactions of methylenecyclopropanes (MCPs) with carbon-
carbon or carbon-heteroatom multiple bonds are efficient
methods for construction of five-membered rings incorporat-
ing an exocyclic carbon-carbon double bond.4 An often
troublesome feature of the [3 + 2] cycloaddition reactions
† Zhejiang University of Technology.
‡ Zhejiang University.
§ Shanghai Institute of Organic Chemistry.
(1) (a) Kim, D. H.; Lee, J. A.; Lee, B. Y.; Chung, Y. K. J. Organomet.
Chem. 2005, 690, 1822. (b) Carpino, L. A. Acc. Chem. Res. 1987, 20, 401.
(c) Mccurdy, C. R.; Bourdonnec, B. Le; Metzger, T. G.; Kouhen, R. E.;
Zhang, Y.; Law, P. Y.; Portoghese, P. S. J. Med. Chem. 2002, 45, 2887.
(d) Watson, M. D.; Fechtenkotter, A.; Mullen, K. Chem. ReV. 2001, 101,
1267.
(2) (a) Hsieh, J. C.; Cheng, C. H. Chem. Commun. 2000, 815. (b) Oishi,
E.; Taido, N.; Iwamoto, K.; Miyashita, A.; Higashino, T. Chem. Pharm.
Bull. 1990, 38, 3268
(3) (a) Ghorai, S. K.; Hazra, N. K.; Mal, D. Tetrahedron Lett. 1998,
39, 689. (b) Carpino, L. A.; Lin, Y. Z. J. Org. Chem. 1990, 55, 247
.
.
10.1021/ol8023083 CCC: $40.75
Published on Web 11/18/2008
2008 American Chemical Society

is the multiform reactivities of the three strained bonds in
the cyclopropane ring, leading to formation of different
products through cleavage of proximal or distal bonds of
the three-membered ring (Scheme 1).
membered ring with an exocyclic carbon-carbon double
bond. To the best of our knowledge, for transition-metal-
mediated reactions, only one example of alkylidenecyclo-
propa[b]naphthalenes 1 with stoichiometric rhodium(I) and
platinum(0) reagents has been studied,7 and no other
catalyzed reaction has been reported. Herein, we report the
first highly regioselective palladium-catalyzed [3 + 2]
cycloaddition reactions of alkylidenecyclopropa[b]naphtha-
lenes 1 with alkenes or alkynes under mild conditions and
provide an efficient synthesis of 1(3)-alkylidene-2,3-dihydro-
1H-benzo[f]indenes and 1-alkylidene-1H-benzo[f]indenes.
Scheme 1
We initially examined the reaction of the 1-(diphenylm-
ethylene)-1H-cyclopropa[b]naphthalene 1a8 with methyl
acrylate under different reaction conditions. The results are
summarized in Table 1. The reaction of 1a with 2a did not
proceed without the palladium catalyst (entry 1, Table 1).
Pd(OAc)2 and Pd(dba)2 could catalyze the reaction to afford
3a in 28% and 41% yield, respectively, within 1 h at room
temperature in acetone (entries 2 and 3, Table 1). Pd(PPh3)4
did not catalyze this reaction under the same conditions (entry
4, Table 1). Using phosphane ligands, such as P(C6H4Me-
o)3 and P(OPr-i)3, did not give better results than Pd(dba)2
(entries 5 and 6, Table 1). However, in the presence of
lithium chloride,9 3a was produced in a better yield under
Pd(dba)2 catalysis (entry 7, Table 1). Lithium bromide and
tetra(n-butyl)ammonium chloride were less effective than
lithium chloride (entries 9 and 10, Table 1). While the
reaction with sodium iodide was totally ineffective due to
the precipitation of palladium black (entry 11, Table 1),
During our systematic study of MCPs chemistry,5 we were
interested in the chemistry of its analogues, alkylidenecy-
clopropa[b]naphthalenes 1. Because of the unusual structure
of alkylidenecyclopropa[b]naphthalenes 1, incorporating
within one molecule a triafulvene, a [3]radialene, and the
cycloproparene, they have attracted much attention from
physical, theoretical, and synthetic viewpoints.6 Especially,
much attention has been paid to the synthesis of otherwise
inaccessible compounds from alkylidenecyclopropa[b]naph-
thalenes. In this paper, we envisioned that the insertion of a
Pd(0) species into alkylidenecyclopropa[b]naphthalenes could
lead to the mild alkenyl metallo-cyclointermediate appending
a naphthalene ring, which would be further annulated with
a carbon-carbon multiple bond in the subsequent [3 + 2]
cycloaddition reaction, thus providing a new efficient method
for construction of naphthalenes incorporating a five-
Table 1. Optimization of Reaction Conditions for the Pd-Catalyzed [3 + 2] Cycloaddition Reaction of 1a with Methyl Acrylate 2aa
entry
catalyst
additive
no
no
no
no
no
no
LiCl
LiCl
LiBr
n-Bu4N+Cl-
NaI
LiCl
LiCl
LiCl
LiCl
LiCl
LiCl
solvent
time
yield (%)b
1
2
3
4
5
6
7
8
no
CH3COCH3
CH3COCH3
CH3COCH3
CH3COCH3
CH3COCH3
CH3COCH3
CH3COCH3
CH3COCH3
CH3COCH3
CH3COCH3
CH3COCH3
CH3COCH3
CH3COCH3
THF
48 h
1 h
1 h
48 h
0.5 h
0.5 h
0.5 h
24 h
1 h
0.5 h
1 h
0.5 h
0.5 h
1 h
0
28
41
0
Pd(OAc)2
Pd(dba)2
Pd(PPh3)4
Pd(dba)2/P(C6H4Me-o)3
Pd(dba)2/P(OPr-i)3
Pd(dba)2
19
15
69
36d
65
61
12e
63
35
55
38
35
18
c
Pd(dba)2
9
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
10
11
12
13
14
15
16
17
f
g
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
MeOH
MeCN
CH3COOH
1 h
1 h
1 h
a The reaction was carried out at rt using 1a (0.164 mmol), 2a (5 equiv), catalyst (10 mol %), and additive (10 equiv) in acetone (2 mL). b Isolated yield
based on 1a. Unless otherwise stated, 1a converted completely. c 5 mol % catalyst was used. d 38% of 1a was recovered. e 50% of 1a was recovered. f The
reaction temperature was 40 °C. g 2 equiv of Et3N was added as the base.
5538
Org. Lett., Vol. 10, No. 24, 2008

elevated reaction temperature or addition of triethylamine
gave a lower yield of 3a (entries 12 and 13, Table 1). Next,
we examined the effect of solvent choice on this reaction
(entries 14-17, Table 1). The reaction ran smoothly in THF,
CH3CN, CH3OH, and CH3COOH, but the yields of 3a were
not as high as those in acetone.
Using the optimal reaction conditions, we carried out the
reaction with various alkylidenecyclopropa[b]naphthalenes
1 and alkenes with electron-withdrawing group 2, and the
results are listed in Table 2. From the results in Table 2, we
Table 2. Pd(dba)2-Catalyzed [3 + 2] Cycloaddition Reaction of
1 with Alkenes Containing Electron-Withdrawing Group 2
Figure 1. NOE experiment of 3a, 3k, 4k, and 6h.
As well as acrylate, general alkenes could also be applied
to this reaction. Some typical examples are summarized in
Table 3. For cyclopentene 2e, hex-1-ene 2f, and styrene 2g,
yield
entry
Ar
R1/R2/E
product time (%)a
Table 3. Pd(dba)2-Catalyzed [3 + 2] Cycloaddition Reaction of
1 with General Alkenes 2
1
2
3
4
5
6
7
C6H5, 1a
1a
H/H/COOMe, 2a
H/H/COOEt, 2b
H/Me/COOMe, 2c
3a
3b
3c
3d
3e
3f
0.5 h 70b
0.5 h 68
1a
6 h
30
4-MeC6H4, 1b 2a
4-FC6H4, 1c 2a
4-ClC6H4, 1d 2a
1a Me/H/CHO, 2d
0.5 h 61
0.5 h 58
0.5 h 63
24 h tracec
3g
entry
R1/R2/R3
product
time
yield (%)a
a Isolated yield based on 1. b 1 mmol 1a was used. c Stereochemistry
unknown.
1
2
3
4
-(CH2)3-/H, 2e
H/H/(CH2)3CH3, 2f
H/H/Ph, 2g
3h
3i
3j
3k/4k
0.5 h
0.5 h
1 h
64
75
50
-OCH2CH2-/H, 2h
0.5 h
65 (50:50)b
could see that the reaction exhibited an excellent regiose-
lectivity of the double bond of acrylate. We only detected
one isomer in the crude product. The regioselectivity of the
double bond was determined by a NOESY experiment (3a,
Figure 1). However, when 2-butenal 2d was used as the
substrate, only a trace amount of the product 3g was formed,
probably due to the steric hindrance of the methyl group in
the substrate (entry 7, Table 2).
a Isolated yield based on 1. b Determined by isolation.
the reactions also proceeded smoothly with high regioselec-
tivity. The regioselectivity of the resulting compounds was
confirmed by X-ray single crystal diffractional analysis of
3i (Figure 2).10 However, when 2,3-dihydrofuran 2h was
(4) For reviews see: (a) Binger, P.; Bu¨ch, H. M. Top. Curr. Chem. 1987,
135, 77. (b) Lautens, M.; Klute, W.; Tam, W. Chem. ReV. 1996, 96, 49. (c)
Binger, P.; Schmidt, T. In Houben-Weyl; Meijere, A. De, Eds.; Thieme:
Stuttgart, 1997; Vol. E17c, p 2217. (d) Chan, D. M. T. In ComprehensiVe
Organic Synthesis; Trost, B. M., Eds.; Pergamon: Oxford, 1991; Vol. 5,
pp 217. (e) Nakamura, I.; Yamamoto, Y. AdV. Synth. Catal. 2002, 344,
111.
(5) (a) Yang, Y.; Huang, X. J. Org. Chem. 2008, 73, 4702. (b) Chen,
W.; Su, C.; Huang, X. Synlett 2006, 1446. (c) Huang, X.; Zhou, H.; Chen,
W. J. Org. Chem. 2004, 69, 839. (d) Zhou, H.; Huang, X.; Chen, W. J.
Org. Chem. 2004, 69, 5471. (e) Chen, W.; Huang, X.; Zhou, H.; Ren, L.
Synthesis 2006, 609. For synthesis of MCPs, see: (f) Brandi, A.; Goti, A.
Chem. ReV. 1998, 98, 589. For recent reviews, see: (g) Brandi, A.; Cicchi,
S.; Cordero, F. M.; Goti, A. Chem. ReV. 2003, 103, 1213. (h) Nakamura,
E.; Yamago, S. Acc. Chem. Res. 2002, 35, 867.
Figure 2. X-ray structure of compound 3i.
(6) (a) Halton, B. Chem. ReV. 2003, 103, 1327. (b) Halton, B. Chem.
ReV. 1989, 89, 1161. (c) Billups, W. E.; Rodin, W. A.; Haley, M. M.
Tetrahedron 1988, 44, 1305.
used as the substrate, regioisomers of 3k and 4k were
obtained with cis-configuration (3k and 4k, Figure 1).
To determine the scope of this transformation, we next
examined the reaction of alkylidenecyclopropa[b]naphtha-
(7) Stang, P. J.; Song, L.; Lu, Q.; Halton, B. Organometallics 1990, 9,
2149.
(8) Halton, B.; Randall, C. J.; Gainsford, G. J.; Stang, P. J. J. Am. Chem.
Soc. 1986, 108, 5949.
Org. Lett., Vol. 10, No. 24, 2008
5539

lenes 1 with alkynes 5. The results are summarized in Table
4. We found alkynes with electron-deficient groups such as
diffractional analysis on the organometallic complexes of
alkylidenecyclopropa[b]naphthalenes with stoichiometric rhod-
ium(I) and platinum(0) reagents,7 a possible mechanism for
the reaction of alkylidenecyclopropa[b]naphthalenes 1 with
alkenes or alkynes catalyzed by Pd(dba)2, are shown in
Scheme 2. First, oxidative addition of palladium(0) to a
Table 4. Pd(dba)2-Catalyzed [3 + 2] Cycloaddition Reaction of
1 with Alkynes 5a
Scheme 2. Proposed Mechanism
entry
Ar
R1
product time yield (%)a
1
2
3
4
5
6
7
8
9
1a
1b
1a
1a
1c
1a
1a
1a
1c
COOEt, 5a
5a
6a
6b
6c
6 day 46
5 day 47
2 day 71
3 day 68
5 day 52
13 h 54
4-FC6H4CO, 5b
4-CH3C6H4CO, 5c 6d
5c
C6H5, 5d
C3H5, 5e
n-C4H9, 5f
5f
6e
6f
6g/7g 2 h
6h/7h 1 h
6i/7i
6j/7j
80 (89:11)b
93 (91:9)b
88 (90:10)b
84 (86:14)b
1 h
2 h
10 4-MeOC6H4, 1e 5f
a Isolated yield based on 1. b The ratio was determined by 1H NMR
analysis.
highly strained three-membered-ring σ-bond of the alky-
lidenecyclopropa[b]naphthalenes 1 leads to the palladacy-
clobutene complex A. Subsequently, the regioselective
insertion reaction of A with alkenes 2 or alkynes 5 at the
less sterically hindered side gives the palladacyclohexene
complex B. Then, reductive elimination of palladium(0) gives
the [3 + 2] cycloadduct 3 or 6.
ethyl propiolate 5a, 1-(4-fluorophenyl)prop-2-yn-1-one 5b,
and 1-(4-methylphenyl)-prop-2-yn-1-one 5c, which were also
effective for this reaction, and the corresponding 1-alky-
lidene-1H-benzo[f]indenes 6 were obtained in moderate
yields with excellent regioselectivity of the acetylene bond
(entries 1-5, Table 4). When general alkynes were applied,
the reactions proceeded smoothly to give the corresponding
products with good regioselectivity (entries 6-10, Table 4)
(Figure 1, 6h). The reactions seem to give much more
competitive yields when alkyl-substituted alkynes were used
(entries 7-10, Table 4).
In summary, we have disclosed a highly regioselective Pd-
catalyzed [3 + 2] cycloaddition reaction of alkylidenecy-
clopropa[b]naphthalenes 1 with alkenes or alkynes, giving
the corresponding 1(3)-alkylidene-2,3-dihydro-1H-benzo[f]in-
denes or 1-alkylidene-1H-benzo[f]indenes in moderate to
good yields under mild conditions. Further studies into the
scope, mechanism, and synthetic applications of this trans-
formation are being carried out in our laboratory.
On the basis of the above results, previous investigation
on Pd-catalyzed [3 + 2] cycloaddition reaction of methyl-
enecyclopropanes4,11 and the NMR and X-ray single crystal
(9) At present, the role for the LiCl additive is not clear. We think this
may have some salt effect or act as the ligand in the reaction. For selected
papers of the LiCl additive, please see: (a) Ma, S.; Zhang, J. Angew. Chem.,
Int. Ed. 2003, 42, 184. (b) Ma, S.; Lu, L.; Zhang, J. J. Am. Chem. Soc.
2004, 126, 9645. (c) Wiskur, S. L.; Korte, A.; Fu, G. C. J. Am. Chem. Soc.
2004, 126, 82. (d) Wang, Z.; Zhang, Z.; Lu, X. Organometallics 2000, 19,
775. (e) Zhang, Z.; Lu, X.; Xu, Z.; Zhang, Q.; Han, X. Organometallics
Acknowledgment. Financial support from the National
Natural Science Foundation of China (Project Nos. 20872127
and 20732005) and National Basic Research Program of
China (973 Program, 2009CB825300) is gratefully acknowl-
edged.
2001, 20, 3724
.
(10) X-ray crystal data for compound 3i: C30H28; MW ) 388.52;
Monoclinic, space group P2(1)/c; a ) 11.8669(13), b ) 9.9929(11), c )
19.656(2) Å; R ) 90, ꢀ ) 101.360(2), µ ) 90, V ) 2285.2(4) Å3, T ) 293
(2) K, Z ) 4, Fcalcd ) 1.129 Mg/m3, µ ) 0.063 mm-1, µ ) 0.71073 Å;
F(000) 832, independent reflections (Rint ) 0.0500), 12 207 reflections
collected; refinement method, full-matrix least-squares refinement on F2;
goodness-of-fit on F2 ) 0.919; final R indices [I > 2σ(I)] R1 ) 0.0577,
wR2 ) 0.1361.
Supporting Information Available: Experimental pro-
cedures and characterization data of all new compounds (PDF
and CIF). This material is available free of charge via the
Internet at http://pubs.acs.org.
(11) Suzuki, T.; Fujimoto, H. Inorg. Chem. 2000, 39, 1113
.
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