Intramolecular cycloisomerization of aryl-substituted alkylidenecyclopropanes via NHC palladium-catalyzed cascade C-C bond cleavage/C-H activation/C-C bond formation

Article abstract of DOI:10.1055/s-2008-1078404

A well-defined N-heterocyclic carbene (NHC) palladium-catalyzed intramolecular cyclization reaction of aryl-substituted alkylidenecyclopropanes (ACP) to 1-aryl dihydronaphthalenes is described. The NHC salts were found to suppress β-hydride elimination from the homoallylpalladium intermediate, which may lead to unwanted alkene formation. A plausible mechanism for the cycloisomerization was proposed. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1078404

1366
LETTER
Intramolecular Cycloisomerization of Aryl-Substituted Alkylidenecyclo-
propanes via NHC Palladium-Catalyzed Cascade C–C Bond Cleavage/C–H
Activation/C–C Bond Formation
I
ntramolecular Cyc
e
loisomeriz
w
a
tion of Aryl-Subs
e
tituted Alk
i
ylidenecyclop
Y
ropanes ang,a Xian Huang*a,b
a
Department of Chemistry, Zhejiang University, (Xixi Campus), Hangzhou 310028, P. R. of China,
Fax +86(571)88807077; E-mail: huangx@mail.hz.zj.cn
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, P. R. of China
b
Received 29 January 2008
β-hydride elimination
R-Pd-X
Abstract: A well-defined N-heterocyclic carbene (NHC) palladi-
um-catalyzed intramolecular cyclization reaction of aryl-substitut-
ed alkylidenecyclopropanes (ACP) to 1-aryl dihydronaphthalenes is
described. The NHC salts were found to suppress b-hydride elimi-
nation from the homoallylpalladium intermediate, which may lead
to unwanted alkene formation. A plausible mechanism for the cy-
cloisomerization was proposed.
XPd
R
R
H
H
M-Pd-H
MPd
M
Nu-Pd-H
NuPd
H
Nu
H
Key words: ring opening, cycloisomerization, N-heterocyclic car-
bene, alkylidenecyclopropanes, dihydronaphthalenes
Scheme 1 Palladium-catalyzed reactions with MCP
ed MCP are used, a new rearrangement reaction occurs in
the presence of Pd–NHC system, affording 1,2-dihy-
dronaphthalenes (Table 1).
Methylenecyclopropanes (MCP) or alkylidenecyclopro-
panes (ACP) are highly strained molecules owing to their
having a three-membered ring attached to a C=C double
bond. The selective cleavage of the three s-bonds in the
cyclopropane ring is of great interest in organic synthe-
sis.1 During the past decades, transition-metal-catalyzed
reactions of MCP with various metals (Pd,2 Pt,3 Ni,4 and
Rh5) have been studied, and such reactions have also been
employed for the construction of complex organic mole-
cules. The palladium-catalyzed addition to MCP involves
the following three reaction patterns (Scheme 1). When
the double bond reacts with R–Pd–X, proximal bond
cleavage takes place first, followed by b-carbon–Pd elim-
ination to give 2-alkylated diene.6 The addition of metal-
hydride species (H–M) can also give proximal bond
cleavage product.2f In contrast, distal bond cleavage pro-
ceeds through Markovnikov hydropalladation of H–Pd–
Nu complex.2e
In recent years there have been several reports of applica-
tions of Pd–NHC catalysts to Negishi,8 Sukuzi,9 Kuma-
da,10 Sonogashira,11 and Heck12 reactions. These
palladium catalysts have been proved to be effective for
coupling unactivated b-hydride-containing alkyl electro-
philes, and have been employed as ‘phosphine mimics’.13
The novelty of this behavior of N-heterocyclic carbenes
prompted us to investigate whether using these catalysts
might afford different cycloisomerization products from
ACP. We initially examined the influence of various imi-
dazolium salts as ligand precursors (Figure 1) using 1a as
a model substrate. Results of this initial screening are
shown in Table 1.
First, Pd(OAc)2 was used as catalyst in the presence of dif-
ferent imidazolium salts (entries 1–7). To our delight, 1,2-
dihydronaphthalene 2a was the major product, accompa-
nied with a byproduct diene 3a. Among the ligands tested,
IBu·HCl minimized the extent of b-hydride elimination
and IMes·HCl14 afforded the best yield (entries 2, 6). Con-
sequently, IMes·HCl was selected as the optimum ligand
precursor and palladium–NHC complexes 12 and 13 were
achieved through the reaction imidazolium salts with
Pd(OAc)2.15 With well-defined catalysts in hand, the reac-
tion was examined and compared to the in situ generated
catalytic system. When 12 was used, we observed the for-
mation of 2a, but in low yield (entry 8). Fortunately, the
yield improved to 55% when an extra amount of imidazo-
lium salt ligand IMes·HCl (8%) was added (entry 9). The
excess IMes·HCl might intercept the formation of palladi-
um black, thereby regenerating the active NHC catalyst.16
Interestingly, 4a was formed in negligible quantities when
Alkylidenecyclopropanes undergo several isomerizations
in the presence of transition metals due to the relief of ring
strain. Previously, Yamamoto and co-workers reported
that 1-phenyl-1,3-butadiene was produced as a byproduct
under Pd-catalyzed hydroamination of MCP.2d Shi’s ob-
servation of formation to 1,3-diene under palladium–
Brønsted acid conditions is noteworthy in this connec-
tion.7a More recently, Fürstner3a and Shi7b have shown that
the cyclobutenes could be obtained in the presence of
PtCl2 or PdBr2. Here, we disclose a new Pd-catalyzed re-
action for the isomerization of ACP. When aryl-substitut-
SYNLETT 2008, No. 9, pp 1366–1370
x
x.
x
x.
2
0
0
8
Advanced online publication: 07.05.2008
DOI: 10.1055/s-2008-1078404; Art ID: W01908ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Intramolecular Cycloisomerization of Aryl-Substituted Alkylidenecyclopropanes
1367
Table 1 Cycloisomerization of 1a under Various Conditionsa
Ph
catalyst
Ph
Ph
Ph
Ph
NHC⋅HCl
+
(1)
Ph
DMA, 160 °C
Ph
1a
2a
3a
Ligand (mol%)
–
4a
Entry
1
Catalyst (mol%)
Pd(OAc)2 (10)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
12 (10)
Time (h)
12
24
24
24
12
12
12
5
Yield of 2a and 3a (%)b Ratio of 2a/3ac
0d,e
31
–
2
6 (15)
7 (15)
8 (15)
9 (15)
10 (15)
11 (15)
–
96:4
3
18
33
18
39
20
33
55
46
40
32
39
48:52
89:11
76:24
95:5
4
5
6
7
92:8
8
55:45
84:16
78:22
71:29
97:3
9
12 (2)
10 (8)
10 (10)
10 (25)
10 (8)
11 (8)
12
9
10
11
12
13
12 (2)
12 (2)
7f
13 (2)
12
12
14 (2)
90:10
a [1a] = 0.5 M.
b Isolated yields.
c Ratio of 2a/3a was determined by NMR.
d Palladium black was formed within 30 min.
e Recovery of the starting material.
f A trace amount (4%) of 4a was obtained as a byproduct.
Cl–
N+
Cl–
N+
Cl–
N+
n-Bu
n-Bu
N
N
N
6
8
7
IBu⋅HCl
SIMes⋅HCl
SIMe⋅HCl
i-Pr
Cl–
i-Pr
Cl–
Cl–
N+
N
N+
N
N+
N
i-Pr
Pr-i
11
IPr⋅HCl
10
IMes⋅HCl
9
IMe⋅HCl
Dipp Dipp
Cl
Mes Mes
Cl
Mes Mes
Cl
N
N
N
N
N
N
Pd
Pd
Cl
N+
Pd
N+
N
Cl–
N
N
Cl–
Dipp
N
Mes
Dipp
Mes Mes
Mes
14
13
12
Figure 1 Active NHC ligand precursors and Pd–NHC complexes
1a was heated to 160 °C in the presence of 25 mol% of We next studied the scope of this methodology by exam-
ligand (entry 11). Similarly, palladium complex 13 gave ining the reaction of various ACP under the optimized re-
2a in 32% yield (entry 12) while structurally related 14 in action conditions (Table 2).17 The substituted group on
the presence of IPr·HCl gave a lower yield of 2a (entry the aromatic rings of the ACP significantly affected their
13).
reactivity. For example, when (di-p-tolyl)methylenecy-
Synlett 2008, No. 9, 1366–1370 © Thieme Stuttgart · New York

1368
Y. Yang, X. Huang
LETTER
Table 2 Pd–NHC-Catalyzed Cycloisomerization of Various ACPa
We also investigated the reaction of a monosubstituted
ACP. Compound 1r did not give the desired product at all,
while compound 1s gave a polymeric product 5s under the
same conditions (Equation 1).
R
R
R
12 (2 mol%)
10 (8 mol%)
We also examined the behavior of an unsymmetric ACP
1p. A 1.8:1 mixture of the two possible products 2p and
2q was obtained in 65% yield, showing that the formation
of the six-membered ring from the electron-rich aromatic
nuclei was preferred (Equation 2).
+
DMA, 160 °C, 12 h
R
R
R
1
2
3
A possible reaction mechanism is shown in Scheme 2.
The initial step of this reaction should be the hydropalla-
dation of the C=C double bond via the hydridopalladium
species.19,20 Elimination of b-carbon leads to intermediate
B, which then gives compound 3a as a byproduct via b-H–
Pd elimination. The electrophilic palladium species B
may undergo intramolecular C–H insertion with the phe-
nyl ring to yield the cyclized palladium intermediate
C,21,22 which followed by elimination of L2Pd(H)Cl to
give the final product and at the same time liberate the cat-
alytically active H–Pd species.23
Entry
ACP 1
R
Yield (%)b
2
3
1
2
1a
1b
1c
1d
1e
1f
H
2a 42
2b 60
2c 55
2d 48
2e 31
2f 52
2g 59
2h 51
2i 64
2j 37
2k 29
3a 7
Me
3b 22
3
MeO
EtO
–
4
–
5
n-PrO
i-PrO
n-BuO
s-BuO
i-BuO
n-C5H11O
n-C6H13O
Me2N
Cl
–
In conclusion, we have discovered a Pd–NHC catalyst
system for the cycloisomerization of ACP to the corre-
sponding 1-aryldihydronaphthalenes. This process pro-
vides a novel route to the synthesis of dihydronaphthalene
derivatives. Control of the unusual cascade C–C bond
cleavage–C–H activation–C–C bond-formation process
would have important synthetic and mechanistic implica-
tions. Investigations focused on understanding the mech-
anistic details of the novel rearrangements are currently
under way.
6
–
7
1g
1h
1i
–
8
–
9
–
10
11
12
13
14
1j
–
1k
1m
1n
1o
3k 13
c
–
–
–
–
2n 25
2o 41
F
Ph
d
15
1r
–
–
a All reactions were run under the following conditions unless other-
wise specified: ACP 1 (0.5 M), 12 (2 mol%), 10 (8 mol%), DMA,
160 °C, 12 h.
b Isolated yield.
c Recovery of starting material.
d Unidentified mixture of products.
clopropane (1b) was employed, 2b and 3b were obtained
in 60% and 22%, respectively (entry 2). The influence of
different electron-donating groups on the aromatic ring
was studied (entries 3–12). When an oxygen atom was di-
rectly attached to the benzene ring, the corresponding six-
membered products were obtained in moderate yields (en-
tries 3–9). However, substrate 1m with amino substituents
(entry 12) was unable to undergo ring formation under the
same conditions. In addition, poor yields were obtained
from substrates with an electron-withdrawing halogen
functionality (entries 13 and 14). The structure of the
product 2f was established by spectroscopic and single-
crystal X-ray diffraction analysis (Figure 2).18
Figure 2 Single-crystal X-ray structure of compound 2f
Acknowledgment
We are grateful to the National Natural Science Foundation of Chi-
na (Project No. 20672095, 20732005) and CAS Academician Foun-
dation of Zhejiang Province for financial support.
Synlett 2008, No. 9, 1366–1370 © Thieme Stuttgart · New York

LETTER
Intramolecular Cycloisomerization of Aryl-Substituted Alkylidenecyclopropanes
1369
Me
12 (2 mol%)
C6H4(4-OMe)
4-MeOC6H4
IMes⋅HCl (8 mol%)
71%
4-MeOC6H4
1s
OMe
Cl
5s
Equation 1
OMe
Cl
12 (2 mol%)
10 (8 mol%)
+
DMA, 160 °C, 12 h
65%
Cl
OMe
OMe
1p
2p
2q
Equation 2
1a
2a
L2Pd(H)Cl
PdL2Cl
H
H
H
A
ClL2Pd
C
β-carbon-Pd
elimination
C–H activation
H
H
H
H
β-hydride elimination
ClL2Pd
H
B
3a
Scheme 2 A plausible mechanism for the cycloisomerization of 1a in the presence of catalyst 12
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Synlett 2008, No. 9, 1366–1370 © Thieme Stuttgart · New York

1370
Y. Yang, X. Huang
LETTER
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91 (47.6). ESI-HRMS: m/z calcd for C16H14 [M+]: 206.1096;
found: 206.1099.
Compound 3a: colorless oil. 1H NMR (400 MHz, CDCl3):
d = 7.38–7.20 (m, 10 H), 6.71 (d, J = 11.0 Hz, 1 H), 6.43 (m,
1 H), 5.38 (ddd, J = 16.8, 0.7, 0.7 Hz, 1 H), 5.11 (ddd,
J = 10.2, 0.9, 0.76 Hz, 1 H). 13C NMR (100 MHz, CDCl3):
d = 143.1, 142.1, 139.6, 134.9, 130.4, 128.5, 128.2, 128.1,
127.6, 127.5, 127.4, 118.6.
(18) The crystal data of 2f have been deposited at the CCDC with
number 671565. Crystal data for 2f: C22H26O2,
MW = 322.43, monoclinic, space group P2(1)/c, final R
indices [I > 2s(I)], R1 = 0.0505, wR2 = 0. 1033,
a = 14.8134(19) Å, b = 16.2215(19) Å, c = 7.7787(10) Å,
a = 90°, b = 100.708(2)°, g = 90°, V = 1836.6(4) Å3, crystal
size: 0.482 × 0.435 × 0.276 mm, T = 293 (2) K, Z = 4,
reflections collected/unique: 10650/ 3977 (Rint = 0.0921),
data: 3977, restraints: 0, parameters: 222.
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2005, 7, 1857.
(17) Preparation of 4-Phenyl-1,2-dihydronaphthalene (2a)
and (1-Phenylbuta-1,3-dienyl)benzene (3a); Typical
Procedure
Under an N2 atmosphere, a mixture of 1a (206 mg, 1 mmol),
Cl2PdL2 (20 mg, 0.02 mmol), IMes·HCl (35 mg, 0.08 mmol)
and DMA (2 mL) was stirred for 12 h at 160 °C. The reaction
was monitored by TLC (eluent: hexane). After the reaction
was judged complete, the reaction mixture was allowed to
cool. The crude mixture was then loaded directly onto SiO2
and purified by column chromatography using hexane as the
eluent to give the products 2a (86 mg, 42%) and 3a (14 mg,
7%).
Compound 2a: colorless oil. IR (film): nmax = 3059, 3026,
2934, 1720, 1662, 1597, 1489, 1447, 1269, 1157 cm–1. 1H
NMR (400 MHz, CDCl3): d = 7.49–7.09 (m, 5 H), 7.00 (d,
J = 7.4 Hz, 1 H), 6.08 (t, J = 4.7 Hz, 1 H), 2.84 (t, J = 8.1 Hz,
2 H), 2.42–2.37 (m, 2 H). 13C NMR (100 MHz, CDCl3): d =
140.8, 139.7, 136.8, 135.1, 128.7, 128.2, 127.6, 127.5,
127.0, 126.9, 126.2, 125.4, 28.3, 23.5.MS (EI): m/z (%) =
207 (22.1) [M+ + 1], 206 (100) [M+], 191 (51.3), 128 (26.7),
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