An Improvement of the Palladium-Catalyzed [4+2] Cycloaddition of o -(Silylmethyl)benzyl Carbonates with Alkenes

Article abstract of DOI:10.1055/s-0034-1379014

The palladium complex, which is generated in situ from Pd(η ³-C₃H₅)Cp and tris(4-methoxy-3,5-dimethylphenyl)phosphine, catalyzed the [4+2] cycloaddition of o-(silylmethyl)benzyl carbonates with alkenes. The reaction of the

Full text of DOI:10.1055/s-0034-1379014

2488▌
LETTER
lAettner Improvement of the Palladium-Catalyzed [4+2] Cycloaddition of o-(Silyl-
methyl)benzyl Carbonates with Alkenes
Palladium-Catalyzed [4+2] Cycloaddition
Yushu Jin,a Kentaro Ishizuka,b Ryoichi Kuwano*a,c
a
Department of Chemistry, Graduate School of Sciences, and International Research Center for Molecular Systems (IRCMS), Kyushu
University, 6-10-1 Hakozaki, Higashi-ku, Fukuoka 812-8581, Japan
b
Education Center for Global Leaders in Molecular Systems for Devices, Kyushu University, 6-10-1 Hakozaki, Higashi-ku, Fukuoka 812-8581,
Japan
c
JST ACT-C, 6-10-1 Hakozaki, Higashi-ku, Fukuoka 812-8581, Japan
Fax +81(92)6422572; E-mail: rkuwano@chem.kyushu-univ.jp
Received: 12.06.2014; Accepted after revision: 01.08.2014
alkenes.11 Herein, we report an improvement of the palla-
dium catalyst for the cycloaddition.
Abstract: The palladium complex, which is generated in situ from
Pd(η3-C3H5)Cp and tris(4-methoxy-3,5-dimethylphenyl)phosphine,
catalyzed the [4+2] cycloaddition of o-(silylmethyl)benzyl carbon-
ates with alkenes. The reaction of the benzyl esters with methyl cro-
tonate gave methyl 3-methyltetralin-2-carboxylate in 84% yield
with 2% catalyst loading.
Various monophosphines were evaluated for the cycload-
dition of 1a with methyl crotonate (2a). The results are
summarized in Table 1. First, a mixture of 1a and 2a was
treated with Pd(η3-C3H5)Cp–L1 catalyst in DMSO at
120 °C. Disappointingly, the desired tetralin 3a was ob-
tained in only 33% yield (Table 1, entry 1). The yield val-
ue was comparable to that of the reaction using Ph3P
ligand (Table 1, entry 2). Bulky trialkylphosphine–palla-
dium complexes could catalyze the cycloaddition, but the
bulkiness of the ligand caused slight deterioration of the
palladium catalysis (Table 1, entries 3 and 4). Next, a se-
ries of para-substituted triarylphosphines L2–L5 were
employed as the ligand for the catalytic cycloaddition.
The formation of 3a is considerably affected by the elec-
tronic property of the substituents. Use of electron-defi-
cient ligands L2 and L3 led to significant decrease in the
yield of 3a (Table 1, entries 5 and 6). In particular, no
product 3a was formed and the substrate 1a remained in-
tact in the reaction employing L2. The electron density of
the metal atom in the L2–palladium(0) complex may be
insufficient for the oxidative addition of the benzylic C–O
bond of 1a. Ligand L4 was similar in the yield to Ph3P
(Table 1, entry 7). The catalyst efficiency was remarkably
improved by using triarylphosphine L5 bearing methoxy
groups (Table 1, entry 8). However, such improvement
was not observed when the reaction of 1a with 2a was
conducted with ortho-substituted ligand L6 or L7 (Table
1, entries 9 and 10). The electronic effect of the methoxy
substituents may be canceled by their steric hindrance.
The yield of 3a was somewhat enhanced by installing
methyl groups at the meta positions of L5 (Table 1, entry
11). Tris(4-methoxy-3,5-dimethylphenyl)phosphine (L8)
is the best ligand for the palladium-catalyzed cycloaddi-
tion of 1a with 2a. The meta substituent influences the cy-
cloaddition electronically rather than sterically, because
the meta phenyl groups of L9 caused a slight decrease in
the yield (Table 1, entry 12). Further improvement of the
catalytic cycloaddition was not achieved by more elec-
tron-rich ligand L10 (Table 1, entry 13). Replacing one or
two of the electron-donating aryl substituents of L8 by
phenyl group caused decrease in the yield of 3a (Table 1,
entries 14 and 15).
Key words: catalysis, cycloaddition, o-quinodimethanes, alkenes,
palladacycles
The Diels–Alder reaction of o-quinodimethanes with
alkenes is a powerful approach for constructing benzo-
fused six-membered carbocycles.1 The [4+2] cycloaddi-
tion is often used for the synthesis of natural products,2
medicines,3 and π-conjugated materials.4 We have devel-
oped the palladium-catalyzed [4+2] cycloadditions of
o-(silylmethyl)benzyl carbonates
1
with alkenes,5
imines,6 and ketones.7 The catalytic cycloaddition is
based on the nucleophilic benzylic substitution through
palladium catalysis, in which the palladium(0) species
cleaves the benzylic C–O bond of benzyl ester to form the
(η3-benzyl)palladium(II) intermediate.8 In the course of
our studies on the catalytic substitution of benzyl esters,
bidentate bisphosphines were mainly used as the spectator
ligand for the homogeneous palladium catalyst. The use
of bisphosphine ligand facilitates the palladium(0) to un-
dergo the oxidative addition of the benzylic C–O bond. As
with the benzylic substitution, bisphosphine ligands were
used for the above palladium-catalyzed cycloadditions of
1.5–7
Recently, we reported the intramolecular SN2′-type aro-
matic substitution of benzylic carbonates, which are teth-
ered to a nucleophile at their meta positions.9 The
cyclization of the benzylic substrates efficiently took
place in the presence of a palladium catalyst bearing bi-
aryldicyclohexylphosphine, SPhos (L1).10 The usefulness
of the monophosphine for the reaction of the benzylic sub-
strates stimulated us to evaluate various monophosphine
ligands for the catalytic [4+2] cycloaddition of 1 with
SYNLETT 210014, 2517, 2488–2492
Advanced online publication: 25.08.2014
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DOI: 10.1055/s-0034-1379014; Art ID: st-2014-u0511-l
© Georg Thieme Verlag Stuttgart · New York

LETTER
Palladium-Catalyzed [4+2] Cycloaddition
2489
Table 1 Optimization of Reaction Conditionsa
ophile 2a allowed the L8–palladium catalyst to produce
3a in 84% yield with 2% catalyst loading (Table 1, entry
18). The cycloaddition proceed with complete stereospe-
cificity, because no cis isomer of 3a was detected in the
reaction mixture.
Pd(η3-C3H5)Cp (5.0mol%)
Me
SiMe3
OCOMe
O
ligand (10 mol%)
CO2Me
2a
CO2Me
Me
1a
3a
DMSO, 24 h
R
The optimized palladium catalyst promoted the cycload-
dition of the o-(silylmethyl)benzyl carbonate (1a) with
various conjugated alkenes 2 as shown in Table 2. Methyl
methacrylate (2b) reacted with 1a to give tetralin 3b in
55% yield (Table 2, entry 1). The L8–palladium catalyst
promoted the cycloadditions of 1a with α,β-unsaturated
ketones 2c and 2d, but the ketone substrates required
higher temperature for affording 3c and 3d (Table 2, en-
tries 2 and 3). It is noteworthy that the use of the mono-
phosphine allows the cycloaddition of 2d to proceed in
moderate yield, while the cyclic enone scarcely reacted
with 1a in the presence of Pd(η3-C3H5)Cp–DPPE cata-
lyst.5 Furthermore, the reaction was accompanied by the
epimerization at the α-carbon of the ketone, giving 3d
without formation of the cis isomer. A series of p-substi-
tuted styrenes work as the alkene substrate in the catalytic
cycloaddition (Table 2, entries 4–6). Electron-donating
and electron-withdrawing substituents did not cause sig-
nificant decrease in the yields of the cycloadducts. Te-
tralin 3h was also obtained in good yield from the reaction
of trans-stilbene (2h) through the L8–palladium catalyst
(Table 2, entry 7). 1,1-Diphenylethene and trans-β-meth-
ylstyrene are possible to react with 1a, but the correspond-
ing cycloadducts were obtained in 27% and 38% yield,
respectively. To our surprise, little formation of the de-
sired tetralin was observed in the reaction of 1a with
methyl acrylate (2i) or cinnamate (2j, Scheme 1).
Ligand:
MeO
OMe
P
3
R
P
PCy2
OMe
L2: R = CF3
L3: R = F
3
R
L4: R = Me
L5: R = OMe
L6: R = H
L1
L7: R = OMe
R2
L8: R1 = OMe, R2 = Me, n = 3
L9: R1 = OMe, R2 = Ph, n = 3
L10: R1 = NMe2, R2 = Me, n = 3
L11: R1 = OMe, R2 = Me, n = 2
L12: R1 = OMe, R2 = Me, n = 1
R1
PPh(3–n)
R2
n
Entry
Ligand
Temp (°C)
Yield (%)b
1
2
L1
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
100
80
33
32
29
22
0
Ph3P
Cy3P
(t-Bu)3P
L2
3
4
5
6
L3
18
34
51
31
29
62
48
46
49
49
70
0
7
L4
8
L5
9
L6
10
11
12
13
14
15
16
17
18c
L7
Pd(η3-C3H5)Cp (2.0 mol%)
L8 (4.0 mol%)
R
R
L8
1a +
DMSO, 100 °C, 48 h
CO2Me
2i R = H
2j R = Ph
CO2Me
L9
<10%
L10
L11
L12
L8
Scheme 1
The L8–palladium catalyst was applied to the reaction of
substituted o-(silylmethyl)benzyl esters 1b–d (Table 3).
As with 1a, the methyl-substituted analogue 1b reacted
with 2a and 2e to give the corresponding cycloadducts in
77% and 65% yield, respectively (Table 3, entries 1 and
2). However, the palladium catalyst failed to control the
regiochemistry of the cycloaddition. The reactions of 1c
with 2a, 2b, and 2e also produced regioisomeric mixtures
of the cycloadducts in good or moderate yield (Table 3,
entries 3–5). The methyl group at the 6-position of 1c
scarcely obstructed the activation of the benzylic C–O
bond with the palladium catalyst and slightly affected the
ratio of 3 to 3′. The ratio was not significantly affected by
the olefinic substrates. The palladium catalyst is useful for
the reaction of the benzofused substrate 1d, which failed
to form 3n through the DPPE–palladium catalyst (Table
3, entry 6).
L8
L8
100
84d
a Reactions were conducted on a 0.2 mmol scale in DMSO (0.5 mL)
for 24 h unless otherwise noted. The molar ratio of 1a/2a/Pd(η3-
C3H5)Cp/ligand was 20:24:1.0:2.0.
b GC yield (average of two runs).
c The reaction was conducted on a 0.5 mmol scale in DMSO (1.0 mL)
for 48 h. The molar ratio of 1a/2a/Pd(η3-C3H5)/ligand was
50:100:1.0:2.0.
d Isolated yield.
As a result of further optimization of reaction conditions
with ligand L8, the cycloadduct 3a was obtained in higher
yield from the reaction of 1a with 2a at 100 °C (Table 1,
entry 16). Furthermore, use of an excess amount of dien-
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 2488–2492

2490
Y. Jin et al.
LETTER
The low regioselectivities in the reactions of 1b and 1c DPPE–palladium catalyst allowed methyl acrylate (2i)
suggest that the present catalytic cycloaddition proceeds and cinnamate (2j) to react with 1, while these olefinic
through the pathway involving a 2-palladaindane 4 substrates failed to form the desired cycloadduct in the
(Scheme 2). The benzylic C–O bond of 1 is cleaved by the presence of the L8–palladium complex. The interaction
L8–palladium(0) 5 to give the (η3-benzyl)palladium(II) 6 between 5 and these π-accepting alkenes might obstruct
and/or (η1-benzyl)palladium(II) 7. The following intra- the approach of 1 to the palladium(0), because 2i and 2j
molecular transmetalation between the silyl group and are stronger in affinity for low-valent metal than other
methoxy ligand in 7 forms the palladaindane 4, in which alkenes 2a–h.12 In the DPPE–palladium catalyst, the bis-
the two Pd–C bonds are almost equivalent. The insertion phosphine tightly chelates the metal atom through its two
of alkene 2 into one of the Pd–C bonds and the following phosphorus atoms to create stiff steric hindrance around
reductive elimination yield the tetralin 3 and palladium(0) the catalytic center. The steric hindrance may weaken the
(5). The catalytic cycle is similar to the mechanism pro- coordination of 2i or 2j to the palladium. Meanwhile, the
posed in our previous reports, where a bisphosphine-che- coordination of L8 to the palladium in 5 is looser than that
lating palladium complex was used as the catalyst.5 The of DPPE. The monodentate ligand furnishes less crowded
Table 2 Cycloaddition of 1a with Alkenes 2a
R3
R4
R1
R2
Pd(η3-C3H5)Cp (2.0 mol%)
L8 (4.0 mol%)
R4
R3
R1
SiMe3
OCOMe
O
+
R2
2b–h
DMSO, 48 h
1a
3b–h
Entry
1
Alkene 2
Temp (°C)
Product 3
Yield (%)b
CO2Me
Me
100
120
55
Me
CO2Me
2b
3b
3c
Me
O
2
3
68
50
Me
Et
COEt
2c
H
H
120
O
O
2d
2e
3d
3e
Ph
4
100
100
100
100
72
59
62
65
Ph
t-Bu
5
C6H4-4-(t-Bu)
2f
3f
CF3
6c
C6H4-4-CF3
2g
3g
Ph
Ph
Ph
Ph
7
2h
3h
a Reactions were conducted on a 0.5 mmol scale in DMSO (1.0 mL) for 48 h unless otherwise noted. The molar ratio of 1a/2/Pd(η3-C3H5)Cp/L8
was 50:100:1.0:2.0.
b Isolated yield.
c The reaction was conducted for 24 h.
Synlett 2014, 25, 2488–2492
© Georg Thieme Verlag Stuttgart · New York

LETTER
Palladium-Catalyzed [4+2] Cycloaddition
2491
Table 3 Cycloadditions of 1b–d with 2a or 2ea
Pd(η3-C3H5)Cp (2.0 mol%)
Me or H
H or Me
SiMe3
OCOMe
O
L8 (4.0 mol%)
R
R
+
2a, 2b, or 2e
DMSO, 100 °C
CO2Me or Ph
1b–d
3i–n
Entry
1
1
Alkene 2 Time (h) Product 3
Ratiob
Yield (%)c
Me
Me
Me
Me
CO2Me
Me
SiMe3
OCOMe
O
2a
2e
2a
48
24
24
52:48
52:48
59:41
77
CO2Me
3i′
3i
1b
1b
Me
Me
Ph
2d
65
79
Ph
3j′
3j
Me
CO2Me
SiMe3
OCOMe
O
CO2Me
Me
3
Me
Me
Me
Me
1c
1c
3k
3k′
CO2Me
Me
Me
4
2b
48
CO2Me
58:42
37
Me
3l
3l′
Ph
Ph
5
6
1c
2e
2a
48
24
67:33
57
53
Me
Me
3m
3m′
Me
SiMe3
OCOMe
O
–
CO2Me
3n
1d
a Reactions were conducted on a 0.5 mmol scale in DMSO (1.0 mL) at 100 °C for 48 h unless otherwise noted. The molar ratio of 1a/2/
Pd(η3-C3H5)Cp/L8 was 50:100:1.0:2.0.
b The ratio was determined by NMR analysis.
c Isolated yield of the mixture of regioisomers.
d The reaction was conducted at 120 °C.
reaction field to the catalyst than DPPE. Therefore, in the
1
3
CO2
R1
Pd0
5
+
cycloaddition thorough L8–palladium catalyst, the olefin-
ic substrates strongly interact to the metal atom as com-
pared with the reaction using DPPE ligand.
R1
PdII
Si
R2
MeO–
R3
In conclusion, we found that some electron-rich triaryl-
phosphines are useful as the spectator ligand for the palla-
dium-catalyzed [4+2] cycloaddition of o-(silylmethyl)-
benzyl carbonates 1 with alkenes 2. In particular, Pd(η3-
C3H5)Cp–tris(4-methoxy-3,5-dimethylphenyl)phosphine
(L8) catalyst give the desired cycloadducts in up to 84%
yield. The observation indicates that triarylphosphine-li-
gated palladium(0) complex is possible to activate the
benzylic C–O bond when the ligand has appropriate elec-
PdII
6
R2
R1
R1
Si
PdII
PdII
R3
2
OMe
4
Si OMe
7
Scheme 2 A possible pathway of the catalytic cycloaddition of 1
with 2
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 2488–2492

2492
Y. Jin et al.
LETTER
Rahmani, R.; Heran, V.; Thibonnet, J.; Commeiras, L.;
Parrain, J. L. Org. Biomol. Chem. 2012, 10, 4712.
(3) Yoshida, H.; Yoshida, R.; Mukae, M.; Ohshita, J.; Takaki,
K. Chem. Lett. 2011, 40, 1272.
(4) Selected examples: (a) Kaur, I.; Stein, N. N.; Kopreski, R.
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tron-donating substituents. The L8–palladium catalyst al-
lows 2-cyclohexenone (2d) and stilbene (2h) to react with
1, while these alkenes failed to form the cycloadduct with
1 through DPPE–palladium catalyst in our previous re-
port.5 Further improvement of the catalytic cycloaddition
of 1 is in progress.
Acknowledgment
This work was supported by ACT-C (JST) and KAKENHI (Nos.
24655085 and 24106732). We thank the Cooperative Research Pro-
gram of ‘Network Joint Research Center for Materials and Devices’
for HRMS measurement.
(5) Kuwano, R.; Shige, T. J. Am. Chem. Soc. 2007, 129, 3802.
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Supporting Information for this article is available online
at
http://www.thieme-connect.com/products/ejournals/journal/
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10.1055/s-00000083.SunpfgIpi
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nr
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Synlett 2014, 25, 2488–2492
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