Heterobimetallic Pd-Sn catalysis: Highly selective intermolecular hydroarylation of α-methyl substituted aryl alkenes

Article abstract of DOI:10.1016/j.tetlet.2012.11.038

The heterobimetallic catalyst [Pd(COD)Cl-SnCl₃] efficiently promotes the intermolecular hydroarylation of α-methyl substituted arenes (otherwise known to be dimerized/polymerized in presence of Lewis Acids) with indoles and other O-, S-heteroar

Full text of DOI:10.1016/j.tetlet.2012.11.038

Tetrahedron Letters 54 (2013) 335–338
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Tetrahedron Letters
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Heterobimetallic Pd–Sn catalysis: highly selective intermolecular
hydroarylation of a-methyl substituted aryl alkenes
Debjit Das a, Sanjay Pratihar a, Sujit Roy b,
⇑
a Organometallics & Catalysis Laboratory, Department of Chemistry, Indian Institute of Technology, Kharagpur 721302, India
b Organometallics & Catalysis Laboratory, School of Basic Sciences, Indian Institute of Technology, Bhubaneswar 751013, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The heterobimetallic catalyst [Pd(COD)Cl–SnCl3] efficiently promotes the intermolecular hydroarylation
Received 3 October 2012
Revised 6 November 2012
Accepted 9 November 2012
Available online 23 November 2012
of
a-methyl substituted arenes (otherwise known to be dimerized/polymerized in presence of Lewis
Acids) with indoles and other O-, S-heteroarenes leading to Markovnikov adducts. The reaction takes
place under air and moisture insensitive condition.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Hydroarylation
a-Methyl substituted arene
Indole
Heterobimetallic catalysis
Regioselective C–C bond formation
Alkylated indoles are important structural motifs frequently
encountered in a broad range of biologically active compounds.1,2
Conventionally, 3-alkylated indoles are synthesized by carbon–
carbon bond-forming reactions such as (a) acid- or base-promoted
alkylation or (b) transition metal catalyzed alkylation. In general
Lewis or Brønsted acid catalyzed activation of electrophiles takes
place through Friedel–Crafts like path2,3 while transition metal-
limited to N-phenylsulfonyl protected indoles.8,9 Che and co-work-
ers developed the hydroarylation of styrene with indole under
thermal or microwave-assisted conditions using a combination of
[AuCl(PPh3)]/AgOTf as catalyst.10 Recently Hiyama and co-workers
reported a nickel-catalyzed hydroheteroarylation of vinylarenes
with electron-poor heteroarenes which leads to 1,1-diaryle-
thanes.11 Pathak and Sigman reported
a palladium-catalyzed
catalyzed alkylations proceed via electrophilic
p
-metal complex.2,4
hydroheteroarylation reaction of alkenes using alkyl chloride as
the sacrificial hydride source; unfortunately the reaction is specific
to vinyl phenols only.12 It is noteworthy that in all the above cases,
Hydroarylation of an alkene represents an atom economic alterna-
tive to Friedel–Crafts like alkylation specially for the construction
of a benzylic stereocenter. Although intermolecular hydroarylation
of indole was well investigated with electron-deficient Michael
acceptor,2,5 only a few examples are available where an unfunc-
tionalized terminal alkene (like aryl alkene) was used. The chal-
lenges associated with intermolecular hydroarylation of aryl
alkene with indole are: (i) to direct the regioselectivity at a selec-
tive site out of the many probable ones in the indole ring and in
the aryl alkene, and (ii) to inhibit the polymerization of aryl al-
kenes as is the case in the presence of Lewis acids6 (Scheme 1).
In this respect Widenhoefer and co-workers demonstrated that
platinum(II) acts as an efficient catalyst for the intermolecular
hydroarylation of unactivated alkenes with indoles; but with high-
er alkenes the regioselectivity observed was poor.7 Liu and
co-workers reported the use of triflic acid (TfOH) as a catalyst for
hydroarylation of alkenes, but the hydroarylation reaction was
⇑
Corresponding author.
E-mail address: sroychem@iitbbs.ac.in (S. Roy).
Scheme 1. Challenge in hydroarylation of aryl alkene with indole.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.11.038

336
D. Das et al. / Tetrahedron Letters 54 (2013) 335–338
Table 1
Table 2
Hydroarylation model study: catalyst screeninga
Pd–Sn catalyzed hydroarylation of aryl alkenes with indoles: substrate scopea
R2
R2
Catalyst (2 mol%)
+
Catalyst C1 (2 mol%)
N
Solvent, 90 °C, 2 h
N
+
Ph
1a
2a
Catalyst
3a
DCE, 90 °C
Ph
N
N
1
R1
2
3
R1
#
Solvent
Yield of 3ab (%)
1c
HCl
pTSA
TfOH
TfOH
SnCl2
ZnCl2
FeCl3
AlCl3
DCE
DCE
DCE
DCM
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
Toluene
Toluene
MeCN
ꢀ0
ꢀ0
15
<5
<10
<5
Entry
1
Alkene
Indole
Time (h)
8
Yield of 3 (%)
3b, 90
2
3c
4c,d
5
N
2b
1a
6
7
8
9
MeO
17
11
2
3b
4
12
10
6
3c, 50
3d, 62
3e, 85
3f, 60
N
InCl3
SnCl4
ꢀ0
<10
<10
<10
12
H
1a
1a
2c
10
11
12
13
14
15
16
17
18
19
20
21
22e
23
24
Bi(OTf)3
Yb(OTf)3
La(OTf)3
Sc(OTf)3
Cu(OTf)2
Ru(PPh3)3Cl2
PtCl2(MeCN)2
PdCl(COD)SnCl3 (C1)
PdCl(PPh3)2SnCl3 (C2)
PdCl2(COD)
N
Me
2d
2a
15
22
ꢀ0
ꢀ0
72
<10
ꢀ0
12
18
<5
<5
N
1b
Ph
Br
5
12
[(PPh3)AuCl]/AgOTf
[(PPh3)AuCl]/AgOTf
PdCl(COD)SnCl3 (C1)
PdCl(COD)SnCl3 (C1)
N
H
1b
2e
6
7
10
12
10
8
3g, 70
3h, 65
3i, 68
3j, 88
N
a
A mixture of 1a (0.5 mmol), 2a (0.25 mmol), and catalyst (2 mol %) in 2 mL of
2f
(CH2)7CH3
1b
1b
solvent was stirred at 90 °C for 2 h.
b
1H NMR yield using triphenyl methane as external standard.
5 mol % catalyst was used.
Carried out at 25 °C for 16 h with 1a:2a = 1:1 according to the Ref. 8.
Carried out according to the Ref. 10.
c
N
H
d
2g
2d
2a
e
8b
N
Me
the reactions were promising with simple styrene derivatives (FG-
Ar-CH@CH2). To our knowledge, an efficient methodology for the
regioselective hydroarylation of a-methyl substituted aryl alkenes
(FG-Ar-C(Me)@CH2) (well known for their propensity to dimerize/
polymerize in presence of LA)6 with indole derivatives is yet to
emerge.
1c
1d
9
N
Ph
10
11
2
4
3k, 90
3l, 65
N
Ph
In continuation of our success with bimetallic catalysis for car-
bon–carbon and carbon–heteroatom bond formation,13 we devel-
oped herein a heterobimetallic ‘Pd–Sn’ catalyst which promotes
2h
2i
1e
MeO
MeO
MeO
the intermolecular hydroarylation of a-methyl substituted aryl al-
N
kenes with indoles with high efficiency and regioselectivity. An
added bonus is the fact that the reactions proceed under moisture
and air insensitive conditions. The intermolecular hydroarylation is
also briefly extended to O- and S- heteroarenes.
The insertion reaction of SnCl2 across ‘Pd–Cl’ was used in the
presence of ligand to generate the corresponding ‘Pd–Cl’ motif
PdCl(COD)–SnCl3 C1 and PdCl(PPh3)2–SnCl3 C2.13g Initially, the per-
formance of different Brønsted acids, monometallic salts, and
bimetallic complexes (2 mol %) was tested for the model reaction
1e
1e
1e
12
4
3m, 85
3n, 83
3o, 76
3p, 80
3q, 60
N
Me
2d
2g
13
2
N
H
MeO
S
Br
of
a-methyl styrene 1a (0.5 mmol) and 1-benzyl-1H-indole 2a
14c
15c
16c
10
6
N
(0.25 mmol) in 1,2-dichloroethane (DCE) as solvent for 2 h at
90 °C. Gratifyingly, the heterobimetallic Pd(COD)Cl–SnCl3 (C1) cat-
alyst showed excellent catalytic efficiency and regioselectivity
leading to the Markovnikov product 3a (Table 1, entry 18). Notably,
it is not necessary to exclude air or moisture in this reaction. Indi-
vidually [Pd(COD)Cl2] was inactive while SnCl2 and the other bime-
tallic ‘Pd–Sn’ catalyst C2 showed poor reactivity. Catalytic amounts
of various Brønsted acids did not show product formation (entries
1 and 2). Even LAs such as ZnCl2, FeCl3, AlCl3, InCl3, and SnCl4 were
ineffective or poorly active (entries 6–10). Likewise, among the
metal triflates screened, only Cu(OTf)2 and Sc(OTf)3 led to the
H
1f
2e
N
N
S
S
2b
2i
1f
1f
10

D. Das et al. / Tetrahedron Letters 54 (2013) 335–338
337
spectra of 1a were examined in CDCl3 in the presence of catalyst
C1 at room temperature, marginal shift was obtained. The detailed
mechanistic description must await further studies.
Table 2 (continued)
Entry
Alkene
Indole
Time (h)
8
Yield of 3 (%)
3r, 72
An interesting observation was found with 2-(thiophen-2-yl)-
1H-indole (2k), in which instead of C-3 alkylation in the indole
ring, solely 5-alkylated thiophene 4a (Fig. 1) was obtained. This re-
sult suggested that besides indoles, other heteroarenes can also be
alkylated in the presence of C1. Therefore to enrich the scope of the
reaction further, we briefly tested different heteroarenes under a
similar reaction condition. The progress of the hydroarylation reac-
tion with O-, S-heteroarenes was satisfactory and the correspond-
ing alkylated O-, S-heteroarenes (4a–4e) were obtained in good
yields (Fig. 1). Notably the addition reaction was highly regioselec-
tive and in all cases only Markovnikov products were obtained.
In summary, the heterobimetallic ‘Pd–Sn’ complex C1 has been
found to be an effective catalyst for highly atom-economical and
regioselective intermolecular hydroarylation of electron-rich
17c
N
N
O
2a
2j
1g
1g
Ph
Ph
18c
19
10
12
3s, 61
O
Et
Nil
N
2a
1h
Br
a
Unless otherwise mentioned, reaction conditions were as follows:
1
(0.30 mmol), 2 (0.25 mmol), cat. C1 (2 mol %), solvent DCE (2 mL), 90 °C.
b
5 mol % cat. C1 was used.
10 equiv. of 1 was used.
c
a-methyl substituted aryl alkenes with indoles and other hetero-
arenes. Extensive catalyst screening clearly established the impor-
tance of the bimetallic core in the catalyst; mechanistic studies are
underway to understand the initial bond activation stages so that
the catalyst can be tuned further. One may also note that ease of
handling of the catalyst (insensitive toward air and moisture)
makes the reaction more attractive, simple, and practical.
desired product in <25% yield. Transition metal complexes like
Ru(PPh3)3Cl2 and PtCl2(MeCN)2 did not show catalytic activity.
Notably the activity of C1 was lost in toluene and acetonitrile as
solvents (entries 23 and 24). Finally, the model reaction has been
tested with reported TfOH (5 mol %)8 and AuCl3/AgOTf
(2 mol %),10 however in both cases 3a was obtained in poor yield
(entries 3, 4, 21 and 22).
Acknowledgment
Having established the optimum condition, we tested the scope
and limitation of the hydroarylation reaction using various
a-
Financial support from DST (to S.R.) and CSIR (to D.D. and S.P.) is
gratefully acknowledged. D.D. thanks Dr. Ujjal Kanti Roy and Mr.
Rupankar Paira for useful discussions and help.
methyl styrenes 1 and N-substituted (alkyl, benzyl, allyl, propargyl,
and phenyl) or ring substituted indoles 2 (Table 2). Gratifyingly, in
most cases the corresponding alkylated indoles 3 were obtained in
moderate to good yields using 1.2 equiv of 1a-1e (entries 1–13).
One may note that in all the cases where we have used free indole,
the reactions were completely C3-selective and no N-alkyl product
was formed. The C1 catalyzed hydroarylation reaction showed
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
11.038.
marked dependency on methyl substitution at the
styrene. The reaction of 2a with simple styrene, -ethyl styrene,
and -phenyl styrene failed to yield the desired alkylated indole
a-position of
a
a
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a
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4d,
2h, 84%
4c,
8h, 80%
4e,
6h, 78%
Figure 1. Hydroarylation with O, S-heteroarenes.

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