Palladium-catalyzed double C-H functionalization of 2-aryl-1,3-dicarbonyl compounds: A facile access to alkenylated benzopyrans

Article abstract of DOI:10.1016/j.tetlet.2016.04.089

The present study reports the development of a palladium-catalyzed oxidative annulation/nucleophilic substitution sequence affording a library of alkenylated benzopyrans using 2-aryl-1,3-dicarbonyl compounds and allylic acetate. The process is compatible

Full text of DOI:10.1016/j.tetlet.2016.04.089

Tetrahedron Letters 57 (2016) 2488–2491
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Palladium-catalyzed double C–H functionalization of 2-aryl-1,
3-dicarbonyl compounds: a facile access to alkenylated benzopyrans
Subrahmanyam Choppakatla a,b, Aravind Kumar Dachepally b, Hari Babu Bollikolla a,
⇑
a Department of Chemistry, Acharya Nagarjuna University, NNagar-522 510, Guntur, AP, India
b Arka Research Labs, Plot No. 16, CFC Area, IDA Nacharam, Hyderabad 500076, Telangana, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The present study reports the development of a palladium-catalyzed oxidative annulation/nucleophilic
substitution sequence affording a library of alkenylated benzopyrans using 2-aryl-1,3-dicarbonyl com-
pounds and allylic acetate. The process is compatible to a wide range of substrates with good functional
group tolerance producing the desired heterocycles in moderate to good yields.
Ó 2016 Elsevier Ltd. All rights reserved.
Received 18 March 2016
Revised 20 April 2016
Accepted 22 April 2016
Available online 23 April 2016
Keywords:
Catalysis
Palladium
Benzopyrans
Allylation
C–H activation
Annulation
(a) Lam et al. [Ref: 7]
Transition metal-catalyzed C–H functionalization of unreactive
bonds has gained eminence as a powerful and transformative tool
in synthetic chemistry,1 with additional applications to natural
product syntheses,2 drug discovery,3 and material sciences.4 The
most advantageous use of this strategy is the atom-economic con-
struction of C–C, C–N, and C–O bonds by functionalization of the
aromatic C(sp2)–H bonds, directed by a coordinating functional
group delivering a diverse variety of heterocyclic compounds.5
Recently, Lam and co-workers have developed catalytic oxidative
O
O
O
Ar
Ar
Ar
OH
OH
O
1
+
2
3
EWG
EWG
EWG
(b) White et al. [Ref: 12]
annulations of
a-aryl cyclic 1,3-dicarbonyl compounds (or their
O
O
S
Ph
enol tautomers) with various coupling partners including alkynes,6
terminal alkenes (Scheme 1a),7 1,3-dienes,8 and 1,3-enynes9 that
provide efficient access to carbo- and heterocycles. On the other
hand, allyl functionality is a versatile tool offering a range of oppor-
tunities for further functionalizations.10 Recently, several methods
have been developed for the direct allylation of aromatic C–H
bonds using transition-metal catalysts.11 In addition, allylic C–H
oxidation is an established and well-studied strategy used to con-
struct complex organic molecules (Scheme 1b).12 In this regard, Pd
(II)/bis-sulfoxide-catalyzed allylic C–H functionalizations of termi-
nal olefins have demonstrated broad applicability in synthetic
methodology.13
S
Ph
R
R
R
R
Pd(OAc)2
(10 mol%)
OH
O
Ar
Ar
Cr(salen)Cl (10 mol%)
BQ (2 equiv), DCE (0.3 M)
45 °C, 16 h
(c) This work
O
X
O
X
Pd(OAc)2 (5 mol%)
Cu(OAc)2 (4.2 equiv)
Ar
Ar
OH
O
DMF, 120 °C, 5 h
H
OAc
Scheme 1. Pd-catalyzed oxidative annulations and allylic C–H oxidation.
⇑
Corresponding author. Tel./fax: +91 863 234 6573.
E-mail address: dr.b.haribabu@gmail.com (H.B. Bollikolla).
http://dx.doi.org/10.1016/j.tetlet.2016.04.089
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.

S. Choppakatla et al. / Tetrahedron Letters 57 (2016) 2488–2491
2489
Table 1
Table 3
Optimization of reaction conditions for the synthesis of 3aa
Scope of Pd(II)-catalyzed synthesis of alkenylated benzopyransa
n
Me
O
Me
Me
n
O
O
N
O
N
O
Me
[M] (cat.)
Pd(OAc)2 (5 mol%)
Cu(OAc)2 (4.2 equiv)
Cu(OAc)2 (4.2 equiv)
Ar
Ar
solvent, temp, 5 h
DMF, 120 °C, 5 h
OH
O
OH
1a
1
OAc
2 (1.5 equiv)
OAc
3a
4a−e
2 (1.5 equiv)
Ph
Me
Bn
Entry
[M]
Mol (%)
Solvent
Temp (°C)
Yieldb (%)
O
N
O
N
O
N
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
—
5
5
10
5
5
2.5
2.5
—
5
DMF
DMF
DMF
t-AmOH
Dioxane
DMF
t-AmOH
DMF
90
120
120
120
120
120
120
120
120
120
40
59
62
20
35
<5
NR
NR
NR
37
O
O
O
MeO
4a 65%
4b 62%
4c 61%
9c
10d
Pd(OAc)2
Pd(OAc)2
DMF
DMF
5
a
b
c
Reactions were conducted using 0.50 mmol of 1a.
Isolated yield.
Reaction conducted without Cu(OAc)2.
Reaction conducted in the presence of K2CO3 (2.0 equiv). DMF = N,N0-
O
N
O
N
d
dimethylformamide, t-Am = tert-amyl.
O
O
Table 2
Pd(II)-catalyzed synthesis of alkenylated benzopyransa
4d 67%
4e 57%
R
R
a
O
O
Reactions were conducted with 0.50 mmol scale. Yields are of isolated material.
R
R
Pd(OAc)2 (5 mol%)
Cu(OAc)2 (4.2 equiv)
Ar
Ar
DMF, 120 °C, 5 h
O
O
OH
O
1
Pd(OAc)2 (5 mol%)
Cu(OAc)2 (4.2 equiv)
OAc
2 (1.5 equiv)
Me
DMF, 120 °C, 5 h
3a−i
OH
O
1d
Me
O
Me
6 (52%)
Ph
5 (1.5 equiv)
O
O
Me
Me
MeO
Me
Ph
Scheme 2. Oxidative annulation reaction of allylbenzene with 3-hydroxy-2-
phenyl-2-cyclohexenone.
O
O
O
Me
3a 59%
3b 65%
3c 45%
In the present work, we report the efficient construction of
alkenylated benzopyrans using a Pd(II)-catalyzed oxidative cou-
pling of 1,3-dicarbonyl compounds with allyl acetate. This process
involves C–H activation of a C(sp2)–H bond to generate an allylated
O
O
O
product which on nucleophilic substitution to a
affords the desired heterocycles (Scheme 1c).
p-allyl Pd-species
O
O
O
Me
MeO
MeO
We initiated our study by exploring the reaction of
2-phenyldimedone (1a) with allyl acetate 2 (1.5 equiv) in the pres-
ence of Pd(OAc)2 (5 mol %) in DMF using Cu(OAc)2 (4.2 equiv) as an
oxidant. Pleasingly, the alkenylated benzopyran product 3a was
obtained in 40% yield after reacting for 5 h at 90 °C (Table 1, entry
1). By elevating the reaction temperature to 120 °C, the yield of the
desired product was increased to 59% (entry 2). A comparable yield
of 3a was achieved using 10 mol % of Pd(OAc)2 in DMF (entry 3).
Other solvents such as t-AmOH and dioxane provided limited reac-
3d 55%
3e 62%
3f 65%
O
O
O
O
O
O
F3C
MeO2C
tion and gave inferior results (entries
4
and 5).
[RuCl2(p-cymene)]2 complex14 commonly employed in C–H func-
tionalizations was completely unproductive in different solvents
(entries 6 and 7). No product formation was observed in the
absence of the palladium catalyst or Cu(OAc)2 (entries 8 and 9).
3g 53%
3h 50%
3i 40%
a
Reactions were conducted with 0.50 mmol scale. Yields are of isolated material.

2490
S. Choppakatla et al. / Tetrahedron Letters 57 (2016) 2488–2491
O
Me
Me
2 CuOAc
2 Cu(OAc)2
Pd(OAc)2
Me
Me
1a
HO
O
2 AcOH
- Pd(0)
LnPd0
11
O
O
Me
Me
3
Me
Me
LnPdII
O
7
O
AcO-OAc
Me
OAc
O
2
Me
Me
OH
Me
O
LnPdII
Pd(OAc)2
O
12
10
O
PdIILn
O
H
Me
Me
8
AcOH
OAc
OH
LnPdII
AcO
9
OAc
Scheme 3. Proposed mechanism for benzopyran formation.
Lower yield (37%) of 3a was obtained with the addition of K2CO3
(entry 10).
insertion then provides a second metallacycle 8 which on protona-
tion by AcOH delivers species 9. b-OAc elimination of 9 releases
palladium (0) 11 and provides the allylated product 10. Palla-
dium-catalyzed oxidative nucleophilic substitution of 10 affords
With the optimized reaction conditions in hand (Table 1, entry
2), the scope of palladium-catalyzed oxidative annulation/nucle-
ophilic substitution reaction was then explored, for the synthesis
of alkenylated benzopyrans (3a–i). Several 1,3-dicarbonyl sub-
strates bearing a variety of functional groups (electron-donating
and electron-withdrawing) were well tolerated affording the ben-
zopyran products in 40–65% yields (Table 2). Initially, substrates
derived from dimedone (3a–c) were tested in the annulation reac-
tion. Apart from phenyl ring at 2-position of 1,3-dicarbonyl com-
pound, aryl ring incorporating functional groups at the para- (3b)
and meta-positions (3c) proceeded efficiently with moderate to
good yields. In case of 3c, the C–H functionalization occurred
exclusively at the sterically more accessible position, para- to the
substituent, which is consistent with the literature.6–8 Next, the
scope of the reaction was extended to substrates derived from
1,3-cyclohexanedione. As illustrated in Table 2 and 1,3-dicarbonyl
compounds incorporating both electron-rich (3e, 3f, and 3i) and
electron-deficient groups (3g and 3h) proceeded efficiently with
moderate to good yields. Again, in case of meta-substituted sub-
strate (3i), the annulated product was obtained through the forma-
tion of C–C bonds at the least sterically hindered position (see
Table 3).
an intermediate 12 with a
p-allyl palladium species which on
intramolecular nucleophilic substitution delivers the desired ben-
zopyran product 3. Meanwhile, Cu(OAc)2-promoted oxidation of
the Pd(0) species 11 regenerates the palladium acetate complex.
Conclusion
In summary, we have developed a palladium-catalyzed oxida-
tive annulation/nucleophilic substitution protocol for the synthesis
of a variety of alkenylated benzopyrans. This approach provides an
atom-economic pathway to access this class of valuable com-
pounds from a diverse range of 2-aryl-1,3-dicarbonyl compounds
and allylic acetate. Good functional group tolerance and broad sub-
strate scope are the advantages of this methodology.
Acknowledgments
The authors are highly thankful to Acharya Nagarjuna Univer-
sity for constant encouragement. Arka Research Labs is gratefully
acknowledged for providing financial help and infrastructure.
Next, the reaction scope was further extended by employing
1,3-dicarbonyl substrates containing various polycyclic ring sys-
tems (4a–e). The annulated products were obtained in 57–67%
yields. Several keto-amide substrates protected with different
groups led to the successful formation of benzopyran products.
Furthermore, the reaction of 3-hydroxy-2-phenyl-2-cyclo-
hexenone (1d) with allylbenzene (5) also afforded the annulated
benzopyran product (6) in 52% yield under the optimized reaction
conditions (Scheme 2).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2016.04.
089.
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