Synthesis of isochromenones and oxepines via Pd-catalyzed cascade cyclization of alkynes and benzynes involving C-H activation

Article abstract of DOI:10.1039/c2cc31807e

A new method for the synthesis of various isochromen-6-ones and phenanthro[1,10-bc]oxepines via a palladium-catalyzed cascade carbocyclization of 2-iodobenzyl-3-phenylpropiolates and 1-iodo-2-(2-(phenylethynyl)benzyloxy) benzenes with arynes is described. The reactions involve interesting biscarbocyclization of alkynes and benzynes and C-H bond activation.

Full text of DOI:10.1039/c2cc31807e

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COMMUNICATION
Synthesis of isochromenones and oxepines via Pd-catalyzed cascade
cyclization of alkynes and benzynes involving C–H activationw
Kanniyappan Parthasarathy, Han Han, Chandran Prakash and Chien-Hong Cheng*
Received 12th March 2012, Accepted 4th May 2012
DOI: 10.1039/c2cc31807e
A new method for the synthesis of various isochromen-6-ones
and phenanthro[1,10-bc]oxepines via a palladium-catalyzed
cascade carbocyclization of 2-iodobenzyl-3-phenylpropiolates
and 1-iodo-2-(2-(phenylethynyl)benzyloxy)benzenes with arynes
is described. The reactions involve interesting biscarbocyclization
of alkynes and benzynes and C–H bond activation.
involve C–H bond functionalization and form two,11 three,12
or four carbon–carbon bonds13 in a one-pot manner, but lead
only to monocyclized products. The carbocyclization reaction
involving a biscyclization process has been less explored.
Grigg et al. reported a palladium-catalyzed intramolecular
bis- or triscyclization of aryl or alkenyl halides bearing carbon–
carbon multiple bonds for the synthesis of highly fused hetero-
cyclic compounds.14 In 2005, Tanaka et al. reported a tandem
biscyclization of bromoenynes through intramolecular carbo-
palladation and functionalization of an aromatic C–H bond.15
We have been interested in C–H bond activation,16a–c,20d,e
carbocyclization16c–f and benzyne reaction.2f–h,k–m In this
communication, we wish to report a new palladium-catalyzed
reaction, which combines these three reactions in one pot, the
biscarbocyclization of 2-iodobenzyl-3-phenylpropiolates and
1-iodo-2-(2-(phenylethynyl)benzyloxy)benzenes with benzynes
to give isochromenone and oxepine derivatives, respectively.
It is noteworthy that the isochromenone and oxepine cores are
present in various natural products and biologically active
compounds.17
Aryne is one of the most interesting substrates in metal-catalyzed
reactions since it can be transformed into a wide range of
synthetically important intermediates in organic synthesis.1,2
In particular, palladium-catalyzed carbocyclization of arynes
has great potential for the synthesis of polycyclic compounds
from simple starting materials.3
The palladium-catalyzed carbocyclization of alkynes or
alkenes is a useful method for multiple carbon–carbon bond
formation reaction in organic synthesis. In 1982, Catellani and
Chiusoli reported carbocyclization of aryl iodides with two
norbornenes to give methanotriphenylene derivatives.4 Heck
et al. and Nomura et al. independently reported that the
cocyclotrimerization of aryl halide with two alkynes leads to
tetrasubstituted naphthalene derivatives.5a,b Apart from alkynes,
arynes are also interesting substrates in carbocyclization reaction.
In this context, the metal-catalyzed cyclotrimerization of arynes6a,b
and the cocyclizations of arynes with a variety of alkynes,6c,d
diynes,6e allyl derivatives,2h,i,6f,g allenes,6h and CO6i,j have been
extensively investigated. Larock et al. reported a partial inter-
molecular carbocyclization of 2-halobiaryl with arynes affording
triphenylene.7 Previously, we have reported a palladium-catalyzed
intermolecular carbocyclization of aromatic halide with two
benzynes leading to the formation of triphenylene8a and
aryliodides/bicyclic alkene/benzyne to give annulated 9,10-
dihydrophenanthrenes.8b In 2007, Larock and Liu reported
the synthesis of substituted phenanthrene derivatives via palladium-
catalyzed sequential intermolecular coupling of aryl halides,
alkynes, and arynes.9 Recently, Zhang et al. demonstrated a
palladium-catalyzed reaction of arynes and 1-(2-bromophenyl)-
1H-indoles, which allows an efficient synthesis of indolo[1,2-f]-
phenanthridine.10 All of the above carbocyclization reactions
Treatment of 2-iodobenzyl-3-phenylpropiolate 1a and ben-
zyne precursor 2a in the presence of Pd(dba)2 (5 mol%), CsF
(4 equiv.) and Tl(OAc) (1.2 equiv.) in a 1 : 1 mixture of
CH3CN and toluene at 85 1C for 8 h gave the expected
isochromenone product 3a in 76% isolated yield (Table 1,
1
entry 1). Product 3a was thoroughly characterized by H and
13C NMR and mass spectral analysis.
Under the same reaction conditions, various substituted
benzyne precursors 2b–d were tested for the reaction with 1a
affording the corresponding phenanthroisochromen-6-ones,
3b–d, in 56–82% yield, respectively (entries 2–4). The effect
of substituents on the benzylic group was also investigated.
Thus, alkyne 1b reacted well with 2a and 2b to give 3e and 3f in
79% and 87% yields, respectively (entries 5 and 6). It is
noteworthy that the structure of compound 3f was further
confirmed by single crystal X-ray diffraction. In a similar
manner, alkyne 1c also reacted with 2a and 2b to provide 3g
and 3h in 75% and 80% yields, respectively (entries 7 and 8).
The present palladium-catalyzed carbocyclization reaction
was also successfully extended to the synthesis of oxepine
derivatives. The results of these studies are listed in Table 2.
Thus, 1d reacted with benzyne precursor 2a to give phenanthro-
[1,10-bc]oxepine derivative 4a in 78% yield (Table 2, entry 1).
Under similar reaction conditions, treatment of alkyne 1d with
Department of Chemistry, National Tsing Hua University, Hsinchu,
30013, Taiwan. E-mail: chcheng@mx.nthu.edu.tw;
Fax: +886-3-5724698; Tel: +886-3-5721454
w Electronic supplementary information (ESI) available. See DOI:
10.1039/c2cc31807e
c
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Table 2 Results of the reaction of alkynes 1d–j with arynes 2a
Table 1 Results of the reaction of alkynes 1a–c with arynes 2a
Yieldb (%)
Product
Entry 1
2
1
2
1a 2a
1a 2b
3a: R = H
3b: R = Me
76
82
Yieldb (%)
Product
Entry 1
2
3
4
1a 2c
1a 2d
3c: X = O
3d: X = CH2
56
74
1
2
1d 2a
1d 2b
4a: R, R =H
4b: R, R = Me
78
86
5
6
7
8
1b 2a
1b 2b
1c 2a
1c 2b
3e: R = H, R1 = Me 79
3f: R = Me, R1 = Me 87
3g: R = H, R1 = Ph 75
3h: R = Me, R1 = Ph 80
a
Unless otherwise mentioned, all reactions were carried out using
alkyne 1 (1.0 mmol), benzyne precursors 2 (1.2 mmol), Pd(dba)2
3
4
1e 2a
1e 2b
4c: R, R = H
4d: R, R = Me
80
82
(5 mol%), CsF (4 equiv.) and 1.2 equiv. Tl(OAc) in CH3CN–toluene
b
(3.0 mL, 1 : 1 mixture) at 85 1C for 8 h. Isolated yields.
aryne precursors 2b having two methyl groups on the phenyl
ring afforded 4b in 86% yield (entry 2). Similarly 1e reacted
with arynes 2a and 2b to give 4c and 4d in 80 and 82% yield,
respectively (entries 3 and 4). It is noteworthy that the
structure of compound 4c was further confirmed by single
crystal X-ray diffraction. The reaction of 1f with 2b also
proceeded smoothly to give 4e in 75% yield (entry 5). In addition
to iodoalkynes, bromoalkyne 1g also reacted successfully with 2b
affording 4f in 77% yield (entry 6). In this reaction, additional
5 mol% of P(o-tolyl)3 was required to achieve a good yield of 4f.
Interestingly, alkyne 1h also reacted efficiently with 2b to provide
oxepine derivative 4g in 80% yield (entry 7).
4e: R, R, R1 = Me,
R3 = H
5
6
1f 2b
1g 2b
75
77c
4f: R, R, R3 = Me,
R1 = H
7
1h 2b
4g
4h
80
79
The present catalytic reaction was also successfully extended
to different aryne precursors 2c–d. As a result, electron-
donating substituent aryne 2c reacted with 1d and 1i to give
the corresponding oxepine derivatives 4h and 4i in 79 and 76%
yield, respectively (entries 8 and 9). Similarly, aryne 2d reacted
efficiently with 1i to give 4j in 85% yield (entry 10). Further, 1j
was treated with 2b under similar reaction conditions to afford
the expected azepine derivative 4k in 80% yield (entry 11).
On the basis of known palladium-catalyzed carbocycliza-
tion reactions,2–8 a mechanism is proposed to account for the
present catalytic reaction (Scheme 1). The first step involves
oxidative addition of 1a to the Pd(0) species to form aryl
palladium p-complex 5, followed by insertion of the Pd–C
bond into the triple bond in 5 to form vinylarylpalladium
species 6, in which the aryl group is Z2-bonded to the
palladium center. It is well-known that Z2-arene complexes
are intermediates in the C–H bond activation of arene systems.18
Cyclopalladation through intramolecular C–H bond activation
affords a five membered palladacycle 7. Further reaction of this
intermediate with benzyne and the subsequent cyclopalladation
8
9
1d 2c
1i 2b
4i: R = Me, R3 = Cl 76
10
1i 2d
85
80
4j
11
1j 2b
4k
a
Unless otherwise mentioned, all reactions were carried out using
alkyne 1 (1.0 mmol), benzyne precursors 2 (1.2 mmol), Pd(dba)2
(5 mol%), CsF (4 equiv.) and 1.2 equiv. Tl(OAc) in CH3CN–toluene
b
c
(3.0 mL, 1 : 1 mixture) at 85 1C for 8 h. Isolated yields. 5 mol% of
P-(o-tolyl)3 was added.
c
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Scheme 1
form a seven-membered palladacycle 8. A second cyclization
occurred via reductive elimination of 8 to give product 3a and
the Pd(0) catalyst.
The role of the TlOAc is unclear at this moment, but it may
be involved in removing the iodide from the palladium center.19
In addition, it would not oxidize Pd(0) generated during the
catalytic reaction. Although silver salts are also well known
halide scavengers, the use of silver(I) salts such as AgBF4,
AgNO3 or AgOAc to replace TlOAc did not lead to the
expected product. This is likely due to the ability of Ag+ to
oxidize Pd(0) to Pd(II)20 terminating the oxidative addition step
in the catalytic reaction (Scheme 1).20
In conclusion, we have developed a new palladium-catalyzed
carbocyclization reaction involving biscyclization of alkynes and
benzynes to afford isochromen-6-one and phenanthro[1,10-bc]-
oxepine derivatives in good to excellent yields. Further studies on
the mechanistic details as well as potential synthetic applications
of the present methodology are underway.
We thank the National Science Council of Republic of
China (NSC-99-2119-M-007-010) for support of this research.
Notes and references
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´
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6582 Chem. Commun., 2012, 48, 6580–6582
This journal is The Royal Society of Chemistry 2012