A palladium-catalyzed oxidative cycloaromatization of biaryls with alkynes using molecular oxygen as the oxidant

Article abstract of DOI:10.1002/anie.200903975

Dual activation of C-H bonds has enabled the preparation of polycyclic aromatics from arylindoles and arylbenzofurans in the absence of a directing group, and with using O₂ as the oxidant (see scheme). Synthetically and medicinally important polycyclic aromatics have been easily prepared, and some of the resulting polycyclic heteroaromatics exhibit intense fluorescence.

Full text of DOI:10.1002/anie.200903975

Angewandte
Chemie
DOI: 10.1002/anie.200903975
Cycloaromatization
A Palladium-Catalyzed Oxidative Cycloaromatization of Biaryls with
Alkynes Using Molecular Oxygen as the Oxidant**
Zhuangzhi Shi, Shengtao Ding, Yuxin Cui, and Ning Jiao*
Polycyclic aromatic hydrocarbons (PAHs) have attracted
considerable attention not only because of their remarkable
biological and pharmacological activity,[1] but also because of
their electrochemical and photochemical properties.[2]
Numerous synthetic methodologies for the construction of
these polycyclic aromatic systems have been developed in the
past decades,[3] among which, the palladium-catalyzed annu-
lation of alkynes by functionally substituted aromatics has
been particularly effective for the synthesis of a wide variety
of carbocycles and heterocycles.[4] Recently, the functionali-
Scheme 1. a) Direct cross-coupling between two arenes. b) Cycloaro-
À
zation of C H bonds using directing groups has presented an
À
matization reaction through the activation of C H bonds between
attractive and powerful strategy for the generation of
heteroaromatic compounds, such as indoles, isoquinolines,
carbazoles, benzothiazoles, and pyridines.[5] However, the
biaryls and alkynes.
cycloaromatization of alkynes with arenes through activation
alkyne to achieve the cycloaromatization, thus leading to
fluorescent polycyclic aromatic compounds (Scheme 1b).
With this hypothesis in mind, we initially focused on
diphenylacetylene (2a) with 1-methyl-2-phenyl-1H-indole
[6]
À
of a C H bond to form benzene rings still poses a challenge.
A major advance in this area has been the polycyclic aromatic
synthesis described by Miura et al.[6a] This progress was
achieved through rhodium-catalyzed annulation of phenyl-
À
(1a), which would induce cleavage of the C H bond at C3
À
azoles with internal alkynes through dual cleavage of C H
by a Friedel–Crafts-type process utilizing electrophilic metal
catalysts.[7,10] Gratifyingly, the desired 11-methyl-5,6-
diphenyl-11H benzo[a]carbazole (3aa) was formed in 45%
yield by using Pd(OAc)2 as the catalyst and O2 (1 atm) as the
oxidant in DMF (Table 1, entry 1). Other oxidants such as
Cu(OAc)2, Ag2CO3, PhI(OAc)2, or BQ gave low yield (see the
Supporting Information). After extensive screening of differ-
ent parameters (Table 1 and the Supporting Information), the
optimum reaction conditions were determined: Pd(OAc)2
(10 mol%), K2CO3 (0.3 equiv), TBAB (0.5 equiv), PivOH
(1.0 equiv), DMF, O2 (1 atm), 1008C, 12 h, under which, the
highest yield (84%) was achieved (Table 1, entry 3). Signifi-
bonds directed by an ortho-azole group using Cu(OAc)2 as
the oxidant. However, the requirement of a directing group
and a copper oxidant may limit its applications. Herein, we
describe the first palladium-catalyzed cycloaromatization of
À
biaryls with alkynes through dual activation of C H bonds
using O2 as the oxidant (Scheme 1).
In 2007, Stuart and Fagnou reported a significant cross-
coupling reaction of unactivated arenes that was catalyzed by
PdII in the presence of Cu(OAc)2 as the oxidant
(Scheme 1a).[7] Very recently, our research group has devel-
oped a palladium-catalyzed synthesis of indoles[8] using O2 as
the oxidant.[9] We envisioned that C H activation of biaryls
À
may occur through a relay-type action involving an internal
Table 1: Palladium-catalyzed cycloaromatization of 1a with alkyne 2a.[a]
[*] Z. Shi, S. Ding, Dr. Y. Cui, Dr. N. Jiao
State Key Laboratory of Natural and Biomimetic Drugs
School of Pharmaceutical Sciences, Peking University
Xue Yuan Road 38, Beijing 100191 (China)
Fax: (+86)10-8280-5297
E-mail: jiaoning@bjmu.edu.cn
Entry Oxidant
(1 atm)
PivOH
(equiv)
TBAB
(equiv)
K2CO3
(equiv)
Yield of
Dr. N. Jiao
3aa [%][b]
State Key Laboratory of Organometallic Chemistry, Chinese Acad-
emy of Sciences
Shanghai 200032 (China)
1
2
3
4
O2
O2
O2
air
1.0
–
1.0
1.0
–
0.3
0.3
0.3
0.3
45
35
84
54
0.5
0.5
0.5
[**] Financial support from Peking University, the National Science
Foundation of China (grant nos. 20702002, 20872003), and the
National Basic Research Program of China (973 Program; grant
no. 2009CB825300) is greatly appreciated. We thank Meng Su for
reproducing the results of 3ma and 3oa in Scheme 2.
[a] Standard reaction conditions: 1a (0.20 mmol), 2a (0.30 mmol),
Pd(OAc)2 (0.02 mmol), K2CO3 (0.06 mmol), TBAB (0.10 mmol), PivOH
(0.20 mmol), DMF (2 mL), 1008C, O2 (1 atm), 12 h. [b] Yield of isolated
product. DMF=N,N-dimethylformamide, Piv=pivaloyl, TBAB=tetra-n-
butylammoniumbromide.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200903975.
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7895

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cantly, a 54% yield was achieved even when using air as the
natural products incorporating the indolo[2,3-a]carbazole
skeletons. These results indicated that most diarylacetylenes
with electron-withdrawing and electron-donating groups
proceeded efficiently (60–90%; Table 2, entries 1–6). Mark-
edly, dialkynes also underwent the reaction despite of their
bulkiness (Table 2, entries 6 and 8). Moreover, alkyl-substi-
tuted alkynes such as 1-phenyl-1-hexyne (2g) and oct-4-yne
(2i) were converted into 3qg and 3qi in moderate yields,
respectively (Table 2, entries 7 and 9).
oxidant instead of O2 (compare Table 1, entries 3 and 4).
Under these optimized reaction conditions, protecting
groups such as Bn and MOM were well tolerated to give 3ca
and 3da, respectively (Scheme 2). Notably, both electron-
Table 2: Palladium-catalyzed cycloaromatization of 1q with alkynes 2.[a]
Entry
Alkyne
Product, yield of 3 [%][b]
1
2
3
4
5
6
2a, E1 =E2 =H
3qa, 87
3qb, 63
3qc, 68
3qd, 79
3qe, 90
3qf, 60
2b, E1 =E2 =OMe
2c, E1 =E2 =CF3
2d, E1 =E2 =Cl
2e, E1 =H; E2 =NO2
1
2
À ꢀ
2 f, E =H; E =Ph C C
7
8
2g, E3 =nBu
À ꢀ
2h, E =Ph C C
3qg, 61
3qh, 65
3
Scheme 2. Palladium-catalyzed cycloaromatization of 1 with alkyne 2a.
Standard reaction conditions: 1 (0.20 mmol), 2a (0.30 mmol), Pd-
(OAc)2 (0.02 mmol), K2CO3 (0.06 mmol), TBAB (0.10 mmol), PivOH
(0.20 mmol), DMF (2 mL), 1008C, O2 (1 atm), 12 h. Yields are of
ioslated products. [a] 2-OMe/4-OMe=56:44, the ratio of the
regioisomers was determined by 1H NMR spectroscopy. Bn=benzyl,
MOM=methoxymethyl.
9
2i
3qi, 73
[a] Standard reaction conditions: 1q (0.20 mmol),
2 (0.30 mmol),
Pd(OAc)2 (0.02 mmol), K2CO3 (0.06 mmol), TBAB (0.10 mmol), PivOH
(0.20 mmol), DMF (2 mL), 1008C, O2 (1 atm), 12 h. [b] Yield of isolated
product.
donating (para-, meta-, and ortho-substituted) and electron-
withdrawing substrates could be smoothly transformed into
the desired products in good yields (3ea–3ja, 64–86%).
Furthermore, the larger aromatic biaryl substrates (Ar2 =
naphthalen-1-yl, benzofuran-3-yl, 1-methyl-1H-indol-3-yl)
proceeded in excellent yields (3ka–3ma, 87–92%), which
indicated that the steric and electronic effect of biaryls did not
significantly affect the reactivity. Notably, 3-arylindole could
A plausible mechanism for the reaction of 1 with alkyne 2
is illustrated in Scheme 3. The initiated electrophilic aromatic
palladation[7,10] affords a PdII intermediate A, and appears to
be the key process for the cycloaromatization. The resulting
intermediate A subsequently inserts into alkyne 2 to produce
a vinylic palladium(II) intermediate B, which is suitable for
acid-promoted electrophilic aromatic palladation and subse-
quent proton abstraction[11] to afford a seven-membered
palladacycle C.[12,13c] Subsequent reductive elimination gen-
erates the cyclic product as well as a Pd0 complex that can be
reoxidized to the PdII species by O2 (1 atm; Scheme 3).
With the 3aa–3pa and 3qa–3qi in hand, a preliminary
survey of their optical properties was carried out.[13] The
photophysical properties of 3aa and 3qa (as the representa-
À
also induce cleavage of the C H bond at C2 (3na, 71%).
Intriguingly, the strategy was also applicable to the annulation
of other biaryl compounds, such as 3-phenylbenzofuran and 2,
2’-bibenzofuran to give 3oa and 3pa, respectively.
To investigate the scope of the internal alkyne, 2,2’-bis(N-
methylindolyl) was chosen as the substrate in view of the
interesting biological properties displayed by numerous
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depth understanding of the mechanism and the synthetic
applications of this reaction are ongoing in our laboratory.
Experimental Section
Synthesis of 11-Methyl-5,6-diphenyl-11H-benzo[a]carbazole (3aa):
Pd(OAc)2 (9.0 mg, 10 mol%), K2CO3 (16.6 mg, 30 mol%), TBAB
(64.5 mg, 0.5 equiv), PivOH (41.0 mg, 1.0 equiv), 1a (82.8 mg,
0.40 mmol), 2a (106.8 mg, 0.30 mmol) were added to a 20 mL Schlenk
tube. The tube was purged with O2 three times before DMF (3.0 mL)
was added. The reaction mixture was stirred at 1008C under O2
(1 atm) for 12 h and was monitored by TLC. The solution was then
cooled to RT, diluted with ethyl acetate (40 mL), washed with H2O
(3 ꢀ 10 mL), dried over MgSO4, filtered, and dried under vaccum. The
crude product was purified by column chromatography on silica gel
(eluent: petroleum ether/ethyl acetate = 50:1) to afford 3aa
max
Scheme 3. Plausible mechanism for the reaction of 1 with 2.
tive examples) are outlined in Figure 1 and Table 3 (for the
photophysical properties of the other products 3, see the
Supporting Information). The absorption bands of these
~
(128.5 mg, 84%). IR: (KBr) n = 1442, 1372, 1330, 1023, 740,
1
702 cmÀ1; H NMR (400 MHz, CDCl3): d = 8.84 (d, J = 8.0 Hz, 1H),
7.71 (d, J = 8.4 Hz, 1H), 7.61 (td, J = 7.6, 1.2 Hz, 1H), 7.55 (d, J =
8.4 Hz, 1H), 7.46–7.38 (m, 2H), 7.33–7.18 (m, 10H), 6.93 (t, J =
7.4 Hz, 1H), 6.66 (d, J = 8.0 Hz, 1H), 4.50 ppm (s, 3H); 13C NMR
(100 MHz, CDCl3): d = 141.2, 140.3, 139.6, 135.2, 134.9, 132.8, 131.8,
131.0, 130.2, 128.4, 127.9, 127.5, 126.7, 126.2, 124.8, 124.7, 124.4, 123.2,
122.1, 122.0, 121.9, 119.3, 117.8, 108.7, 34.4 ppm; MS (70 eV): 383.2
(100) [M]+; HRMS (ESI) calcd for C29H22N ([M+H]+): 384.1747;
found: 384.1734.
Received: July 20, 2009
Published online: September 8, 2009
Figure 1. Absorption spectra (c) and luminescence spectra (c)
of 3aa, 3qa, and p-terphenyl in CH2Cl2.
À
Keywords: alkynes · biaryls · C H activation · oxidation ·
palladium
.
Table 3: Optical properties of 3aa and 3qa.[a]
Compounds
labs [nm] (loge)
lem [nm]
Ff[b]
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0.57
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as 2- and 3-arylbenzofurans) with internal alkynes through
À
dual activation of C H bonds. Molecular oxygen (1 atm) was
used as the oxidant in this catalytic cycle. The reaction
outcomes not only provide a new strategy for constructing
aromatic compounds from biaryls and internal alkynes, but
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