One-step synthesis of the benzocyclo[pentatoocta-]isoindole core

Full text of DOI:10.1002/anie.200901246

Communications
DOI: 10.1002/anie.200901246
Fused Polycycles
One-Step Synthesis of the Benzocyclo[penta- to octa-]isoindole Core**
Yimin Hu,* Chenli Yu, Dong Ren, Qiong Hu, Lidong Zhang, and Dong Cheng
Owing to the prevalence of heterocyclic compounds in
medicinal chemistry and natural products, the development
of new transition-metal-catalyzed reactions for the formation
of fused heterocycles continues to be an active area of
research.[1–3] The construction of such ring systems by means
stereocenters, and the construction of the tetracyclic frame-
work of the complex heterocyclic system, represent signifi-
cant synthetic challenges. In a typical procedure, a mixture of
N-allyl-N-(cyclohex-2-enyl)-4-methylbenzenesulfonamide
(1b), 4-bromobenzonitrile, tributylamine, Pd(OAc)2, and
PPh3 was heated in N,N-dimethylformamide (DMF) under
an argon atmosphere overnight. Standard workup procedures
afforded the coupled products with excellent regio- and
stereoselectivity for most dienes (Table 1). The temperature is
crucial for this reaction: No domino reaction occurred below
1308C; in contrast, higher reaction temperatures (> 1458C)
led to the decomposition of 3bb, as indicated by TLC. The use
of other phosphine compounds, such as PEt3, P(OEt)3, or 1,2-
bis(diphenylphosphanyl)ethane, led to very similar results to
those obtained with PPh3. Among the catalysts tested ([Pd-
(PPh3)4], [Pd(dba)2]/PPh3 (dba = dibenzylideneacetone),
PdCl2/PPh3, Pd(OAc)2/PPh3, [AuCl(PPh3)]/AgSbF6, [Rh-
of C H activation[4] and Heck coupling[5] is a complementary
À
approach to remarkably powerful domino reactions.[6]
À
Recently, Yu and co-workers reported a promising C H
activation route for the preparation of indolines and tetrahy-
droisoquinolines.[7] Fujii and co-workers developed a palla-
3
À
dium-catalyzed C(sp ) H activation for the direct prepara-
tion of indoline derivatives.[8] In a particularly straightforward
approach, Chang and co-workers reported the synthesis of
condensed pyrroloindoles through the intramolecular func-
[9]
À
tionalization of a pyrrole C H bond. These syntheses
exhibit good selectivity and high atom economy, and are
carried out under mild reaction conditions at low catalyst
loadings.[10,11]
(cod)2]+SbF6 (cod = 1,5-cyclooctadiene)), the combination
À
Herein, we report a novel domino cyclization method
involving carbopalladation and the subsequent regioselective
Pd(OAc)2/PPh3 was found to be the most effective. N,N-
Dimethylformamide proved to be a better solvent than N,N-
dimethylacetamide, toluene, or 1,4-dioxane for this reaction;
nBu3N was more effective than any inorganic bases tested.
Thus, the following standard reaction conditions were
selected for this study: The diene (1 equiv) was treated with
an aryl halide (1.1 equiv) in the presence of Pd(OAc)2
(2 mol%), Ph3P (4 mol%), and nBu3N (2 equiv) in DMF at
1408C.
À
functionalization of an unactivated C H bond for the
preparation the benzocyclo[penta- to octa-]isoindole core
(Scheme 1). The fused heterocyclic ring systems contain
A number of dienes and substituted aryl halides are
suitable for this palladium-catalyzed cross-coupling reaction
(Table 1). A range of dodecahydrobenzo[f]cycloocta[cd]-
isoindoles were isolated readily in good to excellent yields
when aryl halides with electron-withdrawing groups were
employed (Table 1; entries 4–13, 16, 17, and 19). The electron-
withdrawing group could be a methoxycarbonyl, keto,
sulfonyl, or cyano group. Electron-donating substituents
could be present on the benzene ring, and ortho- and meta-
substituted aryl halides were also suitable substrates (Table 1;
entries 10 and 18–20). When 1-bromonaphthalene was used in
the reaction with the cyclohexenyl sulfonamide 1b, the
desired isoindole with a fused cyclohexyl ring was obtained
in very good yield (Table 1; entry 3).
Differences in the diene substrates have much influence
on the domino reaction. The output of reactions of substrates
1a and 1c with aryl halides were much lower than that of the
corresponding reactions of 1b, 1d, 1 f, and 1g, probably
because of the high torsional strain of the cycloalkenyl group
(cyclopentenyl or cycloheptenyl). The yield of the desired
product was reduced when 4-iodobenzonitrile was employed
Scheme 1. Target benzocyclo[penta- to octa-]isoindole core structures.
tertiary stereocenters at the A–B and B–D ring junctures.
Control of the relative and absolute configurations of these
[*] Prof. Dr. Y. Hu, C. Yu, D. Ren, Q. Hu, L. Zhang, D. Cheng
Laboratory of Functional Molecular Solids, Ministry of Education
Anhui Key Laboratory of Functional Molecular-Based Materials
Institute of Organic Chemistry
School of Chemistry and Materials Science
Anhui Normal University, Wuhu, Anhui 241000 (China)
Fax: (+86)553-388-3517
E-mail: yiminhu@mail.ahnu.edu.cn
[**] Support of this research by grants from the National Science
Foundation of China (20872002, 20572001) and the Education
Department of Anhui Province (TD200707) is gratefully acknowl-
edged.
À
(Table 1, entry 14). Interestingly, it was found that the C Br
bond reacted selectively with the diene when bromine and
chlorine substituents were both present on the benzene ring
(Table 1; entry 20).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200901246.
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Table 1: Palladium-catalyzed one-pot reaction for the formation of fused heterocycles.[a]
Entry
1
1
ArX
Product (yield [%][b])
Entry
11
1
ArX
Product (yield [%][b])
3aa
(49)
3dc
(65)
1a
1d
3ab
3dd
(36)
(70)
2
1a
12
1d
3ba
3de
(80)
(75)
3
4
5
6
7
1b
1b
1b
1b
1b
13
14
15
16
17
1d
1e
1e
1 f
1 f
3bb
(85)
3ea
(52)
3bc
(67)
3eb
(56)
3bd
(60)
3 fa
(78)
3be
(63)
3 fb
(75)
3ca
3ga
(62)
(67)
8
9
1c
1d
1d
18
19
20
1g
1g
1g
3da
(64)
3gb
(71)
3db
(68)
3gc
(69)
10
[a] General conditions: 1a–g (1.0 equiv), ArX (1.1 equiv), Pd(OAc)2 (2 mol%), PPh3 (4 mol%), nBu3N (2 equiv), DMF (10 mL), 135–1408C. [b] Yield of
the isolated product after flash column chromatography. Bn=benzyl, Ts=p-toluenesulfonyl.
All new products were characterized fully by various
spectroscopic techniques and high-resolution mass spectrom-
etry. The molecular structures of 3ab (Figure 1), 3bb, 3bd,
3dd, 3de (Figure 2), and 3ea were confirmed by single-crystal
X-ray analysis (see the Supporting Information for details).[12]
Scheme 2 shows a plausible mechanism for the formation
of the coupled products. The coordination of an aryl
palladium(II) halide and insertion into the allyl moiety in 1
produces the intermediate A, which then reacts with the
remaining carbon–carbon double bond through carbopalla-
dation to afford B. s-Bond metathesis[13] onto the aryl group
in B, followed by proton abstraction by the base, then
generates 3.
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Communications
Scheme 2. Proposed mechanism of the reaction. PG=protecting
Figure 1. Molecular structure of 3ab.
group.
Experimental Section
Typical procedure: Sulfonamide 1b (1.0 equiv), 4-bromobenzonitrile
(1.1 equiv), Pd(OAc)2 (2 mol%), and PPh3 (4 mol%) were added to a
degassed solution of (nBu)3N (2 equiv) in DMF (10 mL), and the
mixture was stirred at room temperature for half an hour and then
heated at 1408C for 30 h. The reaction mixture was then cooled,
quenched with water, and extracted with ethyl acetate (30 mL). The
combined organic layers were washed with hydrochloric acid (5%),
sodium carbonate (5%), and saturated sodium chloride solution,
dried over MgSO4, and concentrated. The residue was purified by
flash column chromatography to give 3bb (85%).
Received: March 5, 2009
Published online: May 19, 2009
À
Keywords: C H activation · cycloalkenes · domino reactions ·
palladium · polycyclic compounds
.
Figure 2. Molecular structure of 3de.
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In summary, we have developed a palladium-catalyzed
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treatment of cycloalkene-containing dienes with a variety of
aryl halides in the presence of a palladium catalyst and an
À
amine base led to the formation of multiple C C bonds and
À
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