Rapid construction of five contiguous stereocenters in a multi-cascade reaction

Article abstract of DOI:10.1039/b900770a

The first example of a palladium-catalyzed multi-cascade reaction by simple cycloenes with aryl halides in a single operation to furnish five-contiguous-stereocenter hydronaphthoindolones is described. The Royal Society of Chemistry 2009.

Full text of DOI:10.1039/b900770a

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Rapid construction of five contiguous stereocenters in a multi-cascade
reactionw
Yimin Hu,* Ying Ouyang, Yuan Qu, Qiong Hu and Hao Yao
Received (in College Park, MD, USA) 14th January 2009, Accepted 12th June 2009
First published as an Advance Article on the web 6th July 2009
DOI: 10.1039/b900770a
The first example of a palladium-catalyzed multi-cascade
reaction by simple cycloenes with aryl halides in a single
operation to furnish five-contiguous-stereocenter hydro-
naphthoindolones is described.
conditions using N-benzyl-N-(cyclohex-2-enyl)cinnamamide
(a) and ethyl 4-bromobenzoate as a test experiment was
performed (Table 1).
In the test experiment, reaction of a with ethyl 4-bromo-
benzoate in N,N-dimethylformamide (DMF) in the presence of
a catalytic amount of Pd(OAc)2 produced the ethyl 4-benzyl-
5-oxo-6-phenyl-1,2,3,3a,3a1,4,5,5a,6,10b-decahydronaphtho-
[3,2,1-cd]indole-9-carboxylate aa in 84% yield at 150 1C for 18 h.
Altering the experimental conditions indicated that the output
of the multi-cascade reaction producing the product aa was
greatly affected by the reaction temperature (Table 1, entries 1–4),
the additive base (Table 1, entries 5, 10, 11), the catalytic
system (Table 1, entries 1–3, 11, 12), and the solvent (Table 1,
entries 1–3). Thus, the following standard reaction conditions
were selected for carrying out the following studies: dienes
(1 equiv.) reacted with different aryl halides (1.2 equiv.) in the
presence of 2 mol% of palladium(II) catalyst and 4 mol% of
Ph3P with nBu3N (2 equiv.) as an additive in DMF at 150 1C.
In order to probe the scope and limitations of this novel
fused cyclization reaction, a range of substituted aryl halides
and substrates were examined. It was found that the outputs of
the reactions worked well with a variety of dienes (1 equiv.)
(a–d, f) and different aryl halides (1.2 equiv). As shown in
Table 2, this novel catalytic multi-cascade process can be
applied to the construction of functionalized fused hetero-
cycles in a single operation via the Heck reaction and inter- or
intramolecular C–H bond activation.
Discovery of efficient methods to construct complex molecules
with multiple stereogenic centers in excellent regio-, diastereo-
and enantioselectivity continue to be an important goal for
both academic and industrial researchers.1 Multi-cascade
reactions which allow the formation of many C–C bonds
and stereogenic centers in a one-pot manner are useful for
the synthesis of natural products and synthetic building
blocks.2 These processes are usually clean as they generate
less waste by minimizing isolation of intermediates in the
multistep synthesis of complex molecular targets.3 Therefore,
the design of new catalytic and stereoselective cascade reactions
is a continuing challenge at the forefront of synthetic
chemistry.4 Recently, Takahashi5 developed Pd-mediated
spirocyclization leading to a formal synthesis of dimethyl
gloiosiphone and Mulzer6 employed the Vollhardt cyclization
in an enantioselective synthesis of pasteurestin A. In a
particularly straightforward approach, Enquist and co-workers
have reported the total synthesis of the cyathin diterpenoid
(ꢀ)-cyanthiwigin F by means of double catalytic enantio-
selective alkylation.7 These molecules have interesting bio-
logical and pharmaceutical properties, and thus much effort
has been made towards their synthesis.8,9 As a result of our
interest in the development of palladium-catalyzed processes
and directly obtaining physiologically active substances in a
single operation,10 we report herein the palladium-catalyzed
reactions of N-benzyl-N-(cyclohex-2-enyl)cinnamamide (a),
N-benzyl-3-(4-chlorophenyl)-N-cyclohexenylacrylamide (b),
N-benzyl-N-(cyclohex-2-enyl)-3-(4-methoxyphenyl)acrylamide
(c), N-cyclohexenyl-N-phenylcinnamamide (d), N-benzyl-N-
(cyclopent-2-enyl)cinnamamide (e) and N-benzyl-N-(cyclooct-
2-enyl)cinnamamide (f) (Scheme 1) with different aryl halides,
which provide a direct, efficient and economic methodology
for the construction of more stereocentres, non-racemic
carbocycles and heterocycles through both C–C bond
coupling and C–H bond activation. A survey of the reaction
A variety of hydronaphthoindolones were readily isolated in
good to excellent yields (Table 2, entries 1–14, 17–20) when
aryl halides with electron-withdrawing groups (ethoxy-
carbonyl, ketyl, chloro, sulfonyl and cyano) were employed.
However, the corresponding fused heterocyclic compounds
could not be isolated if the aryl halides had electron-donating
substituents on the benzene ring, and a considerable amount
of intramolecular fused products (for example, Fig. 1, h) were
obtained when 4-bromotoluene, 2-bromotoluene or 1-bromo-
4-methoxybenzene were used, indicating the electronic effects
Laboratory of Functional Molecular Solids, Ministry of Education,
Anhui Key Laboratory of Molecular-Based Materials, School of
Chemistry and Materials Science, Anhui Normal University, Wuhu,
Anhui 241000, China. E-mail: yiminhu@mail.ahnu.edu.cn;
Fax: +86 553 388 3517; Tel: +86 553 386 9310
w Electronic supplementary information (ESI) available: Experimental
procedures and characterization of all new compounds. CCDC
715801–715805. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/b900770a
Scheme 1
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Table 1 Palladium-catalyzed one-pot cascade reaction
Yield (%)
Entry
Pd (mol%)
Base (equiv.)
Solvent
t/h
T/1C
aa
g
1
2
3
4
5
6
7
8
[PdCl2]/PPh3 (1 : 2)
[PdCl2]/PPh3 (1 : 2)
[PdCl2]/PPh3 (2 : 4)
[Pd(OAc)2]/PPh3 (2 : 4)
[Pd(OAc)2]/PPh3 (2 : 4)
[Pd(OAc)2]/PPh3 (2 : 4)
[Pd(OAc)2]/PPh3 (2 : 4)
[Pd(OAc)2]/PPh3 (2 : 4)
[Pd(OAc)2]/PPh3 (2 : 4)
[Pd(OAc)2]/PPh3 (2 : 4)
Pd(PPh3)4 (2)
nBu3N (2)
nBu3N (2)
nBu3N (2)
nBu3N (2)
K2CO3 (2)
nBu3N (2)
nBu3N (2)
nBu3N (2)
nBu3N (2)
Cs2CO3 (2)
Cs2CO3 (2)
nBu3N (2)
DMSO
DMSO
DMSO
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
8
8
90
130
150
150
150
140
150
155
150
150
150
150
—
15
34
52
20
76
84
72
80
29
18
15
10
30
25
8
33
15
13
24
15
8
12
12
18
18
18
18
24
18
18
24
9
10
11
12
—
6
[Pd(dba)3] (2)
Table
2
The Pd-catalyzed reaction for the formation of five
stereocentersa
Entry Substrate R3C6H4X
Product Yieldb (%)
Fig. 1 Molecular structure of h. Ellipsoids are drawn at 30%
probability. Selected bond lengths (A) and angles (1) C8–C9
1.523(5), C9–C10 1.510(5), C9–C15 1.513(5), C15–C16 1.521(5);
C8–C9–C10 102.2(3), C8–C9–C15 117.6(3).
1
2
3
4
5
6
7
8
a
a
a
a
a
a
a
b
b
b
b
c
c
d
e
e
f
p-CH3CH2OOCC6H4Br aa
84
70
78
86
77
66
44
57
45
75
76
64
73
51
—
—
82
88
74
78
p-CH3OOCC6H4Br
p-CH3OCC6H4Br
p-NCC6H4Br
p-ClC6H4Br
m-ClC6H4Br
C6H5I
p-CH3OOCC6H4Br
p-CH3O2SC6H4Br
p-ClC6H4Br
m-ClC6H4Br
p-NCC6H4Br
p-CH3OOCC6H4Br
p-CH3O2SC6H4Br
p-CH3O2SC6H4Br
p-CH3OOCC6H4Br
p-CH3OCC6H4Br
p-CH3O2SC6H4Br
p-CH3OOCC6H4Br
p-NCC6H4Br
ab
ac
ad
ae
af
ag
ba
bb
bc
bd
ca
cb
da
ea
eb
fa
of the aryl halides on the reactions. The outputs of the
intermolecular fused compounds was reduced when iodobenzene
was employed (Table 2, entry 7). N-Benzyl-N-(cyclopent-2-
enyl)cinnamamide (e) failed to undergo efficient C–H bond
activation (Table 2, entries 15, 16).
9
10
11
12
13
14
15
16
17
18
19
20
All the resulting five-stereocenter-tetracyclic compounds
were confirmed by one- (1H, 13C), two-dimensional (COSY)
NMR spectral analyses, and elemental or HRMS analyses.
Many of the representative compounds, including fa (Fig. 2),
were additionally characterized by X-ray crystallographic
analyses.z Further details are provided in ESI.w
c
c
f
f
f
fb
fc
fd
a
General conditions: a–f (1.0 equiv.), ArX (X = Br; I) (1.1 equiv.),
Pd(OAc)2 (2 mol%), PPh3 (4 mol%), nBu3N (2 equiv.), DMF 10 mL,
Scheme 2 shows a plausible mechanism for the formation of
the multi-coupled products. Coordination and insertion of
arylpalladium(II) halide into a double bond of cinnamamide
gives the intermediate 1 (‘‘Heck-type’’ products), which then
b
c
150 1C. Isolated yield after flash column chromatography. Other
products formed in reaction.
ꢁc
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Notes and references
z Crystal structure determinations:
a = 10.474(1), b = 11.326(2), c = 12.112(1) A, U = 1239.0(3) A3,
T = 291 K, Z = 2, 4799 reflections measured, 3754 unique
(Rint = 0.051) which were used in all calculations. The final wR(F2)
ꢀ
C31H31NO3 aa,
M
=
465.57, triclinic, space group P1,
was 0.1139 (all data). CCDC 715801.
ꢀ
C28H25Cl2NO bc,
M
=
462.39, triclinic, space group P1,
a = 11.033(1), b = 11.057(2), c = 11.412(2) A, U = 1134.4(3) A3,
T = 291 K, Z = 2, 4126 reflections measured, 3146 unique
(Rint = 0.058) which were used in all calculations. The final wR(F2)
was 0.1206 (all data). CCDC 715802.
C28H26ClNO ae, M = 427.95, monoclinic, space group P21/c,
a = 11.383(2), b = 9.309(2), c = 21.432(4) A, U = 2233.6(8) A3,
T = 291 K, Z = 4, 4060 reflections measured, 2951 unique
(Rint = 0.056) which were used in all calculations. The final wR(F2)
was 0.1129 (all data). CCDC 715803.
ꢀ
C32H33NO2 fa,
M
=
463.59, triclinic, space group P1,
a = 10.331(2), b = 11.398(2), c = 11.513(1) A, U = 1246.9(3) A3,
T = 291 K, Z = 2, 4527 reflections measured, 3380 unique
(Rint = 0.049) which were used in all calculations. The final wR(F2)
was 0.1021 (all data). CCDC 715804.
Fig. 2 Molecular structure of fa. Ellipsoids are drawn at 30%
probability. Selected bond lengths (A) and angles (1) C9–C11
1.566(5), C11–C12 1.560(5), C12–C13 1.543(5), C7–C13 1.516(5),
C9–C11–C12 111.9(3), C7–C13–C12 109.3(3).
C22H22ClNO h, M = 351.86, monoclinic, space group P21/n,
a = 9.402(1), b = 20.083(3), c = 10.376(2) A, U = 1787.6(5) A3,
T = 291 K, Z = 4, 3520 reflections measured, 2233 unique
(Rint = 0.059) which were used in all calculations. The final wR(F2)
was 0.1254 (all data). CCDC 715805.
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Scheme 2
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In summary, we have developed an efficient method for the
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Pd(OAc)2 catalytic system in good yields under mild conditions.
The methodology that we have described converts the simplest
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stereogenic centres—with very high enantioselectivity. The
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The authors thank the National Science Foundation of
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ꢁc
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Chem. Commun., 2009, 4575–4577 | 4577