Catalytic asymmetric synthesis of [2,3]-fused indoline heterocycles through inverse-electron-demand aza-Diels-Alder reaction of indoles with azoalkenes

Article abstract of DOI:10.1002/anie.201400109

An unprecedented catalytic asymmetric inverse-electron-demand aza-Diels-Alder reaction of indoles with in situ formed azoalkenes is reported. A diverse set of [2,3]-fused indoline heterocycles were achieved in generally good yields (up to 97 %) with high regioselectivity and diastereoselectivity (>20:1 d.r.), and with excellent enantioselectivity (up to 99 % ee). In(verse) demand: The unprecedented catalytic asymmetric inverse-electron-demand aza-Diels-Alder reaction of indoles with in situ formed azoalkenes is reported. A diverse set of [2,3]-fused indoline heterocycles were produced in generally good yields with high regioselectivity and diastereoselectivity, and with excellent enantioselectivity.

Full text of DOI:10.1002/anie.201400109

Angewandte
Chemie
DOI: 10.1002/anie.201400109
Asymmetric Catalysis
Catalytic Asymmetric Synthesis of [2,3]-Fused Indoline Heterocycles
through Inverse-Electron-Demand Aza-Diels–Alder Reaction of
Indoles with Azoalkenes**
Min-Chao Tong, Xuan Chen, Jun Li, Rong Huang, Haiyan Tao, and Chun-Jiang Wang*
Abstract: An unprecedented catalytic asymmetric inverse-
electron-demand aza-Diels–Alder reaction of indoles with
in situ formed azoalkenes is reported. A diverse set of [2,3]-
fused indoline heterocycles were achieved in generally good
yields (up to 97%) with high regioselectivity and diastereose-
lectivity (> 20:1 d.r.), and with excellent enantioselectivity (up
to 99% ee).
catalyzed asymmetric C2,C3-annulation of indoles. Most
recently, Tang and co-workers[10] reported a CuII/Box-cata-
lyzed asymmetric C2,C3-cyclopentannulation of indoles with
cyclopropanes.
Azoalkenes (1,2-diaza-1,3-dienes),[11] which are readily
generated in situ from a-halogeno hydrazone, have been
commonly employed as key intermediates for the synthesis of
various five- or six-membered achiral nitrogen-containing
heterocycles.[12] Very surprisingly, azoalkenes have seldom
been employed as synthons in catalytic asymmetric cyclo-
addition reactions. To date, only one example has been
documented,[13] in which Bolm and co-workers pioneered the
catalytic asymmetric formal [4+1]-cycloaddition of azoal-
kenes with sulfur ylides to access five-membered dihydropyr-
azole derivatives. Distinct from their finds, we envisioned that
azoalkenes could be utilized as electron-deficient hetero-
dienes in the inverse-electron-demand aza-Diels–Alder reac-
tion (IEDDA)[14] with indoles through C2,C3-annulation for
the direct construction of biologically attractive and enantio-
pure [2,3]-fused indoline heterocycles. Herein, we report an
unprecedented CuI-catalyzed asymmetric C2,C3-annulation
of simple indoles with in situ formed azoalkenes to afford
highly functionalized [2,3]-fused indolines bearing contiguous
quaternary and tertiary stereogenic centers with excellent
diastereoselectivity and enantioselectivity (Scheme 1).
Another key feature of this annulation process is that
a tetrahydropyridazine moiety was constructed simultane-
ously, which also constitutes the core structure of numerous
pharmaceuticals.[15]
F
used indoline heterocycles are widely found as core
components in a large number of biologically active alkaloids,
natural products, and pharmaceuticals.[1] As such, much
attention and synthetic effort has been paid to developing
efficient and straightforward methods to construct those
molecules based on the cascade annulation of indoles.[2]
Recently, catalytic asymmetric C2,C3-annulation of indoles,[3]
which involves both the nucleophilicity on C3 (enamine-type
reactivity) and electrophilicity on C2 (iminium-ion-type
reactivity), has become one of the most powerful and
diversity-oriented syntheses[4] for constructing enantiomeri-
cally enriched [2,3]-fused indoline derivatives. Most of the
successful examples were intramolecular annulations employ-
ing indoles tethered with a built-in nucleophilic group (such as
tryptamine or tryptanol derivatives) to trap the in situ formed
iminium-ion intermediate.[3] Although the intermolecular
C2,C3-annulation of simple and readily-available substituted
indoles with potential reaction partners is highly desirable
and allows for facile access to complex and diverse chiral
fused-indoline heterocycles, only limited examples have been
reported. In 2009, Barluenga et al. reported the first asym-
metric C2,C3-annulation of indoles with tungsten Fisher
carbenes bearing a chiral auxiliary group.[5] Later on, efficient
transition-metal-catalyzed asymmetric C2,C3-annulation of
simple indoles with vinyldiazoacetates and 2-amidoacylates
were reported by the groups of Davies,[6] using [Rh2{(R)-
Dosp}4], and Reisman,[7] using an (R)-Binol/SnCl4 complex.
The groups of You[8] and Sun[9] recently disclosed an organo-
[*] M.-C. Tong, X. Chen, J. Li, R. Huang, H. Tao, Prof. Dr. C.-J. Wang
College of Chemistry and Molecular Sciences
Wuhan University, Wuhan, 430072 (China)
E-mail: cjwang@whu.edu.cn
Prof. Dr. C.-J. Wang
State Key Laboratory of Elemento-organic Chemistry
Nankai University, Tianjin, 300071 (China)
[**] This work was supported by the 973 Program (2011CB808600),
NSFC (21172176, 21372180), and the Hubei Province NSF
(ZRZ0273).
Scheme 1. [4+1] Annulation of azoalkene with sulfur ylide (previous
work) and [4+2] inverse electron-demand aza-Diels–Alder (IEDDA)
reaction of azoalkene with indole (this work).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201400109.
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We started our investigation with readily available a-
chloro N-benzoyl hydrazone 2a as the 1,2-diazo-1,3-diene
precursor, to probe the feasibility of the aza-Diels Alder
reaction between 1,3-dimethly indole 1a and the in situ
formed azoalkene. With Na2CO3 as the base, the uncatalyzed
inverse-electron-demand aza-Diels–Alder reaction pro-
ceeded smoothly, affording the [2,3]-fused indoline/tetrahy-
dropyridazine cycloadduct 3aa in 75% yield, with exclusive
regioselectivity and excellent diastereoselectivity (Table 1,
When CuI/Binap was employed as the catalyst, the reaction
was finished in less than 12 h affording the desired adduct 3aa
in 91% yield with high diastereoselectivity and 55% ee
(Table 1, entry 2). However, further screening of several
Binap-type axially bisphosphine ligands failed to improve the
enantioselectivity (see the Supporting Information for
details). A chiral CuI/Box (L2) complex was also tested, and
only racemic product was obtained with low conversion
(entry 3). The chiral CuI complex generated from the (S)-
Phox ligand promoted the annulation process smoothly,
leading to the desired adduct in good yield, albeit with very
low enantioselectivity (entry 4). To our delight, by switching
the backbone of the chiral P,N-ligand ligand from benzene to
ferrocene, both the conversion and the enantioselectivity of
this cycloaddition were improved significantly (entry 5).
Remarkably, (S,Sp)-tBu-Phosferrox[16] (L7) bearing bulky
tert-butyl group on the oxazoline ring delivered the best
results in terms of the yields and stereoselectivity (entry 8).
When N-unsubstituted 3-methyl indole was employed, much
lower conversion and moderate enantioselectivity were
observed, probably owing to reduced nucleophilicity at C3
and reduced electrophilicity at C2 of 3-methyl indole
(entry 9). A study of this cycloaddition with CuI/(S)-L7 in
various solvents identified MeCN as a suitable alternative to
CH2Cl2, whereas toluene and THF had a detrimental effect on
this transformation (entries 8 and 10–12). Reducing the
reaction temperature proved beneficial to the control of
enantioselectivity, and 97% ee with full conversion were
achieved at À208C (entry 14).
Table 1: Optimization of the reaction conditions.[a]
Entry Ligand Solvent T [8C] Time [h] Yield [%][c] ee [%][d]
1[b]
2
3
4
5
6
7
8
–
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
CH3CN
THF
0
0
0
0
0
0
0
0
0
24
12
12
12
12
12
8
8
24
8
75
91
30
83
92
71
91
94
35
29
79
13
95
95
–
55
0
L1
L2
L3
L4
L5
L6
L7
L7
L7
L7
L7
L7
L7
3
79
52
87
95
66
5
92
7
92
97
9[e]
10
11
12
13
14
0
0
0
8
8
8
18
Under the optimized reaction conditions, we tested
various substituted indoles to examine the generality of this
annulation, and the results are shown in Table 2. In general,
a broad range of differently substituted indoles, bearing
electron-neutral (Table 1, entry 1) or electron-deficient
(entries 2–4) on the indole framework, reacted with N-
benzoyl hydrazone 1a smoothly to form a series of [2,3]-
fused indoline molecules in high yields (85–95%) with high
diastereoselectivities (> 20:1 d.r.) and excellent enantioselec-
tivities (93–98% ee). Remarkably, this method was also
compatible with the sterically hindered 4-bromo- (1b), 4-
methyl- (1e), and 7-methyl-substituted (1h) indoles in terms
of enantioselectivity and reactivity (entries 2, 5, and 8).
Various C3-substituted indoles have also been employed as
the reaction partners. It was found that both simple alkyl
groups and functionalized alkyl groups containing ether,
amide, and ester moieties were tolerated at the C3-position of
the indoles, affording the desired cycloadducts in good yields
with high stereoselectivities (entries 10–16). Notably, indoles
bearing a sterically hindered C3-substituted group, such as
iso-propyl and phenyl, also worked well in this transformation
(entries 11 and 13). No annulation occurred when indoles
without C3-substitution were employed under the optimized
reaction conditions. Subsequent studies revealed that N-allyl-
and N-benzyl-substituted indoles 1q and 1r are also viable
substrates in this catalytic system, affording the correspond-
ing heterocycles in good yields and with excellent enantiose-
lectivity (entries 17 and 18). Further exploration revealed that
1,2,3-trimethyl indole 1s was also a suitable substrate,
providing the cycloadduct 3sa, which bears two contiguous
CH2Cl2
CH2Cl2
RT
À20
[a] All reactions were carried out with 1a (0.3 mmol) and 2a (0.5 mmol)
in solvent (4.0 mL). [b] Without catalyst. [c] Yield of isolated product.
[d] ee value was determined by HPLC analysis; >20:1 d.r. was estab-
lished by 1H NMR analysis of the crude product. [e] N-unsubstituted 3-
methylindole was used.
entry 1). Thus, an efficient catalyst for this challenging
transformation needs to 1) control the annulation process
between heterodienes and dienophiles in stereoselective
manner, and 2) exhibit higher reactivity than the uncatalyzed
background reaction.
We envisioned that the reactivity of the in situ formed
azoalkene could be enhanced by coordination with a chiral
transition-metal complex, and therefore realize this annula-
tion with stereoselective control. Hence, different transition-
metal sources and some readily available chiral ligands were
examined, and the representative results are shown in Table 1.
2
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Table 2: Substrate scope of the CuI-catalyzed aza-Diels–Alder reaction of
various indoles 1 with hydrazone 2a.[a]
Consistently high diastereoselectivity and excellent enantio-
selectivity were obtained with various substituted N-benzoyl
groups (entries 12–15). The substrate N-thiophene-2-carbonyl
hydrazone 2p also worked well in this transformation, leading
to 88% yield and 97% ee (entry 16). Noticeably, 96% ee and
94% ee were achieved even for the challenging N-acetyl (2q)
and N-Boc (2r) hydrazones (entries 17 and 18); these
hydrazones had been shown to be relatively challenging
substrates in a previous report.[13] Remarkably, the branched
a,a-dichloro hydrazone 2s was also well tolerated, affording
the heterocycle 3as, which bears three contiguous stereogenic
centers, in good yield with exclusive diastereoselectivities and
excellent enantioselectivity (entry 19). The absolute config-
uration of the cycloadducts 3ab and 3as was unequivocally
determined to be (4aS,9aS) and (4S,4aS,9aS), based on X-ray
diffraction analysis (Figure 1).[17]
To further probe the scalability of this aza-Diels–Alder
reaction, we carried out the reaction of 1,3-dimethyl indole 1a
with a-chloro hydrazone 2a and a,a-dichloro hydrazone 2s
on a gram scale, and the fused indolines 3aa and 3as were
isolated in good yields with excellent enantioselectivity
(Scheme 2). The optically active fused indoline heterocycle
3aa can be readily elaborated, as shown in Scheme 2. Under
Entry R1
R2
R3
1
3
Yield
[%][b]
ee
[%][c]
1
2
3
4
5
6
7
8
9
H
Me
Me
Me
Bn
Me
Me
Me
Me
Me
Me
1a
1b
1c
1d
1e
1 f
1g
1h
1i
3aa
3ba
3ca
3da
3ea
3 fa
3ga
3ha
3ia
95
85
87
90
88
89
92
89
91
97
97
95
98
96
97
98
93
96
4-Br Me
5-Br Me
6-Cl Me
4-Me Me
5-Me Me
6-Me Me
7-Me Me
7-
Me
MeO
H
H
H
H
H
H
H
H
10
11
12
13
14
15
16
17
18
Et
Me
Me
Me
Me
1j
1k
1l
1m
1n
1o
1p
1q
1r
3ja
3ka
3la
3ma
3na
3on
3pa
3qa
3ra
88
90
89
91
93
88
91
89
87
97
97
97
97
97
96
97
97
94
iPr
Bn
Ph
(CH2)2OTBS Me
(CH2)2NBoc Me
(CH2)2CO2Me Me
Me
Me
allyl
Bn
Table 3: Substrate scope of the CuI-catalyzed aza-Diels–Alder reaction of
indole 1a with various hydrazones 2.[a]
H
19
3sa
97
92
[a] All reactions were carried out with 1 (0.3 mmol) and 2a (0.5 mmol) in
CH2Cl2 (4.0 mL). [b] Yield of isolated product. [c] ee value was deter-
mined by HPLC analysis; >20:1 d.r. was established by 1H NMR analysis
of the crude product. Bn=benzyl, Boc=tert-butyloxycarbonyl,
TBS=tert-butyldimethylsilyl.
Entry R1
R2
2
3
Yield [%][b] ee [%][c]
1
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
2a
2b
2c
3aa
3ab
3ac
95
86
84
82
81
89
86
84
87
88
85
87
88
85
82
88
85
84
97
98
99
93
94
98
97
93
78
93
93
96
97
98
95
97
96
94
2
3
p-BrC6H4
o-ClC6H4
p-CF3C6H4
m-MeC6H4
p-MeC6H4
p-MeOC6H4
2-naphthyl
3-pyridyl
4[d]
5[d]
6
2d 3ad
quaternary stereogenic centers, in good yield with excellent
diastereoselectivity and 92% ee (entry 19).
2e
2 f
2g
2h 3ah
2i
2j
3ae
3af
3ag
Encouraged by the excellent results with various substi-
tuted indoles as the dieneophiles, we then investigated the
aza-Diels Alder cycloaddition with respect to the hetero-
dienes. As shown in Table 3, a variety of a-chloro- or a-bromo
N-benzoyl hydrazones have proven to be excellent azoalkene
precursors in this cycloaddition reaction, affording the
expected heterocycles (3aa–3ai) in high yields and with high
diastereoselectivities and excellent enantioselectivities. Both
electronic properties (e.g., electron-neutral, -deficient, or
-rich) and substitution pattern (e.g., para-, meta-, or ortho-) of
the substituted groups on the aromatic ring in N-benzoyl
hydrazones had little effect on the reactivity and stereoselec-
tivity (Table 3, entries 1–8). In addition, the challenging
heteroaromatic 3-pyridyl-substituted N-benzoyl hydrazone
2i also proceeded well with indole 1a, affording adduct 3ai in
87% yield and 78% ee (entry 9). Alkenyl- and alkyl-
substituted hydrazone 2j and 2k also worked well, leading
to good yields of adducts with 93% ee (entries 10 and 11). The
generality of hydrazones with different N-acyl groups was
further investigated under the optimized reaction conditions.
7
8[d]
9[d]
10
11[d]
12
13
14
15
16
17
18
3ai
3aj
3ak
3al
=
PhCH CH
Me
Ph
Ph
Ph
Ph
Ph
Ph
Ph
o-MeOC6H4 2k
p-MeOC6H4 2l
o-MeOC6H4 2m 3am
m-MeC6H4
p-CF3C6H4
2-thienyl
Me
2n 3an
2o 3ao
2p 3ap
2q
2r
3aq
3ar
OtBu
19
3as
95
99
[a] All reactions were carried out with 1a (0.3 mmol) and 2a (0.5 mmol)
in CH2Cl2 (4.0 mL). [b] Yield of isolated product. [c] ee value was
determined by HPLC analysis; >20:1 d.r. was established by H NMR
analysis of the crude product. [d] a-bromo-N-benzoylhydrazone was
used.
1
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method provides facile access to a diverse set of biologically
important [2,3]-fused indoline tetrahydropyridazine hetero-
cycles in good yields (up to 97%) with high regioselectivity
and diastereoselectivity (> 20:1 d.r.), and excellent enantio-
selectivity (up to 99% ee). Mechanistic studies aimed at
understanding the origin of the excellent stereoselective
control, and further investigation of the substrate scope and
synthetic application of this method are ongoing in our
laboratory.
Received: January 6, 2014
Published online: && &&, &&&&
Keywords: asymmetric catalysis · azoalkenes · cycloaddition ·
.
indoles · indolines
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catalyzed by a CuI/tBu-Phosferrox complex. The current
4
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Dong, X. Zhao, L. Lin, X. Liu, X. Feng, Chem. Eur. J. 2011, 17,
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this manuscript, Xiao and co-workers reported a 20 mol%
Cu(II)-catalyzed reaction of azoalkene with enol ethers in 2 – 5
days that afforded chiral pyridazines in good yields with 14 –
[17] CCDC 971351 (3ab) and 979241 (3as) contain the supplemen-
tary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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Angewandte
Communications
Communications
Asymmetric Catalysis
M.-C. Tong, X. Chen, J. Li, R. Huang,
H. Tao, C.-J. Wang*
&&&& — &&&&
Catalytic Asymmetric Synthesis of [2,3]-
Fused Indoline Heterocycles through
Inverse-Electron-Demand Aza-Diels–
Alder Reaction of Indoles with Azoalkenes
In(verse) demand: The unprecedented
catalytic asymmetric inverse-electron-
demand aza-Diels–Alder reaction of
indoles with in situ formed azoalkenes is
reported. A diverse set of [2,3]-fused
indoline heterocycles were produced in
generally good yields with high regiose-
lectivity and diastereoselectivity, and with
excellent enantioselectivity.
6
www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
These are not the final page numbers!