Asymmetric friedel-crafts alkylation of α-substituted β-nitroacrylates: Access to β2,2-amino acids bearing indolic all-carbon quaternary stereocenters

Article abstract of DOI:10.1021/ol403480v

A highly enantioselective Friedel-Crafts alkylation reaction of indoles with acyclic α-substituted β-nitroacrylates is developed under the catalysis of Ni(ClO₄)₂-bisoxazoline complex at 1 mol % catalyst loading, affording chiral indolic β-nitroesters bearing all-carbon quaternary stereocenters in excellent yields and ees of up to 97%. Transformation of one of the products to β^2,2-amino ester and tetrahydro-β-carboline through nitro reduction and sequential Pictet-Spengler cyclization was exemplified.

Full text of DOI:10.1021/ol403480v

Letter
pubs.acs.org/OrgLett
Asymmetric Friedel−Crafts Alkylation of α‑Substituted β-
Nitroacrylates: Access to β2,2-Amino Acids Bearing Indolic All-Carbon
Quaternary Stereocenters
Jian-Quan Weng, Qiao-Man Deng, Liang Wu, Kai Xu, Hao Wu, Ren-Rong Liu, Jian-Rong Gao,
and Yi-Xia Jia*
College of Chemical Engineering and Material Sciences, Zhejiang University of Technology, Chaowang Road 18#, Hangzhou310014,
China
S
* Supporting Information
ABSTRACT: A highly enantioselective Friedel−Crafts alkylation reaction of indoles with acyclic α-substituted β-nitroacrylates is
developed under the catalysis of Ni(ClO4)2−bisoxazoline complex at 1 mol % catalyst loading, affording chiral indolic β-
nitroesters bearing all-carbon quaternary stereocenters in excellent yields and ees of up to 97%. Transformation of one of the
products to β2,2-amino ester and tetrahydro-β-carboline through nitro reduction and sequential Pictet−Spengler cyclization was
exemplified.
documented,10 and excellent enantioselectivities were recently
achieved independently by Arai’s and Zhang’s groups in the
β-Amino acids are important substructural motifs of β-peptides,
β-lactams, and many other biologically active compounds.1 As a
result, extensive attention has been focused on the asymmetric
synthesis of β-amino acids.2 In the context of β2-amino acid (α-
substituted-β-amino acid) synthesis, a variety of catalytic
asymmetric methods have been developed, and most of them
appear to be for the construction of tertiary stereogenic
center.2e,f In comparison, the synthesis of enantiomerically pure
β2,2-amino acids bearing all-carbon quaternary stereocenters is
much less explored and has remained as a very challenging
task.3 Undoubtedly, asymmetric conjugate addition of a carbon-
based nucleophile to α-substituted-β-nitroacrylate would be a
reliable strategy for this purpose.4 However, only a few
examples were reported so far on the enantioselective additions
of aldehydes,5 thiols,6 and oximes7 to α-substituted-β-nitro-
acrylates.8 Extension of carbon-based nucleophiles in this
reaction would be highly valuable for the challenging β2,2-amino
acid synthesis.
Indole has become a popular nucleophile in the asymmetric
Michael-type Friedel−Crafts reaction, which serves as an
important carbon−carbon-forming reaction to access optically
active aromatic compounds.9 Various electron-deficient olefins
have been used for indole alkylation. However, reaction with
the β,β-disubstituted unsaturated system to generate an all-
carbon quaternary stereocenter has met with very limited
success, probably due to the steric repulsion of the two
substituents in the substrates toward the nucleophilic attack of
indole ring. Nevertheless, two pioneering examples have been
reactions of indoles with isatin-derived cyclic electron-deficient
olefins,11 as well as our group in the reaction of
trifluoromethylated β,β-disubstituted nitroalkenes.12 However,
the specific demand of the substrates and the high catalyst
loading in these transformations still remained the major issue.
Herein, we report a highly enantioselective alkylation reaction
of indoles with acyclic α-substituted-β-nitroacrylates under the
catalysis of 1 mol % of Ni−bisoxazoline complex,13 providing
reliable access to the potential biologically active β-tryptophan
derivatives bearing all-carbon quaternary stereocenters (Scheme
1).14 It is noteworthy that good results are also obtained at the
lowest catalyst loading of 0.1 mol %, which represents a rare
Scheme 1. Ni-Catalyzed Enantioselective Friedel−Crafts
Alkylation Reaction of Indoles with α-Substituted β-
Nitroacrylates
Received: December 2, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ol403480v | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
case of highly active Lewis acid catalyst in the asymmetric
Friedel−Crafts reaction.15
isopropyl esters (4 and 5) gave slightly lower enantioselectiv-
ities (Table 2, entries 2 and 3), while the ee value for tert-butyl
Based on our previous result,12 we identified the complex of
Ni(ClO4)2·6H2O16 with chiral bisoxazoline as an efficient
catalyst for the model reaction between (Z)-methyl 3-nitro-2-
phenylacrylate (1) and indole (2a). Thus, the reaction in the
presence of 10 mol % of Ni(ClO4)2·6H2O and 12 mol % of L1
proceeded smoothly in toluene at 50 °C for 18 h to afford the
product (S)-3 in 81% ee with excellent yield (Table 1, entry 1).
Table 2. Optimization of the Ester Group and Catalyst
a
Loading
a
Table 1. Reaction Condition Optimization
b
c
entry
x
R
temp (°C) time (h) yield (%) ee (%)
1
2
3
4
5
10
Me
Et
50
50
50
50
50
50
50
80
18
18
18
4
96
95
95
97
96
98
52
79
90
89
86
96
96
96
96
93
10
10
10
1
iPr
tBu
tBu
tBu
tBu
tBu
24
15
36
20
d
6
1
d
e
e
7
d
0.1
0.1
8
a
Reaction conditions: nitroacrylate (0.4 mmol), indole 2a (0.6 mmol),
b
c
toluene (4.0 mL). Isolated yield. Determined by chiral HPLC.
d
Ni(ClO4)2·6H2O was dried under vacuum at 160 °C for 2 h before
b
c
e
entry
LA
L*
solvent
yield (%)
ee (%)
complex with ligand. For operation, see the Supporting Information.
1
Ni(ClO4)2·6H2O
Zn(ClO4)2·6H2O
Ni(OTf)2
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L5
L6
L7
L8
toluene
toluene
toluene
toluene
toluene
Et2O
96
91
96
94
34
90
89
82
94
92
56
95
96
96
81
70
78
75
79
50
53
<10
33
55
39
81
81
90
2
ester 6a was greatly improved to 96% and with a fast reaction
rate (entry 4). This high reactivity inspired us to examine the
reaction at a lower catalyst loading. As shown in entry 5, the
same result could be obtained with 1 mol % of catalyst, albeit
longer reaction time was needed. However, the catalyst activity
could be enhanced after dehydration, and the reaction finished
in 15 h (entry 6). Further lowering the catalyst loading to 0.1
mol % led to a sharp decrease of the yield, while a high level of
enantioselectivity was retained (entry 7). Gratifyingly, the yield
could be improved to 79% at 80 °C with slight loss of ee (entry
8).
3
4
Zn(OTf)2
5
Cu(OTf)2
6
Ni(ClO4)2·6H2O
Ni(ClO4)2·6H2O
Ni(ClO4)2·6H2O
Ni(ClO4)2·6H2O
Ni(ClO4)2·6H2O
Ni(ClO4)2·6H2O
Ni(ClO4)2·6H2O
Ni(ClO4)2·6H2O
Ni(ClO4)2·6H2O
7
CH2Cl2
toluene
toluene
toluene
toluene
toluene
toluene
toluene
8
9
10
11
12
13
14
The optimal reaction conditions were then applied to the
reactions of a variety of nitroacrylates (6a−n). As shown in
Table 3, the yields and enantioselectivities are generally
excellent for α-aryl-β-nitroacrylates (6a−i) bearing either
electron-donating groups or electron-withdrawing groups on
the phenyl ring (entries 1−11). But no reaction occurred for o-
methyl-substituted substrate, implying a negative steric effect
on the reactivity. Heteroaryl (6j, 6k) and 2-naphthyl (6l)
substrates also react well with indole to furnish the
corresponding products in similarly excellent yields and ees
(entries 12−14). To our delight, alkylated substrates 6m and
6n are suitable for this transformation to afford the products in
slightly lower yield and enantioselectivity with 5 mol % of
catalyst (entries 15 and 16). It should be noted that in the
presence of 0.1 mol % catalyst the reactions of substrates 6e
and 6g occurred smoothly to afford the corresponding products
in modest yields and good enantioselectivities (entries 6 and 9).
We have also investigated the substituent effect of indole.
Excellent enantioselectivities were achieved for indoles bearing
substituents at the C5−C7 positions (Table 4, entries 2−6),
while an electron-withdrawing substituent (Br) resulted in a
lower yield. The yield could be improved to 95% at 80 °C with
slight erosion of the enantioselectivity (entry 4). Furthermore,
the reactions were unfavorably influenced by the steric effect.
Poor to modest yields and enantioselectivities were obtained
for 2b and 2g bearing substituents at the C2 or C4 position of
a
The reaction of (Z)-methyl 3-nitro-2-phenylacrylate 1 (0.4 mmol)
and indole 2a (0.6 mmol) was performed in the presence of 10 mol %
of Lewis acid and 12 mol % of chiral ligand in solvent (4.0 mL) at 50
°C for 18 h. Isolated yield. Determined by chiral HPLC.
b
c
Subsequent optimization of Lewis acid showed Ni(ClO4)2·
6H2O was the best catalyst. Although Zn(ClO4)2·6H2O,
Ni(OTf)2, and Zn(OTf)2 could efficiently promote the
reaction, the resulting enantioselectivities were below 80%
(entries 2−4). Simple examination of solvent disclosed ether
and dichloromethane were inferior to toluene (entries 6 and 7).
We then turned our attention to ligand screening, and as shown
in entries 8−10, chiral isopropyl, benzyl, and 2-naphthyl
substituents on the oxazoline ring led to poor enantioselectiv-
ities. To our delight, ligand L8 bearing trans-diphenyl
substituents was revealed as the best choice, giving 90% ee of
the product (entry 14). Modifications on the linker of L1 and a
cis-diphenyl ligand L7 did not improve the enantiomeric excess
(entries 11−13).
To further improve the enantioselectivity, we next
investigated the effect of ester group on the reaction. Ethyl,
isopropyl, and tert-butyl 2-phenylnitroacrylate were then
synthesized and treated with indole under the conditions
showed in entry 14 of Table 1. The reactions of ethyl and
B
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Organic Letters
Letter
a
Table 3. Substrate Scope of Nitroacrylate
b
c
entry
R
product
yield (%)
ee (%)
1
2
3
4
5
C6H5 (6a)
9a
9b
9c
9d
9e
9e
9f
98
98
98
97
97
63
93
98
70
98
98
97
97
98
89
87
96
95
97
97
93
86
93
93
87
95
97
96
95
95
88
88
3-MeC6H4 (6b)
3-MeOC6H4 (6c)
3-FC6H4 (6d)
4-MeOC6H4 (6e)
4-MeOC6H4 (6e)
4-ClC6H4 (6f)
d
6
7
8
Figure 1. Proposed asymmetric induction model.
4-CF3C6H4 (6g)
4-CF3C6H4 (6g)
3,4-MeO2C6H3 (6h)
3,5-Me2C6H3 (6i)
2-thienyl (6j)
9g
9g
9h
9i
d
9
at the α-position of β-nitroacrylate is favored to furnish the
product in the observed S configuration.
We next investigated the synthetic transformations of
product 9a to the corresponding potential biologically active
compounds β2,2-amino ester and tetrahydro-β-carboline. As
shown in Scheme 2, chiral β2,2-amino ester 10 was readily
10
11
12
13
14
9j
2-furyl (6k)
9k
9l
2-naphthyl (6l)
2-phenylethyl (6m)
benzyl (6n)
e
15
9m
9n
e
16
Scheme 2. Synthetic Transformations of Product 9a
a
Reaction conditions: nitroacrylate 6a−n (0.4 mmol), indole 2a (0.6
mmol), 1 mol % of Ni(ClO4)2 (dried from Ni(ClO4)2·6H2O under
vacuum at 160 °C for 2 h) toluene (4.0 mL), and 1.2 mol % L8 in
b
c
toluene (4.0 mL) at 50 °C for 12−36 h. Isolated yield. Determined
d
e
by chiral HPLC. 0.1 mol % catalyst loading at 80 °C for 24 h. With 5
mol % of catalyst.
a
Table 4. Substrate Scope of Indole
b
c
entry
R
product
yield (%)
ee (%)
1
2
3
4-MeO (2b)
5-MeO (2c)
5-Br (2d)
5-Br (2d)
6-Cl (2e)
9o
9p
9q
9q
9r
61
97
75
95
95
98
43
62
57
77
97
95
93
93
96
54
64
76
obtained in 92% yield by the reduction of nitro group with
NaBH4/NiCl2·6H2O in methanol at room temperature.
Through a CF3CO2H-mediated Pictet−Spengler cyclization
with benzaldehyde, β2,2-amino ester 10 was further converted
to tetrahydro-β-carboline 11 bearing an all-carbon quaternary
stereocenter, isolated as a single isomer in 65% yield and with
98% ee.
In summary, we have developed a highly enantioselective
Michael-type Friedel−Crafts alkylation reaction of indoles with
acyclic α-substituted-β-nitroacrylates as a reliable approach to
β2,2-amino acids bearing all-carbon quaternary stereocenters.
One of the products was readily converted to chiral tryptophan-
type β2,2-amino ester and tetrahydro-β-carboline as important
potential biologically active compounds. High activity of the Ni
catalyst was observed, and the catalyst loading could be lowered
to 0.1 mol %. Further extension of this methodology in organic
synthesis is currently underway in our laboratory.
d
4
d
5
6
7
7-Me (2f)
2-Me (2g)
1-Me (2h)
1-allyl (2i)
9s
9t
e
8
e
9u
9v
9
a
Reaction conditions: nitroacrylate 6a (0.4 mmol), indole 2b−i (0.6
mmol), 1 mol % of Ni(ClO4)2 (dried from Ni(ClO4)2·6H2O under
vacuum at 160 °C for 2 h), toluene (4.0 mL), and 1.2 mol % of L8 in
toluene (4.0 mL) at 50 °C for 12−36 h. Isolated yield. Determined
by chiral HPLC. At 80 °C for 12 h. At 80 °C for 36 h.
b
c
d
e
indole (entries 1 and 7). Also, modest ee’s were observed in the
reaction of N-methylindole 2h and N-allylindole 2i at 80 °C
(entries 8 and 9).
The absolute configuration of product 9q was determined to
be S on the basis of its single-crystal X-ray structure. Proposed
asymmetric induction model was then depicted in Figure 1. As
observed in our previous result,12 nitroacrylate interacts with
Ni(II) through a 1,3-coordinate fashion and is hence activated,
followed by the nucleophilic attack of indole ring. The Re-attack
ASSOCIATED CONTENT
■
S
* Supporting Information
Typical experimental procedure and characterization for all
products. This material is available free of charge via the
Internet at http://pubs.acs.org.
C
dx.doi.org/10.1021/ol403480v | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Chen, L.-A.; Tang, X.; Xi, J.; Xu, W.; Gong, L.; Meggers, E. Angew.
Chem., Int. Ed. 2013, 52, 14021−14025.
AUTHOR INFORMATION
■
Corresponding Author
(14) For reports on the Friedel−Crafts reaction of β-nitroacrylates to
form tertiary stereocenters, see: (a) Ganesh, M.; Seidel, D. J. Am.
Chem. Soc. 2008, 130, 16464−16465. (b) Trost, B. M.; Mueller, C. J.
Am. Chem. Soc. 2008, 130, 2438−2439. (c) Arai, T.; Awata, A.; Wasai,
M.; Yokoyama, N.; Masu, H. J. Org. Chem. 2011, 76, 5450−5456.
(15) For the Friedel−Crafts reaction with less steric hindered
eletron-deficient alkenes as substrates at lower catalyst loading, see:
organocatalyst: (a) Sheng, Y.-F.; Li, G.-Q.; Kang, Q.; Zhang, A.-J.; You,
S.-L. Chem.Eur. J. 2009, 15, 3351−3354. Lewis acid catalyst:
(b) Liu, Y.; Shang, D.; Zhou, X.; Zhu, Y.; Lin, L.; Liu, X.; Feng, X. Org.
Lett. 2010, 12, 180−183.
*E-mail: yxjia@zjut.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the National Natural
Science Foundation of P. R. China (21002089, 21372202), the
New Century Excellent Talents in University (NCET-12-
1086), and young scholarship for the doctoral program of
higher education (20103317120001).
(16) Dalpozzo, R.; Bartoli, G.; Sambri, L.; Melchiorre, P. Chem. Rev.
2010, 110, 3501−3551.
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D
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