Catalytic asymmetric aza-Michael-Michael addition cascade: Enantioselective synthesis of polysubstituted 4-aminobenzopyrans

Article abstract of DOI:10.1021/ol1031188

A catalytic asymmetric aza-Michael-Michael addition cascade of anilines to nitroolefin enoates in the presence of chiral bifunctional thiourea catalysts has been disclosed. This reaction provides a mild and efficient approach to polysubstituted chiral 4-a

Full text of DOI:10.1021/ol1031188

ORGANIC
LETTERS
2011
Vol. 13, No. 4
808–811
Catalytic Asymmetric Aza-
Michael-Michael Addition Cascade:
Enantioselective Synthesis of
Polysubstituted 4-Aminobenzopyrans
Xu-Fan Wang, Jing An, Xiao-Xiao Zhang, Fen Tan, Jia-Rong Chen,*
and Wen-Jing Xiao*
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education,
College of Chemistry, Central China Normal University, 152 Luoyu Road, Wuhan,
Hubei 430079, China
wxiao@mail.ccnu.edu.cn; jiarongchen2003@yahoo.com.cn
Received December 23, 2010
ABSTRACT
A catalytic asymmetric aza-Michael-Michael addition cascade of anilines to nitroolefin enoates in the presence of chiral bifunctional thiourea
catalysts has been disclosed. This reaction provides a mild and efficient approach to polysubstituted chiral 4-aminobenzopyrans bearing three
consecutive stereocenters in high yields with excellent stereoselectivities.
Densely functionalized complex molecules bearing a
heterocycle architecture are featured in many naturally
occurring products and medicinally relevant compounds
that display a diverse range of biological activities.1 In this
context, benzopyrans and in particular their 4-amino
derivatives are of great importance due to a number of
drugs containing this ubiquitous motif.2 For instance, they
can function as modulators of calcium and potassium
channels for influencing the activity of the heart and blood
(3) (a) Rovnyak, G. C.; Ahmed, S. Z.; Ding, C. Z.; Dzwonczyk, S.;
Ferrara, F. N.; Humphreys, W. G.; Grover, G. J.; Santafianos, D.;
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B. V. S.; Reddy, P. N. Chem. Lett. 2004, 1436. (e) Anniyappan, M.;
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B.; Kumar, S. K.; Kunwar, A. C. Tetrahedron Lett. 2001, 42, 6381. (g)
Yadav, J. S.; Reddy, B. V. S.; Sekhar, K. C.; Geetha, V. Tetrahedron
Lett. 2001, 42, 4405.
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103, 893. (b) Eicher, T.; Hauptmann, S.; Speicher, A. The Chemistry of
Heterocycles, 2nd ed.; Wiley-VCH GmbH & Co. KGaA: New York, 2004.
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and Chromones; Wiley-Interscience: New York, 1977. (b) Keay, B. A. In
Comprehensive Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W.,
Scriven, E. F. V., Eds.; Pergamon: Oxford, UK, 1996; Vol. 2, p 395. (c)
Hepworth, J. In Comprehensive Heterocyclic Chemistry; Katrizky, A. R.,
Rees, C. W., Eds.; Pergamon; Oxford, UK, 1984; Vol. 3, p 11. For reviews of
benzopyrans, see: (d) Shen, H. C. Tetrahedron 2009, 65, 3931. (e) Zeni,
G.; Larock, R. C. Chem. Rev. 2004, 104, 2285. (f) Buckle, D. R.; Arch,
J. R. S.; Fenwick, A. E.; Hough-Frydrych, C. S. V.; Pinto, I. L.; Smith,
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r
10.1021/ol1031188
Published on Web 01/19/2011
2011 American Chemical Society

pressure.3 The development of highly efficient, selective,
and environmentally benign methods to construct this
fused cyclic structure has received much attention in the
chemical community.4 Compared with many nonasym-
metric procedures, however, catalytic asymmetric ap-
proaches to 4-aminobenzopyrans are relatively rare.5
Notably, Rueping and co-workers recently reported an
elegant example of enantioselective Mannich-ketaliza-
tion reactions to provide 4-aminobenzopyrans in high
enantioselectivities, albeit with fair diastereoselectivities.6
Despite advances, the search for new catalytic asym-
metric methods to form polysubstituted 4-aminobenzo-
pyrans, especially with multiple consecutive stereocenters,
is still highly desirable.
During the past decades, organocatalytic cascade/dom-
ino reactions have emerged as a powerful synthetic tool for
the construction of multiple carbon-carbon or carbon-
heteroatom bonds in a single operation.7 In this regard,
Michael addition initiated Michael-Michael addition cas-
cade was identified as a useful strategy to make complex
molecules.8 Although there are many reports on organo-
catalytic asymmetric aza-Michael addition reactions, to
our knowledge, enantioselective aza-Michael-Michael
cascade reactions remain largely unexplored.9 As part
of our ongoing research program addressing carba- and
heterocycle-orientedmethodology development,10 we here-
in wish to disclose a mild and efficient organocatalyzed
asymmetric cascade aza-Michael-Michael addition reac-
tion of anilines withnitroolefin enoates. This novel method
allows an efficient and straightforward formation of two
carbon-carbon bonds and three consecutive stereocenters
(including one quaternary stereocenter) in one operation
with high yields (up to 96%) and excellent stereoselectiv-
ities (up to >99% ee, mostly >95:5 dr).
Scheme 1. Proposed Reaction Pathway for the Cascade
Sequence
(5) One example describes the conversion of chiral 4-chromanols into
the corresponding amino derivatives. See: Burgard, A.; Lang, H.-J.;
Gerlach, U. Tetrahedron 1999, 55, 7555.
(6) Rueping, M.; Lin, M.-Y. Chem.;Eur. J. 2010, 16, 4169. During
the preparation of this work, Ricci and co-workers reported a catalytic
asymmetric inverse-electron-demand [4 þ 2] cycloaddition of salicyla-
dimines with electron-rich alkenes to synthesize the 4-aminobenzopyran
derivatives. See: Bernardi, L.; Comes-Franchini, M.; Fochi, M.; Leo, V.;
Mazzanti, A.; Ricci, A. Adv. Synth. Catal. 2010, 362, 3399.
(7) (a) Tietze, L. F.; Gordon, B.; Kersten, G. M., Eds. Domino
Reactions in Organic Synthesis: Wiley-VCH, Weinheim, Germany, 2006.
For selected reviews on cascade (domino) reactions, see: (b) Hussian, M. M.;
Patrick, J. W. Acc. Chem. Res. 2008, 41, 883. (c) Li, Z.-G.; Chad, B.; He,
Our designed approach to chiral 4-aminobenzopyrans is
described in Scheme 1. Mechanistically, the chiral bifunc-
tional thiourea catalyst VI activated nitroolefin enoates
through multiple hydrogen-bonding interactions while its
basic tertiary amino site activated the nucleophilic ani-
lines.11 The intermolecular aza-Michael reaction of ni-
troolefin enoates proceeded through Si-face attack,
followed by the intramolecular Michael addition through
Re-face attack, to form highly functionalized 4-aminoben-
zopyrans.
€
C. Chem. Rev. 2008, 108, 3239. (d) Enders, D.; Grondal, C.; Huttl,
M. R. M. Angew. Chem., Int. Ed. 2007, 46, 1570. (e) Guo, H.; Ma, J.
Angew. Chem., Int. Ed. 2006, 45, 354. (f) Pellissier, H. Tetrahedron 2006,
62, 2143. (g) Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Angew.
Chem., Int. Ed. 2006, 45, 7134. (h) Tietze, L. F.; Rackelmann, N. Pure
Appl. Chem. 2004, 76, 1967.
(8) For an excellent review of cacade Michael/Michael reaction, see:
(a) Ihara, M.; Fukumoto, K. Angew. Chem., Int. Ed. 1993, 32, 1010. For
selected examples of organocatalytic cascade Michael-Michael reac-
tions, see:(b) Wang, X.-F.; Hua, Q.-L.; Cheng, Y.; An, X.-L.; Yang, Q.-
Q.; Chen, J.-R.; Xiao, W.-J. Angew. Chem., Int. Ed. 2010, 49, 8379. (c)
Wang, J.; Xie, H.; Li, H.; Zu, L.; Wang, W. Angew. Chem., Int. Ed. 2008,
47, 4177. (d) Sriramurthy, V.; Barcan, G. A.; Kwon, O. J. Am. Chem.
Soc. 2007, 129, 12928. (e) Sun, X.; Sengupta, S.; Petersen, J. L.; Wang,
H.; Lewis, J. P.; Shi, X.-D. Org. Lett. 2007, 9, 4495. (f) Li, H.; Zu, L.; Xie,
H.; Wang, J.; Jiang, W.; Wang, W. Angew. Chem., Int. Ed. 2007, 46,
3732. (g) Li, H.; Zu, L. S.; Xie, H. X.; Wang, J.; Jiang, W.; Wang., W.
Org. Lett. 2007, 9, 1833. (h) Hoashi, Y.; Yabuta, T.; Yuan, P.; Miyabe,
H.; Takemoto, Y. Tetrahedron 2006, 62, 365.
To examine the feasibility of the proposed aza-Michael-
Michael addition cascade of anilines with nitroolefin
enoates, the reaction was initially performed in CH2Cl2
at room temperature in the presence of bifunctional
(9) For a review on organocatalytic aza-Michael additions, see: (a)
Enders, D.; Wang, C.; Liebich, J. X. Chem.;Eur. J. 2009, 15, 11058.
There is only one example of organocatalytic asymmetric aza-
Michael-Michael addition reactions, see:(b) Li, H.; Zu, L.-S.; Xie,
H.-X.; Wang, J.; Wang, W. Chem. Commun. 2008, 5636.
(10) (a) Lu, L.-Q.; Zhang, J.-J.; Li, F.; Cheng, Y.; An, J.; Chen, J.-R.;
Xiao, W.-J. Angew. Chem., Int. Ed. 2010, 49, 4495. (b) Wang, X.-F.;
Chen, J.-R.; Cao, Y.-J.; Cheng, H.-G.; Xiao, W.-J. Org. Lett. 2010, 12,
1140. (c) Lu, L.-Q.; Li, F.; An, J.; Zhang, J.-J.; An, X.-L.; Hua, Q.-L.;
Xiao, W.-J. Angew. Chem., Int. Ed. 2009, 48, 9542. (d) Chen, C.-B.;
Wang, X.-F.; Cao, Y.-J.; Cheng, H.-G.; Xiao, W.-J. J. Org. Chem. 2009,
74, 3532. (e) Lu, L.-Q.; Cao, Y.-J.; Liu, X.-P.; An, J.; Yao, C.-J.; Ming,
Z.-H.; Xiao, W.-J. J. Am. Chem. Soc. 2008, 130, 6946. (f) Chen, J.-R.; Li,
C.-F.; An, X.-L.; Zhang, J.-J.; Zhu, X.-Y.; Xiao, W.-J. Angew. Chem.,
Int. Ed. 2008, 47, 2489. (g) Li, C.-F.; Liu, H.; Liao, J.; Cao, Y.-J.; Liu, X.-
P.; Xiao, W.-J. Org. Lett. 2007, 9, 1847.
(11) Reviews on bifunctional Cinchona alkaloid amino thiourea
catalysis: (a) Connon, S. J. Chem. Commun. 2008, 2499. (b) Marcelli,
T.; Maarseveen, J. H.; Van; Hiemstra, H. Angew. Chem., Int. Ed. 2006,
45, 7496. For selected examples, see:(c) Liu, X.-Q.; Lu, Y.-X. Org. Lett.
2010, 12, 5592. (d) Liu, X.-Q.; Lu, Y.-X. Org. Biomol. Chem. 2010, 8,
4063. (e) Gioia, C.; Hauville, A.; Bernardi, L.; Fini, F.; Ricci, A. Angew.
Chem., Int. Ed. 2008, 47, 9236. (f) Wang, B.; Wu, F.; Wang, Y.; Liu, X.;
Deng, L. J. Am. Chem. Soc. 2007, 129, 768. (g) Biddle, M. M.; Lin, M.;
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Org. Lett., Vol. 13, No. 4, 2011
809

Although excellent levels of stereoselectivities were ob-
served, longer reaction times were needed for nonpolar,
aprotic solvents (Table 1, entries 6-11). Suprisingly and
interestingly, polar and protic solvents, which were usually
deemed to disrupt the hydrogen-bonding interactions
between the catalyst and substrates,10f gave the most en-
couraging results (Table 1, entries 12-15) for the reaction
of 1a and 2a. When the catalyst loading was decreased to 2
mol %, the reaction gave comparable results albeit with
somewhat prolonged reaction times (Table 1, entry 16).
Lowering the temperature to 0 °C, the reaction gave the
product in 95% yield and 95:5 dr. But much longer
reaction time was needed, and the enantioselectivity was
decreased to 89% (Table 1, entry 17). The best results can
be obtained with the use of 2-propanol as the solvent
atroom temperature in the presence of 10 mol % of catalyst
VI (Table1, entry14, 2h, 96%yield, 96%eeand>95:5dr).
Figure 1. Screened organocatalysts.
organocatalyst I (10 mol %) (Figure 1 and Table 1). To
our delight, the reaction proceeded smoothly to provide
the desired chroman 3a in moderate yield (67%) with good
enantioselectivity (86% ee) and excellent diastereoselec-
tivity (97:3) (Table 1, entry 1). On this basis, several com-
monly used bifunctional organocatalysts (Figure 1) were
screened to further improve the reaction efficiency and
stereoselectivities. Among them, cinchona alkaloid amino
thiourea VI (10 mol %) was found to be the best one for
this cascade process (Table 1, entry 6, 70% yield, 96% ee
and 97:3dr). We alsoinvestigatedthe effects of the reaction
medium on this cascade reaction. As revealed in Table 1,
the solvents had a dramatic influence on the reaction.
Table 2. Asymmetric Aza-Michael-Michael Addition of
Anilines 1 to Nitroolefin Enoates 2 in the Presence of 10 mol %
of Organocatalyst VIa
entry
R1
R3
R4
X
yield (%)b ee (%)c
drc
1
2
H
H
Me
Me
Me
Me
Me
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
S
96 (3a)
71 (3b)
92 (3c)
84 (3d)
92 (3e)
94 (3f)
83 (3g)
82 (3h)
85 (3i)
94 (3j)
81 (3k)
94 (3l)
94 (3m)
89 (3n)
91 (3o)
91 (3p)
89 (3q)
95 (3r)
93 (3s)
96
>99
94
94
94
94
96
94
93
93
94
96
>99
93
94
96
93
91
94
>95:5
>95:5
>95:5
>95:5
>95:5
95:5
H
H
H
H
H
4-F
Table 1. Asymmetric Aza-Michael-Michael Addition
Reaction of Aniline 1a with Nitroolefin Enoate 2a under
Various Conditionsa
3
4-Cl
4-Br
4-Me
4
5
6
4-MeO Me
7
4-Me 5-MeO Me
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
65:35
95:5
8
4-Me 4-Br
5-Me 4-Br
Me
Me
Me
9
10
11
12
6-Me
H
entry solvent catalyst time (h) yield (%)b ee (%)c
drc
6-Me 5-MeO Me
4-Me
H
H
H
H
H
H
H
H
Me
Me
Me
Me
Et
1
2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DCE
I
48
48
48
48
48
48
72
20
24
12
48
8
67
69
56
43
75
70
73
82
77
86
65
83
95
96
95
92
95
-86
-86
-71
-31
88
97:3
91:9
13d 4-Br
II
14
15
16
17
18
19e
4-Cl
4-tBu
H
3
III
IV
V
96:4
4
65:35
98:2
5
H
Bn
Me
Me
6
VI
VI
VI
VI
VI
VI
VI
VI
VI
VI
VI
VI
96
97:3
H
7
93
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
H
S
8
Et2O
90
a Unless noted, reactions were carried out with 1 (1a-h) (0.75 mmol),
9
THF
88
i
10
11
12
13
14
15
CH3CN
toluene
CH3OH
EtOH
iPrOH
tBuOH
92
2 (2a-k) (0.30 mmol), and VI (10 mol %) in 2.0 mL of PrOH at
room temperature. b Isolated yield. c Determined by chiral HPLC. d The
absolute configuration of 3m was determined by X-ray analysis. e The
cofiguration of R,β-unsaturated ester on the nitroolefin enoate is Z type.
97
94
4
95
2
96
2
96
Having established the optimal reaction conditions, we
next examined the scope of the aza-Michael-Michael
addition cascade by employing a variety of anilines and
nitroolefin enoates. As highlighted in Table 2, this trans-
formation has a broad scope of both substrates. Variation
in the electronic or steric contribution of anilines (1) and
nitroolefin enoates (2) can be tolerated in the reaction. For
16d iPrOH
17e iPrOH
11
24
96
89
a Unless noted, reactions were carried out with 1a (0.75 mmol), 2a
(0.30 mmol), and I-VI (10 mol %) in 2.0 mL of solvent at 23 °C.
b Isolated yield. c Determined by chiral HPLC. d 2 mol % VI was used.
e The reaction was performed at 0 °C. DCE = 1,2-dichloroethane.
810
Org. Lett., Vol. 13, No. 4, 2011

example, nitroolefin enoates (2), bearing electron-with-
drawing or electron-donating groups on the aromatic ring
at the para- and/or meta-positions to the oxygen atom,
generally afforded the products without loss in reaction
efficiency (71% to 96% yield) or stereoselective outcomes
(94% to >99% ee, g95:5 dr, entries 1-7 in Table 2). The
ethyl or benzyl group in the R position of nitroolefin enoates
could also be accommodated in this cascade procedure,
providing the corresponding products 3p and 3q with 91%
yield, 96% ee, >95:5 dr and 89% yield, 93% ee, >95:5 dr
(Table 2, entries 16 and 17), respectively. Furthermore,
structural variation in anilines 1 was also tolerated in this
aza-Michael-Michael addition cascade. The aromatic ring
bearing methyl group at the para, meta, or ortho position
of the aniline could undergo the desired cascade reaction
efficiently (Table 2, entries 7-11). For instance, anilines
with electron-rich (Table 2, entries 12 and 15) or electron-
deficient groups (Table 2, entries 13 and 14) proceeded
smoothly with excellent results. As for sulfur-containing
nitroolefin enoates, both Z and E configuration substrates
could be successfully used in this cascade sequence. It is
worth noting that substrate 2 with Z configuration gave a
slightly better result (Table 2, entry 19, 93% yield, 94% ee,
95:5 dr) than the one with E configuration (Table 2, entry
18, 95% yield, 91% ee, 65:35 dr). The relative and absolute
configuration of the product was unambiguously deter-
mined to be 2S, 3R, 4S by using X-ray crystallographic
analysis of 3m (Figure 2).12
Scheme 2. Reaction of o-Toluidine 1i and 2-Methoxyaniline 1j
with Nitroolefin Enoate 2a
the presence of only 2 mol % of catalyst VI. As outlined in
Scheme 3, the reaction proceeded very well to afford ethyl
2-((2S,3R,4S)-4-(2-hydroxyphenylamino)-3-methyl-3-
nitrochroman-2-yl)acetate (3a) in 98% isolated yield
without any loss of stereoselectivities (96% ee, >95:5 dr).
Scheme 3. The Cascade Reaction Was Performed on a Gram
Scale
In summary, we have developed a mild and efficient
organocatalytic aza-Michael-Michael addition cascade of
anilines with nitroolefin enoates by using a readily available
chiral bifunctional thiourea catalyst. This methodology
provides an atom economic and straightforward ap-
proach to optically active 4-aminobenzopyrans with three
consecutive stereogenic carbons including one quaternary
stereocenter in excellent yields and stereoselectivities. Ap-
plication of this reaction to other substrates and to the
preparation of biologicallyrelevant compoundsiscurrently
underway.
Figure 2. X-ray crystal structure of 3m.
Perhaps more importantly, the anilineswithno hydroxyl
group on the aromatic ring can also participate in the
present transformation. Thus, o-toluidine (1i) and 2-meth-
oxyaniline (1j) underwent the aza-Michael-Michael addi-
tion reaction to afford the corresponding benzopyrans
in good yield (88% and 70%, respectively), with excellent
enantioselectivity (98% and 93%, respectively) and di-
astereoselectivity (both drs = 95:5) (Scheme 2).
To demonstrate preparative utility of this aza-
Michael-Michael addition reaction, the reactionof2-ami-
nophenol (1a) and (E)-ethyl 3-(2-((E)-2-nitroprop-1-enyl)
phenoxy)acrylate (2a) was performed on a gram scale in
Acknowledgment. We are grateful to the National
Science Foundation of China (Nos. 20872043, 21002036,
and 21072069), the National Basic Research Program of
China (2011CB808600), and the Program for Changjiang
Scholars and Innovative Research Team in University
(IRT0953) for supporting this research.
Supporting Information Available. Experimental pro-
cedures and compound characterization data including
X-ray crystal data (CIF) for 3m. This material is available
free of charge via the Internet at http://pubs.acs.org.
(12) The configuration of 3m was determined by X-ray crystallo-
graphic analysis. CCDC 803691 (3m) contains the supplementary
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/daa_request/cif.
Org. Lett., Vol. 13, No. 4, 2011
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