Asymmetric synthesis of polysubstituted 4-amino- and 3,4-diaminochromanes with a chiral multifunctional organocatalyst

Article abstract of DOI:10.1021/ol300798t

A series of multifunctional catalysts with two chiral diaminocyclohexane units were developed and successfully applied in the asymmetric oxa-Michael-aza-Henry cascade reaction of salicylaldimines with nitroolefins. This approach provides a simple and effi

Full text of DOI:10.1021/ol300798t

ORGANIC
LETTERS
2012
Vol. 14, No. 9
2378–2381
Asymmetric Synthesis of Polysubstituted
4-Amino- and 3,4-Diaminochromanes with
a Chiral Multifunctional Organocatalyst
Wenduan Hou, Bo Zheng, Jun Chen, and Yungui Peng*
School of Chemistry and Chemical Engineering, Southwest University, Chongqing
400715, P. R. China
pengyungui@hotmail.com
Received March 29, 2012
ABSTRACT
A series of multifunctional catalysts with two chiral diaminocyclohexane units were developed and successfully applied in the asymmetric oxa-
Michaelꢀaza-Henry cascade reaction of salicylaldimines with nitroolefins. This approach provides a simple and efficient entry to polysubstituted
chiral 4-aminobenzopyrans with three consecutive stereocenters and in high yield (up to 97%) with excellent stereoselectivity (up to 98% ee and
>99:1 dr). Facile access to the nonsymmetric optically pure 3,4-diaminochromanes was also obtained.
4-Aminochromanes are ubiquitous in biologically
active compounds,1 as subunits in antihypertensive2 and
anti-ischemic drugs,3 and as modulators of calcium and
potassium channels to control cardiac activity and
blood pressure.4 Recent research has shown that 4-amino-
chromane-substituted 2-alkylimidazopyridine derivatives
could be used as selective acid pump antagonists for the
treatment of gastresophageal reflux disease.5 Because of
the importance of the 4-aminochromane framework,
synthesis6 and, in particular, catalytic asymmetric prepara-
tion of 4-aminochromanes have attracted considerable
attention. The existing syntheses for 4-aminochromane
and its analogues mainly involve reactions of salicylaldi-
mines with electron-rich alkenes,7 alkynals,8 azalactones,9
or allenic esters.10 Xiao and co-workers designed complex
nitroolefin-tethered enoates as substrates and used the
catalytic asymmetric aza-MichaelꢀMichael cascade reac-
tion triggered by anilines to obtain a series of 4-amino-
benzopyrans derivatives with functional acetate sub-
stituents at the 2-position in high yields and with
excellent stereoselectivities.11
(1) (a) Schweizer, E. E.; Meeder-Nycz, O. Chromenes, Chromanes,
Chromones; Ellis, G. P., Eds.; Wiley-Interscience: New York, 1977. (b)
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Rees, C. W., Eds.; Pergamon: Oxford, 1984; Vol. 3.
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(3) Bergmann, R.; Gericke, R. J. Med. Chem. 1990, 33, 492.
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Ferrara, F. N.; Humphreys, W. G.; Grover, G. J.; Santafianos, D.;
Atwal, K. S.; Baird, A. J.; McLaughlin, L. G.; Normandin, D. E.; Sleph,
P. G.; Traeger, S. C. J. Med. Chem. 1997, 40, 24. (b) Evans, J. M.; Fake,
C. S.; Hamilton, T. C.; Poyser, R. H.; Watts, E. A. J. Med. Chem. 1983,
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Bernardi, L.; Comes-Franchini, M.; Fochi, M.; Leo, V.; Mazzanti, A.;
Ricci, A. Adv. Synth. Catal. 2010, 352, 3399. (c) Zhang, Y. L.; Dong,
S. X.; Liu, X. H.; Xie, M. S.; Zhu, Y.; Lin, L. L.; Feng, X. M. Chem.;
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Takahashi, N.; Aihara, T.; Hirao, A.; Kato, T.; Sakakibara, M.;
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Jagannadh, B.; Kumar, S. K.; Kunwar, A. C. Tetrahedron Lett. 2001, 42,
6381. (b) Yadav, J. S.; Reddy, B. V. S.; Sekhar, K. C.; Geetha, V.
Tetrahedron Lett. 2001, 42, 4405. (c) Anniyappan, M.; Muralidharan, D.;
Perumal, P. T. Tetrahedron 2002, 58, 10301. (d) Kumar, R. S.; Nagarajan,
R.; Perumal, P. T. Synthesis 2004, 949. (e) Anniyappan, M.; Perumal, P. T.;
Vittal, J. J. Tetrahedron 2004, 60, 2965. (f) Yadav, J. S.; Muralidharan, D.;
Reddy, B. V. S.; Reddy, P. N. Chem. Lett. 2004, 1436. (g) Wang, J.; Xu,
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Ruano, J. L. G. Chem.;Eur. J. 2010, 16, 9453.
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r
10.1021/ol300798t
Published on Web 04/12/2012
2012 American Chemical Society

We first investigated the use of bifunctional catalyst I17
in the model reaction of salicylaldimine 1a with nitrostyr-
ene 2a in chlorobenzene (Cl-Ph) at ꢀ20 °C. Molecular
Scheme 1. Asymmetric Synthesis of 4-Aminochromane Using a
Tandem Oxa-MichaelꢀAza-Henry Reaction Strategy
˚
sieves (4 A) were added as water scavengers to prevent
decomposition of the aldimine. The reaction proceeded
smoothly to give the desired product 4 in good yield and
diastereoselectivity, but with moderate enantioselectivity
(Table 1, entry 1). In this reaction, only a small amount of
the desulfonamidation product 3 was detected. Addition-
ally, 4 was stable during workup, and no more of the
desulfonamidation byproduct 3 was produced after the
product was stored for several weeks at rt. Using multi-
functional catalyst II18 in the reaction increased the en-
antioselectivity (37% ee to 54% ee) and retained the
diastereoselectivity (97:3), while the yield decreased (88%
to 38%) (Table 1, entry 2). The improved enantioselec-
tivity prompted us todesignand synthesize a series of novel
trifunctional catalysts IIIꢀIX, which were derived from
two chiral 1, 2-diaminocyclohexane units and had tertiary
amine, thiourea, and sulfonamide functional groups. The
efficiencies of these catalysts were evaluated further. Using
catalyst III, increases were observed in the reaction yield
(38% to 78%) and enantioselectivity (54% ee to 60% ee)
(Table 1, entries 2 and 3). After replacement of the
methanesulfonyl subunit (catalyst III) with trifluoro-
methanesulfonyl (catalyst IV), the enantioselectivity in-
creased to 67% ee, while the yield decreased to 67%
(Table 1, entry 4). After the aliphatic sulfonamide moiety
was changed to an aromatic sulfonamide, some promising
results were observed. The enantioselectivity of the pro-
duct increased when the terminal sulfonamide substituent
of the catalyst was changed from 2,4,6-trimethylbenzene-
sulfonyl (V) (56% ee) to 4-methylbenzenesulfonyl (VI)
(70% ee), 4-(trifluoromethyl)benzenesulfonyl (VII) (74%ee),
or 4-nitrobenzenesulfonyl (VIII) (84% ee) (Table 1,
entries 5ꢀ8). These increases may be caused by enhance-
ment of the hydrogen bond donating ability of the sulfo-
namide hydrogen. The hydrogen-bond-donating ability
increases with acidity and is governed by the electronic
status of the aromatic substituent R. After introducing
another NO2 at the 2-position of catalyst VIII to produce
catalyst IX, the enantioselectivity of the product decreased
unexpectedly (Table 1, entry 9). The additional NO2
probably disrupted the hydrogen bond interaction be-
tween the catalyst and the substrate. By comparing the
results with catalysts VI and X, we can conclude that the
chiral central configuration in the two diaminocyclohex-
ane units in VI (1S,2S,10S,20S) was a good match for
Very recently, Schreiner and co-workers12 reported an
asymmetric oxa-Michaelꢀaza-Henry domino reaction of
salicyl-N-tosylimine 1 with nitrostyrenes 2 catalyzed by
quinine thiourea and achieved only product 3 with one
chiral center (Scheme 1), which was thought to be pro-
duced by desulfonamidationꢀelimination from the oxa-
Michaelꢀaza-Henry addition intermediate 4. If the sub-
sequent desulfonamidation reaction could be suppressed,
the optically active 4-aminochromane 4 bearing three
chiral centers could be obtained as the main product.
Further reduction of the nitro group of 4 would pro-
vide direct access to the nonsymmetric diamine com-
pounds 5. Chiral diamines play an important role in
pharmaceuticals13 and show potential application in
catalytic asymmetric synthesis as auxiliaries13a,14 and
organocatalysts15 and as ligands in metal catalysis.16
Therefore, weinvestigateddevelopmentofafacile catalytic
methodology to synthesize enantiomeric pure 4-amino-
chromanes 4 and their derivatives. Herein, we describe the
use of multifunctional catalysts VIII in an efficient asym-
metric oxa-Michaelꢀaza-Henry cascade reaction with
high product yields (up to 97%) and excellent stereoselec-
tivities (up to 98% ee and >99:1 dr).
(15) Reviews: (a) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed.
2004, 43, 5138. (b) Dondoni, A.; Massi, A. Angew. Chem., Int. Ed. 2008,
47, 4638. (c) Melchiorre, P.; Marigo, M.; Carlone, A.; Bartoli, G. Angew.
Chem., Int. Ed. 2008, 47, 6138. (d) Doyle, A. G.; Jacobsen, E. N. Chem.
Rev. 2007, 107, 5713.
Figure 1. Screened organocatalysts.
(16) Reviews: (a) Somanathan, R.; Cortez, N. A.; Parra-Hake, M.;
ꢀ
Chavez, D.; Aguirre, G. Mini-Rev. Org. Chem. 2008, 5, 313. (b)
Vaclavık, J.; Kacer, P.; Kuzma, M.; Cerveny, L. Molecules 2011, 16,
5460.
(17) Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X.; Takemoto, Y. J.
Am. Chem. Soc. 2005, 127, 119.
(18) Wang, C. J.; Zhang, Z. H.; Dong, X. Q.; Wu, X. J. Chem.
ꢁ
ꢀ
ꢁ
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(12) Zhang, Z. G.; Jakab, G.; Schreiner, P. R. Synlett 2011, 9, 1262.
(13) (a) Lucet, D.; Gall, T. L.; Mioskowski, C. Angew. Chem., Int. Ed.
1998, 37, 2580. (b) Zyner, E.; Ochocki, J. Acta Pol. Pharm. Drug Res.
1999, 56, 159. (c) Penio, P.; Parthasarathi, R.; Merrill, S. R.
EP0260555A1.
(14) Mukaiyama, T. Tetrahedron 1981, 37, 4111.
Commun. 2008, 12, 1431.
Org. Lett., Vol. 14, No. 9, 2012
2379

Table 1. Asymmetric Oxa-MichaelꢀAza-Henry Reaction of
Salicylaldimines 1aꢀc with Nitrostyrenes 2a under Various
Conditionsa
Table 2. Asymmetric Oxa-MichaelꢀAza-Henry Reaction of
Salicylaldimines 1 with Nitrostyrenes 2 in the Presence of
Catalyst VIIIa
entry R1
R2
time (h) yieldb (%)
92 (4ca) 97:3
drc
eec (%)
entry imine
cat.
solvent
yieldb (%)
drc
eec (%)
1
H
H
H
H
H
H
H
Ph
72
24
65
38
66
66
66
53
42
42
42
42
113
112
54
42
42
93
93
29
83
93
92
79
89
90
90
90
91
92
92
91
95
94
90
90
86
98
89
90
90
2d
3d
4d
5
m-MePh
o-MePh
p-MePh
m-BrPh
m-ClPh
m-FPh
85 (4cb) 98:2
76 (4cc) 99:1
72 (4cd) 95:5
91 (4ce) 95:5
85 (4cf) 96:4
91 (4cg) 96:4
97(4ch) 96:4
93 (4ci) 95:5
93 (4cj) 96:4
91 (4ck) 98:2
89 (4cl) 97:3
72 (4cl) 92:8
1
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1c
1c
1c
1c
I
Cl-Ph
Cl-Ph
Cl-Ph
Cl-Ph
Cl-Ph
Cl-Ph
Cl-Ph
88
38
78
67
80
93
94
93
94
8
97:3
97:3
97:3
97:3
98:2
98:2
98:2
99:1
97:3
99:1
97:3
98:2
98:2
97:3
97:3
95:5
37
54
60
67
56
70
74
84
74
ꢀ9
80
76
81
78
78
72
2
II
3
III
IV
V
4
6
5
7
6
VI
VII
8
5-Me Ph
7
9
5-Me m-BrPh
8
VIII Cl-Ph
10 5-Me m-ClPh
11 5-Me m-FPh
12 5-Me m-MePh
13e 5-Me m-MeOPh
14e 5-Me m-NO2Ph
15 5-Me Pr
9
IX
X
Cl-Ph
Cl-Ph
10
11
12
13
14
15
16
17
18
19
20e
21f
22g
23h
VIII F-Ph
VIII Me-Ph
VIII o-xylene
VIII DCM
VIII DCE
VIII CH3CN
VIII THF
VIII Cl-Ph
VIII Cl-Ph
VIII Cl-Ph
VIII Cl-Ph
VIII Cl-Ph
VIII Cl-Ph
95
90
93
95
95
67 (4cn) 85:15
81 (4co) 97:3
82 (4cp) 99:1
95 (4cq) 98:2
73 (4cr) 92:8
67 (4cs) 92:8
88 (4ct) 95:5
16 5-Me iBu
17 5-But m-MePh
18 5-Br m-MePh
19 5-Cl m-MePh
20 5-F m-MePh
97
d
85
76
79
92
93
81
>99:1
99:1
96:4
97:3
96:4
98:2
88
91
91
93
93
93
21f
H
m-BrPh
85 (4bb) 96:4g (>99:1) 85g (98)
a Unless noted, reactions were carried out with 1 (Ar = 2,4,6-(iPr)3-
˚
C6H2ꢀ, 0.3 mmol), 2 (0.45 mmol), 4 A MS (85 mg), and VIII (10 mol %)
in 1.0 mL of solvent at ꢀ40 °C. b Isolated yield. c Determined by chiral
HPLC. d Performed at ꢀ20 °C. e Performed at ꢀ30 °C. f Ar = 2,4,6-(Me)3-
C6H2ꢀ. g The results in parentheses are after recrystallization.
a Unless noted, reactions were carried out with 1 (0.3 mmol), 2
˚
(0.45 mmol), 4 A MS (85 mg) and cat. (10 mol %) in 1.0 mL of solvent
at ꢀ20 °C for 24 h. b Isolated yield. c Determined by chiral HPLC. d Trace
amount of product. e Performed at ꢀ30 °C. f Performed at ꢀ40 °C for
3 d. g 15 mol % of VIII was used for 70 h. h 5 mol % of VIII was used for
3 d.
enantioselectivity (93% ee) with a long reaction time (3 d)
(Table 1, entry 21). Desulfonamidation product 3 was not
detected in the reaction at ꢀ40 °C. Decreasing the catalyst
load from 15 to 5 mol % resulted in no large change in the
enantioselectivity or diastereoselectivity (Table 1, entries
22 and 23), but the yield decreased to 81%.
achieving the stereocontrol of the product and that in
catalyst X (1R,2R,10S,20S) was a mismatch. We also
screened other multifunctional catalysts (Supporting
Information), but none of these performed better than
catalyst VIII (Figure 1). Various solvents, including Cl-Ph,
F-Ph, Me-Ph, DCM, DCE, CH3CN, THF, and o-xylene,
were screened for the reaction, and Cl-Ph performed the
best (Table 1, entries 8 and 11ꢀ17). By increasing the steric
hindrance of the sulfonyl groups at the N-terminal of the
salicylaldimine and using 1b and 1c as substrates in the
reaction, the desired products were obtained with im-
proved stereoselectivity (88% ee and 91% ee) but de-
creased yield (85% and 76%) (Table 1, entries 18 and
19). Taking the enantioselectivity into consideration, 1c
was selected as the substrate for further study. Lowering
the reaction temperature to ꢀ30 °C increased the yield
from 76% to 79% and retained enantioselectivity of 91%
ee (Table 1, entries 19 and 20). Witha reaction temperature
of ꢀ40 °C, increases were observed in the yield (92%) and
After establishing the optimized domino reaction con-
ditions, the reaction was extended to a variety of nitroole-
fins and salicylaldimines. The position of the substituent
on the aryl ring of nitrostyrene affected the enantioselec-
tivity and reactivity (Table 2). Nitroolefins with meta-
substituents gave better results in shorter reaction times
than those with ortho- or para-substituents (Table 2, entry
2 vs entries 3 and 4). The electronic effect of the substituent
on the benzene ring of the nitroolefin (Table 2, entries
5ꢀ14) or salicylaldimine had some influence on reactivity
but only a small effect on the stereoselectivity (Table 2,
entries 2, 12, and 17ꢀ20). The best outcome was obtained
for the product of 4cq, with 95% yield and 98% ee
(Table 2, entry 17). The less reactive aliphatic nitroalk-
enes could also be used in the reaction and gave good
yields (g81%), good enantioselectivities (g86% ee),
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Org. Lett., Vol. 14, No. 9, 2012

of polysubstituted 4-aminobenzopyrans with three chiral
centers. This method also provides novel, facile access to the
nonsymmetric 3,4-diaminochromanes compounds. Further
application of these nonsymmetric diamines in catalytic
asymmetric synthesis is currently underway.
Figure 2. X-ray crystal structure of 4bb.
and excellent diastereoselectivities (g97:3 dr) (Table 2, entries
15 and 16). The optical purity of the product could be
improved by recrystallization. For example, almost optically
pure 4bb was achieved (98% ee, >99:1 dr) after recrystalliza-
tion of the initial product (85% ee, 97:3 dr) (Table 2, entry 21).
The relative and absolute configuration of the product
was unambiguously determined to be 2S,3R,4R by X-ray
crystallographic analysis of 4bb (Figure 2).19 A transition-
state model that accounts for the stereochemical outcome
is shown in Figure 3.17 In this model, the protons of the
thiourea and the sulfonamide simultaneously activate the
nitrostyrene and the imine, respectively, through hydrogen
bonds. The tertiary nitrogen deprotonates and activates
the phenolic hydroxyl to attack the β-position of the
nitrostyrene from the Si-face. This forms a negatively
charged intermediate, which is involved in nucleophilic
attack of the carbon of the imine from the Re-face succes-
sively to afford the observed products.
Figure 3. Proposed transition-state model.
Scheme 2. Reduction of 4-Aminochromane to Produce 3,4-
Diaminochromane
The oxa-Michaelꢀaza-Henry adducts were also investi-
gated in the synthesis of the nonsymmetric diamine com-
pound. As outlined in Scheme 2, treatment of 4cq with Zn/
HCl at rt gave 3,4-diaminochromane 5cq in >99% yield
without loss of enantiomeric purity (Scheme 2). Thus, both
4-aminochromanes and 3,4-diaminochromanes could be
synthesized efficiently.
In conclusion, a series of multifunctional organocatalysts
were designed and synthesized. The catalysts were successfully
applied in the asymmetric oxa-Michaelꢀaza-Henry cascade
reaction of salicylaldimines with nitroolefins for the synthesis
Acknowledgment. We are grateful for financial support
from the National Science Foundation of China (21172180
and 20872120) and Specialized Research Fund for the
Doctoral Programof HigherEducation(20110182110006).
Supporting Information Available. Catalysts synthesis,
spectroscopic data, enantioselectivities measurement, and
X-ray crystal data (CIF) for 4bb. This material is available
free of charge via the Internet at http://pubs.acs.org.
(19) CCDC 870994 (4bb) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of charge
from the Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/datarequest/cif.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 9, 2012
2381