Enantioselective synthesis of 2-Aryl-3-nitro-2 H -chromenes catalyzed by a bifunctional thiourea

Article abstract of DOI:10.1055/s-0030-1259956

A bifunctional thiourea-catalyzed tandem approach of oxa-Michael-aza-Henry- desulfonamidation was used to synthesize chiral 2-aryl-3-nitro-2H-chromenes. This method provides direct access to the corresponding products in moderate to good yields and enanti

Full text of DOI:10.1055/s-0030-1259956

1262
CLUSTER
Enantioselective Synthesis of 2-Aryl-3-nitro-2H-chromenes Catalyzed by a
Bifunctional Thiourea
E
nantioselective
h
Synthesis
o
i
f
2-Ar
y
g
l-3-nitro-
2
H
u
-chromeneso Zhang, Gergely Jakab, Peter R. Schreiner*
Institut für Organische Chemie, Justus-Liebig-Universität Gießen, Heinrich-Buff-Ring 58, 35392 Gießen, Germany
Fax +49(641)9934309; E-mail: prs@org.chemie.uni-giessen.de
Received 2 February 2011
In the past decade, thiourea derivatives have emerged as
Abstract: A bifunctional thiourea-catalyzed tandem approach of
oxa-Michael–aza-Henry–desulfonamidation was used to synthesize
chiral 2-aryl-3-nitro-2H-chromenes. This method provides direct
access to the corresponding products in moderate to good yields and
enantioselectivities.
powerful noncovalent organocatalysts for a broad range
of chemical transformations employing primarily hydro-
gen-bonding interactions with various reactants.4 In par-
ticular, synergistic activation of two reactants by a
bifunctional thiourea catalyst has been introduced as a
very useful strategy for the design of novel asymmetric
catalysts, and several privileged catalyst features have
been developed.5 Amongst others, thiourea 5a (Scheme 2)
developed independently by Soós and Connon has been
widely employed as an effective catalyst in a wide range
of asymmetric transformations.6 As part of our ongoing
project in noncovalent organocatalysis, we were interest-
ed in the development of novel tandem reactions driven
by a single organocatalyst.7 Herein, we report the first
thiourea-catalyzed stereoselective synthesis of optically
active 3-nitro-2H-chromenes in tandem oxa-Michael–
aza-Henry–desulfonamidation reactions of salicyl N-
tosylimine with nitroolefins (Scheme 1, equation 2).
Key words: bifunctional organocatalysis, H bond, nitrochromene,
tandem reaction, thiourea
3-Nitro-2H-chromenes are not only the core units in a
number of natural products but also serve as privileged
precursors to a variety of bioactive molecules.1 Optically
active 2-substituted 3-nitro-2H-chromenes are particular-
ly useful building blocks. However, synthetic methodolo-
gies regarding enantioselective construction of 2-aryl-3-
nitro-2H-chromenes have not been fully explored. In this
context, catalytic asymmetric tandem oxa-Michael–
Henry reactions of salicylaldehyde with nitroolefins,
though considered to be a straightforward process, has
only been recently reported using proline derivatives as
catalysts, which unfortunately give 3-nitro-2H-chromenes
with poor to moderate enantioselectivities (Scheme 1, eq.
1).2 Recently, Xie et al. reported an alternative strategy
employing kinetic resolution of racemic 3-nitro-2H-
chromenes with Takemoto’s organocatalyst.3 Although
this approach provides the products in good enantioselec-
tivities, racemic 3-nitro-2H-chromenes must be prepared
first. In spite of the aforementioned synthetic advances, to
the best of our knowledge, a general solution to produce
2-substituted nitrochromenes with high enantioselectivi-
ties has not been reported.
Our investigation began with the reaction of salicylalde-
hyde and nitroolefin in the presence of several quinine de-
rivatives as the catalysts, in the hope of obtaining the
corresponding nitrochromene with high enantioselectivity
(Scheme 2). Among all the compounds tested, thiourea 5a
was the most effective in promoting this transformation,
but provided the desired product only in poor yield (21%)
and stereoinduction (9% ee). In addition, intermediate ni-
trochromane 4 was isolated in moderate yield (66%),
which exists exclusively as a single diastereoisomer
(>99% de), but gave no ee, as confirmed with chiral
HPLC.8 Performing the reaction at lower temperature re-
sulted in drastic decrease in yield but without improve-
ment of ee.
NO2
Ph
CHO
OH
NO2
Ar
(1)
Along with catalyst modifications, we also turned our at-
tention to apply an indirect, but equally efficient strategy
to counter this problem by using activated aldimines as al-
dehyde surrogates, assuming that the substrate shows en-
hanced binding ability with the known thiourea catalysts
and may thus improve the reaction. Intrigued by the emer-
gence of sulfone derivatives as effective hydrogen-
bonding acceptors, we applied salicyl N-tosylimine as the
corresponding substrate.9 As expected, the reaction pro-
ceeds smoothly in the presence of thiourea 5a at room
temperature to furnish the product in 65% yield with
much improved enantioselectivity (46%, Table 1, entry
1). Quinine 5d promoted this reaction as well, but gave the
product in poor ee (Table 1, entry 4), whereas epi-9-
*
imine organocatalysis
O
Ts
N
NO2
Ph
NO2
Ar
(2)
*
Brønsted acid
organocatalysis
O
OH
Scheme 1 Enantioselective synthesis of 2-aryl-3-nitrochromenes
SYNLETT 2011, No. 9, pp 1262–1264
x
x.
x
x.
2
0
1
1
Advanced online publication: 20.04.2011
DOI: 10.1055/s-0030-1259956; Art ID: Y03611ST
© Georg Thieme Verlag Stuttgart · New York

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Enantioselective Synthesis of 2-Aryl-3-nitro-2H-chromenes
1263
Table 1 Catalysts Screening and Reaction Condition Optimizationsa
CHO
NO2
Ph
Ts
N
OH
O
1
3
NO2
catalyst (10 mol%)
toluene, r.t., 24 h
catalyst (10 mol%)
NO2
+
+
+
Ph
toluene
*
OH
NO2
Ph
OH
O
Ph
NO2
Ph
2
*
Entry
Catalyst 5
Temp (°C) Yield (%)b
ee (%)c
46
*
*
O
4
1
2
3
4
5d
6
7
5a
5b
5c
5d
5a
5a
5a
r.t.
r.t.
r.t.
r.t.
r.t.
65
0
n.d.
n.d.
11
0
N
N
H
H
N
N
CF3
OH
53
63
31
0
MeO
S
MeO
36
CF3
N
N
0
92
5a
5b
–20
n.d.
a Reactions were performed at 0.2 mmol scale.
b Yield of 3 after column chromatography.
c Determined by chiral HPLC.
N
N
H
H
N
N
CF3
OH
d CH2Cl2 as the solvent.
MeO
S
MeO
CF3
N
N
elution after 24 hours, which further confirmed the exist-
ence of the intermediate. Efforts on isolating the interme-
diate failed, owing to its spontaneous decomposition to
the desired product 3. In light of our observations, the high
enantioselectivity is likely produced by a kinetically con-
trolled desulfonamidation step controlled by thiourea 5a.
5c
5d
Scheme 2 Initial catalyst investigations
quinine 5b and thiourea 5c were ineffective for this trans-
formation, suggesting that a proper steric arrangement of
functional motifs is a prerequisite for catalyst activity
(Table 1, entries 2 and 3). Toluene is a superior solvent to
dichloromethane in terms of enantioselectivity (Table 1,
entry 5). The reaction can be easily monitored in toluene
as the tosylamide co-product precipitates as a white solid
from the solution as the reaction proceeds. Notably, un-
precedented enantioselectivity up to 92% at lower temper-
ature can be accomplished, albeit at the expense of the
yield of isolated product (Table 1, entry 6). Further de-
crease in reaction temperature resulted in the loss of reac-
tivity (Table 1, entry 7).
We next examined the scope of this reaction with regard
to nitrostyrenes and salicylaldimines. Nitrostyrenes bear-
ing both electron-donating and electron-withdrawing sub-
stituents are tolerated, affording the product at room
temperature in moderate to good yields. While salicyl N-
tosylimine bearing electron-withdrawing groups gives the
product in higher yield with moderate enantioselectivity
(Table 2, entry 11), N-tosylimine bearing electron-donat-
ing groups resulted in low yields, but afforded high ee val-
ues (Table 2, entry 10). In view of the critical role of
reaction temperature on both the yields and enantioselec-
tivities, most of the reactions were carried out at room
temperature and 0 °C, respectively (Table 2). Generally,
reactions at low temperature afforded the products in high
ee with the erosion of yields.
With regard to the variable results at different tempera-
tures, we undertook further investigations. First, the reac-
tion time at 0 °C was prolonged, but the reaction
conversions and ee values were not improved. The ee val-
ues were then monitored over time at 0 °C. At the start of
the reaction, the ee value was 45%, and it rose to 92% af-
ter six hours. From this point the ee remains at this value
until the end of the reaction. GC-MS and TLC revealed
that the two substrates were completely consumed, sug-
gesting that the low yield was due to an incomplete elim-
ination process of tosylamide from the oxa-Michael–aza-
Henry addition intermediate under such reaction condi-
tions. In addition, during the separation of the reaction
mixture on flash silica gel, we found that an additional
fraction of product with low ee can be collected by re-
In conclusion, we have developed an enantioselective
synthesis of 3-nitro-2H-chromenes by reaction of salicyl
N-tosylimine with nitroolefins utilizing bifunctional thio-
urea as the catalyst. A broad range of substituted nitrosty-
renes undergo
a tandem oxa-Michael–aza-Henry–
desulfonamidation process to afford the corresponding 2-
aryl-3-nitro-2H-nitrochromenes by a kinetically con-
trolled desulfonamidation step. Mechanistic details and
further improvement of this reaction are currently under
investigation.
Synlett 2011, No. 9, 1262–1264 © Thieme Stuttgart · New York

1264
Z. Zhang et al.
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Table 2 Investigation of the Reaction Scopea
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50 (80)
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35
H
2-MeOC6H4
4-MeOC6H4
4-MeC6H4
4-BrC6H4
2,3-(MeO)2C6H3
2,6-Cl2C6H3
3,4-Cl2C6H3
furyl
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H
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H
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H
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H
81 (42)
34 (23)
93 (68)
87 (54)
20
48 (97)
37 (52)
31 (46)
43 (51)
80
7
H
8
H
9
H
10
11
5-MeO
4-Br
Ph
Ph
75
41
a Reactions were performed at 0.2 mmol scale.
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d Values in parentheses are obtained at 0 °C.
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Acknowledgment
Generous financial support by the Deutsche Forschungsgemein-
schaft (SPP1179) and a fellowship of the Junior Science and
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Synlett 2011, No. 9, 1262–1264 © Thieme Stuttgart · New York