Organocatalyzed synthesis of 2-amino-8-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitriles

Article abstract of DOI:10.1016/j.tetlet.2009.12.139

2-Amino-8-oxo-tetrahydro-4H-chromene-3-carbonitriles were synthesized for the first time from a tandem Michael addition-cyclization reaction between cyclohexane-1,2-dione and benzylidenemalononitriles. An enantioselective synthesis of these compounds was achieved in moderate ee values (up to 63% ee) by using a cinchona alkaloid-derived thiourea catalyst.

Full text of DOI:10.1016/j.tetlet.2009.12.139

Tetrahedron Letters 51 (2010) 1322–1325
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Organocatalyzed synthesis of
2-amino-8-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitriles
*
Derong Ding, Cong-Gui Zhao
Department of Chemistry, University of Texas at San Antonio, One UTSA Circle, San Antonio, TX 78249-0698, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
2-Amino-8-oxo-tetrahydro-4H-chromene-3-carbonitriles were synthesized for the first time from a tan-
dem Michael addition-cyclization reaction between cyclohexane-1,2-dione and benzylidenemalononitr-
iles. An enantioselective synthesis of these compounds was achieved in moderate ee values (up to 63% ee)
by using a cinchona alkaloid-derived thiourea catalyst.
Received 12 November 2009
Revised 21 December 2009
Accepted 30 December 2009
Available online 11 January 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Chromene
Tandem reaction
Enantioselective
Cinchona alkaloid
Organocatalysis
1,2-Cyclohexanedione
Benzylidenemalononitrile
Polysubstituted 2-amino-4H-pyran-3-carbonitrile derivatives
are very important heterocyclic compounds, which frequently exhi-
bit a variety of biological activities.1,2 Among these compounds, 2-
amino-4H-chromene-3-carbonitrile derivatives have been reported
to possess anticancer, anticoagulant, and fungicidal activities.2
Thesecompoundsalso findapplicationsaspigmentsandaspotential
biodegradableagrochemicals.3 Duetotheirusefulness, thesynthesis
of these compounds has attracted a lot of interest.4 Most recently,
asymmetric syntheses of some of these 2-amino-4H-pyran-3-carbo-
nitrile derivatives have also been reported.5 Furthermore, the syn-
thesis of partially saturated 2-amino-4H-chromene-3-carbonitrile
derivatives has also been reported.6 For example, the cyclization
reaction between 1,3-dicarbonyl compounds and benzylidenemal-
ononitriles in the presence of a suitable base gives 2-amino-5-oxo-
5,6,7,8-tetrahydro-4H-chromene-3-carbonitriles,6 which have also
been demonstrated to have biological activities.6a Nonetheless, the
synthesis of their 8-oxo analogues has not been reported, although
such compounds reportedly are able to alter the lifespan of eukary-
otic organisms.7
diones and a,b-unsaturated aldehydes catalyzed by an N-heterocy-
clic carbene.9b In 2006, we reported a direct cross aldol reaction of
1,2-diones and ketones catalyzed by proline derivatives.9c Most
recently, Rueping and coworkers reported a tandem5,10 Michael-al-
dol reaction of cyclohexane-1,2-dione and
a,b-unsaturated
aldehydes.9d
We are interested in developing novel enantioselective methods
for the synthesis of 2-amino-4H-pyran-3-carbonitrile derivatives. In
this regard, we developed the first enantioselective synthesis of 6-
amino-5-cyanodihydropyrano[2,3-c]pyrazoles through a tandem
Michael addition-cyclization reaction between 2-pyrazolin-5-ones
and benzylidenemalononitriles.5b The fact that cyclohexane-1,2-
dione may be enolized and used in a Michael addition reaction under
organocatalysis9d prompted us to use this compound as a potential
Michael donor in a tandem Michael addition-cyclization reaction
with benzylidenemalononitriles. Herein we wish to report the first
general and enantioselective synthesis of 2-amino-8-oxo-5,6,7,8-
tetrahydro-4H-chromene-3-carbonitriles on the basis of a tandem
Michaeladdition-cyclization reactionbetweenbenzylidenemalono-
nitriles and cyclohexane-1,2-dione.
Cyclohexane-1,2-dione (1) and benzylidenemalononitrile (2a)
were adopted as the starting materials for the proposed Michael
addition reaction. On the basis of Rueping’s results, the reaction
was studied with several readily available organic and inorganic
bases as the catalysts. The results are summarized in Table 1.
As shown in Table 1, when the reaction was carried out with
10 mol % DABCO as the base catalyst in toluene at room tempera-
ture for 27 h (entry 1), a product, which was identified to be 3a,
On the other hand, 1,2-diones are highly reactive compounds and
have found many applications in organic synthesis.8 Nevertheless,
they have been seldom used in organocatalyzed reactions.9 These
few examples are collected below: Göbel and coworkers utilize the
dione as an ene-activator in an organocatalyzed Diels–Alder reac-
tion.9a Nair et al. reported a lactonization reaction between 1,2-
* Corresponding author. Tel.: +1 210 458 5432; fax: +1 210 458 7428.
E-mail address: cong.zhao@utsa.edu (C.-G. Zhao).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.12.139

D. Ding, C.-G. Zhao / Tetrahedron Letters 51 (2010) 1322–1325
1323
Table 1
electron-withdrawing group substituted at the para position (en-
tries 11–14). Benzylidenemalononitriles with a meta substituent
(entry 15) or an electron-donating group (entry 16) also led to
good results. Heterocyclic thiophen-2-ylmethylidenemalononitrile
gave the highest yield of 79% of the desired product (entry 17).
Alkylidenemalononitrile 2i also reacted to produce the expected
product 3i, although the yield is lower and the reaction is sluggish
(entry 18). However, other 1,2-diones, such as butane-2,3-dione
and 3-methylcyclopentane-1,2-dione, do not yield the expected
product (data not shown), with the former giving no product at
all and the latter some unidentified products.
Tandem Michael addition-cyclization reaction between 1,2-cyclohexanedione (1) and
benzylidenemalononitriles (2)a
O
O
O
O
R
NH2
CN
CN
CN
catalyst
R
3
2
1
Entry
R
2/3
Solvent
Catalyst
Time (h)
Yieldb (%)
Since one stereogenic center is created at the 4-position of prod-
uct 3 during this reaction, it was our intention to develop an asym-
metric version of this reaction by using chiral Lewis base
organocatalysts. Thus, with 1 and 2a as the model substrates,
several readily available chiral Lewis base organocatalysts (Fig. 1)
were screened. The results of this screening are collected in Table
2. As detailed in Table 2, out of the 10 catalyst screened, only the qui-
nine-derived thiourea catalysts 4a, 4b, and 4c are giving slightly
higher ee values (about 35% ee) when they were applied in toluene
at room temperature (entries 1–3), while the rest all generated ee
values no greater than 30% (entries 4–10). It should be pointed out
that catalysts 4d, 4e, 4f, 4g, and 4j (entries 4–7, and 10) produce
the other enantiomer as the major product as compared to the rest
catalysts. Because catalyst 4a yields the best yields and the highest
ee values among the three best catalysts, further optimizations were
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
a
a
a
a
a
a
a
a
a
a
b
c
d
e
f
Toluene
Toluene
Toluene
Toluene
Toluene
CH2Cl2
THF
EtOAc
Acetone
EtOH
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
DABCO
DBU
Et3N
27
30
38
48
72
24
28
27
29
30
24
30
23
22
20
25
26
32
75
43
67
29
0
K2CO3
NaHCO3
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
71
74
64
51
61
73
59
45
64
65
67
79
39
4-ClC6H4
4-BrC6H4
4-CNC6H4
4-NO2C6H4
3-BrC6H4
4-CH3C6H4
Thiophen-2-yl
CH3(CH2)5
g
h
i
a
All reactions were conducted with the indicated arylidenemalononitrile (2,
0.30 mmol), 1,2-cyclohexanedione (1, 0.32 mmol), and the catalyst (10 mmol %,
CF3
CF3
0.03 mmol) in the specified solvent (1.5 mL) at room temperature.
b
Yield of isolated product after column chromatography.
S
S
NH
N
H
CF3
F3C
HN
N
H
was isolated in 75% yield. Unlike Rueping’s results,9d no formation
of bridged bicyclic products was observed.11 Formation of 3a may
be rationalized by the tandem enolization–Michael addition–enoli-
zation–cyclization reaction–tautomerization sequence as shown in
Scheme 1. DBU, Et3N, and K2CO3 also catalyze this reaction (entries
2–4), albeit in lower efficiency. However, a weaker base NaHCO3
cannot catalyze the reaction, as no product could be obtained (en-
try 5). Further screening of the reaction solvents identified that tol-
uene (entry 1), CH2Cl2 (entry 6), and THF (entry 7) are good
solvents for this reaction, while EtOAc, acetone, and EtOH (entries
8–10) are worse ones. Under the optimized conditions, several
substituted benzylidenemalononitriles were applied as the sub-
strate. As shown by the results in Table 1, acceptable to good yields
(45–73%) were obtained with benzylidenemalononitriles with an
N
N
R1
N
H
H
N
R2
OMe
4a R1 = -CH=CH2; R2 = OMe
4b R1 = -CH2CH3; R2 = OMe
4c R1 = -CH=CH2; R2 = H
4d
R
R
N
TsHN
H
N
H
N
CF3
N
S
N
H
CF3
OMe
4e R = H
4f R = Me
4g
O
CN
O
O
OH
O
CN
CN
Ph CN
O
B:
BH
O
O
N
Ph
Ph
H
N
H2N
NH2
Ph
O
HO
O
O
N
4h
4i
BH
B:
CN
CN
CN
OH
Ph
Ph
N
O
O
NH
CN
N
H
tautomerization
3a
OH
4j
Ph
Scheme 1. Proposed mechanism for the formation of product 3.
Figure 1. Chiral catalyst screened for the enantioselective synthesis of 3a.

1324
D. Ding, C.-G. Zhao / Tetrahedron Letters 51 (2010) 1322–1325
Table 2
Table 3
Catalyst screening for the enantioselective synthesis of 3aa
Enantioselective synthesis of 2-amino-8-oxo-tetrahydro-4H-chromene-3-carbonitrilesa
O
O
O
O
*
NH2
CN
O
O
O
NH2
CN
CN
CN
CN
catalyst
4a
toluene, 0 ºC
Ph
CN
R
*
O
Ph
R
3a
2a
3
1
2
1
Yieldb (%)
eec (%)
Entry
Solvent
Catalyst
Time (h)
Yieldb (%)
eec (%)
Entry
R
3
Time (h)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18e
19e
20f
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
CH2Cl2
Et2O
EtOAc
THF
CHCl3
CH3CN
EtOH
4a
4b
4c
4d
4e
4f
4g
4h
4i
26
30
30
28
240
40
26
168
28
28
30
28
28
40
38
28
28
72
28
28
56
41
47
37
21
34
70
31
61
72
43
55
35
33
33
31
53
58
64
43
35
35
34
30d
1d
1
2
3
4
5
6
7
8
9
Ph
3a
28
24
30
24
26
24
28
30
96
64
60
55
51
55
63
49
37
12
63
58
57
43
48
52d
50
47e
9d
4-ClC6H4
4-BrC6H4
4-CNC6H4
4-NO2C6H4
3-BrC6H4
4-CH3C6H4
Thiophen-2-yl
CH3(CH2)5
3b
3c
3d
3e
3f
3g
3h
3i
27d
25d
3
16
4j
3d
a
All reactions were conducted with the benzylidenemalononitrile (0.30 mmol),
cyclohexane-1,2-dione (0.32 mmol), and catalyst 4a (10 mol %, 0.030 mmol) in
toluene (1.5 mL) at 0 °C.
Yield of isolated product after column chromatography.
Unless otherwise specified, ee values were determined by HPLC analysis on a
ChiralCel OD-H column.
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
18
17
25
33
6
15
40
40
63
59
b
c
d
Determined by HPLC analysis on a ChiralPak AD-H column.
Determined by HPLC analysis on a ChiralPak AS column.
e
EtOH
Toluene
Toluene
a
Unless otherwise indicated, all reactions were conducted with benzylidene-
reaction was also realized (with ee value up to 63%) by using a qui-
nine-derived thiourea catalyst.
malononitrile 2a (0.30 mmol), cyclohexane-1,2-dione (0.32 mmol), and the catalyst
(10 mmol %, 0.030 mmol) in the specified solvent (1.5 mL) at room temperature.
b
Yield of isolated product after column chromatography.
Determined by HPLC analysis on a ChiralCel OD-H column.
The opposite enantiomer was obtained as the major product in these cases.
The reaction was conducted at 0 °C.
c
Acknowledgments
d
e
This research is financially supported by the Welch Foundation
(Grant No. AX-1593) and partly by the National Institute of General
Medical Sciences (Grant No. 1SC1GM082718-01), for which the
authors are most grateful.
f
The reaction was conducted at À15 °C.
focused on catalyst 4a. Screening different organic solvents revealed
that most of these solvents (entries 11–16) produce worse ee values
of the product than toluene does (entry 1). Only in ethanol a higher
ee value of 40% was achieved (entry 17). Nevertheless, the attemptto
further increase the ee value through lowering the reaction temper-
ature failed in this solvent, since at 0 °C the same ee value was
obtained (entry 18). We then went back to toluene and tried to in-
crease the ee value by employing the temperature effects. To our
pleasure, with toluene, the ee value of the product 3a may be
increased to 63% at 0 °C (entry 19). However, further dropping of
the temperature (to À15 °C) proves to have detrimental effects on
both the reactivity and the enantioselectivity of this reaction (entry
20). Once the optimized reaction conditions were found, the other
benzylidenemalononitrileswereappliedtothisreactionunderthese
conditions. The results are collected in Table 3.
As shown in Table 3, benzylidenemalononitriles with various
substituents all produce the desired product in mediocre to good
ee values (43–63% ee, entries 1–7). The yields (49–64%) obtained
are usually low because of the formation of some unidentified
products in the reaction. The heterocyclic thiophen-2-ylmethylid-
enemalononitrile also gives the expected product in 47% ee and
37% yield (entry 8). However, the alkylidenemalononitrile 2i reacts
very slowly and leads to a poor ee value of the product (entry 9).
Again, butane-2,3-dione and 3-methylcyclopentane-1,2-dione
failed to yield the desired products (data not shown).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.12.139.
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11. The reaction does produce some unidentified products, which lowers the yield
of the reaction.