Solvent-free cascade reaction: direct multicomponent assembling of 2-amino-4H-chromene scaffold from salicylaldehyde, malononitrile or cyanoacetate and nitroalkanes

Article abstract of DOI:10.1016/j.tet.2010.04.024

The new type of solvent-free cascade reaction was found: the direct heating of the mixture of salicylaldehyde, malononitrile or cyanoacetate and nitroalkanes at 60 °C in the presence of catalytic amounts of KF or NaOAc results in the formation of 2-amino-

Full text of DOI:10.1016/j.tet.2010.04.024

Tetrahedron 66 (2010) 4043–4048
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Solvent-free cascade reaction: direct multicomponent assembling of 2-amino-
4H-chromene scaffold from salicylaldehyde, malononitrile or cyanoacetate
and nitroalkanes
*
Michail N. Elinson , Alexey I. Ilovaisky, Valentina M. Merkulova, Pavel A. Belyakov, Alexander O. Chizhov,
Gennady I. Nikishin
N. D. Zelinsky Institute of Organic Chemistry, Leninsky prospect 47, 119991 Moscow, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
The new type of solvent-free cascade reaction was found: the direct heating of the mixture of salicyl-
aldehyde, malononitrile or cyanoacetate and nitroalkanes at 60 ꢀC in the presence of catalytic amounts of
KF or NaOAc results in the formation of 2-amino-4-(1-nitroalkyl)-4H-chromene-3-carbonitriles or
methyl 2-amino-4-(1-nitroalkyl)-4H-chromene-3-carboxylates in 80–90% yields. Thus, the new simple
and efficient solvent-free `one-pot' way to substituted medicinally privileged 2-amino-4H-chromene
scaffold was found directly from such simple and reasonable starting compounds as salicylaldehyde,
malononitrile or cyanoacetate and nitroalkanes.
Received 26 November 2009
Received in revised form 16 March 2010
Accepted 6 April 2010
Available online 10 April 2010
Keywords:
Solvent-free reactions
Salicylaldehyde
Malononitrile
Ó 2010 Elsevier Ltd. All rights reserved.
Cyanoacetate
Nitroalkanes
2-Amino-4H-chromenes
1. Introduction
have played ever increasing role in the synthetic approaches to
promising compounds in the field of medicinal chemistry.6 Among
The discovery of new synthetic methodologies to facilitate the
preparation of organic compounds is a pivotal focal point of re-
search activity in the field of modern organic, bioorganic and me-
dicinal chemistry.1 One approach to address this challenge involves
the development of multicomponent reactions (MCRs), in which
three or more reactants are combined together in a single reaction
flask to generate a product incorporating most of the atoms con-
tained in the starting materials.2
In recent years the concept of `privileged medicinal structures or
scaffolds'3 has emerged as one of the guiding principles of drug
discovery process. It involves the utilization of molecular frame-
works with inherent potential for biological activity. These privi-
leged scaffolds commonly consist of rigid hetero ring system that
assigns well-defined orientation of appended functionalities for
target recognition.4
different types of chromene systems, 2-amino-4H-chromenes (or
2-amino-4H-benzo[b]pyranes) are of particular utility as they be-
long to privileged medicinal scaffolds serving for generation of
small-molecule ligands with highly pronounced spasmolitic-, di-
uretic-, anticoagulant- and antianaphylactic activities.3a,3c,7 The
current interest in 2-amino-4H-chromene derivatives arises from
their potential application in the treatment of human inflammatory
TNFa-mediated diseases, such as rheumatoid and psoriatic arthritis
and in cancer therapy.8
Recently we suggested an electrocatalytic process as facile and
convenient way to create diversely substituted medicinally privi-
leged 2-amino-4H-chromene scaffold directly from salicylalde-
hydes and two different C–H acids.9 The developed electrocatalytic
system afforded the distinction between two C–H acids according
to their reactivity and for the first time offered an efficient approach
to the design and actual synthesis of privileged 2-amino-4H-chro-
mene scaffold with a predefined arrangement of desired sub-
stituents. The electrocatalytic multicomponent reaction smoothly
proceeded with salicylaldehydes bearing both electron-donating
and electron-withdrawing groups, and allows for the selective and
combined one-step introduction of the wide range of medicinally
promising functionalities into privileged 2-amino-4H-chromene
framework. Thus, fifteen previously inaccessible close structural
The chromene moiety often appears as an important structural
component in both biologically active and natural compounds. It is
widely performed in natural alkaloids, flavonoids, tocopherols and
anthocyanins.5 Moreover, in recent years functionalized chromenes
* Corresponding author. Tel.: þ7 499 137 38 42; fax: þ7 499 135 53 28; e-mail
address: elinson@ioc.ac.ru (M.N. Elinson).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.04.024

4044
M.N. Elinson et al. / Tetrahedron 66 (2010) 4043–4048
Table 1
analogues of tumour antagonists HA14-1 and MX58151 have been
synthesized. The electrocatalytic process was found to be advan-
tageous in terms of selectivity and yields compare to classic
chemical base catalysis.
Solvent-free cascade transformation of salicylaldehyde 1, methyl cyanoacetate 2a
and nitromethane 3a into 2-amino-4H-chromene 4aa
Entry
Base
Base (mmol)
t (h)
Yield of 4ab (%)
1
2
3
4
5
7
8
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
KF
1
3
5
5
5
1
3
3
3
3
2
1
1
1
75
83
91
But in the case of the nitroalkanes as one of C–H acids used in
the electrocatalytic process the yields of the corresponding
substituted 2-amino-4H-chromenes were only in the range of
65–70%, which could be connected with the undesired reduction of
the nitro group at cathode.
65c,d
39c,e
78
KF
93
Recently the progress in the field of solvent-free reactions have
provided organic chemists with a new simple efficient synthetic
method of great promise. This is connected with high efficiency and
operational simplicity of the solvent-free processes.10 The de-
velopment of solvent-free organic synthesis methods has become
an important research area. This is not only due to the need for the
more efficient and less labour-intense methodologies for the syn-
thesis of organic compounds, but also consequence of the in-
creasing importance of the environmental considerations in
chemistry. The elimination of volatile organic solvents in organic
synthesis is also a most important goal in green chemistry.
Thus, solvent-free reactions have significant economical and
ecological benefits when one performs several synthetic steps in
one operation without isolating the reaction intermediates. The
implication of the solvent-free process in base-activated multi-
component reactions (MCR) is highly promising as it allows for the
combination of the synthetic virtues of the conventional MCR
strategy with the ecological benefits and convenience of the sol-
vent-free procedure. Thus, we were prompted to use a convenient
and facile solvent-free MCR methodology for the synthesis of 2-
amino-4H-chromene scaffold from salicylaldehydes, cyanoacetate
or malononitrile and nitroalkanes.
a
10 mmol of salicylaldehyde 1, 10 mmol of methyl cyanoacetate 2a, 10 mmol of
nitromethane 3a, 60 ꢀC.
b
Isolated yield.
c
1H NMR data yields.
d
Conversion of 1d93%, 2-amino-4-(1-cyano-2-methoxy-2-oxoethyl)-4H-chro-
mene-3-carboxylate 5a was also found in the reaction mixture in 16% yield.
e
Conversion of 1d74%, 2-amino-4-(1-cyano-2-methoxy-2-oxoethyl)-4H-chro-
mene-3-carboxylate 5a was also found in the reaction mixture in 29% yield.
The best 91–93% yield of 2-amino-4H-chromene 4a was ach-
ieved when the reaction was carried in the presence of 5 mmol of
NaOAc (3 h at 60 ꢀC) or 3 mmol of KF (1 h at 60 ꢀC); entries 3 and 8
(Table 1).
Under the optimal conditions thus found, i.e., 5 mmol of NaOAc
(3 h at 60 ꢀC) or 3 mmoles of KF (1 h at 60 ꢀC), salicylaldehyde 1,
C–H acids 2a,b and nitrocompounds 3a–j were transformed into
corresponding substituted 2-amino-4H-chromenes 4a–o in
80–93% yields (Table 2).
2-Amino-4H-chromenes 4b,f–j,l–o were isolated as mixtures of
diastereomers, the ratio was established by NMR data and is given
in Table 2. For the compounds 4g and 4f NMR HSQCED and HMBC
spectra were recorded to establish the position of all C-atoms. The
comparison of experimental and calculated11 NMR 13C spectra in-
dicated a (R
*
, R
*
) configuration for the main isomer of 4g and (R
*
*
, S )
2. Results and discussion
for the main isomer of 4f.
In order to examine the mechanism of the new solvent-free
multicomponent reaction, some other solvent-free reactions were
In the present study we report our results on the solvent-free
direct `one-pot' cascade transformation of salicylaldehyde 1, cya-
noacetate or malononitrile 2a,b and nitroalkanes 3a–j into the
carried out. The solvent-free reaction of salicylaldehyde
1
(10 mmol) with 2 equiv of nitromethane 3a (20 mmol) in the
presence of NaOAc (5 mmol) at 60 ꢀC during 3 h resulted only in
2-(1-hydroxy-2-nitroethyl)phenol (Henry reaction adduct, NMR-
data) formation in 8% yield (conversion of salicylaldehyde was 9%).
Thus, nitromethane practically did not react with salicylaldehyde
under these conditions. Analogous reactions of salicylaldehyde 1
(10 mmol) with 2 equiv of methyl cyanoacetate 2a (20 mmol) led to
substituted
(Scheme 1).
2-amino-4-(1-nitroalkyl)-4H-chromenes
4a–o.
First, to evaluate the synthetic potential of the procedure pro-
posed and to optimize the general conditions, the solvent-free base
initiated cascade transformation of salicylaldehyde 1, methyl cya-
noacetate 2a and nitromethane 3a into 2-amino-4H-chromene 4a
was studied (Table 1).
R2
R1
NO2
CHO
X
X
Solvent-free
NaOAc/KF
R1R2CHNO2
+
+
CN
OH
3a-j
O
NH2
2
1
4a-o
a R1 = R2 = H
a X = CO2CH3
b X = CN
b R1 = CH3, R2 = H
c R1 = C2H5, R2 = H
d R1 = R2 = CH3
e R1 + R2 = -(CH2)5-
f R1 = Ph, R2 = H
a R1= R2 = H, X = CO2CH3
b R1 = CH3, R2 = H, X = CO2CH3
c R1 = C2H5, R2 = H, X = CO2CH3
d R1= R2 = CH3, X = CO2CH3
e R1 + R2 = -(CH2)5-, X = CO2CH3
f R1 = Ph, R2 = H, X = CO2CH3
g R1 = CH2CH2COCH3, R2 = H
h R1 = CH2CH2COCH3, R2 = CH3
i R1 = CO2CH3, R2 = H
g R1 = CH2CH2COCH3, R2 = H, X = CO2CH3
h R1 = CH2CH2COCH3, R2 = CH3, X = CO2CH3
i R1 = CO2CH3, R2 = H, X = CO2CH3
j R1 = CH2CH2CO2CH3, R2 = CH3, X = CO2CH3
k R1 = R2 = H, X = CN
j R1 = CH2CH2CO2CH3, R2 = CH3
l R1 = C2H5, R2 = H, X = CN
m R1= CH2CH2COCH3, R2 = H, X = CN
n R1 = CH2CH2COCH3, R2 = CH3, X = CN
o R1 = CH2CH2CO2CH3, R2 = CH3, X = CN
Scheme 1.

M.N. Elinson et al. / Tetrahedron 66 (2010) 4043–4048
4045
Table 2
2a,b and nitroalkanes 3a–j into the substituted 2-amino-4H-chro-
menes 4a–o (Scheme 2). The initiation step of the catalytic cycle
begins with the deprotonation of a molecule of the more active C–H
acid by the action of catalyst, which leads to the formation of an
anion A, which then reacts with salicylaldehyde 1 with the elimi-
nation of hydroxide anion and the formation of the Knoevenagel
adduct 6 (Scheme 2).12
Solvent-free multicomponent transformation of salicylaldehyde 1, C–H acids 2a,
b and nitro- compounds 3a–j into 2-amino-4H-chromenes 4a–oa
Entry C–H Nitro-
acid compound
Base
Base
(mmol)
t (h) 2-amino-
Ratio of
4H-chromene, diastereomersc
yield (%)b
1
2
3
4
5
6
7
8
2a
2a
3a
3b
KF
3
5
5
5
3
3
3
3
3
3
3
5
3
3
5
3
5
3
1
3
3
3
1
1
1
1
1
1
1
3
1
1
3
1
3
1
4a, 93
4b, 90
4c, 87
4d, 83
4d, 85
4e, 81
4f, 89
4g, 85
4h, 82
4i, 80
4j, 85
4k, 82
4l, 81
4m, 83
4n, 79
4n, 82
4o, 80
4o, 83
d
NaOAc
NaOAc
NaOAc
KF
KF
KF
KF
KF
KF
KF
NaOAc
KF
KF
NaOAc
KF
NaOAc
KF
1:1
d
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b 3a
2b 3c
2b 3g
2b 3h
2b 3h
2b 3j
2b 3j
3c
3d
3d
3e
3f
3g
3h
3i
d
_
d
X
X
B
_
d
1.6:1
4.5:1
30:1
1:1
12:1
d
CN
-BH
CN
A
9
10
11
12
13
14
15
16
17
18
Catalytic activation of C-H acid
3j
_
X
_
1:1
1:1
1:1
1:1
1.2:1
1.2:1
O
_
X
CHO
OH
CN
X
-OH
CN
OH
CN
OH
6
1
a
Knoevenagel adduct formation
10 mmol of salicylaldehyde 1, 10 mmol of C–H acid 2, 10 mmol of nitro-
compound 3, 60 ꢀC.
Scheme 2.
b
Isolated yield.
c
1H NMR data.
methyl
2-amino-4-(1-cyano-2-methoxy-2-oxoethyl)-4H-chro-
Next, three reaction pathways are possible for Knoevenagel
adduct 6 (Scheme 3).
mene-3-carboxylate 5a in 88% yield.
The solvent-free reaction of salicylaldehyde
1
(10 mmol),
The Michael addition of anion of C–H acid 2 to the Knoevenagel
nitromethane 3a (10 mmol) and methyl 2-amino-4-(1-cyano-
2-methoxy-2-oxoethyl)-4H-chromene-3-carboxylate 5a (10 mmol)
in the presence of NaOAc (5 mmol) at 60 ꢀC during 3 h resulted in
methyl 2-amino-4-(nitromethyl)-4H-chromene-3-carboxylate 4a
formation in 88% yield and the solvent-free reaction of
salicylaldehyde 1 (10 mmol), nitromethane 3a (10 mmol) and
(2-amino-3-cyano-4H-chromen-4-yl)malononitrile 5b (10 mmol)
in the presence of NaOAc (5 mmol) at 60 ꢀC during 3 h resulted in
2-amino-4-(nitromethyl)-4H-chromene-3-carbonitrile 4k forma-
tion in 85% yield.
adduct 6 followed by intramolecular cyclization leads to
corresponding 2-amino-4H-chromene 5 (pathway A). 2-Amino-
4H-chromene (5a X¼COOMe) was detected in the reaction mix-
tures obtained when the solvent-free reaction of salicylaldehyde 1,
methyl cyanoacetate 2a and nitromethane 3a in the presence of
NaOAc was accomplished in more short time (2 and 1 h instead of
3 h) in 16 and 29% yield based on starting salicylaldehyde 1 (Table 1,
entries 4 and 5). Recently, O'Callaghan et al. have noted that in
alcoholic solution (2-amino-3-cyano-4H-chromen-4-yl)malononi-
trile (5b, X¼CN) could exist in equilibrium with corresponding
2-imino-2H-chromene-3-carbonitrile (7b, X¼CN) and malononi-
trile (2b) under certain reaction conditions.13 If such equilibrium
exists in our case, the uptake of stronger C–H acid 2 from the
Taking into consideration all obtained data, the following re-
action scheme was proposed for the direct solvent-free cascade
transformation of salicylaldehyde 1, cyanoacetate or malononitrile
X
CN
_
X
CN
X
CN
Pathway A
X
CN
CN
X
X
X
X
H2O
_
CN
_
O
_
-OH
OH
O
NH2
O
N
5
X
_
Uptake by 1
to form 6
-
2
CN
Pathway B
X
X
X
X
_
H2O
OH
_
_
_
-OH
CN
CN
-H2O
O
N
O
NH
7
O
OH
_
6
OH
R1R2CHNO2
3
_
R2
O
OH
R1R2CHNO2
3
-H2O
R1
NO2
X
-H2O
R2
R2
R2
O
R2
R1
R1
NO2
X
X
NO2
X
R1
R1
NO2
NO2
X
Pathway C
CN
_
X
NH2
4
_
_
_
O
CN
CN
O
NH
N
OH
+
_
8
X
The beginning of
new catalytic cycle
CN
Scheme 3.

4046
M.N. Elinson et al. / Tetrahedron 66 (2010) 4043–4048
equilibrium by salicylaldehyde 1 could facilitate the base-promoted
addition of weaker C–H acid 3 (nitroalkane) to 2-imino-2H-
chromene 7, what results in the full conversion of 5 into desired
2-amino-4H-chromene 4 during the solvent-free cascade process.
This suggestion was especially confirmed by above mentioned
solvent-free reaction of salicylaldehyde 1 (10 mmol), nitromethane
3a (10 mmol) and methyl 2-amino-4-(1-cyano-2-methoxy-
2-oxoethyl)-4H-chromene-3-carboxylate 5a (10 mmol) in the
presence of NaOAc (5 mmol) (60 ꢀC, 3 h), which resulted in methyl
2-amino-4-(nitromethyl)-4H-chromene-3-carboxylate 4a forma-
tion in 88% isolated yield (Scheme 4).
were isolated by easy work-up procedure and do not need any
further purification steps. Therefore, this novel type of MCR brings
us a step closer to the notion of `ideal synthesis'.14
4. Experimental section
4.1. General remarks
All melting points were measured with a Gallenkamp melting
point apparatus and are uncorrected. 1H and 13C NMR spectra were
recorded with a Bruker Avance II-300 and Bruker Avance II-600
CH3O2C
CN
NO2
CHO
CO2CH3
CO2CH3
NH2
Solvent-free
NaOAc
CH3NO2
3a
+
+
OH
O
4a
NH2
O
5a
1
88%
Scheme 4.
Thus, the solvent-free catalytic cascade transformation found
offers a facile exchange of the substituent at 4-position of corre-
sponding 4H-chromene cycle for another nucleophilic fragment
under mild reaction conditionsda promising synthetic opportu-
nity in the design of functionalized 2-amino-4H-chromene scaffold.
As for the pathway B (Scheme 3), it includes the hydroxide-
promoted intramolecular cyclization of Knoevenagel adduct 6 into
spectrometers at ambient temperature. HSQCED and HMBC spectra
were recorded with Bruker Avance II-600 instrument. Chemical
shifts values are relative to Me4Si. IR spectra were registered with
a
SPECORD M82 spectrometer in KBr pellets. Mass-spectra
(EI¼70 eV) were obtained directly with a Finningan MAT INCOS 50
spectrometer. The ES mass spectra were recorded with a Finnigan
MAT LCQ instrument. Spray capillary voltage 4530 V. A methanolic
reactive 2-imino-2H-chromene 713 with
a
subsequent base-
solution of the sample was injected by syringe at 10 mL/min; MS
promoted Michael addition of weaker C–H acid 3. The following
protonation of the combined adduct 8 by a molecule of C–H acid
leads to the formation of 2-amino-4H-chromene 4 with the
regeneration of anion of C–H acid 2, which thus continues the
catalytic cycle. The contribution of pathway C into the overall
mechanistic scheme seems to be less probable, as it initially in-
cludes the addition of the anion of the weaker C–H acid 3 to 6 in the
presence of stronger C–H acid 2. Nevertheless, the pathway C could
not be excluded from the overall scheme of the solvent-free cata-
lytic cascade process (Scheme 3).
spectra were measured at positive mode (registration range from
m/z 100 to m/z 2000). Interface capillary temperature was 220 ꢀC,
sheath gas flow (nitrogen) 19.4 a.u., auxiliary gas flow 0.4 a.u.
Activation time was 30 ms. Activation energy was 30% from relative
max. collision energy. Nitrocompounds 3f15, 3g16, 3h17, 3j18
,
2-amino-4-(1-cyano-2-methoxy-2-oxoethyl)-4H-chromene-3-car-
boxylate 5a and (2-amino-3-cyano-4H-chromen-4-yl)malononi-
trile 5b19 were synthesized by known methods. All other chemicals
were purchased from commercial sources.
4.2. Typical procedure
3. Conclusion
4.2.1. Synthesis of methyl 2-amino-4H-chromene-3-carboxylates. A
mixture of salicylaldehyde (1.22 g, 10 mmol), methyl cyanoacetate
(0.99 g, 10 mmol), nitromethane (0.61 g, 10 mmol) and sodium
acetate (0.41 g, 5 mmol) was stirred for 3 h at 60 ꢀC. Afterwards, the
reaction mixture was cooled, diluted with water (50 ml) and
extracted with chloroform (2ꢁ20 mL). The organic phase was
washed with water (2ꢁ20 mL), dried (MgSO4) and concentrated
under reduced pressure. The residue obtained was triturated with
ether (2 mL) and filtered to isolate the solid product, which was
then twice washed with ether (2 mL), and dried under reduced
pressure.
In conclusion, the new simple solvent-free catalytic cascade
process can produce, under mild conditions, an effective multi-
component transformation of salicylaldehydes, nitroalkanes and
malononitrile or cyanoacetate into 4-nitroalkyl substituted
2-amino-4H-chromenes in high 80–90% yields. This novel solvent-
free catalytic cascade process offers a facile and convenient way to
create substituted medicinally privileged 2-amino-4H-chromene
scaffolddthe approved basis for the generation of small-molecule
ligands with different biomedical properties including highly pro-
nounced anticancer activities. Compared to known MCR protocols,
the solvent-free catalytic cascade procedure represents the most
efficient approach to the 4-nitroalkyl substituted 2-amino-
4H-chromene scaffold. The reversibility of 2-amino-4H-chromenes
5 formation revealed during mechanistic investigations seems to be
an important feature of the solvent-free catalytic cascade process,
that is, promising for the synthesis of novel types of functionalized
2-amino-4H-chromenes by the exchange of the corresponding C–H
acid residue in 4-position of 4H-chromene cycle for another nu-
cleophilic species. The developed solvent-free multicomponent
procedure utilizes simple equipment and requires reasonable
starting materials. It is easily carried out, the reaction products
4.2.2. Synthesis of methyl 2-amino-4H-chromene-3-carbonitriles.
The procedure was the same as given above, except after the
reaction mixture was diluted with water (50 mL), the solid was
filtered and washed with water (2ꢁ20 mL), ether (2ꢁ5 mL) and
dried under reduced pressure.
4.2.3. Methyl 2-amino-4-(nitromethyl)-4H-chromene-3-carboxylate
(4a). White solid. Yield 2.45 g (93%); mp 108–110 ꢀC (lit. mp9
108–110 ꢀC); 1H NMR (300 MHz, CDCl3)
(dd, JH,H¼11.2 Hz, JH,H¼7.9 Hz, 1H), 4.54 (dd, JH,H¼11.2 Hz, JH,
d 3.79 (s, 3H, OCH3), 4.38
2
3
2
3

M.N. Elinson et al. / Tetrahedron 66 (2010) 4043–4048
4047
3
3
¼4.6 Hz, 1H), 4.63 (dd, JH,H¼7.9 Hz, JH,H¼4.6 Hz, 1H), 6.50 (br s,
168.6 ppm; IR (KBr):
n
¼3400, 3288, 2896, 1672, 1624, 1552, 1528,
H
2H, NH2), 7.02 (d, 3JH,H¼8.5 Hz, 1H, Ar), 7.07–7.28 (m, 3H, Ar) ppm.
1484, 1448 cmꢂ1; MS (EI): m/z (%)¼294 (0.5) [MꢂNO2]þ, 262 (4),
204 (100), 172 (55), 145 (34), 143 (28), 116 (12), 91 (62), 63 (15), 39
(13). Anal. Calcd (%) for C18H16N2O5: C, 63.52; H, 4.74; N, 8.23. Found
(%): C, 63.42; H, 4.53; N, 8.17.
4.2.4. Methyl 2-amino-4-(1-nitroethyl)-4H-chromene-3-carboxylate
(4b). Viscous yellow oil. Yield 2.50 g (90%); diastereomeric ratio
1:1; H NMR (300 MHz, CDCl3)
1.37 (d, JH,H¼5.9 Hz, 1.5H, CH3), 3.70 (s, 1.5H, CH3), 3.82 (s, 1.5H,
CH3), 4.49–4.60 (m, 1H), 4.69–4.81 (m, 1H), 6.1–6.9 (br s, 2H, NH2),
6.93–7.32 (m, 4H, Ar) ppm; 13C NMR (75 MHz, CDCl3, 24 signals for
l
3
d
1.18 (d, JH,H¼6.6 Hz, 1.5H, CH3),
3
4.2.9. Methyl 2-amino-4-(1-nitro-4-oxopentyl)-4H-chromene-3-car-
boxylate (4g). White solid. Yield 2.84 g (85%); diastereomeric ratio
l
(R
*
,R
*
)-4g : (R
*
,S
*
)-4g¼4.5:1; mp 131–132 ꢀC; (R
,R
* *
)-4g: H NMR
13 carbons)
d
11.7, 14.3, 39.5 (2C), 50.8, 51.3, 72.1, 73.6, 85.8, 88.1,
(300 MHz, CDCl3)
d
1.85–2.0 (m,1H), 2.06 (s, 3H, CH3), 2.11–2.52 (m,
115.8, 116.2, 119.6, 122.2, 124.9 (2C), 128.4, 128.5, 128.7, 128.9, 150.5,
3H), 3.72 (s, 3H, CH3), 4.42–4.54 (m, 2H), 6.1–6.9 (br s, 2H, NH2),
6.94–7.32 (m, 4H, Ar) ppm; 13C NMR (75 MHz, CDCl3)
23.1, 29.8,
39.1, 39.2, 50.8, 72.6, 92.5, 116.2, 121.9, 124.8, 128.4, 128.7, 150.6,
162.6, 168.8, 206.2 ppm; (R ,S
)-4g: lH NMR (300 MHz, CDCl3)
1.65–1.75 (m, 1H), 2.06 (s, 3H, CH3), 2.11–2.52 (m, 3H), 3.81 (s, 3H,
CH3), 4.61–4.68 (m, 2H) 6.1–6.9 (br s, 2H, NH2), 6.94–7.32 (m, 4H,
Ar) ppm; 13C NMR (75 MHz, CDCl3)
20.6, 29.7, 39.5, 39.8, 51.3,
73.5, 90.8, 115.9, 119.8, 124.7, 128.6, 128.9, 150.5, 162.5, 168.6,
150.6, 162.5, 162.6, 168.7, 169.1 ppm; IR (KBr):
n
¼3456, 3316, 2992,
d
2952, 1684, 1628, 1548, 1488, 1440, 1300 cmꢂ1; MS (EI): m/z (%)¼
278 (1) [M]þ, 232 (8), 204 (91), 172 (100), 145 (78), 143 (62), 116
(55), 89 (95), 63 (80), 39 (75). Anal. Calcd (%) for C13H14N2O5: C,
56.11; H, 5.07; N, 10.07. Found (%): C, 55.85; H, 4.89; N, 9.85.
*
*
d
d
4.2.5. Methyl 2-amino-4-(1-nitropropyl)-4H-chromene-3-carboxyl-
ate (4c). White solid. Yield 2.54 g (87%); mp 138 ꢀC; lH NMR
206.5 ppm; IR (KBr):
n
¼3392, 3288, 2952, 1688, 1708, 1628, 1548,
3
(300 MHz, CDCl3)
d
0.86 (t, JH,H¼7.3 Hz, 3H, CH3), 1.53–1.69
1488, 1440, 1296 cmꢂ1; MS (EI): m/z (%)¼288 (0.5) [MꢂNO2]þ, 230
(2), 204 (100), 172 (66), 145 (22), 143 (15), 116 (9), 89 (12), 63 (7), 43
(91). Anal. Calcd (%) for C16H18N2O6: C, 57.48; H, 5.43; N, 8.38. Found
(%): C, 57.22; H, 5.65; N, 8.12.
(m, 1H), 1.95–2.14 (m, 1H), 3.73 (s, 3H, CH3), 4.27–4.38 (m, 1H), 4.47
3
3
(d, JH,H¼6.2 Hz, 1H), 6.0–6.9 (br s, 2H, NH2), 7.03 (d, JH,H¼8.1 Hz,
1H, Ar), 7.09–7.21 (m, 2H, Ar), 7.23–7.31 (m, 1H, Ar) ppm; 13C NMR
(75 MHz, CDCl3)
d 10.5, 22.7, 38.9, 50.9, 73.2, 95.5, 116.2, 122.4,
124.8, 128.3, 128.6, 150.7, 162.6, 169.0 ppm; IR (KBr):
n
¼3456, 3316,
4.2.10. Methyl 2-amino-4-(1-methyl-1-nitro-4-oxopentyl)-4H-chro-
2952, 1684, 1640, 1544, 1488, 1440, 1228 cmꢂ1; MS (EI): m/z (%)¼
204 (100) [MꢂEtCHNO2]þ, 172 (40), 145 (5), 116 (6), 89 (7), 63 (4),
39 (13). Anal. Calcd (%) for C14H16N2O5: C, 57.53; H, 5.52; N, 9.58.
Found (%): C, 57.39; H, 5.48; N, 9.42.
mene-3-carboxylate (4h). White solid. Yield 2.85 g (82%); di-
l
astereomeric ratio 30:1; mp 160–162 ꢀC; major diastereomer: H
NMR (300 MHz, CDCl3) d 1.19 (s, 3H, CH3), 1.76–1.94 (m, 1H), 2.11 (s,
3H, CH3), 2.12–2.42 (m, 2H), 2.55–2.72 (m, 1H), 3.79 (s, 3H, CH3),
4.72 (s, 1H), 6.0–6.9 (br s, 2H, NH2), 6.93–7.17 (m, 3H, Ar), 7.20–7.33
4.2.6. Methyl 2-amino-4-(1-methyl-1-nitroethyl)-4H-chromene-3-
carboxylate (4d). Yellow solid. Yield 2.48 g (85%); mp 133 ꢀC; H
(m, 1H, Ar) ppm; 13C NMR (75 MHz, CDCl3)
d 16.0, 29.9, 30.3, 38.0,
l
44.0, 50.9, 73.4, 97.4, 115.8, 121.8, 125.0, 128.5, 128.6, 151.2, 163.3,
l
NMR (300 MHz, CDCl3)
(s, 3H, CH3), 4.69 (s, 1H), 5.9–6.9 (br s, 2H, NH2), 6.99–7.12 (m, 3H,
Ar), 7.21–7.30 (m, 1H, Ar) ppm; 13C NMR (75 MHz, CDCl3)
20.1,
24.2, 43.1, 50.8, 73.5, 94.1, 115.7, 122.0, 124.8, 128.5, 128.6, 151.0,
d
1.27 (s, 3H, CH3), 1.51 (s, 3H, CH3), 3.75
169.3, 206.2 ppm; minor diastereomer: H NMR (300 MHz, CDCl3)
d
1.37 (s, 3H, CH3), 2.10 (s, 3H, CH3), 3.70 (s, 3H, CH3), 4.57 (s, 1H) (all
other signals are hidden by the signals of the major diastereomer);
13C NMR (75 MHz, CDCl3)
18.7, 27.6, 38.1, 45.0, 50.8, 96.1, 116.1,
124.6, 128.7, 129.3 ppm (all other signals are hidden by the signals
d
d
163.1, 169.3 ppm; IR (KBr):
n
¼3432, 3324, 2996, 2944, 1684, 1636,
1536, 1484, 1440, 1348 cmꢂ1; MS (EI): m/z (%)¼246 (2) [MꢂNO2]þ,
204 (100), 172 (55), 145 (16), 116 (9), 89 (16), 63 (8), 39 (42). Anal.
Calcd (%) for C14H16N2O5: C, 57.53; H, 5.52; N, 9.58. Found (%): C,
57.37; H, 5.39; N, 9.44.
of the major diastereomer); IR (KBr):
n
¼3432, 3312, 2952, 1712,
1688, 1604, 1544, 1484, 1440, 1300 cmꢂ1; MS (ES): m/z¼371
[MþNa]þ, 349 [MþH]þ, 226, 204. Anal. Calcd (%) for C17H20N2O6: C,
58.61; H, 5.79; N, 8.04. Found (%): C, 58.47; H, 5.65; N, 8.12.
4.2.7. Methyl 2-amino-4-(1-nitrocyclohexyl)-4H-chromene-3-car-
4.2.11. Methyl 2-amino-4-(2-methoxy-1-nitro-2-oxoethyl)-4H-chro-
l
boxylate (4e). White solid. Yield 2.69 g (81%); mp 152 ꢀC; H NMR
mene-3-carboxylate (4i). White solid. Yield 2.58 g (80%); di-
l
(300 MHz, CDCl3)
d
0.99–1.46 (m, 5H), 1.50–1.68 (m, 3H), 2.08
astereomeric ratio 1:1; mp 144–146 ꢀC; H NMR (300 MHz, CDCl3)
(d, J¼13.0 Hz, 1H), 2.58 (d, J¼13.0 Hz, 1H), 3.74 (s, 3H, CH3), 4.42 (s,
d
3.54 (s, 1.5H, CH3), 3.78 (s, 3H, CH3), 3.81 (s, 1.5H, CH3)3, 4.93 (d, 3JH,
3
1H), 6.0–6.9 (br s, 2H, NH2), 6.99–7.14 (m, 3H, Ar), 7.22–7.31 (m, 1H,
¼5.8 Hz, 0.5H), 5.00 (d, JH,H¼2.9 Hz, 0.5H), 5.31 (d, JH,H¼2.9 Hz,
H
Ar) ppm; 13C NMR (75 MHz, CDCl3)
d
21.8, 22.1, 24.3, 28.4, 31.5, 44.6,
0.5H), 5.40 (d, 3JH,H¼5.8 Hz, 0.5H), 6.1–6.9 (br s, 2H, NH2), 6.98–7.41
50.8, 73.6, 98.0, 115.7, 121.8, 124.5, 128.4, 129.0, 151.2, 163.3,
(m, 4H, Ar) ppm; 13C NMR (75 MHz, CDCl3, 27 signals for 14 car-
169.4 ppm; IR (KBr):
n
¼3372, 3284, 2932, 2852, 1680, 1628, 1540,
bons)
d 36.8, 37.2, 51.2, 51.2, 52.9, 53.3, 71.7, 72.6, 91.2, 91.3, 115.8,
1484, 1444, 1300 cmꢂ1; MS (ES): m/z¼355 [MþNa]þ, 333 [MþH]þ,
226, 204. Anal. Calcd (%) for C17H20N2O5: C, 61.44; H, 6.07; N, 8.43.
Found (%): C, 61.27; H, 6.35; N, 8.32.
116.3, 119.4, 120.1, 124.8 (2C), 128.2, 129.0, 129.1, 129.2, 150.5, 150.9,
162.5, 162.8, 163.5, 163.9, 168.3, 168.4 ppm; IR (KBr):
n
¼3440, 3316,
2972, 1744, 1692, 1628, 1560, 1532, 1488, 1444 cmꢂ1; MS (EI): m/z
(%)¼204 (33), 172 (42), 145 (81), 143 (54), 89 (38), 73 (100), 63 (36),
42 (42). Anal. Calcd (%) for C14H14N2O7: C, 52.18; H, 4.38; N, 8.69.
Found (%): C, 52.07; H, 4.30; N, 8.53.
4.2.8. Methyl 2-amino-4-[nitro(phenyl)methyl]-4H-chromene-3-car-
boxylate (4f). White solid. Yield 3.03 g (89%); diastereomeric ratio
(R
*
,S
*
)-4f : (R
*
,R
*
)-4f¼1.6:1; mp 112–118 ꢀC; (R
*
,S
)–4f: lH NMR
*
(300 MHz, CDCl3)
d
3.33 (s, 3H, CH3), 4.86 (d, J¼8.8 Hz, 1H), 5.32 (d,
4.2.12. Methyl 2-amino-4-(4-methoxy-1-methyl-1-nitro-4-oxobutyl)-
J¼8.8 Hz, 1H), 6.0–6.9 (br s, 2H, NH2), 6.77–6.91 (m, 1H, Ar), 6.99–
7.47 (m, 8H, Ar) ppm; 13C NMR (75 MHz, CDCl3)
40.1, 50.3, 72.9,
95.8, 116.0, 122.6, 124.7, 127.7, 127.9 (2C), 128.5 (2C), 129.2, 129.3,
131.7, 150.8, 162.6, 168.5 ppm; (R ,R
)-4f: lH NMR (300 MHz, CDCl3)
3.82 (s, 3H, CH3), 5.08 (d, J¼4.8 Hz, 1H), 5.55 (d, J¼4.8 Hz, 1H) 6.0–
6.9 (br s, 2H, NH2), 6.77–6.91 (m, 1H, Ar), 6.99–7.47 (m, 8H, Ar)
ppm; 13C NMR (75 MHz, CDCl3)
40.2, 51.1, 73.2, 93.7, 115.6, 120.5,
124.4, 128.5 (2C), 128.6 (2C), 128.8, 129.1, 129.2, 131.1, 150.9, 162.6,
-4H-chromene-3-carboxylate (4j). White solid. Yield 3.09 g (85%);
l
d
diastereomeric ratio 12:1; mp 134–136 ꢀC; major diastereomer: H
NMR (300 MHz, CDCl3)
d 1.22 (s, 3H, CH3), 1.83–1.96 (m, 1H), 2.02–
*
*
2.16 (m, 1H), 2.16–2.31 (m, 1H), 2.67–2.82 (m, 1H), 3.66 (s, 3H, CH3),
3.79 (s, 3H, CH3), 4.73 (s, 1H), 5.9–6.9 (br s, 2H, NH2), 6.99–7.17 (m,
d
3H, Ar), 7.21–7.34 (m, 1H, Ar) ppm; 13C NMR (75 MHz, CDCl3)
d 15.8,
d
28.6, 31.4, 43.9, 50.8, 51.7, 73.2, 97.1, 115.8, 121.7, 124.9, 128.5, 128.6,
151.1, 163.3, 169.2, 172.4 ppm; minor diastereomer: lH NMR

4048
M.N. Elinson et al. / Tetrahedron 66 (2010) 4043–4048
(300 MHz, CDCl3)
d
1.42 (s, 3H, CH3), 3.64 (s, 3H, CH3), 3.72 (s, 3H,
DMSO-d6)
3.58 (s, 3H, OCH3), 4.16 (s, 1H), 7.00–7.38 (m, 4H, Ar), 7.43 (s, 2H,
NH2) ppm; 13C NMR (151 MHz, DMSO-d6)
16.5, 28.2, 31.2, 45.6,
d 1.24 (s, 3H, CH3), 2.04–2.18 (m, 2H), 2.27–2.46 (m, 2H),
CH3), 4.59 (s, 1H) ppm (all other signals are hidden by the signals of
the major diastereomer); 13C NMR (75 MHz, CDCl3)
18.6, 44.9, 95.9,
116.0, 124.6, 129.1 ppm (all other signals are hidden by the signals of
d
d
49.1, 51.7, 96.4, 116.2, 119.7, 120.8, 124.9, 128.4, 129.4, 150.7, 164.2,
the major diastereomer); IR (KBr):
n¼3432, 3308, 3000, 2952, 1728,
172.2 ppm; minor diastereomer: lH NMR (600 MHz, DMSO-d6)
1688, 1604, 1544, 1484, 1440 cmꢂ1; MS (ES): m/z¼387 [MþNa]þ, 365
[MþH]þ, 226, 204. Anal. Calcd (%) for C17H20N2O7: C, 56.04; H, 5.53;
N, 7.69. Found (%): C, 55.87; H, 5.45; N, 7.53.
d
1.35 (s, 3H, CH3), 1.84–1.91 (m, 1H), 2.04–2.18 (m, 1H), 2.27–2.46
(m, 2H), 3.56 (s, 3H, OCH3), 4.18 (s, 1H), 7.00–7.38 (m, 1H, Ar), 7.39
(s, 2H, NH2) ppm; 13C NMR (151 MHz, DMSO-d6)
18.0, 28.1, 29.6,
45.7, 49.2, 51.6, 95.6, 116.2, 119.7, 120.3, 124.6, 128.4, 129.4, 150.7,
d
4.2.13. 2-Amino-4-(nitromethyl)-4H-chromene-3-carbonitrile (4k).
Yellowish solid. Yield 1.89 g (82%); mp 139–140 ꢀC (lit.mp9
164.4, 172.3 ppm; IR (KBr):
n
¼3432, 3324, 3204, 2196, 1740, 1648,
1604,1576,1528 cmꢂ1; MS (ES): m/z¼354 [MþNa]þ,171. Anal. Calcd
(%) for C16H17N3O5: C, 58.00; H, 5.17; N,12.68. Found (%): C, 58.15; H,
5.37; N, 12.49.
l
3
139–140 ꢀC); H NMR (300 MHz, DMSO-d6)
d
4.31 (t, JH,H¼5.1 Hz,
2
3
2
1H), 4.66 (dd, JH,H¼12.5 Hz, JH,H¼5.1 Hz, 1H), 4.79 (dd, JH,
3
3
¼12.5 Hz, JH,H¼5.1 Hz, 1H), 7.03 (d, JH,H¼8.0 Hz, 1H, Ar), 7.17 (s,
H
2H, NH2), 7.17 (t, 3JH,H¼8.0 Hz, 1H, Ar), 7.32 (t, 3JH,H¼8.0 Hz, 1H, Ar),
Acknowledgements
7.34 (d, 3JH,H¼8.0 Hz, 1H, Ar) ppm.
The authors gratefully acknowledge the financial support of the
4.2.14. 2-Amino-4-(1-nitropropyl)-4H-chromene-3-carbonitrile
Russian Foundation for Basic Research (Project No. 09-03-00003).
(4l). Yellowish solid. Yield 2.10 g (81%), diastereomeric ratio 1:1;
l
mp 189–190 ꢀC; H NMR (300 MHz, DMSO-d6)
d
0.83 (t, J¼7.3 Hz,
References and notes
1.5H, CH3), 0.85 (t, J¼7.3 Hz, 1.5H, CH3), 1.68–2.10 (m, 2H), 4.06 (d,
J¼6.6 Hz, 0.5H), 4.14 (d, J¼4.8 Hz, 0.5H), 4.47–4.57 (m, 0.5H), 4.58–
4.67 (m, 0.5H), 6.98–7.11 (m, 1H, Ar), 7.14–7.38 (m, 5H, Ar, NH2)
1. (a) Thompson, L. A. Curr. Opin. Chem. Biol. 2000, 4, 324–337; (b) Nefzi, A.;
Ostresh, J. M.; Houghten, R. A. Chem. Rev. 1997, 97, 449–472.
2. (a) Weber, L. Drug Disc. Today 2002, 7, 143–147; (b) Domling, A. Curr. Opin.
€
ppm; 13C NMR (75 MHz, DMSO-d6, 26 signals for 13 carbons)
d 10.2,
Chem. Biol. 2002, 6, 306–313.
3. The term `privileged scaffolds or structures' was originally introduced by Merck
researchers in their work on benzodiazepins: Evans, B. E.; Rittle, K. E.; Bock, G.;
DiPardo, R. M.; Freidinger, R. M.; Whitter, W. L.; Lundell, G. F.; Veber, D. F.;
Anderson, P. S.; Chang, R. S. L.; Lotti, V. G.; Cerino, D. J.; Chen, T. B.; Kling, P. J.;
Kunkel, K. A.; Springer, J. P.; Hirshfield, J. J. Med. Chem. 1988, 31, 2235–2246 for
reviews see: (a) DeSimone, R. W.; Currie, K. S.; Mitchell, S. A.; Darrow, J. W.;
Pippin, D. A. Comb. Chem. High Throughput Screen. 2004, 7, 473–493; (b) Triggle,
D. J. Cell. Mol. Neurobiol. 2003, 23, 293–303; (c) Patchett, A. A.; Nargund, R. P.
Annu. Rep. Med. Chem. 2000, 35, 289–298.
10.3, 23.1, 23.3, 39.7, 39.8, 48.9, 49.7, 94.6, 95.2, 116.2, 116.3, 120.1,
120.2, 120.4, 120.8, 124.8, 124.9, 128.6, 128.9, 129.2, 129.3, 149.9,
150.2, 163.3, 163.5 ppm; IR (KBr):
n¼3436, 3332, 3212, 2976, 2204,
1648, 1608, 1540, 1492, 1416 cmꢂ1; MS (ES): m/z¼282 [MþNa]þ,
193, 171. Anal. Calcd (%) for C13H13N3O3: C, 60.22; H, 5.05; N, 16.21.
Found (%): C, 60.03; H, 4.95; N, 15.98.
4. Poupaert, J.; Carato, P.; Colacino, E. Curr. Med. Chem. 2005, 12, 877–885.
5. For examples of natural compounds containing the chromene fragment, see:
(a) The FlavonoidsdAdvances in Research; Harborne, J. B., Ed.; Chapman & Hall:
London, UK, 1988; (b) Parmar, V. S.; Jain, S. C.; Bisht, K. S.; Jain, R.; Taneja, P.; Jha,
A.; Tyagi, O. D.; Prasad, A. K.; Wengel, J.; Olsen, C. E.; Boll, P. M. Phytochemistry
1997, 46, 597–674; (c) Gill, M. Aust. J. Chem. 1995, 48, 1–26; (d) Bohm, B. A.;
Choy, J. B.; Lee, A. Y.-M. Phytochemistry 1989, 28, 501–504; (e) Iacobucci, G. A.;
Sweeny, J. G. Tetrahedron 1983, 39, 3005–3038.
4.2.15. 2-Amino-4-(1-nitro-4-oxopentyl)-4H-chromene-3-carbon-
itrile (4m). Yellowish solid. Yield 2.50 g (83%), diastereomeric ratio
l
1:1; mp 139–140 ꢀC; H NMR (300 MHz, DMSO-d6)
d 2.02 (s, 1.5H,
CH3), 2.04 (s, 1.5H, CH3), 2.40–2.57 (m, 4H), 4.14 (d, J¼5.9 Hz, 0.5H),
4.20 (d, J¼4.0 Hz, 0.5H), 4.55–4.62 (m, 0.5H), 4.62–4.72 (m, 0.5H),
7.01–7.10 (m, 1H, Ar), 7.13–7.39 (m, 5H, Ar, NH2) ppm; 13C NMR
6. For recent reports, see: (a) Sun, W.; Cama, L. J.; Birzin, E. T.; Warrier, S.; Locco, L.;
Mosley, R.; Hammond, M. L.; Rohrer, S. P. Bioorg. Med. Chem. Lett. 2006, 16,
1468–1472; (b) Stachulski, A. V.; Berry, N. G.; Low, A. C. L.; Moores, S.; Row, E.;
Warhurst, D. C.; Adagu, I. S.; Rossignol, J.-F. J. Med. Chem. 2006, 49, 1450–1454;
(c) Garino, C.; Bihel, F.; Pietrancosta, N.; Laras, Y.; QuÅlÅver, G.; Woo, I.; Klein,
P.; Bain, J.; Boucher, J.-L.; Kraus, J.-L. Bioorg. Med. Chem. Lett. 2005, 15, 135–138.
7. (a) Bonsignore, L.; Loy, G.; Secci, D.; Calignano, A. Eur. J. Med. Chem. 1993, 28,
517–520; (b) Foye, W. O. Prinicipi di Chemico Farmaceutica; Piccin: Padova, PD,
1991; p 416; (c) Witte, E.C.; Neubert, P.; Roesch, A. Ger. Offen. DE 3427985, 1986.
Chem. Abstr. 1986, 104, 224915f; (d) Andreani, L. L.; Lapi, E. Boll. Chim. Farm.
1960, 99, 583–587.
8. (a) Skommer, J.; Wlodkowic, D.; Matto, M.; Eray, M.; Pelkonen, J. Leukemia Res.
2006, 30, 322–331, and references therein; (b) Kemnitzer, W.; Kasibhatla, S.;
Jiang, S.; Zhang, H.; Zhao, J.; Jia, S.; Xu, L.; Crogan-Grundy, C.; Denis, R.; Bar-
riault, N.; Vaillancourt, L.; Charron, S.; Dodd, J.; Attardo, G.; Labrecque, D.; La-
mothe, S.; Gourdeau, H.; Tseng, B.; Drewe, J.; Cai, S. X. Bioorg. Med. Chem. Lett.
2005, 15, 4745–4751; (c) Gourdeau, H.; Leblond, L.; Hamelin, B.; Desputeau, C.;
Dong, K.; Kianicka, I.; Custeau, D.; Bourdeau, C.; Geerts, L.; Cai, S. X.; Drewe, J.;
Labrecque, D.; Kasibhatla, S.; Tseng, B. Mol. Cancer Ther. 2004, 3, 1375–1384.
9. Elinson, M. N.; Dorofeev, A. S.; Miloserdov, F. M.; Ilovaisky, A. I.; Feducovich, S.
K.; Belyakov, P. A.; Nikishin, G. I. Adv. Synth. Catal. 2008, 350, 591–601.
10. Tanaka, K. Solvent-free Organic Synthesis; Wiley-VCH: Weinheim, 2003.
11. Ananikov, V. P. Cent. Eur. J. Chem. (CEJC) 2004, 2, 196–213.
(75 MHz, DMSO-d6, 28 signals for 15 carbons) d 23.2, 23.4, 29.7 (2C),
38.5, 38.7, 39.9 (2C), 49.0, 49.4, 91.9, 92.4, 116.2, 116.3, 119.8, 119.9,
120.2, 120.5, 124.8, 124.9, 128.6, 128.7, 129.2, 129.3, 150.0, 150.1,
163.3, 163.4, 206.8, 206.9 ppm; IR (KBr):
n
¼3384, 3320, 3204, 2196,
1712, 1644, 1608, 1544,1416 cmꢂ1; MS (ES): m/z¼324 [MþNa]þ, 171.
Anal. Calcd (%) for C15H15N3O4: C, 59.79; H, 5.02; N, 13.95. Found
(%): C, 59.52; H, 4.95; N,13.74.
4.2.16. 2-Amino-4-(1-methyl-1-nitro-4-oxopentyl)-4H-chromene-3-
€
€
carbonitrile
diastereomeric ratio 1:1; mp 141–143 ꢀC; lH NMR (600 MHz,
DMSO-d6) 1.19 (s, 1.5H, CH3), 1.31 (s, 1.5H, CH3), 1.77–1.84 (m,
(4n). Yellowish
solid.
Yield
2.58 g
(82%);
d
0.5H), 2.05–2.11 (m, 0.5H), 2.04 (s, 1.5H, CH3), 2.06 (s, 1.5H, CH3),
2.16–2.34 (m, 2H), 2.46–2.58 (m, 1H), 4.14 (s, 0.5H), 4.16 (s, 0.5H),
6.97–7.37 (m, 4H, Ar), 7.37 (s, 2H, NH2) ppm; 13C NMR (151 MHz,
DMSO-d6, 30 signals for 16 carbons)
d 16.5, 18.0, 28.3, 29.7, 29.8,
29.9, 37.07 (2C), 45.6, 45.7, 49.2, 49.3, 95.7, 96.6, 116.1, 116.2, 119.88
(2C), 120.3, 120.9, 124.3, 124.5, 128.3, 129.2, 129.3, 129.6, 150.6,
12. Patai, S.; Israeli, Y. J. Chem. Soc. 1960, 2025–2030.
ꢀ
ꢀ
150.7, 164.1, 164.4, 206.4, 206.7 ppm; IR (KBr):
n
¼3456, 3328, 3208,
13. OCallaghan, C. N.; McMurry, T. B.; OBrein, J. E. J. Chem. Soc., Perkin Trans. 1 1995,
2192, 1712, 1652, 1600, 1575, 1540 cmꢂ1; MS (ES): m/z¼338
[MþNa]þ, 171. Anal. Calcd (%) for C16H17N3O4: C, 60.94; H, 5.43; N,
13.33. Found (%): C, 60.72; H, 5.35; N, 13.15.
4, 417–420.
14. `Towards the ideal synthesis' Wender, P. A.; Handy, S. T.; Wright, D. L. Chem. Ind.
1997, 765–769.
15. Kornblum, N.; Larson, H. O.; Blackwood, R. K.; Mooberry, D. D.; Oliveto, E. P.;
Graham, G. E. J. Am. Chem. Soc. 1956, 70, 1497–1501.
16. Lewellyn, M. E.; Tarbell, D. S. J. Org. Chem. 1974, 39, 1407–1410.
17. Ballini, R.; Bosica, G. Tetrahedron Lett. 1996, 37, 8027–8030.
18. Ballini, R.; Bosica, G. Eur. J. Org. Chem. 1998, 355–357.
19. Roudier, J. F.; Foucaud, A. Synthesis 1984, 159–160.
4.2.17. Methyl
4-(2-amino-3-cyano-4H-chromen-4-yl)-4-nitro-
pentanoate (4o). Yellowish solid. Yield 2.75 g (83%); diastereomeric
ratio 1.2:1; mp 121–123 ꢀC; major diastereomer: lH NMR (600 MHz,