Convenient one-step synthesis of 4-unsubstituted 2-amino-4H-chromene-2- carbonitriles and 5-unsubstituted 5H-chromeno[2,3-b]pyridine-3-carbonitriles from quaternary ammonium salts

Article abstract of DOI:10.1016/j.tet.2012.04.065

We have reported DBU catalyzed synthesis of 4-unsubstituted 2-amino-4H-chromene-2-carbonitriles in water under reflux. The attractive features of this process are mild reaction conditions, short reaction times, easy isolation of products and good yields.

Full text of DOI:10.1016/j.tet.2012.04.065

Tetrahedron 68 (2012) 5612e5618
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Convenient one-step synthesis of 4-unsubstituted 2-amino-4H-chromene-2-
carbonitriles and 5-unsubstituted 5H-chromeno[2,3-b]pyridine-3-carbonitriles
from quaternary ammonium salts
*
Vitaly A. Osyanin , Dmitry V. Osipov, Yuri N. Klimochkin
Department of Organic Chemistry, Samara State Technical University, 244 Molodogvardeiskaya St., 443100 Samara, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
We have reported DBU catalyzed synthesis of 4-unsubstituted 2-amino-4H-chromene-2-carbonitriles in
water under reflux. The attractive features of this process are mild reaction conditions, short reaction
times, easy isolation of products and good yields. 5H-chromeno[2,3-b]pyridine-3-carbonitriles were
obtained by refluxing excess of malononitrile and quaternary ammonium salts in ethanol in the presence
of NaOH as catalyst. The mechanisms of these reactions are believed to involve the formation of the
o-quinone methide intermediate.
Received 15 February 2012
Received in revised form 2 April 2012
Accepted 16 April 2012
Available online 21 April 2012
Keywords:
o-Quinone methides
Ó 2012 Elsevier Ltd. All rights reserved.
2-Amino-4H-chromene-2-carbonitriles
5H-Chromeno[2,3-b]pyridine-3-
carbonitriles
Synthesis in water
1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU)
1. Introduction
One of the main objectives of organic and medicinal chemistry is
the design and synthesis of molecules having value as human
therapeutic agents. 2-Amino-4H-chromenes are of particular utility
as they belong to privileged medicinal scaffolds serving for gener-
ation of small-molecule ligands with highly pronounced spasmo-
litic-, diuretic-, anticoagulant-, antibacterial- and antianaphylactic
activities.1 Substituted 2-amino-4H-benzochromenes were pro-
posed for the treatment of immune system diseases and diabetic
complications resulted from an increase in permeability of blood
vessels and a change in blood pressure.2 The current interest in
2-amino-4H-chromenes arises from their application in the treat-
ment of human inflammatory TNF
rheumatoid and psoriatic arthritis and in cancer therapy (com-
pounds AeC, Scheme 1).1,3 Besides,
-enaminonitrile derivatives of
a-mediated diseases, such as
b
4H-chromenes are useful synthetic intermediates for the prepara-
tion of heterocyclic systems having potential biological activity.4e8
That is why the development of novel, highly efficient methods for
the synthesis of 4-unsubstituted 2-amino-4H-chromene-2-
carbonitriles is still of current interest.
Scheme 1. 2-Amino-4H-chromenes and chromeno[2,3-b]pyridines as privileged
medicinal scaffolds.
The chromeno[2,3-b]pyridine scaffold also is of significant me-
dicinal relevance. The examples of approved therapeutic agents
incorporating this molecular framework include pranoprofen D and
* Corresponding author. Tel./fax: þ7 846 332 2122; e-mail address: VOsyanin@
mail.ru (V.A. Osyanin).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.04.065

V.A. Osyanin et al. / Tetrahedron 68 (2012) 5612e5618
5613
amlexanox E (Scheme 1).9 In addition, many of these compounds
possess anti-bacterial, anti-proliferative, anti-myopic, hypotensive,
anti-histaminic, anti-rheumatic and anti-asthmatic activities.10 For
example, chromeno[2,3-b]pyridine F has reported to inhibit mito-
gen activated protein kinase-activated protein kinase 2 and atten-
uate the production of pro-inflammatory TNFa.
11 Compound G has
reported to inhibit histamine-stimulated gastric acid secretion.12
A number of methods have been reported for the syntheses of 2-
amino-4H-chromene-2-carbonitriles. These compounds are gen-
erally prepared by the three-component condensation of malono-
nitrile, an aromatic aldehyde and an activated phenol in the
presence of a catalyst (organic bases, ammonium salts, basic alu-
mina) in an organic solvent (i.e., acetonitrile, ethanol).7,13e18 How-
ever, phenols with electron-withdrawing substituents in the ring
are inert under the reaction conditions, which considerably limits
the scope of accessible structures. Besides, 2-amino-4H-chromene-
2-carbonitriles have been synthesized in two steps.4e6,8 The first
step consisted in preparing and isolating benzylidenmalononitrile.
The second step involved the reaction of these compounds with the
corresponding phenol or naphthol. It should be noted that only 4-
arylsubstituted 2-amino-4H-chromene-2-carbonitriles can be pre-
pared by these methods. Several 4-unsustituted 2-amino-4H-
chromene-2-carbonitriles were prepared from salicylic aldehydes,
malononitrile and Hantzsch dihydropyridine ester using a catalytic
amount of InCl3.19 However, the resulting products must be purified
by column chromatography from Hantzsch pyridine ester.
R = 6-CH3O (2a); 6-Ad (2b); 6-CH3-8-Ad (2c); 6-(CH3)3C (2d); 6-CH3O2C
(2e); 7-CH3O2C (2f); 6,7-(CH3)2 (2g); 6-Bn (2h); 6-Cl (2i).
Scheme 2.
elimination of the tertiary amines as an ammonium salt makes the
process irreversible.25
In order to evaluate the efficiency of this method the synthesis
of 2-amino-6-methoxy-4H-chromene-2-carbonitrile 2a, via re-
action of 2-hydroxy-5-methoxybenzyl(trimethyl)ammonium io-
dide 1a and malononitrile as a model system, was carried out in
water using DBU as a catalyst. DBU is an organic base (pKa¼12) and
þM effect of the adjacent nitrogen stabilizes the protonated spe-
cies. DBU is an effective catalyst for Michael addition.18
First, we investigated the effect of quantity of DBU on the syn-
thesis of 2a. The reaction was investigated in the presence of 0.1,
0.5. 1.0, 1.5 and 2.0 equiv of DBU. In all cases, the reaction times
were 1 min. It was observed that the use of 1 equiv of DBU in
aqueous medium under reflux yielded the desired product in 88%
yield in 1 min (Table 1, entry 3). A stoichiometric amount of DBU is
required to generate the phenolate and to keep the system basic.
Increasing of the catalyst to 1.5 and 2 equiv results in decreasing the
reaction yields to 77% and 54%, respectively. When this reaction was
repeated at room temperature, no desired product formation was
observed. Refluxing in ethanol was also found to be a successful
procedure in the preparation of the 2a. The product is separated
from the reaction mixture and isolated by filtration. Besides, the
model reaction was carried out simply by stirring equimolar
amounts of malononitrile, quaternary salt 1a and DBU at 25 ꢀC for
15 min without any solvent to afford the product 2a in 63% yield.
Conventional chromatographic purification was not required.
A few methods have been reported for the synthesis of chro-
meno[2,3-b]pyridine derivatives by multi-component reactions of
malononitrile dimer or 2 equiv of malononitrile with salicylic al-
dehydes and different nucleophiles (secondary amines,20 thiols,10,21
anion of malononitrile11). Besides, chromeno[2,3-b]pyridines were
prepared from resorcinol and arylmethylidene derivatives of
malononitrile dimer,22 quaternary ammonium salt and malononi-
trile dimer.11
As part of our current studies23 on the development of new
routes to heterocyclic systems from o-quinone methides (o-QMs),
we now report an efficient synthetic route to 2-amino-4H-chro-
mene-2-carbonitriles
and
5H-chromeno[2,3-b]pyridine-3-
carbonitriles from quaternary ammonium salts.
Table 1
Effect of quantity of DBU on the synthesis of 2aa
o-QMs are important intermediates in many chemical and bi-
ological processes. These reactive species are efficient DNA alky-
lating and cross-linking agents, play a key role in the biological
action of several antibiotics, such as mitomycin and anthracyclines.
o-QMs act as heterodienes in inter- and intramolecular cycloaddi-
tions with olefins to give various substituted chromanes. Like vinyl
ketones, o-QMs also act as Michael acceptor.24
Entry
Quantity (equiv)
Yieldb (%)
1
2
3
4
5
0.1
0.5
1.0
1.5
2.0
42
83
88
77
54
a
Reaction conditions: Compound 1a (1.5 mmol), malononitrile (1.5 mmol), DBU,
12 mL of water, 100 ꢀC, 1 min.
b
Isolated yields.
2. Results and discussion
Herein, we report a simple, efficient method for the synthesis of
4-unsubstituted 2-amino-4H-chromene-2-carbonitriles 2aei from
quaternary ammonium salts 1aei and malononitrile in high yields
using water or ethanol as the reaction medium (Scheme 2). The use
of water as a solvent has many advantages in organic processes and
reactions, both in industry and in green chemistry applications. It is
economical, non-toxic and environmentally friendly. The hydro-
phobic products produced when using water as the solvent are
separable by extraction with an organic solvent or filtration.
It should be noted that the synthetic potential of the Mannich
bases for an o-QM formation has remained largely underestimated
in relation to the high temperature needed for the thermal elimi-
nation of the amine. The formation of quaternary ammonium
salts by alkylation of the Mannich adducts is a way to induce easier
removal of the amino residue and, therefore, trapping of the tran-
sient electrophilic species at lower temperature. Furthermore,
Next, the reaction was attempted at different temperatures
ranging from 25 to 100 ꢀC (Table 2). It was found that below 80 ꢀC
the yield of the product significantly decreased. Below 50 ꢀC, only
traces of 2a were detected. The reaction worked best at 100 ꢀC.
However, we succeeded in carrying out this reaction at room
temperature under solvent-free condition.
In order to evaluate the effect of the base on the reaction, a range
of both organic and inorganic bases were examined (Table 3).
Among the different catalysts tested, DBU and NaOH were the most
effective, whereas weaker bases, such as pyridine, N-methyl-
imidazole and DABCO, led to lower yields. In the absence of any
catalyst, no reaction was observed.
The scope of this method for the synthesis of other 2-amino-4H-
chromene-2-carbonitriles using the optimized conditions was
studied (Table 4). In each case good yields of products were
obtained and no by-products were found.

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V.A. Osyanin et al. / Tetrahedron 68 (2012) 5612e5618
Table 2
Effect of temperature and time on the synthesis of 2a in the presence of DBUa
Entry
Temperature (ꢀC)
Time
Yieldb (%)
1
2
3
4
5
6
7
8
9
25
25
50
50
50
24 h
0
15 min
5 min
15 min
1 h
15 min
1 min
5 min
15 min
1 h
63c
6
22
19
73
88
89
90
90
80
Scheme 3.
100
100
100
100
10
a
Reaction conditions: Compound 1a (1.5 mmol), malononitrile (1.5 mmol), DBU
(1.5 mmol), 12 mL of water.
b
Isolated yields.
Reaction was carried out under solvent-free condition.
c
Table 3
The results of the optimization of basesa
Entry
Base
pKa26
Yieldb (%)
Ratio of 2a/3b
1
2
3
4
5
6
7
8
NaOH
TMG
DBU
DIPEA
TEA
K2CO3
DMAP
TMEDA
DABCO
N-Methylimidazole
Py
15.74
13.6
12.0
11.4
10.75
10.38
9.2
8.97
8.82
7.4
83
69
88
71
67
62
64
74
52
43
41
95:5
94:6
96:4
92:8
91:9
88:12
97:3
95:5
89:11
96:4
97:3
9
10
11
5.25
a
Reaction conditions: Compound 1a (1.5 mmol), malononitrile (1.5 mmol), base
(1.5 mmol), 12 mL of water, 100 ꢀC, 1 min.
b
Isolated yields.
Scheme 4. Plausible mechanism for the synthesis of 2-amino-4H-chromene-2-
carbonitriles 2aej.
Table 4
DBU catalyzed synthesis of 2-amino-4H-chromene-2-carbonitriles 2aei
a Michael-type addition of the deprotonated malononitrile to the
o-QM affords the 2-hydroxybenzylmalononitrile. The driving force
of the reaction is the resulting rearomatization of the molecule.
The intramolecular nucleophilic addition reaction, involving the
hydroxyl group and the cyano group (Pinner reaction27), takes
place and the imine is generated. The chromene is afforded through
tautomerization of imine.
This procedure showed some limitations. We could not prepare
the chromene 2k from the quaternized 2-dimethylaminomethyl-
4,6-di-tert-butylphenol because the obtain of pure salt is very
complicated.28 However, compound 2k has been prepared in low
yield (9%) from the Mannich base 1k just in the case of slow ad-
dition of the malononitrile to a mixture of 1k and DBU in a boiling
DMF. This reaction proceed along with formation of 2,4-diamino-
Entry
R
Solvent
Time (min)
Yielda (%)
2a
2b
2c
2d
2e
2f
2g
2h
2i
6-CH3O
6-Ad
H2O
1
1
20
1
10
5
1
88
80
69
82
76
74
82
85
61
EtOH
EtOH
EtOH
H2O
H2O
H2O
6-CH3-8-Ad
6-(CH3)3C
6-CH3O2C
7-CH3O2C
6,7-(CH3)2
6-Bn
EtOH
H2O
1
5
6-Cl
a
Isolated yields.
The reactions of quaternary salts containing electron-
withdrawing (such as CO2CH3, Cl) or bulky (adamantyl) groups
show a slightly slower reaction rate and lower yields than those
containing electron-donating groups (such as methoxy group, alkyl
group). Products can be easily purified from impurities by single
recrystallization. The reaction was repeated on several different
scales (up to 20 mmol), all with comparable yields.
In order to broaden the scope of the present method, we
attempted the present protocol for the naphthaline derivative.
When a mixture of quaternary salt 1j, malononitrile and DBU
(each 1 equiv) in ethanol was refluxed for 4 h, the corresponding
2-aminochromene derivative 2j was obtained in 71% yield
(Scheme 3).
7,9-di-tert-butyl-5H-chromeno[2,3-b]pyridine-3-carbonitrile
3a
(25%) and unexpected product of formal DielseAlder reaction be-
tween compound 2k and corresponding o-QM as a major product 4
(48%) (Scheme 5). It should be noted that the formation of chro-
mene 2k assumed to be a limiting stage. This assumption was
confirmed by the reaction of Mannich base 1k with malononitrile
in presence of DBU e only pyridine 3a and by-product 4 has been
obtained. It means that steric factors for ortho-substituted o-QM
precursors can significantly reduce the reaction yield.
Attempts to extend this reaction to the quaternized 2-
dimethylaminomethyl-4-nitrophenol also failed may be due to the
relatively greater thermal stability of this quaternary salt and con-
sequent difficulty in generating the o-QM under the conditions
mentioned in this paper. Nevertheless, in the reaction with
ammoniophenolate 1l,29 which is more reactivity precursor of o-QM
corresponding chromene 2l was prepared in 70% yield (Scheme 6).
A mechanistic rationale portraying the probable sequence of
events is given in Scheme 4. We suppose that the reaction proceeds
via the o-QM intermediate, which is formed by the thermal de-
composition of the quaternary ammonium salts. Subsequent

V.A. Osyanin et al. / Tetrahedron 68 (2012) 5612e5618
5615
Probably, the reaction proceeds via the intermediate formation
of 2-amino-4H-chromene-2-carbonitriles, which react with an-
other equivalent of malononitrile to form chromeno[2,3-b]pyri-
dines 3aed (Scheme 9).
Scheme 5.
Scheme 9.
The 1H NMR spectra of products 3aed show characteristic sin-
glet peaks at
spectra of 3aed exhibit
d
3.53e3.64 ppm for benzylic protons. The 13C NMR
a
specific peak in the region of
70.5e70.8 ppm, that is, related to C-3. A signal in the region of
85.5e86.4 ppm was assigned to C-4a. Protons of NH2 groups appear
as two broad singlets in the region of 6.26e6.52 ppm (D2O ex-
changeable). The IR spectra show NH2 stretch at
n ,
3472e3129 cmꢁ1
2203e2191 cmꢁ1
.
Scheme 6.
CN stretch at
n
The structures of all products were determined on the basis of
3. Conclusions
their analytical data. The 1H NMR spectra of products (2ael) show
characteristic 2-H singlets at
d 3.31e3.48 ppm for benzylic protons.
We have described a general and highly efficient procedure for
the preparation of 4-unsubstituted 2-amino-4H-chromene-2-
carbonitriles catalyzed by DBU under refluxing water. The re-
action is easily carried out, and the reaction products are directly
crystallized from the reaction mixture. Access to these heterocyclic
compounds may prove to be of some therapeutic interest in the
future including highly pronounced anticancer activities. The direct
use of inexpensive reagents, short reaction times and mild reaction
conditions make this domino MichaelePinner reaction very at-
tractive and practical.
A
distinguishing resonance at 23.8e24.9 ppm for C-4,
49.0e49.7 ppm for C-3 and 161.1e161.6 ppm for C-2 are observed in
the 13C NMR spectra. Enamine NH2 signal appears as a singlet at
6.64e6.90 ppm (D2O exchangeable). The IR spectra show NH2
stretch at
CN stretch at 2218e2183 cmꢁ1
1674e1638 cmꢁ1
n
3468e3406, 3337e3318 and 3233e3194 cmꢁ1, strong
,
C]C vinylnitrile stretch at
.
In an effort to expand the scope of the method, the replacement
of malononitrile with ethyl cyanoacetate was examined. It was
observed that with ethyl cyanoacetate, which is a less reactive
methylene component compared with malononitrile, the yield of
the chromene derivative 5 significantly decreased (Scheme 7).
4. Experimental
4.1. Materials and methods
FTIR-spectra were taken on a Shimadzu FTIR-8400S spectro-
photometer in KBr pellets. 1H, 13C and DEPT NMR spectra were
recorded on a JEOL JNM-ECX400 spectrometer (400 and 100 MHz,
respectively) in DMSO-d6 solutions with TMS as internal standard.
Chemical shifts and coupling constants were recorded in units of
parts per million and hertz, respectively. Mass spectra were
obtained on a Finnigan Trace DSQ instrument, energy of ionizing
electrons was 70 eV. Melting points were determined on Electro-
thermal melting point apparatus and are uncorrected. Elemental
analysis was carried out on an Euro Vector EA-3000 automatic
CHNS-analyzer. Thin-layer chromatography was carried out on
aluminium-backed silica gel plates (Merck 60 F254) with visual-
isation of components by UV light (254 nm) or exposure to I2. Non-
commercial Mannich bases and their quaternary ammonium salts
were prepared according to the well known methods.23a,30e32
Scheme 7.
When the quaternary ammonium salts 1a,g,i and excess
of malononitrile were heated in ethanolic solution in the
presence of NaOH, the 2,4-diamino-5H-chromeno[2,3-b]pyridine-
3-carbonitriles 3bed were formed in moderate yields (30e52%)
(Scheme 8).
4.2. General procedure for the synthesis of 2-amino-4H-
chromene-2-carbonitriles
A mixture of a quaternary ammonium salt 1aei (3 mmol),
malononitrile (0.20 g, 3 mmol) and DBU (0.45 mL, 3 mmol) in water
(20 mL) or ethanol (10 mL) was heated under reflux for the
Scheme 8.

5616
V.A. Osyanin et al. / Tetrahedron 68 (2012) 5612e5618
appropriate time (Table 4). After completion of the reaction, the
mixture was cooled to 0 ꢀC, solid was filtered off and washed with
H2O or ethanol. The crude products were purified by re-
crystallization from ethanol.
3213 (NH2), 2193 (CN), 1711 (CO), 1661 (C]C, vinylnitrile), 1614,
1585 (C]C, aromatic), 1501, 1441, 1400, 1308, 1265, 1194, 1175,
1126, 1040, 766 cmꢁ1 1H NMR (400 MHz, DMSO-d6)
; d: 3.48 (s,
2O, SO2), 3.79 (s, 3O, SO3), 6.90 (s, 2O, NH2), 7.03 (d, 1H,
J¼9.2 Hz, O-8), 7.75e7.77 (m, 2O, O-5,7) ppm; 13C NMR
4.2.1. 2-Amino-6-methoxy-4H-chromene-2-carbonitrile (2a). Creamy
solid; mp 193e194 ꢀC; IR nmax (KBr): 3406, 3337, 3221 (NH2), 2841
(CH3O), 2193 (CN), 1659 (C]C, vinylnitrile), 1622, 1587 (C]C, aro-
matic), 1501, 1435, 1410, 1265, 1211, 1184, 1152, 1040, 872, 800,
(100 MHz, DMSO-d6) d: 23.9 (CH2), 49.5 (C-3), 52.7 (CH3), 117.0
(CH), 120.7 (C), 121.2 (C), 126.1 (C), 129.8 (CH), 130.8 (CH), 153.2
(C), 160.8 (C-2), 165.9 (CO) ppm. Anal. Calcd (%) for C12H10N2O3:
C, 62.60; H, 4.38; N, 12.17. Found (%): C, 62.70; H, 4.43; N,
12.12.
696 cmꢁ1; 1H NMR (400 MHz, DMSO-d6)
d: 3.38 (s, 2H, CH2), 3.67 (s,
3H, CH3O), 6.65 (s, 2H, NH2), 6.69 (d, 1H, J¼2.8 Hz, O-5), 6.72 (dd,1O,
J¼8.7, 2.8 Hz, O-7), 6.84 (d, 1O, J¼8.7 Hz, O-8) ppm; 13C NMR
4.2.6. Methyl 2-amino-3-cyano-4H-chromene-7-carboxylate
(2f). White solid; mp 216e217 ꢀC (decomp.); IR nmax (KBr): 3410,
3333, 3210 (NH2), 2189 (CN), 1703 (CO), 1655 (C]C, vinylnitrile),
1612, 1578 (C]C, aromatic), 1441, 1425, 1412, 1308, 1292, 1250, 1096,
(100 MHz, DMSO-d6) d: 24.7 (CH2-4), 49.0 (C-3), 55.9 (CH3O), 113.2
(CH), 114.1 (CH), 117.3 (CH), 120.9 (C), 121.7 (C), 143.7 (C), 156.1 (C),
161.6 (C-2) ppm. Anal. Calcd (%) for C11H10N2O2: C, 65.34; H, 4.98; N,
13.85. Found (%): C, 65.26; H, 5.07; N, 13.80.
1040, 903, 760 cmꢁ1 1H NMR (400 MHz, DMSO-d6)
; d: 3.48 (s, 2O,
SO2), 3.80 (s, 3O, SO3), 6.88 (s, 2O, NH2), 7.28 (d, 1H, J¼7.8 Hz,
Synthesis of 2a under solvent-free condition
O-5), 7.36 (d, 1O, J¼1.4 Hz, O-8), 7.61 (dd, 1O, J¼7.8, 1.4 Hz, O-6)
ppm; 13C NMR (100 MHz, DMSO-d6)
d: 24.3 (CH2), 49.1 (C-3), 52.9
Malononitrile (0.20 g, 3 mmol), quaternary ammonium salt 1a
(0.65 g, 2 mmol) and DBU (0.45 mL, 3 mmol) were stirred at room
temperature for 15 min. The crude solid was washed with cold
water and purified by crystallization from ethanol. Yield 0.25 g
(63%).
(CH3), 116.8 (CH), 121.3 (C), 125.4 (CH), 126.0 (C), 129.8 (CH), 129.9
(C), 149.8 (C), 161.1 (C-2), 165.8 (CO) ppm. Anal. Calcd (%) for
C12H10N2O3: C, 62.60; H, 4.38; N, 12.17. Found (%): C, 62.65; H, 4.36;
N, 12.21.
4.2.7. 2-Amino-6,7-dimethyl-4H-chromene-2-carbonitrile (2g). Light
yellow solid; mp 242e244 ꢀC (decomp.) (from DMF); IR nmax (KBr):
3453, 3333, 3217 (NH2), 2187 (CN), 1659 (C]C, vinylnitrile), 1612,
1578 (C]C, aromatic), 1501, 1454, 1412, 1300, 1223, 1180, 1099, 1030,
4.2.2. 6-(1-Adamantyl)-2-amino-4H-chromene-2-carbonitrile
(2b). White solid; mp 241e243 ꢀC (decomp.); IR nmax (KBr): 3418,
3327, 3208 (NH2), 2911, 2847 (CH Ad), 2187 (CN), 1647 (C]C,
vinylnitrile), 1609, 1585 (C]C, aromatic), 1501, 1420, 1271, 1233,
991, 872 cmꢁ1; 1H NMR (400 MHz, DMSO-d6)
d
: 2.10 (s, 3H, CH3), 2.12
(s, 3H, CH3), 3.31 (s, 2H, CH2), 6.68 (s, 1H, Ar), 6.69 (s, 2H, NH2), 6.87
(s, 1H, Ar) ppm; 13C NMR (100 MHz, DMSO-d6)
: 19.1 (CH3), 19.6
1215, 1157, 1032, 808 cmꢁ1 1H NMR (400 MHz, DMSO-d6)
; d: 1.67
(br s, 6O, Ad),1.78 (br s, 6H, Ad), 2.00 (br s, 3H, Ad), 3.42 (s, 2H, CH2),
6.71 (s, 2H, NH2), 6.85 (d, 1H, J¼8.7 Hz, O-8), 7.10 (d, 1O, J¼2.3 Hz,
O-5), 7.16 (dd, 1O, J¼8.7, 2.3 Hz, O-7) ppm; 13C NMR (100 MHz,
d
(CH3), 23.8 (CH2-4), 49.4 (C-3), 116.6 (C), 117.0 (CH), 121.8 (C), 129.7
(CH),132.7 (C),136.5 (C),147.6 (C),161.5 (C-2) ppm. Anal. Calcd (%) for
C12H12N2O: C, 71.98; H, 6.04; N,13.99. Found (%): C, 72.03; H, 6.09; N,
14.05.
DMSO-d6) d: 24.5 (CH2-4), 28.8 (CH Ad), 35.9 (C Ad), 36.6 (CH2 Ad),
43.1 (CH2 Ad), 49.4 (C-3), 115.9 (CH), 119.4 (C), 121.7 (C), 124.8 (CH),
125.5 (CH), 147.6 (C), 147.7 (C), 161.5 (C-2) ppm. Anal. Calcd (%) for
C20H22N2O: C, 78.40; H, 7.24; N, 9.14. Found (%): C, 78.49; H, 7.19;
N, 9.22.
4.2.8. 2-Amino-6-benzyl-4H-chromene-2-carbonitrile (2h). White
solid; mp 156e157 ꢀC; IR nmax (KBr): 3418, 3318, 3194 (NH2), 2195
(CN), 1659 (C]C, vinylnitrile), 1612, 1589 (C]C, aromatic), 1497,
1435, 1404, 1312, 1269, 1223, 1207, 1038 cmꢁ1; 1H NMR (400 MHz,
4.2.3. 8-(1-Adamantyl)-6-methyl-2-amino-4H-chromene-2-
carbonitrile (2c). White solid; mp 275e276 ꢀC (decomp.); IR nmax
(KBr): 3468, 3337 (NH2), 2905, 2851 (CH Ad), 2195 (CN),1667 (C]C,
vinylnitrile), 1597 (C]C, aromatic), 1454, 1400, 1315, 1211, 1157,
DMSO-d6) d: 3.38 (s, 2H, 4-CH2), 3.83 (s, 2H, CH2Ph), 6.73 (s, 2H,
NH2), 6.84 (d, 1H, J¼8.2 Hz, H-8), 7.00e7.03 (m, 2H, Ar), 7.12e7.19
(m, 3H, Ar), 7.22e7.26 (m, 2H, Ar) ppm; 13C NMR (100 MHz, DMSO-
1038, 856 cmꢁ1
;
1H NMR (400 MHz, DMSO-d6)
d: 1.63 (d, 3O,
d6) d: 24.2 (CH2-2), 40.8 (CH2Ph), 49.3 (C-3), 54.9 (C-4), 116.5 (CH),
J¼11.7 Hz, Ad), 1.82 (d, 3O, J¼11.7 Hz, Ad), 1.95e1.97 (m, 9H, Ad),
120.0 (C), 121.7 (C), 126.5 (CH), 128.7 (CH), 129.0 (CH), 129.2 (CH),
137.9 (C), 141.7 (C), 148.1 (C), 161.5 (C-2) ppm. Anal. Calcd (%) for
C17H14N2O: C, 77.84; H, 5.38; N, 10.68. Found (%): C, 77.78; H, 5.31;
N, 10.73.
3.06 (s, 3H, CH3), 3.33 (s, 2H, CH2), 6.64 (s, 2H, NH2), 6.77 (s, 1H, Ar),
6.85 (s, 1O, Ar) ppm; 13C NMR (100 MHz, DMSO-d6)
d: 21.0 (CH3),
24.7 (CH2-4), 28.9 (CH Ad), 36.7 (CH2 Ad), 36.8 (C Ad), 40.9 (CH2 Ad),
49.7 (C-3), 120.5 (C), 121.7 (C), 126.3 (CH), 127.1 (CH), 133.2 (C), 137.2
(C), 146.9 (C), 161.3 (C-2) ppm. Anal. Calcd (%) for C21H24N2O: C,
78.71; H, 7.55; N, 8.74. Found (%): C, 78.65; H, 7.64; N, 8.68.
4.2.9. 2-Amino-6-chloro-4H-chromene-2-carbonitrile
(2i). Light
yellow solid; mp 213e215 ꢀC; IR nmax (KBr): 3418, 3331, 3208
(NH2), 2183 (CN), 1661 (C]C, vinylnitrile), 1609, 1580 (C]C, ar-
omatic), 1481, 1450, 1422, 1406, 1308, 1261, 1233, 1180, 1036,
4.2.4. 2-Amino-6-tert-butyl-4H-chromene-2-carbonitrile (2d). White
solid; mp 153e154 ꢀC; IR nmax (KBr): 3426, 3325, 3210 (NH2), 2959,
2862 (CH3, CH2), 2191 (CN), 1651 (C]C, vinylnitrile), 1612, 1589 (C]
C, aromatic), 1504, 1412, 1273, 1234, 1180, 1126, 1037 cmꢁ1; 1H NMR
812 cmꢁ1; 1H NMR (400 MHz, DMSO-d6)
d: 3.42 (s, 2H, CH2), 6.84
(br s, 2H, NH2), 6.95 (d, 1O, J¼8.7 Hz, H-8), 7.23 (dd, 1H, J¼8.7,
2.3 Hz, H-7), 7.26 (d, 1H, J¼2.3 Hz, H-5) ppm; 13C NMR (100 MHz,
(400 MHz, DMSO-d6)
d: 1.21 (s, 9O, C(CH3)3), 3.40 (s, 2H, CH2), 6.71
DMSO-d6) d: 24.1 (CH2), 49.1 (C-3), 118.3 (CH), 121.3 (C), 122.5 (C),
(br s, 2H, NH2), 6.84 (d, 1O, J¼8.7 Hz, H-8), 7.14 (d, 1H, J¼2.3 Hz, H-5),
128.3 (CH), 128.4 (C), 128.8 (CH), 148.6 (C), 161.2 (C-2) ppm. Anal.
Calcd (%) for C10H7ClN2O: C, 58.13; H, 3.41; N, 13.56. Found (%): C,
58.21; H, 3.37; N, 13.65.
7.19 (dd, 1H, J¼8.7, 2.3 Hz, H-7) ppm; 13C NMR (100 MHz, DMSO-d6)
d: 24.5 (CH2), 31.7 (CH3), 34.6 (C), 49.4 (C-3), 115.9 (CH), 119.3 (C),
121.7 (C), 125.3 (CH), 125.8 (CH), 147.3 (C), 147.7 (C), 161.5 (C-2) ppm.
Anal. Calcd (%) for C14H16N2O: C, 73.66; H, 7.06; N, 12.27. Found (%):
C, 73.70; H, 7.01; N, 12.32.
4.2.10. 3-Amino-1H-benzo[f]chromene-2-carbonitrile (2j). A mix-
ture of 1 g (2.9 mmol) of quaternary ammonim salt 1h,33 0.19 g
(2.9 mmol) of malononitrile and 0.43 mL (2.9 mmol) of DBU in
ethanol (20 mL) was refluxed for 4 h and then stored at ꢁ10 ꢀC
overnight. The precipitate formed was then filtered, washed ice-
4.2.5. Methyl 2-amino-3-cyano-4H-chromene-6-carboxylate
(2e). White solid; mp 211e212 ꢀC; IR nmax (KBr): 3414, 3327,

V.A. Osyanin et al. / Tetrahedron 68 (2012) 5612e5618
5617
cold ethanol and recrystallized from ethanol. Yield 0.46 g (71%).
Light yellow solid; mp 209e211 ꢀC; IR
(KBr): 3441, 3333
(NH2), 2187 (CN), 1674 (C]C, vinylnitrile), 1589 (C]C, aro-
matic), 1408, 1296, 1234, 1177, 1080, 1026, 945, 806, 741 cmꢁ1
1H NMR (400 MHz, DMSO-d6)
: 3.73 (s, 2H, CH2), 6.86 (br s,
11), 283 (100), 269 (18), 203 (12). Anal. Calcd (%) for C33H46N2O2: C,
78.84; H, 9.22; N, 5.57. Found (%): C, 79.05; H, 9.18; N, 5.65.
n
;
4.4. Synthesis of 2-amino-6-nitro-4H-chromene-2-
carbonitrile (2l)
d
2H, NH2), 7.14 (d, 1H, J¼9.0 Hz, H-5), 7.47 (dd, 1H, J¼8.0, 6.9 Hz,
Ar), 7.57 (dd, 1H, J¼8.0, 6.9 Hz, Ar), 7.79 (d, 1H, J¼8.0 Hz, Ar),
7.82 (d, 1H, J¼9.0 Hz, H-6), 7.89 (d, 1H, J¼8.0 Hz, Ar) ppm; 13C
A mixture of 0.15 g (0.6 mmol) of 4-nitro-2-[(triethylammonio)
methyl]phenolate,29 0.04 g (0.6 mmol) of malononitrile, 1 mL of
water and 1 mL of acetonitrile was refluxed for 1.5 h and then
stored at 0 ꢀC overnight. The precipitate formed was then filtered
and recrystallized from ethanol. Yield 0.09 g (70%). Yellow solid; mp
211e212 ꢀC (decomp.); IR nmax (KBr): 3468, 3329 (NH2), 2218 (CN),
1638 (C]C, vinylnitrile), 1578, 1502 (NO2), 1378 (NO2), 1164,
NMR (100 MHz, DMSO-d6) d: 22.2 (CH2), 49.8 (C-2), 112.3 (C),
117.2 (CH), 121.8 (C), 123.5 (CH), 125.6 (CH), 127.8 (CH), 128.8
(CH), 129.2 (CH), 130.7 (C), 131.3 (C), 146.7 (C), 160.7 (C-3) ppm.
Anal. Calcd (%) for C14H10N2O: C, 75.66; H, 4.54; N, 12.60. Found
(%): C, 75.73; H, 4.47; N, 12.63.
823 cmꢁ1; 1H NMR (400 MHz, DMSO-d6)
d: 3.55 (s, 2H, SO2), 7.03
(br s, 2H, NH2), 7.16 (d, 1O, J¼8.9 Hz, H-8), 8.06 (dd, 1O, J¼8.9,
4.3. Reaction of Mannich base 1k with malononitrile in
presence of DBU
2.8 Hz, O-7), 8.13 (d, 1O, J¼2.8 Hz, H-5) ppm; 13C NMR (100 MHz,
DMSO-d6) d: 24.0 (CH2), 49.3 (C-3), 117.8 (CH), 120.9 (C), 122.0 (C),
124.4 (CH), 125.3 (CH), 144.0 (C), 154.4 (C), 160.6 (C-2) ppm. Anal.
Calcd (%) for C10H7N3O3: C, 55.30; H, 3.25; N, 19.35. Found (%): C,
55.40; H, 3.19; N, 19.41.
To a boiling solution of 1 g (3.8 mmol) of Mannich base 1l and
0.57 mL (3.8 mmol) of DBU in DMF (10 mL) a solution of 0.25 g
(3.8 mmol) of malononitrile in DMF (2 mL) was added for 15 min
under an Ar atmosphere. Afterwards, the reaction mixture was
refluxed for 1 h, cooled, poured into 50 mL of cold water to yield the
cream solid, which was filtered, washed with water, dried and
separated by column chromatography (silica gel, EtOAc/di-
chloroethane/1:3) to give 4 (0.46, 48%), 2k (0.10 g, 9%) and 3a
(0.33 g, 25%).
4.5. General procedure for synthesis of 2,4-diamino-5H-
chromeno[2,3-b]pyridine-3-carbonitrile
A mixture of 3 mmol of quternary ammonim salt (1a,j or i), 2 g
(30 mmol) of malononitrile and 0.12 g (3 mmol) of NaOH in ethanol
(10 mL) was refluxed for 4 h and then stored at ꢁ10 ꢀC overnight.
The precipitate formed was then filtered, washed ice-cold ethanol
and recrystallized from DMF.
4.3.1. 2-Amino-6,8-di-tert-butyl-4H-chromene-2-carbonitrile
(2k). White solid; mp 195e196 ꢀC (from EtOH); IR nmax (KBr): 3460,
3321, 3287, 3233, 3186 (NH2), 2967, 2870 (CH3, CH2), 2195 (CN),
1663 (C]C, vinylnitrile), 1605, 1593 (C]C, aromatic), 1477, 1404,
1315, 1234, 1204, 1165, 1179, 1030 cmꢁ1; 1H NMR (400 MHz, DMSO-
4.5.1. 2,4-Diamino-7-methoxy-5H-chromeno[2,3-b]pyridine-3-
carbonitrile (3b). Yield 0.41 g (51%). White solid; decomposed
>325 ꢀC; IR nmax (KBr): 3441, 3356, 3260, 3129 (NH2), 2199 (CN),
1655, 1639, 1609, 1578, 1501, 1481, 1435, 1404, 1339, 1258, 1215,
d6)
6.76 (br s, 2H, NH2), 6.98 (d, 1H, J¼2.3 Hz, Ar), 7.10 (d, 1H, J¼2.3 Hz,
Ar) ppm; 13C NMR (100 MHz, DMSO-d6)
: 24.9 (CH2), 30.6 (3CH3),
d: 1.21 (s, 9O, C(CH3)3), 1.32 (s, 9H, C(CH3)3), 3.37 (s, 2H, CH2),
d
1142, 1119, 1034, 795, 768 cmꢁ1 1H NMR (400 MHz, DMSO-d6)
; d:
31.7 (3CH3), 34.7 (C), 35.1 (C), 49.3 (C-3), 120.3 (C), 121.7 (C), 122.1
(CH), 123.8 (CH), 136.6 (C), 146.2 (C), 146.6 (C), 161.5 (C-2) ppm.
Anal. Calcd (%) for C18H24N2O: C, 76.02; H, 8.51; N, 9.85. Found (%):
C, 75.97; H, 8.47; N, 9.90.
3.61 (s, 2H, CH2), 3.69 (s, 3H, CH3O), 6.28 (br s, 2H, NH2), 6.47 (br s,
2H, NH2), 6.63 (d, 1H, J¼2.8 Hz, H-6), 6.76 (dd, 1H, J¼9.2, 2.8 Hz, H-
8), 6.91 (d,1H, J¼9.2 Hz, H-9) ppm; 13C NMR (100 MHz, DMSO-d6)
d:
23.6 (CH2), 55.9 (CH3), 70.5 (C-3), 85.7 (C-4a), 113.7 (CH), 114.0 (CH),
117.3 (C), 117.7 (CH), 120.8 (C), 144.8 (C), 155.7 (C), 157.6 (C), 159.2
(C), 160.0 (C) ppm. Anal. Calcd (%) for C14H12N4O2: C, 62.68; H, 4.51;
N, 20.88. Found (%): C, 62.75; H, 4.44; N, 20.91.
4.3.2. 2,4-Diamino-7,9-di-tert-butyl-5H-chromeno[2,3-b]pyridine-3-
carbonitrile (3a). White solid; mp 262e264 ꢀC (decomp.) (from
EtOH/DMF); IR nmax (KBr): 3464, 3372, 3252, 3306, 3156 (NH2),
2959, 2905, 2870 (CH2, CH3), 2191 (CN), 1639, 1574, 1485, 1439,
4.5.2. 2,4-Diamino-7,8-dimethyl-5H-chromeno[2,3-b]pyridine-3-
carbonitrile (3c). Yield 0.34 g (43%). Pink solid; decomposed
>330 ꢀC; IR nmax (KBr): 3472, 3364, 3233 (NH2), 2199 (CN), 1628,
1605, 1570, 1477, 1404, 1323, 1308, 1204, 1180, 1157, 1076 cmꢁ1; 1H
1404, 1331, 1227, 1204, 1169 cmꢁ1; 1H NMR (400 MHz, DMSO-d6)
d:
1.22 (s, 9H, C(CH3)3), 1.36 (s, 9H, C(CH3)3), 3.63 (s, 2H, CH2), 6.40 (br
s, 2H, NH2), 6.46 (br s, 2H, NH2), 6.94 (d, 1H, J¼2.3 Hz, Ar), 7.10 (d,
1H, J¼2.3 Hz, Ar) ppm; 13C NMR (100 MHz, DMSO-d6)
d
: 23.8 (CH2),
NMR (400 MHz, DMSO-d6)
CH2), 6.26 (br s, 2H, NH2), 6.46 (br s, 2H, NH2), 6.64 and 6.86 (s, 2H,
H-6,9) ppm; 13C NMR (100 MHz, DMSO-d6)
: 19.1 (CH3), 19.6 (CH3),
d: 2.12 and 2.14 (s, 6H, 2CH3), 3.53 (s, 2H,
30.3 (3CH3), 31.8 (3CH3), 34.6 (C), 35.2 (C), 70.6 (C-3), 86.4 (C-4a),
117.3 (C), 120.1 (C), 122.1 (CH), 123.9 (CH), 136.5 (C), 145.4 (C), 147.7
(C), 157.4 (C), 159.4 (C), 160.2 (C) ppm. Anal. Calcd (%) for
C21H26N4O: C, 71.97; H, 7.48; N, 15.99. Found (%): C, 72.05; H, 7.51;
N, 16.09.
d
22.8 (CH2), 70.5 (C-3), 86.3 (C-4a), 116.6 (C), 117.3 (C), 117.4 (CH),
130.0 (CH), 132.0 (C), 136.4 (C), 148.8 (C), 157.6 (C), 159.2 (C), 159.9
(C) ppm. Anal. Calcd (%) for C15H14N4O: C, 67.65; H, 5.30; N, 21.04.
Found (%): C, 67.72; H, 5.21; N, 20.98.
4.3.3. 5a-Amino-2,4,7,9-tetra-tert-butyl-5a,11,11a,12-tetrahydrochro-
meno[2,3-b]chromene-11a-carbonitrile (4). White
solid; mp
4.5.3. 2,4-Diamino-7-chloro-5H-chromeno[2,3-b]pyridine-3-
carbonitrile (3d). Yield 0.25 g (30%). White solid; decomposed
>310 ꢀC; IR nmax (KBr): 3429, 3360, 3294, 3252, 3171 (NH2), 2203
(CN), 1647, 1628, 1605, 1570, 1477, 1423, 1400, 1331, 1261, 1223,
208e209 ꢀC (from MeOH); IR nmax (KBr): 3395, 3325 (NH2), 2963,
2909, 2870 (CH3, CH2), 2241 (CN, weak), 1605, 1477, 1362, 1223,
1200, 980 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d: 1.24 (s, 18H, C(CH3)3),
1.33 (s, 18H, C(CH3)3), 2.70 (br s, 2H, NH2), 3.07 (d, 2H, J¼16.5 Hz,
1192 cmꢁ1; 1H NMR (400 MHz, DMSO-d6)
d: 3.64 (s, 2H, CH2), 6.34
CH2), 3.37 (d, 2H, J¼16.5 Hz, CH2), 6.86 (d, 2H, J¼2.3 Hz, Ar), 7.16 (d,
(br s, 2H, NH2), 6.52 (br s, 2H, NH2), 7.00 (d, 1H, J¼8.7 Hz, H-9), 7.14
2H, J¼2.3 Hz, Ar) ppm; 13C NMR (100 MHz, DMSO-d6)
d: 29.9
(d, 1H, J¼2.5 Hz, H-6), 7.23 (dd, 1H, J¼8.7, 2.5 Hz, H-8) ppm; 13C
(6CH3), 31.6 (6CH3), 34.3 (2CH2), 34.4 (2C), 35.0 (2C), 35.9 (C-11a),
102.0 (C-5a), 116.6 (2C), 121.0 (CN), 122.9 (2CH), 123.6 (2CH), 137.2
(2C), 144.1 (2C), 147.2 (2C) ppm. MS (EI, 70 eV): m/z (%)¼402 (Mþ,
NMR (100 MHz, DMSO-d6) d: 23.2 (CH2), 70.8 (C-3), 85.5 (C-4a),
117.1 (C), 118.7 (CH), 122.4 (C), 127.7 (C), 128.3 (CH), 128.9 (CH),
149.9 (C), 157.6 (C), 158.7 (C), 160.0 (C) ppm. Anal. Calcd (%)

5618
V.A. Osyanin et al. / Tetrahedron 68 (2012) 5612e5618
6. Elagamey, A. G. A.; El-Taweel, F. M. A.-A.; Khodeir, M. N. M.; Elnagdi, M. H. Bull.
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3.28; N, 20.62.
45, 5056e5063.
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4.6. Synthesis of 6-methoxy-2-oxochromane-3-carbonitrile
(5)
Ethyl cyanoacetate (0.32 mL, 3 mmol), quaternary ammonium
salt 1a (1 g, 3 mmol) and DBU (0.45 mL, 3 mmol) were stirred at
80 ꢀC for 10 min. The crude solid was washed with water, dried,
purified by column chromatography (silica gel, dichloroethane) and
recrystallized from methanol. Yield 0.14 g (22%). White solid; mp
153e155 ꢀC; IR nmax (KBr): 2264 (CN), 1767 (CO), 1597, 1501, 1443,
1358, 1292, 1250, 1207, 1192, 1180, 1150, 1026, 1003, 880, 864,
10. Evdokimov, N. M.; Kireev, A. S.; Yakovlenko, A. A.; Antipin, M. Y.; Magedov, I. V.;
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7194e7196.
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829 cmꢁ1
;
1H NMR (400 MHz, DMSO-d6)
d
: 3.29 (dd, 1H, J¼15.1,
6.0 Hz, CH2), 3.53 (dd, 1H, J¼15.1, 13.3 Hz, CH2), 3.71 (s, 3H, CH3),
4.76 (dd, 1H, J¼13.3, 6.0 Hz, H-3), 6.85 (dd, 1H, J¼8.7, 2.8 Hz, H-7),
6.89 (d, 1H, J¼2.8 Hz, H-5), 7.03 (d, 1H, J¼8.7, H-8) ppm; 13C NMR
(100 MHz, DMSO-d6) d: 27.7 (CH2), 33.1 (CH3), 56.1 (CH-3), 113.6
(CH), 114.5 (CH), 117.0 (C), 117.9 (CH), 122.2 (C), 145.2 (C), 156.5 (C),
162.9 (C) ppm. Anal. Calcd (%) for C11H9NO3: C, 65.02; H, 4.46; N,
6.89. Found (%): C, 64.97; H, 4.53; N, 6.96.
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Acknowledgements
This work was supported by the program of the President of the
Russian Federation for state support of young Russian scientists e
Candidates of sciences (grant MK-3368.2011.3) and the Russian
Ministry of Education and Science with use of equipment of
Multiple-Access Center ‘Investigation of the physicochemical
properties of substances and materials’.
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Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2012.04.065. These data in-
clude MOL files and InChiKeys of the most important compounds
described in this article.
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