Cross reactions of cyanoacetic acid derivatives with carbonyl compounds 3. One-step synthesis of substituted 2-amino-5-oxo-4,5-dihydropyrano[3,2-c] chromenes

Article abstract of DOI:10.1007/s11172-005-0346-9

Three-component reactions of 4-hydroxycoumarin, carbonyl compounds, and malono-nitrile or alkyl cyanoacetates in ethanol in the presence of Et ₃N as a catalyst give substituted 2-amino-5-oxo-4,5-dihydropyrano[3, 2-c]chromenes.

Full text of DOI:10.1007/s11172-005-0346-9

992
Russian Chemical Bulletin, International Edition, Vol. 54, No. 4, pp. 992—996, April, 2005
Cross reactions of cyanoacetic acid derivatives
with carbonyl compounds
3.* Oneꢀstep synthesis of substituted 2ꢀaminoꢀ5ꢀoxoꢀ
4,5ꢀdihydropyrano[3,2ꢀc]chromenes**
ꢀ
A. A. Shestopalov, L. A. Rodinovskaya, A. M. Shestopalov, and V. P. Litvinov
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (095) 135 5328. Eꢀmail: shchem@dol.ru
Threeꢀcomponent reactions of 4ꢀhydroxycoumarin, carbonyl compounds, and malonoꢀ
nitrile or alkyl cyanoacetates in ethanol in the presence of Et3N as a catalyst give substituted
2ꢀaminoꢀ5ꢀoxoꢀ4,5ꢀdihydropyrano[3,2ꢀc]chromenes.
Key words: malononitrile, alkyl cyanoacetates, 4ꢀhydroxycoumarin, 2ꢀaminoꢀ5ꢀoxoꢀ4,5ꢀ
dihydropyrano[3,2ꢀc]chromenes, spiro[indolineꢀ3,4´]pyrano[3,2ꢀc]chromenes, cross reactions,
6ꢀaminoꢀ2,1´ꢀbis(benzyloxycarbonyl)ꢀ5,7,7ꢀtricyanospiro[3,7,8,8aꢀtetrahydroꢀ1Hꢀisoquinoꢀ
lineꢀ8,4´ꢀpiperidine].
A key compound in the synthesis (Scheme 1) of warꢀ
also obtained4,7 by morpholineꢀcatalyzed reactions of
farin (rodenticide, a blood anticoagulant) is 2ꢀaminoꢀ3ꢀ
cyanoꢀ5ꢀoxoꢀ4ꢀphenylꢀ4,5ꢀdihydropyrano[3,2ꢀc]chroꢀ
mene (3) prepared by heating of 4ꢀhydroxycoumarin 1
with benzylidenemalononitrile 2 in pyridine2 or water.3
Acid hydrolysis of substituted pyrano[3,2ꢀc]chromene 3
gives compound 4, which is used to synthesize warꢀ
farin 5.2—6
4ꢀhydroxycoumarin with arylidenecyanothioacetamide,
alkyl arylidenecyanoacetates, or arylidenemalononitrile
in hot benzene or ethanol. Despite some achievements
attained in recent years in the synthesis of compounds of
the type 3 with other substituents in position 4, preparaꢀ
tion and isolation of unsaturated nitriles 2, which are
analogs of toxic agents CS,8 substantially complicated the
aforementioned synthesis (see Scheme 1). In some cases,
the condensation does not yield the target unsaturated
nitrile at all: in the reaction of pyridineꢀ4ꢀcarbaldehyde
with malononitrile, 1ꢀaminoꢀ2,4,4,6,6ꢀpentacyanoꢀ3,5ꢀ
di(4ꢀpyridyl)cyclohexꢀ1ꢀene was obtained instead.9 This
2ꢀAminoꢀ4ꢀarylꢀ3ꢀ(thiocarbamoyl, alkoxycarbonyl, or
cyano)ꢀ5ꢀoxoꢀ4,5ꢀdihydropyrano[3,2ꢀc]chromenes were
* For Part 2, see Ref. 1.
** Dedicated to Academician V. I. Minkin on the occasion of
his 70th birthday.
Scheme 1
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 4, pp. 968—972, April, 2005.
1066ꢀ5285/05/5404ꢀ0992 © 2005 Springer Science+Business Media, Inc.

Synthesis of substituted pyranochromenes
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 4, April, 2005
993
Table 1. Physicochemical characteristics of substituted 2ꢀaminoꢀ
5ꢀoxoꢀ4,5ꢀdihydropyrano[3,2ꢀc]chromenes 8 and 20
heterocycles, we studied threeꢀcomponent reactions of
4ꢀhydroxycoumarin, cyanoacetic acid derivatives (maloꢀ
nonitrile and alkyl cyanoacetates), and carbonyl comꢀ
pounds (aromatic and heterocyclic aldehydes, cyclic aliꢀ
phatic ketones, or isatin). To obtain potential biologically
active compounds, we introduced into this reaction not
only heterocyclic aldehydes but also alkoxyꢀ or dialkoxyꢀ
benzaldehydes, the residues of which are found in many
natural physiologically active compounds.6
The brief heating of 4ꢀhydroxycoumarin 1 with aldeꢀ
hydes 6 and cyanoacetic acid derivatives 7 in boiling ethaꢀ
nol in the presence of Et3N as a catalyst gave substituted
2ꢀaminoꢀ5ꢀoxoꢀ4,5ꢀdihydropyrano[3,2ꢀc]chromenes 8a,f
in high yields (67—93%). Using this method, we avoided
side processes and obtained 4ꢀ(4ꢀpyridyl)ꢀ, 4ꢀ(4ꢀalkoxyꢀ
phenyl)ꢀ, and 4ꢀ(3,4ꢀdialkoxyphenyl)pyranochromenes
8a,b,d—f (Table 1). Such a high regioselectivity is probꢀ
ably associated with the fixed sequence of reaction steps.
Apparently, the initial Knoevenagel reaction of aldehyde
6 with cyanoacetic acid derivative 7 gives unsaturated
nitrile 9, which, when at the "reaction intersection", enꢀ
ters into the Michael reaction with coumarin anion 10.
The resulting Michael adduct 11 undergoes intramolecuꢀ
lar cyclization into annelated iminopyran 12. Subsequent
tautomeric [1,3]sigmatropic shift gives compounds 8
(Scheme 2).
Comꢀ M.p.
pound /°C
Yield
(%)
Found
Calculated
Molecular
formula
(%)
N
C
H
8a
238—240
(decomp.)
188—189
78
67
68
90
74
93
85
92
89
90
68.32 3.21 13.04 C18H11N3O3
68.14 3.49 13.24
63.87 4.66 7.19 C21H18N2O6
63.96 4.60 7.10
67.41 3.85 8.82 C18H12N2O4
67.50 3.78 8.75
70.69 4.75 7.39 C22H18N2O4
70.58 4.85 7.48
68.39 4.85 6.74 C23H20N2O5
68.31 4.98 6.93
63.32 3.92 9.86 C22H17N3O6
63.01 4.09 10.02
63.24 3.71 3.61 C21H15F2NO5
63.16 3.79 3.51
67.04 2.93 11.38 C20H11N3O4
67.23 3.10 11.76
8b
8c
190—192
(decomp.)
232—233
8d
8e
277—229
204—206
221—222
>300
8f
8g
20a
20b
20c
>300
67.68 3.35 11.07 C21H13N3O4
67.92 3.53 11.32
63.73 2.45 10.94 C20H10FN3O4
64.00 2.69 11.20
>300
precludes the synthesis of pyrano[3,2ꢀc]chromones conꢀ
taining the 4ꢀpyridyl substituent in position 4.
In further investigations of cross reactions of cyanoaceꢀ
tic acid derivatives with carbonyl compounds1,10 with the
aim of developing oneꢀstep syntheses of functionalized
Under these conditions, the reaction sufficiently rapꢀ
idly and smoothly affords target chromenes 8 in high
yields; no Michael adducts 11 were detected. However,
this scheme is confirmed to some degree by isolation of
analogous Michael adducts (Z = CSNH2) in the previꢀ
Scheme 2
Z = CN (7a, 8a,c—f), COOEt (7b, 8g), COO(CH2)2OMe (7c, 8b)
6, 8: Ar = 4ꢀPy (a, b), 2ꢀ(5ꢀMeC4H2O) (c), 4ꢀPriOC6H4 (d), 3ꢀMeOꢀ4ꢀPriOC6H3 (e), 3ꢀMeOꢀ4ꢀ(OCH2CONH2)C6H3 (f), 2,4ꢀF2C6H3 (g)
Reagents and conditions: i. EtOH, Et3N, ∆, 5 min.

994
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 4, April, 2005
Shestopalov et al.
Scheme 3
Reagents and conditions: i. EtOH, Et3N, ∆.
ously studied reactions of 4ꢀhydroxycoumarin with arylꢀ
idenecyanothioacetamides.4
The pyranochromenes 8 and 20 obtained are airꢀstable
colorless solid powders, which are well soluble in acꢀ
etone, DMF, and DMSO. The structures of these comꢀ
pounds were confirmed by elemental analysis and IR and
1H NMR spectroscopy (Tables 1, 2). The IR spectra of
pyranochromenes 8 and 20 contain characteristic absorpꢀ
tion bands of the enamino nitrile and enamino carboꢀ
nyl fragments: δ(NH2) 1660—1678 cm–1, ν(NH2)
The threeꢀcomponent reaction between coumarin 1,
malononitrile 7a, and 1ꢀbenzyloxycarbonylpiperidinꢀ4ꢀ
one (13) as the carbonyl compound follows a different
pathway. Under analogous conditions (see above), maloꢀ
nonitrile 7a reacts with piperidinꢀ4ꢀone 13 to give unsatꢀ
urated nitrile 14, which dimerizes into spiroheterocycle
15 rather than reacting with coumarin 1. The suggested
scheme involves dimerization of unsaturated nitrile 14
into Michael adduct 16, its Thorpe—Ziegler cyclization
into spiroheterocycle 17, and final tautomerization into
compound 15 through intermediate 18. Thus, coumarin 1
is out the process. Indeed, we obtained compound 15
from malononitrile 7a and ketone 13 in ethanol in the
presence of Et3N (Scheme 3). An analogous dimerization
was observed earlier in the reaction of 1ꢀmethylpiperidinꢀ
4ꢀone with malononitrile.10 This reaction pathway is probꢀ
ably due to a higher γꢀCH acidity of unsaturated nitrile 14
compared to 4ꢀhydroxycoumarin 1.
Our assumption was confirmed by a threeꢀcomponent
reaction with isatin 19 (containing no γꢀCH acid fragꢀ
ment) as the carbonyl compound, which gives spiro(indoꢀ
lineꢀ3,4´ꢀpyrano[3,2ꢀc]chromenes) 20 rather than dimerꢀ
ization products from unsaturated nitriles 21 (Scheme 4).
The yields of spiro compounds 20 were high (89—92%),
regardless of the type of substituent in the benzene ring of
isatin 19.
3135—3378 cm–1
, , and
ν(CN) 2190—2208 cm–1
ν(COOR) 1673—1696 cm–1. An analogous spectral patꢀ
tern was observed for 2ꢀaminoꢀ4Hꢀpyrans containing
similar fragments.1,9—12 The IR spectra of pyranochroꢀ
menes 8 and 20 show a peculiar absorption band of the
lactone group at 1688—1720 cm–1. The 1H NMR spectra
of pyranochromenes 8 exhibit, apart from signals for proꢀ
tons of the aromatic and chromene fragments, characterꢀ
istic singlets for the C(4)H and NH2 protons at δ 4.37 to
4.90 and 7.09 to 7.85, respectively. Signals of the C(4)H
group are absent from the spectra of spiroheterocycles 20;
instead, signals for the protons of the isatin fragment are
present.
In conclusion, it should be noted that the cross reacꢀ
tions studied are based on simultaneous double generaꢀ
tion of a nucleophile (4ꢀhydroxycoumarin anion) and an
electrophile (unsaturated nitrile) in the reaction mixture.
At the "intersection point", the reaction between intermeꢀ
diates can give pyranochromenes 8 and 20 or isoquinoꢀ
line 15.

Synthesis of substituted pyranochromenes
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 4, April, 2005
995
Scheme 4
19, 21: R = H (a), 7ꢀMe (b), 5ꢀF (c)
Reagents and conditions: i. EtOH, Et3N, ∆, 10 min.
of the compounds obtained was checked by TLC on Silufol
UVꢀ254 plates with hexane—acetone (5 : 3) as an eluent; spots
were visualized with the iodine vapor.
2ꢀAminoꢀ5ꢀoxoꢀ4,5ꢀdihydropyrano[3,2ꢀc]chromenes 8 and
20 (general procedure). A stirred mixture of 4ꢀhydroxycoumarin 1
(1.62 g, 10 mmol), carbonyl compound 6 or 19 (10 mmol), a
corresponding cyanoacetic acid derivative 7 (11 mmol), and
Et3N (0.5 mL, 0.5 mmol) in anhydrous EtOH (50 mL) was
refluxed for 5 to 10 min and allowed to crystallize at 4 °C
Experimental
Melting points were determined on a Kofler unit. IR spectra
were recorded on Specord Mꢀ80 and Perkin—Elmer 577 instruꢀ
ments (pellets with KBr, 1/200). 1H NMR spectra were reꢀ
corded on a Bruker ACꢀ300 spectrometer (300 MHz) in
DMSOꢀd6; chemical shifts were referenced to Me4Si. Elemenꢀ
tal analysis was performed with a Perkin—Elmer C,H,Nꢀanaꢀ
lyzer. The course of the reactions was monitored and the purity
Table 2. Spectroscopic characteristics of substituted 2ꢀaminoꢀ5ꢀoxoꢀ4,5ꢀdihydropyrano[3,2ꢀc]chromenes 8 and 20
Comꢀ
pound
IR, ν/cm–1
1H NMR
(300 MHz, δ, J/Hz)
δ(NH2) NH2 C≡N C=O
8a
8b
1673 3175, 2200 1718
4.72 (s, 1 H, C(4)H); 7.25 (d, C(3)H, C(5)H, py, J = 5.6); 7.15 (s, 2 H, NH2);
7.36 (d, 1 H, CH, J = 7.8); 7.44 (t, 1 H, CH, J = 7.7); 7.62 (t, 1 H, CH, J = 7.8);
7.96 (d, 1 H, CH, J = 7.7); 8.40 (d, 2 H, C(2)H, C(6)H, py, J = 5.6)
3.25 (s, 3 H, Me); 3.44, 4.09 (both m, 2 H each, CH2); 4.73 (s, 1 H, C(4)H);
7.23 (d, 2 H, C(3)H, C(5)H, py, J = 5.5); 7.38 (d, 1 H, CH, J = 7.9);
7.44, 7.65 (both t, 1 H each, CH, J = 7.9); 7.85 (s, 2 H, NH2);
3280,
3384
1668 3190,
3256,
—
1673,
1683
3360
7.99 (d, 1 H, CH, J = 7.9); 8.39 (d, 2 H, C(2)H, C(6)H, py, J = 5.5)
2.22 (s, 3 H, Me); 4.53 (s, 1 H, C(4)H); 5.92, 6.08 (both d, 1 H each, CH,
furyl, J = 2.2); 7.16 (s, 2 H, NH2); 7.40 (d, 1 H, CH, J = 7.9);
7.42, 7.67 (both t, 1 H each, CH, J = 7.9); 7.92 (d, 1 H, CH, J = 7.9)
1.28 (s, 6 H, Me2, J = 5.5); 4.39 (s, 1 H, C(4)H); 4.53 (m, 1 H, CHO);
6.79 (d, 2 H, CHPh, J = 7.7); 7.09 (s, 2 H, NH2); 7.16 (d, 2 H, CHPh, J = 7.7);
7.36 (d, 1 H, CH, J = 7.8); 7.41, 7.64 (both m, 1 H each, CH); 7.93 (d, 1 H, CH, J = 7.9)
1.25 (s, 6 H, Me2, J = 4.9); 3.76 (s, 3 H, Me); 4.37 (s, 1 H, C(4)H);
4.44 (m, 1 H, CHO); 6.72, 6.78 (both d, 1 H each, CHPh, J = 8.0); 6.85 (s, 1 H, CHPh);
7.18 (s, 2 H, NH2); 7.39 (m, 2 H, CHCH); 7.64 (m, 1 H, CH);
8c
8d
8e
1672 3187, 2200 1720
3288,
3376
1672 3185, 2205 1712
3200,
3312
1668 3192,
2208,
—
1708
3218,
3312
7.91 (d, 1 H, CH, J = 7.9)
(to be continued)

996
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 4, April, 2005
Shestopalov et al.
Table 2 (continued)
Comꢀ
pound
IR, ν/cm–1
1H NMR
(300 MHz, δ, J/Hz)
δ(NH2) NH2 C≡N C=O
8f
1663 3200, 2207 1707
3.77 (s, 3 H, Me); 4.37 (s, 2 H, CH2); 4.44 (s, 1 H, C(4)H);
6.74, 6.88 (both d, 1 H each, CHPh, J = 7.9); 6.91 (s, 1 H, CHPh);
7.34 (br.s, 4 H, (NH2)2); 7.45 (d, 1 H, CH, J = 8.1);
3250,
3320,
3360
7.48, 7.71 (both m, 1 H each, CH); 7.91 (d, 1 H, CH, J = 8.3)
8g
1660 3210,
3312
—
1696,
1702
1.15 (t, 3 H, Me, J = 7.8); 4.01 (q, 2 H, CH2, J = 7.8); 4.90 (s, 1 H, C(4)H);
6.84 (m, 2 H, CHPh); 7.37 (d, 1 H, CH, J = 7.6); 7.43 (t, 1 H, CH, J = 7.6);
7.73 (s, 2 H, NH2); 7.76 (t, 1 H, CH, J = 7.5); 7.99 (d, 1 H, CH, J = 7.5)
6.75—7.18 (m, 4 H, (CH)4, isatin); 7.32 (d, 1 H, CH, J = 7.7); 7.42 (m, 1 H, CH);
7.48 (s, 2 H, NH2); 7.72 (m, 1 H, CH); 7.95 (d, 1 H, CH, J = 7.4);
10.40 (s, 1 H, NH)
2.32 (s, 3 H, Me); 6.72—7.20 (m, 3 H, (CH)3, isatin); 7.28 (d, 1 H, CH, J = 7.6);
7.38 (m, 1 H, CH); 7.44 (s, 2 H, NH2); 7.75 (m, 1 H, CH);
7.98 (d, 1 H, CH, J = 7.3); 10.35 (s, 1 H, NH)
20a
20b
20c
1678 3138,* 2195 1695,
3295,
3360
1724
1672 3140,* 2192 1695,
3285,
3357
1718
1670 3135,* 2190 1690,
7.25—7.68 (m, 8 H, CH (isatin), CH (pyranochromene), J = 7.5);
10.35 (s, 1 H, NH)
3278,
3355
1715
* Overlap with ν(NH) in the isatin fragment.
for 12 h. The precipitate that formed was filtered off, washed
with ethanol and hexane, and recrystallized from nitromethane
to give compounds 8 and 20 (see Tables 1, 2).
Ser. Khim., 2004, 546 [Russ. Chem. Bull., Int. Ed., 2004,
53, 573].
2. US Pat. 3 097 213; Ref. Zh., Khim., 1965, 12N257P.
3. Jpn Pat. 12 901; Ref. Zh., Khim., 1968, 12N568P.
4. Yu. A. Sharanin, M. P. Goncharenko, and V. P. Litvinov,
Usp. Khim., 1998, 67, 442 [Russ. Chem. Rev., 1998, 67 (Engl.
Transl.)].
5. A. M. Shestopalov and Yu. M. Emeliyanova, in Seꢀ
lected Method for Synthesis and Modification of Heteroꢀ
cycles, Ed. V. G. Kartsev, IBS PRESS, Moscow,
2003, 2, 363.W
6. The Merck Index, Ed. V. J. O´Neil, Merck and Co., Inc.,
Whitehouse Station, New York, 2001, 1818.
7. S. M. A. Mousawi, Y. M. Elkholy, M. A. Mohammad, and
M. H. Elnagdi, Org. Prep. Proc. Int., 1999, 31, 305.
8. F. Freeman, Chem. Rev., 1980, 80, 329.
9. A. M. Shestopalov, Z. I. Niazimbetova, D. H. Evans, and
M. E. Niyazymbetov, Heterocycles, 1999, 51, 1101.
10. A. M. Shestopalov, Yu. M. Emeliyanova, A. A. Shestopalov,
L. A. Rodinovskaya, Z. I. Niazimbetova, and D. H. Evans,
Tetrahedron, 2003, 59, 7491.
11. A. M. Shestopalov, Yu. M. Emeliyanova, and V. N. Nesterov,
Izv. Akad. Nauk, Ser. Khim., 2002, 2079 [Russ. Chem. Bull.,
Int. Ed., 2002, 51, 2238].
6ꢀAminoꢀ2,1´ꢀbis(benzyloxycarbonyl)ꢀ5,7,7ꢀtricyanoꢀ
spiro[3,7,8,8aꢀtetrahydroꢀ1Hꢀisoquinolineꢀ8,4´ꢀpiperidine] (15).
An equimolar mixture of ketone 13 (0.47 g, 2 mmol) and
malononitrile 7a (0.13 g, 2 mmol) in anhydrous EtOH (15 mL)
was stirred at 50 to 55 °C to homogenization and triethylamine
(0.32 mL, 2.3 mmol) was added. The reaction mixture was reꢀ
fluxed for 5 min and allowed to crystallize. The precipitate that
formed was filtered off, washed with ethanol and hexane, and
recrystallized from nitromethane to give spiro compound 15
(0.78 g, 70%), m.p. 248—250 °C. Found (%): C, 68.16; H, 5.18;
N, 14.67. C32H30N6O4. Calculated (%): C, 68.31; H, 5.37;
N, 14.94. IR, ν/cm–1: 1668 (δ(NH2)); 1690 (CO); 2223 (CN);
3208, 3346, 3367 (NH2). 1H NMR, δ: 1.68 (m, 1 H, C(5´)Heq);
1.79 (m, 1 H, C(3´)Heq); 2.22 (m, 2 H, C(3´)Hax, C(5´)Hax);
2.67 (m, 1 H, C(8a)H); 3.08 (m, 1 H, C(1)Heq); 3.36 (m, 2 H,
C(1)Hax, C(2´)Heq); 3.76 (m, 2 H, C(2´)Hax, C(6´)Heq); 3.95
(m, 1 H, C(6´)Hax); 4.39 (m, 2 H, C(3)H2); 5.08 (m, 4 H,
(CH2)2); 5.78 (m, 1 H, C(4)H); 7.22 (s, 2 H, NH2); 7.32
(m, 10 H, Ph2).
This work was financially supported by the Russian
Foundation for Basic Research (Project No. 05ꢀ03ꢀ
32031).
12. A. M. Shestopalov and O. A. Naumov, Izv. Akad. Nauk, Ser.
Khim., 2003, 1306 [Russ. Chem. Bull., Int. Ed., 2003,
52, 1380].
References
1. A. M. Shestopalov, S. G. Zlotin, A. A. Shestopalov, V. Yu.
Mortikov, and L. A. Rodinovskaya, Izv. Akad. Nauk,
Received October 18, 2004