Cross-condensation of derivatives of cyanoacetic acid and carbonyl compounds. 2. One-pot synthesis of substituted 2-amino-7-methyl-5-oxo-4,5- dihydropyrano[4,3-b]pyrans in ethanol and ionic liquid [bmim][PF6]

Article abstract of DOI:10.1023/B:RUCB.0000035640.47443.a4

The three-component reaction of 4-hydroxy-6-methylpyran-2(2H)-one with cyanoacetic acid derivatives and carbonyl compounds in EtOH or in the ionic liquid, viz., 1-butyl-3-methylimidazolinium hexafluorophosphate ([bmim][PF ₆]), affords substitut

Full text of DOI:10.1023/B:RUCB.0000035640.47443.a4

Russian Chemical Bulletin, International Edition, Vol. 53, No. 3, pp. 573—579, March, 2004
573
Crossꢀcondensation of derivatives of cyanoacetic acid and carbonyl compounds
2.* Oneꢀpot synthesis of substituted 2ꢀaminoꢀ7ꢀmethylꢀ5ꢀoxoꢀ
4,5ꢀdihydropyrano[4,3ꢀb]pyrans in ethanol and ionic liquid [bmim][PF6]
A. M. Shestopalov,ꢀ S. G. Zlotin, A. A. Shestopalov, V. Yu. Mortikov, and L. A. Rodinovskaya
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
The threeꢀcomponent reaction of 4ꢀhydroxyꢀ6ꢀmethylpyranꢀ2(2H )ꢀone with cyanoacetic
acid derivatives and carbonyl compounds in EtOH or in the ionic liquid, viz., 1ꢀbutylꢀ3ꢀ
methylimidazolinium hexafluorophosphate ([bmim][PF6]), affords substituted 2ꢀaminoꢀ7ꢀ
methylꢀ5ꢀoxoꢀ4,5ꢀdihydropyrano[4,3ꢀb]pyrans. The yield of substituted pyrano[4,3ꢀb]pyrans
in [bmim][PF6] is by 10—14% higher than that in EtOH.
Key words: malononitrile, carbonyl compounds, 2ꢀaminoꢀ7ꢀmethylꢀ5ꢀoxoꢀ4,5ꢀdihydroꢀ
pyrano[4,3ꢀb]pyrans, isatin, 4ꢀhydroxyꢀ6ꢀmethylpyranꢀ2(2H )ꢀone, spiropiperidinoisoꢀ
quinoline, ionic liquids.
Methods for synthesis of substituted 2ꢀaminoꢀ4Hꢀpyrꢀ
ans are being intensely developed because of their practiꢀ
cal use as drugs, pesticides, and starting substances
in syntheses of blood anticoagulants, antidepressants,
immunomodulators, calcium antagonists, and other bioꢀ
logically active compounds.2
Earlier,2—5 these compounds were synthesized in two
steps: unsaturated nitriles or unsaturated carbonyl comꢀ
pounds were synthesized in the first step, and then they
were used in the reaction with 1,3ꢀdicarbonyl compounds
or cyanoacetic acid derivatives. The oneꢀpot method of
synthesis based on the threeꢀcomponent condensation of
carbonyl compounds (aldehydes, ketones) and CH acids
(1,3ꢀdicarbonyl compounds, substituted pyrazolinꢀ5ꢀ
ones, benzoannelated 3ꢀoxoꢀ2Hꢀpyrroles, 3ꢀoxoꢀ2Hꢀ
thiophenes, and others) with cyanoacetic acid derivatives
(cyanoacetic esters, malononitrile) is widely used in the
recent time.1,2,6—15
Continuing our studies of multicomponent reactions
of carbonyl compounds with cyanoacetic acid derivaꢀ
tives,2,6—17 we studied the reactions of 4ꢀhydroxyꢀ
6ꢀmethylpyranꢀ2(2H )ꢀone with cyanoacetic acid
derivatives in EtOH or in the ionic liquid, viz.,
1ꢀbutylꢀ3ꢀmethylimidazolinium hexafluorophosphate
([bmim][PF6]). We have previously found18,19 that the
use of [bmim][PF6] as the solvent in multicomponent
reactions involving CH acids increases the yield of cycloꢀ
propanes, pyrazolopyrans, and thiopyrans. The ionic
liquid can be used several times in the reaction. Aromatic
aldehydes, some of which contain groupꢀcomponents of
many biologically active substances, aliphatic aldehydes,
and heterocyclic ketones were chosen as carbonyl comꢀ
pounds. Unlike the authors of the cited publication4 on the
reaction of arylmethylenemalononitriles with pyranone
only, we studied the multicomponent reaction and enꢀ
larged considerably the scope of the starting reagents and
reaction media.
The reactions of pyranone 1 with cyanoacetic acid
derivatives 2 and aromatic aldehydes 3 on short refluxing
in EtOH in the presence of Et3N as the catalyst (Scheme 1,
method A) are established to afford substituted 2ꢀaminoꢀ4ꢀ
arylꢀ7ꢀmethylꢀ5ꢀoxoꢀ4,5ꢀdihydropyrano[4,3ꢀb]pyrans 4.
Unlike the reaction in EtOH (method А), the reacꢀ
tions of pyranone 1 and malononitrile 2a with aldeꢀ
hydes 3с,e,i containing electronꢀwithdrawing groups in
[bmim][PF6] occur without addition of the main catalyst
(method C). It is likely that the role of the catalyst is
played by the ionic liquid itself. Using the procedure of
ionic liquid saturation (the reaction is conducted three
times in the same [bmim][PF6] sample), we succeeded to
increase the yield of the target compounds by 10—14%
compared to similar transformations in EtOH. When the
reactions of pyranone 1, malononitrile 2а, and aldehydes
3b,g containing electronꢀreleasing substituents and the
reactions of pyranone 1, cyanoacetic ester 2b, and aldeꢀ
hyde 3d containing the electronꢀwithdrawing substituent
are carried out in the ionic liquid, the main catalyst Et3N
should be added additionally (method C). Probably, this
is related to different reactivities of intermediates 5 formed
by the Knoevenagel reaction from aldehydes 3 and cyanoꢀ
acetic acid derivatives 2. Unsaturated nitriles 5 containꢀ
ing electronꢀreleasing substituents or one ester group
* For Part 1, see Ref. 1.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 546—552, March, 2004.
1066ꢀ5285/04/5303ꢀ0573 © 2004 Plenum Publishing Corporation

574
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 3, March, 2004
Shestopalov et al.
Scheme 1
The yield of pyrano[4,3ꢀb]pyrans 12a,b also increases
(by 11—12%) when EtOH is replaced by [bmim][PF6] in
the reaction of pyranone 1, malononitrile 2a, and aliꢀ
phatic aldehydes 8. In this case, the addition of Et3N as
the catalyst is needed for the reaction to occur. The favorꢀ
able effect of [bmim][PF6] is probably related to the difꢀ
ferent rates of water elimination from intermediate aldol
9 in the ionic liquid and in EtOH (Scheme 2).
Scheme 2
B = Et3N, [bmim][PF6]
2: Z = CN (a); COOEt (b); COO(CH2)2OMe (c); COOCHMe2 (d)
3, 4
a
b
c
d
Ar
3, 4
f, k
g
h
i
Ar
2ꢀF,5ꢀMeOC6H3
3ꢀMeO,4ꢀPrnOC6H3
4ꢀMeOOCC6H4
2ꢀFC6H4
4ꢀCF3C6H4
3ꢀMeO,4ꢀPriOC6H3
2,4,5ꢀ(MeO)3C6H2
3,4ꢀF2C6H3
4ꢀCF3SC6H4
e
2,4ꢀF2C6H3
j
4: Z = CN (a—c,e,g—j); COOEt (d); COO(CH2)2OMe (f);
COOCHMe2 (k)
Reagents and conditions: (А) EtOH, Et3N,
∆
or
(B) [bmim][PF6], Et3N, 80—90 °C, or (C) [bmim][PF6],
80—90 °C.
(Z = COOR) are less electrophilic than arylmethyleneꢀ
malononitriles (Z = CN) containing electronꢀwithdrawꢀ
ing substituents in the benzene ring. Therefore, Et3N
should be added for the formation of Michael adducts 7
and their intramolecular ring closure to form pyraꢀ
no[4,3ꢀb]pyrans 4. The Knoevenagel reaction affording
unsaturated nitriles 5 should also be easier when malonoꢀ
nitrile 2а is used and aldehydes 3 contain electronꢀwithꢀ
drawing substituents.
8, 12: Alk = CHMe2 (a); CH2CHMe2 (b)
Reagents and conditions: i) EtOH, Et3N, ∆; ii) [bmim][PF6],
Et3N, 70 °C.
Our results agree well with the data in the publicaꢀ
tions,20,21 which show that the aldol condensation in ionic
liquids increases the reaction rate and yield of the conꢀ

Reactions in ionic liquids
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 3, March, 2004
575
Scheme 3
Reagents and conditions: i) EtOH, Et3N, ∆; ii) [bmim][PF6], Et3N, 70 °C.
Scheme 4
densation products. The further transformations of niꢀ
triles 10 via the scheme presented afford substituted
4ꢀalkylpyrano[4,3ꢀb]pyrans 12.
When we attempted to conduct the threeꢀcomponent
condensation of pyranone 1, malononitrile 2а, and
piperidinꢀ4ꢀone (13), the reaction proceeded via the difꢀ
ferent route, regardless of the type of the solvent used,
and afforded spiroheterocycle 18. Evidently, pyranone 1
is not involved in the reaction (Scheme 3).
Probably, the reaction proceeds through the formaꢀ
tion of unsaturated nitrile 14, which does not react with
pyranone 1 but is dimerized to form Michael adduct 15.
The Thorpe—Ziegler ring closure of the latter affords
isoquinoline 16, whose further tautomeric transforꢀ
mations to intermediate 17 and spiroheterocycle 18 comꢀ
plete the reaction. In fact, we obtained compound
18 from malononitrile 2a and ketone 13 in EtOH in
the presence of Et3N. We earlier observed the similar
dimerization with the formation of spiropiperidinoꢀ
isoquinoline in the reaction of Nꢀmethylpiperidinꢀ4ꢀone
with malononitrile.1 This reaction is probably related to
the enhanced CH acidity of intermediate 14 compared to
pyranone 1.
This assumption is favored by the following fact. When
isatin 19 containing no βꢀCH acidic moiety is introduced
into the system, spiro[indolineꢀ3,4´ꢀpyrano[4,3ꢀb]pyraꢀ
nes] 21 are formed instead of dimerization products. The
Z = CN (2a, 21a); COOMe (2e, 21b); COOBn (2f, 21c)
yields of spiroheterocycles 21a—c in the reactions in EtOH
and in the ionic liquid are comparable and achieve
92—97% (Scheme 4).
Reagents and conditions: i) EtOH, Et3N, ∆ or ii) [bmim][PF6],
Et3N, 70 °C.

576
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 3, March, 2004
Shestopalov et al.
The resulting pyrans 4, 12, and 21 are solid colorless
spiroheterocycles 21 contain the absorption band of the
amide group with the endocyclic nitrogen atom of the
isatin moiety at νCON 1728—1730 cm–1. In addition to
signals of the aromatic and CH3 groups, the 1H NMR
spectra of pyrans 4 contain characteristic signals of
protons of the C(4)H and NH2 groups as singlets at
4.23—4.74 and 6.89—7.64 ppm, respectively. The spectra
of spiroheterocycles 21 contain no signals of the C(4)H
group but exhibit signals of protons of the isatin moiety.
The signal of a proton of the C(4)H groups in pyrans
12a,b appears as a doublet at 3.17 ppm or a triplet at
3.22 ppm with the spinꢀspin coupling constants J = 2.7
and 2.8 Hz, respectively.
powders, which are stable in air and well soluble in acꢀ
etone, DMF, or DMSO. The structures of these comꢀ
pounds were confirmed by the data of elemental analysis,
IR spectroscopy, and 1H NMR spectroscopy (Tables 1
and 2). The IR spectra of pyrans 4, 12, and 21 exhibit
the characteristic absorption bands of the enaminonitrile
or enaminocarbonyl moieties at δNH 1663—1688,
νNH 3140—3994, νCN 2192—2206, or 2νCOOR 1692—
2
1696 cm–1. An analogous pattern was observed in the
IR spectra of the previously synthesized 4Hꢀpyrans conꢀ
taining similar moieties.1,7,9—12 A distinctive feature of
the IR spectra of pyrano[4,3ꢀb]pyrans 4, 12, and 21 is
the absorption band of the cyclic ester group at
ν 1702—1718 cm–1. In addition, the IR spectra of
We can conclude that the crossꢀcondensation reacꢀ
tions studied are based on the method of simultaneous
Table 1. Physicochemical characteristics of substituted 2ꢀaminoꢀ7ꢀmethylꢀ5ꢀoxoꢀ4,5ꢀdihydropyraꢀ
no[4,3ꢀb]pyrans 4, 12, and 21
Comꢀ
pound
M.p./°C
Yield (%)
EtOH/[bmim][PF6]*
Found
Calculated
Molecular
formula
(%)
C
H
N
4a
226—228
215—216
245—246
205—206
217—218
141—142
181—182
89
68/78
87/98
62/76
80/91
78
62.30
62.20
65.10
65.21
63.85
63.90
62.67
62.60
60.51
60.76
56.25
56.47
65.07
65.21
61.47
61.62
60.32
60.76
53.85
53.69
58.37
58.68
63.16
63.40
64.85
64.60
63.18
63.55
60.85
61.02
66.68
66.97
4.11
3.99
5.53
5.47
4.29
4.17
4.55
4.67
3.07
3.19
4.12
4.27
5.18
5.47
4.73
4.90
3.26
3.19
2.84
2.92
4.22
4.43
5.51
5.73
6.47
6.20
3.14
3.45
3.63
3.98
4.03
4.22
8.43
8.53
7.49
7.60
8.19
8.29
4.14
4.06
8.64
8.86
3.02
3.29
7.36
7.60
7.29
7.56
8.97
8.86
7.45
7.37
3.14
3.42
11.14
11.38
10.95
10.76
12.83
13.08
7.64
7.91
6.32
6.51
C17H13FN2O4
C20H20N2O5
C18H14N2O5
C18H16FO5
4b
4c
4d
4e
C16H10F2N2O3
C20H18F3NO6
C20H20N2O5
C19H18N2O6
C16H10F2N2O3
C17H11F3N2O3S
C20H18F3NO5
C13H14N2O3
C14H16N2O3
C17H11N3O4
C18H14N2O6
C24H18N2O6
4f
4g
76/87
86
4h
4i
251—253
(decomp.)
198—199
79/89
92
4j
238—239
150—151
225—226
193—194
>300
4k
12a
12b
21a
21b
21c
77
57/69
62/73
76/75
57
258—260
(decomp.)
189—190
61
* The average yields of compounds after three experiments in the same portion of the ionic liquid are presented
for [bmim][PF6] (see Experimental).

Reactions in ionic liquids
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 3, March, 2004
577
Table 2. Spectral characteristics of substituted 2ꢀaminoꢀ7ꢀmethylꢀ5ꢀoxoꢀ4,5ꢀdihydropyrano[4,3ꢀb]pyrans 4, 12, and 21
Comꢀ
pound
IR, ν/cm–1
1H NMR (300 MHz, DMSOꢀd6), δ (J/Hz)
δNH2 NH2 C=N C=O CH3
C(8)H C(4)H
NH2
Z
Ar, Alk, NH
(s, 3 H) (s, 1 H) (s, 1 H) (s, 2 H)
4a
4b
1669 3208, 2196 1708 2.22
6.26
4.48
7.16
—
3.70 (s, 3H, Me);
3316,
3388
6.79 (s, 1 H, C(6)H, Ar);
6.83 (d, 1 H, C(4)H, Ar, J = 7.9);
7.05 (d, 1 H, C(3)H, Ar, J = 7.9)
1.03 (t, 3 H, Me, J = 8.4);
1.71—1.79 (m, 2 H, CH2);
3.29 (s, 3 H, OMe);
1663 3201, 2198 1703 2.23
6.13
4.23
6.89
—
—
3307,
3390
3.90 (q, 2 H, CH2O, J = 8.8);
6.65 (s, 1 H, C(2´)H, Ar);
6.78 (d, 1 H, C(5´)H, Ar, J = 7.7);
6.85 (d, 1 H, C(6´)H, Ar, J = 7.7)
3.84 (s, 3 H, OMe); 7.34 (d, 2 H,
C(2´)H, C(6´)H, Ar, J = 8.2);
7.91 (d, 2 H, C(3´)H, C(5´)H,
Ar, J = 8.2)
4c
4d
1672 3216, 2192 1688, 2.24
6.28
6.16
4.38
4.74
7.23
3296,
3360
1708
1688 3300,
3428
—
1696, 2.23
1702
7.55 1.09 (t, 3 H,
Me, J = 8.4);
6.93—7.24 (m, 4 H, C6H4)
3.97 (q, 2 H,
CH2, J = 8.4)
4e
4f
1675 3207, 2197 1710 2.22
6.18
6.20
4.32
4.65
6.95
7.64
—
7.04—7.28 (m, 3 H, C6H3)
3322
3400
1683 3295,
3367
—
1692, 2.21
1718
3.21 (s,
3 H, OMe);
3.32—3.44
(m, 2 H, CH2);
3.96—4.11
(m, 2 H,
7.41 (d, 2 H, C(2´)H, C(6´)H,
Ar, J = 8.5); 7.51 (d, 2 H,
C(3´)H, C(5´)H, Ar, J = 8.5)
CH2O)
4g
1665 3205, 2195 1708
2.21
6.21
4.24
6.99
1.22, 1.25 (both d, 3 H each,
Me, J = 0.73);
3.73 (s, 3 H, OMe);
3318,
3396
4.46 (m, 1 H,CHO);
6.65 (d, 1 H, C(5´)H, Ar,
J = 7.9); 6.80 (s, 1 H, C(2´)H,
Ar); 6.87 (d, 1 H, C(6´)H,
Ar, J = 7.9)
4h
1668 3185, 2198 1705 2.23
6.18
4.38
6.70
—
3.70, 3.75, 3.80
3310,
3458
(all s, 3 H each, OMe);
6.58 (s, 1 H, C(3´)H, Ar);
6.86 (s, 1 H, C(6´)H, Ar)
7.04—7.28 (m, 3 H, C6H3)
4i
1664 3196, 2193 1705 2.24
6.17
6.26
6.22
4.33
4.38
4.58
6.97
7.24
7.68
—
—
3328,
3992
4j
1668 3205, 2195 1710 2.22
7.37 (d, 2 H, C(3´)H, C(5´)H,
Ar, J = 7.2); 7.68 (d, 2 H,
C(2´)H, C(6´)H, Ar, J = 7.2)
7.39 (d, 2 H, C(2´)H, C(6´)H,
Ar, J = 8.4); 7.51 (d, 2 H,
3317,
3994
1682 3308,
3407
4k
—
1717, 2.24
1695
0.87, 1.20
(both d,
3 H each, Me,
J = 5.9);
C(3´)H, C(5´)H, Ar, J = 8.4)
4.58 (m, 1 H,
CHO)
(to be continued)

578
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 3, March, 2004
Shestopalov et al.
Table 2 (continued)
Comꢀ
pound
IR, ν/cm–1
δNH2 NH2 C=N C=O CH3
1H NMR (300 MHz, DMSOꢀd6), δ (J/Hz)
C(8)H C(4)H
NH2
Z
Ar, Alk, NH
(s, 3 H) (s, 1 H) (s, 1 H) (s, 2 H)
12a
12b
1665 3203, 2206 1708 2.23
6.18
6.17
3.17
7.08
7.06
—
0.68, 0.97 (both d, 3 H each,
Me, J = 6.71);
1.94 (m, 1 H, CHMe)
0.82, 0.93 (both d, 3 H each,
Me, J = 6.5);
1.40 (m, 2 H, CH2);
1.77 (m, 1 H, CHMe)
6.80—7.22 (m, 4 H, isatin);
10.41 (s, 1 H, NH)
3325,
3984
(d, 1 H,
J = 2.7)
3.22
(t, 1 H,
J = 2.8)
1667 3208, 2203 1705 2.22
—
—
3337,
3985
21a
1680 3140,* 2196 1708, 2.22
6.30
—
7.23
3300
3352
1732
21b
21c
1686 3288,*
3436
1680 3312,*
3444
—
—
1720, 2.21
1728
1720, 2.20
1729
6.22
6.25
—
—
7.87 3.30 (s, 3 H,
OMe)
9.97 4.84 (s, 2 H,
CH)
6.68—7.11 (m, 4 H, isatin):
10.10 (s, 1 H, NH)
6.56—7.24 (m, 9 H, isatin, Ph);
10.20 (s, 1 H, NH)
* Overlapped with the absorption band of NH of the isatin moiety.
Scheme 5
Perkin—Elmer C,H,NꢀAnalyzer instrument. The course of reꢀ
actions and individual character of the compounds synthesized
were monitored by thin layer chromatography on Silufol UVꢀ254
plates using hexane—acetone (5 : 3) mixtures as eluants. Spots
were detected by iodine vapor.
General procedure of synthesis of 2ꢀaminoꢀ7ꢀmethylꢀ5ꢀoxoꢀ
4,5ꢀdihydropyrano[4,3ꢀb]pyrans (4, 12, 21). A. A mixture of
carbonyl compound 3, 8, or 19 (10 mmol), the corresponding
cyanoacetic acid derivative 2 (11 mmol), and 4ꢀhydroxyꢀ6ꢀ
methylpyranꢀ2(2H )ꢀone 1 (1.39 g, 11 mmol) was stirred with
heating in 95% EtOH (20 mL) until the reactants were disꢀ
solved, and Et3N (0.5 mL, 0.5 mmol) was added. The reaction
mixture was refluxed for 5—10 min and left for crystallizaꢀ
tion. The precipitate formed was filtered off and washed with
95% EtOH and hexane.
double generation of a nucleophile (pyranone anion) and
an electrophile (unsaturated nitrile) in the reaction meꢀ
dium. The interaction of intermediates at the "reaction
crossing" can afford pyranopyrans (Scheme 5, route a) or
isoquinoline (route b).
Experimental
Melting points were determined on the Köffler heating
stage. IR spectra were recorded on Specord Mꢀ80 and
Perkin—Elmer 577 instruments in KBr pellets (1/200). 1H NMR
spectra were recorded on a Bruker ACꢀ300 spectrometer
(300 MHz) in DMSOꢀd6. Chemical shifts are presented relaꢀ
tively to Me4Si in the δ scale in ppm. The proposed assignments
of signals in 1H NMR spectra are the authors´ opinion and based
on various analogies. Elemental analysis was conducted on a
B. Triethylamine (0.33 mL, 2.3 mmol) was added to a mixꢀ
ture of equimolar amounts of pyranone 1 (0.25 g, 2 mmol),

Reactions in ionic liquids
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 3, March, 2004
579
carbonyl compound 3, 8, or 19, and the corresponding cyanoaceꢀ
tic acid derivative 2 in [bmim][PF6] (10 mL). The reaction
mixture was stirred at 80—90 °C for 10 min and cooled to 20 °C,
and then stirring was continued for 4—5 h. The precipitate
formed was filtered off and washed successively with ethanol
and hexane. Pyranopyrans 4, 12, and 21 were obtained after
recrystallization from ethanol.
2. A. M. Shestopalov and Yu. M. Emeliyanova, in Selected
Method for Synthesis and Modification of Heterocycles,
Ed. V. G. Kartsev, IBS PRESS, Moscow, 2003, 2, p. 363.
3. A. G. A. Elagamey, S. Z. A. Sowellim, F. M. A. A. ElꢀTaweel,
and M. H. Elnagdi, Coll. Czechosl. Chem. Commun., 1988,
53, 1534.
4. M.ꢀZ. Piao and K. Imafuku, Tetrahedron Lett., 1997,
38, 5301.
5. R. M. Shaker, Pharmazie, 1996, 51, 148.
C. To synthesize compounds 4c,e,i, the reaction in
[bmim][PF6] was carried out without Et3N.
The ionic liquid can be used in the same reaction three times
without regeneration. After several reaction cycles, the ionic
liquid can easily be purified by washing with water followed by
evacuation. Thus regenerated [bmim][PF6] can be used in furꢀ
ther transformations without decreasing the yield of the final
products.
6. A. M. Shestopalov, Yu. M. Emeliyanova, A. A. Shestopalov,
L. A. Rodinovskaya, Z. I. Niazimbetova, and D. H. Evans,
Org. Lett., 2002, 4, 423.
7. A. M. Shestopalov, Z. I. Niazimbetova, D. H. Evans, and
M. E. Niyazymbetov, Heterocycles, 1999, 51, 1101.
8. A. M. Shestopalov, Yu. M. Emeliyanova, and V. N. Nesterov,
Izv. Akad. Nauk, Ser. Khim., 2002, 2079 [Russ. Chem. Bull.,
Int. Ed., 2003, 51, 2238].
9. A. M. Shestopalov, O. A. Naumov, and V. N. Nesterov, Izv.
Akad. Nauk, Ser. Khim., 2003, 169 [Russ. Chem. Bull., Int.
Ed., 2003, 52, 179].
10. A. M. Shestopalov and O. A. Naumov, Izv. Akad. Nauk, Ser.
Khim., 2003, 911 [Russ. Chem. Bull., Int. Ed., 2003, 52, 961].
11. A. M. Shestopalov, Yu. M. Emeliyanova, and V. N. Nesterov,
Izv. Akad. Nauk, Ser. Khim., 2003, 1103 [Russ. Chem. Bull.,
Int. Ed., 2003, 52, 1164].
12. A. M. Shestopalov and O. A. Naumov, Izv. Akad. Nauk, Ser.
Khim., 2003, 1306 [Russ. Chem. Bull., Int. Ed., 2003,
52, 1380].
13. D. Heber and E. V. Stoyanov, Synthesis, 2003, 227.
14. A. M. Shestopalov, A. P. Yakubov, V. V. Tsyganov, Yu. M.
Emeliyanova, and V. N. Nesterov, Khim. Geterotsikl. Soedin.,
2002, 1345 [Chem. Heterocycl. Compd., 2002, 38, 1180 (Engl.
Transl.)].
15. G. V. Klokol, S. G. Krivokolysko, V. D. Dyachenko, and
V. P. Litvinov, Khim. Geterotsikl. Soedin., 1999, 1363 [Chem.
Heterocycl. Compd., 1999, 35, 1174 (Engl. Transl.)].
16. A. M. Shestopalov, Yu. M. Emeliyanova, and V. N. Nesterov,
Abstr. 7ꢀth Blue Danube Symposium on Heterocyclic Chemisꢀ
try. Hungary, Eger, 1998, P032.
17. Yu. M. Emeliyanova, Ph. D. (Chem.) Thesis, Institute of
Organic Chemistry, RAS, Moscow, 2002, 112 pp. (in
Russian).
6ꢀAminoꢀ5,7,7ꢀtricyanoꢀ2,1´ꢀbis(ethoxycarbonyl)spiroꢀ
[3,7,8,8аꢀtetrahydroꢀ1Hꢀisoquinolineꢀ8,4´ꢀpiperidine] (18).
A. Triethylamine (0.33 mL, 2.3 mmol) was added to a mixture of
equimolar amounts of pyranone 1 (0.25 g, 2 mmol), ketone 13
(0.34 g, 2 mmol), and malononitrile 2a (0.13 g, 2 mmol) in
[bmim][PF6] or 95% EtOH (10 mL). The reaction mixture was
stirred at ~70 °C for 10 min and cooled to 20 °C, and then
stirring was continued for 4—5 h. The precipitate formed was
filtered off and successively washed with 95% EtOH and hexꢀ
ane. After recrystallization from 95% EtOH, spiro compound 18
was obtained in 62% yield (0.27 g), m.p. 86—187 °C. Found (%):
C, 60.02; H, 5.86; N, 19.35. C22H26N6O4. Calculated (%):
C, 60.26; H, 5.98; N 19.17. IR, ν/cm–1: 1672 (δNH2),1692
(CO), 2220 (CN), 3204, 3332, 3352 (NH2). 1H NMR (300 MHz,
DMSOꢀd6), δ: 1.14—1.26 (m, 7 H, (CH3)2, C(8а)H); 1.53—1.65
(m, 1 H, C(5´)Heq); 1.70—1.79 (m, 1 H, C(5´)Hax); 2.10—2.21
(m, 2 H, C(3´)Hax, C(3´)Heq); 2.55—2.62 (m, 1 H, C(6´)Heq);
3.01—3.11 (m, 1 H, C(6´)Hax); 3.19—3.24 (m, 1 H, C(2´)Heq);
3.58—3.79 (m, 2 H, C(2´)Hax, C(1)He); 3.89 (m, 1 H, C(1)Hax);
4.06 (m, 4 H, (CH2O)2); 4.30 (m, 2 H, C(3)H2); 5.78 (s, 1 H,
C(4)H); 7.46 (s, 2 H, NH2).
B. A mixture of equimolar amounts of ketone 13 (0.34 g,
2 mmol) and malononitrile 2a (0.13 g, 2 mmol) was stirred with
heating in 95% EtOH (20 mL) until the reactants dissolved, and
Et3N (0.32 mL, 2.3 mmol) was added. The reaction mixture was
refluxed for 5—10 min and left for crystallization. The precipiꢀ
tate formed was filtered off and washed with 95% EtOH and
hexane. Compound 18 was obtained in 78% yield (0.34 g).
18. A. A. Shestopalov, L. A. Rodinovskaya, A. M. Shestopalov,
and S. G. Zlotin, Tez. dokl. XVII Mendeleevskogo s"ezda po
obshchei i prikladnoi khimii [Abstrs. XVII Mendeleev Congress
on General and Applied Chemistry], Kazan, 2003, vol. 2, 422
(in Russian).
19. A. A. Shestopalov, L. A. Rodinovskaya, A. M. Shestopalov,
S. G. Zlotin, and V. N. Nesterov, Synlett, 2003, 2309.
20. C. P. Mehnert, N. C. Dispenziere, and R. A. Cook, Chem.
Commun., 2002, 1610.
A part of this work concerning the study of ionic liqꢀ
uids was financially supported by the Russian Foundation
for Basic Research (Project No. 03ꢀ03ꢀ32659) and the
Complex Program of Scientific Research of the Presidium
of the Russian Academy of Sciences.
References
21. C. P. Mehnert and N. C. Dispenziere, WO 03/002502 A1,
filed 26.06.2001, published 09.01.2003.
1. A. M. Shestopalov, Yu. M. Emeliyanova, A. A. Shestopalov,
L. A. Rodinovskaya, Z. I. Niazimbetova, and D. H. Evans,
Tetrahedron, 2003, 59, 7491.
Received January 23, 2004