Cyanoethylation of substituted 4-azafluorenes. Synthesis of spiro-[4-azafluorene-9-cyclopentenes]

Article abstract of DOI:10.1007/s10593-006-0237-5

Cyanoethylation of 9-phenacyl(β-hydroxy-β-phenylethyl-, or acetamido)-4-azafluorenes under conditions of the Michael reaction occurs regioselectively at position 9. 1-Amino-4-azafluorene under these conditions forms 1-[N,N-di-(β-cyanoethyl)amino)]-(9-β-cy

Full text of DOI:10.1007/s10593-006-0237-5

Chemistry of Heterocyclic Compounds, Vol. 42, No. 10, 2006
CYANOETHYLATION OF SUBSTITUTED
4-AZAFLUORENES. SYNTHESIS OF SPIRO-
[4-AZAFLUORENE-9-CYCLOPENTENES]
N. M. Mikhailova, A. N. Levov, S. V. Gozun, O. O. Timonina, F. Toze, and A. V. Varlamov
Cyanoethylation of 9-phenacyl(β-hydroxy-β-phenylethyl-, or acetamido)-4-azafluorenes under
conditions of the Michael reaction occurs regioselectively at position 9. 1-Amino-4-azafluorene under
these conditions forms 1-[N,N-di-(β-cyanoethyl)amino)]-(9-β-cyanoethyl)-4-azafluorene. The
cyclization of 9-(β-cyanoethyl)-9-phenacyl-4-azafluorene has been carried out into 1'-cyano-2'-
phenylspiro[4-aza-fluorene-9,4'-cyclopentene and 1'-imino-2'-hydroxybenzylidenespiro[4-azafluorene-
9.3'-cyclopentane]-substituted in the five-membered fragment.
Keywords: azafluorene, spiroazafluorenecyclopentane, spiroazafluorene-cyclopentene, intramolecular
cyclization, cyanoethylation.
4-Azafluorene is readily alkylated under the conditions of the Michael reaction with the formation of
9,9-di-(β-R-ethyl)-substituted derivatives, from which 4-azafluorenes spiroannelated at position 9 may be
obtained [1]. Such a family of spiro compounds are of interest from the point of view of their potential biological
activity. The behavior under Michael reaction conditions of azafluorenes having two reaction centers has not
been studied.
In the present work the regiodirection of cyanoethylation under Michael reaction conditions of
9-phenacyl(β-hydroxy-β-phenylethyl-, or acetamido)-4-azafluorenes 1a-c and 1-amino-4-azafluorene (1d) has
been studied in the presence of Triton B. The synthesis of compounds 1c and 1d was described in [2, 3].
Azafluorene 1b was obtained by the reduction of the 9-phenacyl derivative 1a with lithium aluminum hydride in
ether. The Michael reaction of azafluorenes 1a-d may proceed both at position C(9), and at the methylene (or
hydroxyl, amide) group of the substituent at atom C(9) or at the amino group in position 1.
N
N
CH2=CHCN
Triton B
R1
R 1
R
R
2a–d
1a–d
NC
1 a-c R = H, d R = NH2; 2 a-c R = H, d R = N(CH2CH2CN)2;
1, 2 a R1 = CH2COPh, b R1 = CH2CH(OH)Ph, c R1 = NHAc, d R1 = H
__________________________________________________________________________________________
Russian People's Friendship, Moscow 117198; e-mail: avarlamov@sci.pfu.edu.ru. Translated from
Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1496-1501, October, 2006. Original article submitted June
14, 2002; revision submitted February 24, 2005.
0009-3122/06/4210-1291©2006 Springer Science+Business Media, Inc.
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Cyanoethylation of compounds 1a-c proceeds regioselectively at the C(9) atom with the formation of
β-cyano-substituted azafluorenes 2a-c in 26-55% yield. Such a direction for the reaction is caused by the high
stability of the intermediate C(9)-carbanion due to delocalization of the negative charge through the azafluorene
system. The cyanoethylation of compound 1d occurs both at position 9 and at the amino group with the
formation of tri-β-cyanoethyl-substituted compound 2d (30% yield). In the absence of catalyst the
cyanoethylation of compound 1d at the amino group in boiling acetonitrile does not take place, which is
probably caused by its low nucleophilicity. Cyanoethylation of compounds 1a-c was accompanied by
resinification. On cyanoethylation of compound 1a 9-phenacylidene-4-azafluorene is formed in 5% yield, probably
due to oxidation of the intermediate C(9)-carbanion. Alkylation of the 9-phenacyl-substituted compound 1a with
acrylamide, or ethyl or butyl acrylates under conditions analogous to cyanoethylation was unsuccessful.
Reduction of the carbonyl group in compound 2a to hydroxyl with sodium borohydride gave azafluorene
2b in 60% yield which, unlike the product isolated on cyanoethylation of the single isomer 1b, was a mixture
(1:1.5) of two diastereomers (Table 1) according to data of 1 H NMR spectra.
Cyclization of compound 2a was effected by the action of sodium ethylate with the aim of obtaining
spiro compounds containing 4-azafluorene, which may be promising in a biological project. Under these
conditions both possible directions of cyclization occur with the participation of the methylene groups of both
CH2CN and CH2CO. 1'-Cyano-2'-phenylspiro[4-azafluorene-9,4'-cyclopentene] (3) and 2'-benzoyl-1'-imino-
spiro[4-azafluorene-9-3'-cyclopentane] (4) (existing in the enolic form according to IR spectroscopy) were
isolated chromatographically from the reaction mixture in equal yields (20%).
N
N
N
+
4'
Ph
5'
3'
OH
1'
2'
NC
NH
Ph
O
NC
Ph
4
2a
3
A characteristic band was present in the IR spectra of compounds 2a-d and 3 at 2218-2252 cm-1 for the
stretching vibrations of the CN group. The stretching vibration of CO in compound 2a corresponds to the band at
1670, and in compound 2c at 1650 cm-1. A broad band for a bonded hydroxyl at 3200 cm-1 was present in the IR
spectrum of azafluorene 2b. The absorption bands in the region of CO stretching vibrations were absent from the
IR spectrum of spiro compound 4. An intense band at 1603 cm-1 is caused by the presence of the –C(OH)=C–
C=NH grouping and shows the existence of compound 4 in the enolic form, stabilized by a hydrogen bond. In
the IR spectrum of compound 4 in CHCl3 solution (concn. = 0.0296 M), together with a broad band for the
stretching vibrations of NH and OH groups at 3291 cm-1, narrow bands were displayed at 3491 and 3403 cm-1,
which may be assigned to the stretching vibrations of OH and NH groups linked by an intramolecular bond
with one bridge. Molecular ion peaks of various intensity, corresponding to their empirical formulae, were
observed in the mass spectra of compounds 1b, 2a-c, 3, and 4.
In the 1H NMR spectra of all compounds (Table 1) signals were present for all the protons existing in the
molecules. The signals of the pyridine fragment protons of the molecule H-1, 2, 3 are observed as three groups
of signals as doublets of doublets with coupling constants J12 = 7.6-8.0, J13 = 1.5-1.8, and J23 = 4.9-5.8 Hz
characteristic of pyridines. The methylene protons of the β-cyanoethyl group at C(9) are displayed as two
multiplets at 1.36-1.80 (2H) and 2.36-3.22 ppm (2H).
1
In the H NMR spectra of the phenacyl-substituted azafluorene 2a the protons of the CH2CN group are
chemically nonequivalent and are observed as two multiplets at 2.55-2.80 and 2.90-3.10 ppm, each with an
integral intensity of 1H. The methylene protons of the R1 group on the C(9) atom appear in the spectra of
compounds 2a,b as a doublet of doublets (2a) and a multiplet (2b) with geminal coupling constants J = 16.8 and
J = 14.4 Hz respectively.
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EXPERIMENTAL
The IR spectra were obtained on a IR-75 spectrometer in KBr disks. The mass spectra were recorded on
a Varian MAT 112 instrument with direct insertion of samples into the ion source at an ionizing voltage of
70 eV. The 1H NMR spectra of ~3% solutions of the synthesized substances in CDCl3 were recorded at 30°C on
a Bruker WP 200 (200 MHz) instrument, internal standard was TMS. Silufol UV 254 plates were used for TLC
(visualizing with iodine vapor), Al2O3 of Brockmann activity grade I was used for column chromatography.
9-Phenacyl-4-azafluorene (1a). Zinc dust (1.85 g, 28.2 mmol) and ammonium acetate (2.17 g,
28.2 mmol) were added to a solution of 9-phenacylidene-4-azafluorene (4 g, 14.4 mmol) in a mixture (140 ml)
of ethanol and 25% ammonia solution (1:1) and the mixture boiled for 4 h (check by TLC). The solution was
decanted and cooled. The precipitated crystals were filtered off and washed with water. Compound 1a (3.17 g,
79%) was obtained as colorless crystals; mp 104-106°C (hexane–ethyl acetate, 2:1), Rf 0.53 (hexane–ethyl
acetate, 1:1). IR spectrum, ν, cm-1: 1673 (C=O). Mass spectrum, m/z (Irel, %): 285 (41) [M]+, 180 (71), 179 (25),
166 (29), 152 (13), 105 (100), 77 (51). Found, %: C 84.01; H 5.14; N 4.77. C20H15NO. Calculated, %: C 84.20;
H 5.26; N 4.91. M 285.
9-(β-Hydroxy-β-phenylethyl)-4-azafluorene (1b). A fivefold excess of lithium aluminum hydride was
added to a solution of compound 1a (0.41 g, 1.44 mmol) in absolute ether (150 ml). The mixture was stirred for
4 h (check by TLC). The mixture was carefully decomposed with water, and extracted with ether. The extract
was dried over MgSO4. Compound 1b (0.37 g, 92%) was obtained as light yellow crystals; mp 39-42°C, Rf 0.31
(hexane–ethyl acetate, 1:1). IR spectrum, ν, cm-1: 3100-3500 (OH). Found, %: C 83.92; H 6.02; N 4.62. M+ 287.
C20H17NO. Calculated, %: C 83.62; H 5.92; N 4.88. M 287.
9-(β-Cyanoethyl)-9-phenacyl-4-azafluorene (2a). A solution of 1a (3 g, 10.5 mmol), Triton B in
alcohol (1.2 ml), and acrylonitrile (8.4 g, 158.5 mmol) in absolute benzene (120 ml) was stirred for 6 h at 20°C
(check by TLC). The benzene was distilled off. The residue was chromatographed on aluminum oxide
(1 × 20 cm), eluent hexane–ethyl acetate, 1:1. Compound 2a (1.94 g, 55%) was eluted first as colorless crystals;
mp 117-121°C (hexane–ethyl acetate, 1:1), Rf 0.42 (hexane–ethyl acetate, 1:2). IR spectrum, ν, cm-1: 2252
(C≡N), 1670 (C=O). Found, %: C 81.96; H 5.12; N 8.38. M+ 338. C23H18N2O. Calculated, %: C 81.66; H 5.33;
N 8.28. M 338. 9-Phenacylidene-4-azafluorene (0.2 g, 5%) was eluted next; mp 147-149°C (heptane) [4]. Found:
M+ 283. C20H13NO. Calculated: M 283.
9-(β-Cyanoethyl)-9-(β-hydroxy-β-phenylethyl)-4-azafluorene (2b). A. A solution of compound 1b
(0.64 g, 2.2 mmol), Triton B (0.25 ml), and acrylonitrile (1.42 g, 27 mmol) in absolute toluene (50 ml) was
stirred at 0°C (check by TLC). Water was added, the organic layer was separated, and the aqueous layer was
extracted with ether. The combined extracts were dried over MgSO4. After distilling off the solvent, the residue
(0.6 g) was crystallized from hexane–ethyl acetate. Compound 2b (0.2 g, 26%) was obtained as colorless crystals
of mp 182-184°C, Rf 0.27 (hexane–ethyl acetate, 1:1). IR spectrum, ν, cm-1: 2250 (C≡N), 3100-3300 (OH). Mass
spectrum, m/z (Irel, %): 340 (12) [M]+; 233 (3.5); 194 (100); 180 (69); 107 (31); 77 (30). Found, %: C 81.40; H
5.91; N 8.40. C23H20N2O. Calculated, %: C 81.18; H 5.88; N 8.24. M 340.
B. Sodium borohydride (0.025 g, 0.59 mmol) was added to a solution of 2a (0.2 g, 0.59 mmol) in
acetonitrile (20 ml) and the mixture was boiled for 1 h (check by TLC). The acetonitrile was distilled off in
vacuum, water (20 ml) was added, and the mixture was extracted with ether (3 × 20 ml). The extract was dried
over MgSO4. After distillation of the ether, the residue (0.2 g) was crystallized from hexane–ethyl acetate, 1:1.
Compound 2b (0.12 g, 60%) was obtained as colorless crystals; mp 151-155°C, Rf 0.31 (hexane–ethyl acetate,
1:2). IR spectrum, ν, cm-1: 2253 (C≡N), 3100-3300 (OH). Found, %: C 81.48; H 6.13; N 8.38. M+ 340.
C23H20N2O. Calculated, %: C 81.18; H 5.88; N 8.24. M 340.
9-Acetamido-9-(β-cyanoethyl)-4-azafluorene (2c). A solution of compound 1c (1 g, 4.5 mmol), Triton
B (0.6 ml), and acrylonitrile (3.6 g, 67 mmol) in absolute benzene (100 ml) was stirred at 20°C for 4 h (check by
TLC). Water (20 ml) was added, the organic layer was separated, and the aqueous layer was extracted with
1294

chloroform. The combined extracts were dried over MgSO4. After distilling off the solvents, the residue was
crystallized from ethyl acetate-ethanol. Compound 2c (0.65 g, 52%) was obtained as colorless crystals;
mp 223-225°C, Rf 0.34 (2-propanol). IR spectrum, ν, cm-1: 2250 (C≡N), 1670 (C=O), 3300, 3070 (NH).
Found, %: C 73.80; H 5.50; N 15.16. M+ 277. C17H15N3O. Calculated, %: C 73.65; H 5.42; N 15.16. M 277.
1-[N,N-Di-(β-cyanoethyl)amino]-9-(β-cyanoethyl)-4-azafluorene (2d). A solution of compound 1d
(0.3 g, 1.65 mmol), Triton B (10 drops), and acrylonitrile (1 ml, 16.5 mmol) in absolute benzene (5 ml) was
heated for 10 h at 45-50°C (TLC check). The benzene was distilled off, and the residue was chromatographed on
aluminum oxide (1 × 30 cm), eluent was hexane–ethyl acetate, 1:1. Compound 2d (0.16 g, 30%) was isolated as
yellow crystals; mp 98-100°C (hexane–ethyl acetate, 1:1), Rf 0.4 (ethyl acetate). IR spectrum, ν, cm-1: 2230
(C≡N). Mass spectrum, m/z (Irel, %): 341 (35) [M]+; 301 (30); 287 (100); 260 (15); 246 (30); 234 (40); 219 (22);
194 (20); 178 (150); 166 (10); 151 (15); 139 (5); 126 (5); 110 (10); 83 (15); 54 (30); 43 (25). Found, %:
C 74.20; H 5.61; N 20.73. C21H19N5. Calculated, %: C 73.90; H 5.57; N 20.53. M 341.
1'-Cyano-2'-phenylspiro[4-azafluorene-9,4'-cyclopentene]
(3)
and
1'-Imino-2'-hydroxy-
benzylidenespiro[4-azafluorene-9,3'-cyclopentane] (4). A solution of compound 2a (0.5 g, 1.47 mmol) and
sodium ethylate (0.3 g, 4.43 mmol) in absolute ethanol (40 ml) was boiled for 2 h (TLC check). The alcohol was
distilled off, water (50 ml) was added to the residue, and the mixture was extracted with ether. The extract was
dried over MgSO4. After distilling off the ether, the residue was chromatographed on aluminum oxide
(1 × 35 cm), eluent was hexane–ethyl acetate, 1:1. Spiro compound 3 (90 mg, 20%) was eluted first as colorless
crystals; mp 143-145°C (hexane–ethyl acetate, 1:1), Rf 0.4 (ethyl acetate–hexane, 1:1). IR spectrum, ν, cm-1:
2218 (C≡N). Mass spectrum, m/z (Irel, %): 320 (100) [M]+; 319 (75); 293 (10); 267 (12); 243 (15); 193 (8); 180
(12); 166 (22); 103 (9). Found, %: C 86.25; H 5.20; N 8.46. C23H16N2. Calculated, %: C 86.25; H 5.0; N 8.75.
M 320. Spiro compound 4 (0.1 g, 20%) was eluted next as yellowish crystals; mp 218-222°C (hexane–ethyl
acetate, 1:1), Rf 0.30 (ethyl acetate–hexane, 1:1). IR spectrum (CHCl3), ν, cm-1: 3433-3643 (OH), 3233-3553
(NH), 2276 and 3450 (NH···OH and bonded OH and NH). Mass spectrum, m/z (Irel, %): 338 (58) [M]+; 337
(100); 294 (10); 233 (42); 217 (12); 192 (10); 180 (12); 167 (5); 105 (22); 77 (40). Found, %: C 81.89; H 5.40;
N 8.19. C23H18N2O. Calculated, %: C 81.66; H 5.33; N 8.28. M 338.
REFERENCES
1.
N. S. Prostakov, B. Kh. Sisimbina, S. A. Soldatova, B. P. Shalimov, K. G. Montenegro, N. I. Leonova,
and L. A. Murugova, Khim. Geterotsikl. Soedin., 1668 (1982). [Chem. Heterocycl. Comp., 18, 1290
(1982)].
2.
3.
4.
N. S. Prostakov, Hanna Bu Habib, L. M. Kirillova, O. I. Sorokin, and A. V. Varlamov, Khim.
Geterotsikl. Soedin., 967 (1983). [Chem. Heterocycl. Comp., 19, 778 (1983)].
A. V. Varlamov, A. N. Levov, F. Toze, A. I. Chernyshev, V. V. Davydov, M. A. Ryabov, and
O. A. Egorova, Khim. Geterotsikl. Soedin., 1682 (2002). [Chem. Heterocycl. Comp., 30, 1484 (2002)]
N. S. Prostakov, Mikhalis Makuli, N. M. Mikhailova, and N. D. Sergeeva, Khim. Geterotsikl. Soedin.,
510 (1984). [Chem. Heterocycl. Comp., 20, 413 (1984)].
1295