Synthesis of amino acid derivatives of hydrazones and oximes of spirodihydropyranochromen-2-ones

Article abstract of DOI:10.1007/s10593-008-0033-5

Sulfur-and nitrogen-containing derivatives of spirodihydropyranochromen-2- ones at the exocyclic oxygen atom have been synthesized. Modification of the oximes and hydrazones of the spiro-substituted pyranocoumarins with N-substituted amino acids were carried out using activated ester and symmetrical anhydride methods.

Full text of DOI:10.1007/s10593-008-0033-5

Chemistry of Heterocyclic Compounds, Vol. 44, No. 2, 2008
SYNTHESIS OF AMINO ACID DERIVATIVES OF
HYDRAZONES AND OXIMES OF SPIRODIHYDRO-
PYRANOCHROMEN-2-ONES
M. V. Veselovska1, M. M. Garazd1, O. S. Ogorodniychuk1,
Ya. L. Garazd2, and V. P. Khilya2
Sulfur- and nitrogen-containing derivatives of spirodihydropyranochromen-2-ones at the exocyclic
oxygen atom have been synthesized. Modification of the oximes and hydrazones of the spiro-substituted
pyranocoumarins with N-substituted amino acids were carried out using activated ester and symmetrical
anhydride methods.
Keywords: amino acid derivatives, benzopyran-2-thiones, hydrazones, coumarins, oximes,
spirodihydropyranochromen-2-ones.
It is well known that coumarins are an important class of heterocyclic compounds in practice, and
possess a broad spectrum of physiological activity. Many of them are promising pharmaceutical substances and
have been introduced into medical practice. Derivatives of spirodihydropyranochromen-2-ones, which are
practically unstudied to this day [1, 2], are of particular interest in the search for new biologically active
substances. The important role of amino acids in vital processes has for a long time stimulated investigations on
the search for new biologically active compounds among the natural amino acids, their synthetic analogs, and
various compounds containing amino acid residues. It is evident that the introduction into the coumarin system
of a fragment with an amino acid structure as a substituent is of interest both for the chemistry of amino acids
and of coumarins, and also for the expedient synthesis of new biologically active compounds.
In a continuation of our investigations on the study of the synthesis and properties of
spirodihydropyranochromen-2-ones [3], the functionalization of benzopyran bioregulators by introducing
pharmacophoric groupings of an amino acid nature into their molecules has been effected in the present work.
The spiro[(7-hydroxychromane)-2,1'-cyclohexane] (1) necessary for further conversions was obtained by
Kabbe condensation [4, 5] of 2,4-dihydroxyacetophenone with cyclohexanone in the presence of pyrrolidine with
subsequent reduction of the resulting spirochroman-4-one under conditions of the Clemmensen reaction [3].
The Pechman condensation of spirochromanol 1 with β-ketoacid esters in the presence of concentrated
sulfuric acid led to annelation of the pyran-2-one ring to a spirochromanone with the formation of
spirodihydropyranocoumarins 2-7 [3]. To obtain compounds 2-7 ethyl acetoacetate, methyl propionylacetate,
methyl 3-oxoheptanoate, ethyl 2-benzylacetoacetate, ethyl cyclopentanone-2-carboxylate, and ethyl
cyclohexanone-2-carboxylate respectively were used in the indicated reaction (Scheme 1).
__________________________________________________________________________________________
1Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences (NAN) of Ukraine,
2
Kiev 02094; e-mail: gmm@i.com.ua; Taras Shevchenko National University, Kiev 01033, Ukraine; e-mail:
vkhilya@mail.univ.kiev.ua. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 208-220, February,
2008. Original article submitted June 7, 2007.
0009-3122/08/4402-0153©2008 Springer Science+Business Media, Inc.
153

Scheme 1
5'
2'
6'O
O
O
R
4'
10
5
R1COCHRCOOEt,
2
O
OH
H2SO4
LR
3'
3
7
4
6
R1
1
2–7
NH2NH2
O
O
NNH2
O
O
S
14, 15
16–19
R1
O
R
NH2OH
R1
O
N
8–13
OH
R
R1
2, 8, 14 R = H, R1 = Me; 3, 9, 15 R = H, R1 = Et; 4, 10, 16 R = H, R1 = Bu; 5, 11, 17 R = CH2Ph, R1 = Me;
6, 12, 18 RR1 = (CH2)3; 7, 13, 19 RR1 = (CH2)4; LR, Lawesson reagent
The Lawesson reagent was used by us for the thionation of the exocyclic oxygen atom of the
benzopyran-2-one system [3, 6, 7]. On heating spirodihydropyranocoumarins 2-7 with a 10% excess of
Lawesson reagent in toluene, benzopyran-2-thiones 8-13 were synthesized smoothly and in high yield (Scheme
1). Unlike the colorless initial coumarins 2-7, compounds 8-13 were bright-yellow substances, the color of which
is caused by the presence in their molecules of a C=S grouping.
The hydrazones of spirodihydropyranochromenes 14 and 15 were synthesized by treating alcohol
solutions of the appropriate thiones 8 and 9 with hydrazine hydrate [3, 7] (Scheme 1). The oximes of
spirodihydropyranochromen-2-ones 16-19 were obtained by the interaction of benzopyran-2-thiones 10-13 with
hydroxylamine hydrochloride in pyridine [3, 7] (Scheme 1). The structures of the obtained compounds 14-19
1
were confirmed by data of elemental analysis and NMR spectroscopy. Signals were present in the H NMR
spectra of these compounds characteristic of a spirodihydropyranochromene residue. In addition, in the spectra
of hydrazones 14 and 15 a two-proton broadened singlet of the amino group was present at 5.60-5.70 ppm, but
the spectra of oximes 16-19 were characterized by the presence of a one-proton singlet for the hydroxyl group at
10.00-10.20 ppm.
The active ester method [8], widely used in peptide synthesis, proved to be the most effective for the
directed synthesis of amino acid derivatives of the spirodihydro-pyranochromene hydrazones. The
N-hydroxysuccinimide esters of N-substituted amino acids [9] were obtained by the interaction of the
appropriate N-protected amino acid with N-hydroxysuccinimide (N-HOSu) in the presence of diisopropyl-
carbodiimide (DIC) as condensing agent. The activated esters obtained reacted smoothly and in high yield with
hydrazones 14 and 15, forming the corresponding N-acylhydrazones of spirodihydropyranochromen-2-ones
20-27 (Scheme 2), containing residues of DL-2-aminobutyric (20, 25), trans-4-(aminomethyl)cyclo-
hexanecarboxylic (22) and 6-aminohexanoic (23) acids, L-2-phenylglycine (21, 26, 27), and β-alanine (24).
The structures of the obtained amino acid derivatives 20-27 were confirmed by data of elemental
1
analysis and NMR spectroscopy. Doubled signals were observed in the H NMR spectra of these compounds
both for the spirodihydropyranochromene system and for the amino acid fragment as a result of the existence of
compounds 20-27 as a mixture of Z- and E- isomers in almost equal amounts. Signal was also present in the
1H NMR spectra for the hydrazide proton at 8.50-10.40 ppm.
154

155

156

Scheme 2
O
H
N
Me
Me
O
O
N
N
H
R 1
Me
O
R
O
20, 21
O
N
N
H
H
Me
Me
O
N
O Me
Me
O
22
O
H
Me
Me
O
NNH2
O
N
N
N
N
N
H
Me
O
R
23
Et
O
14, 15
O
O
N
O
Ph
N
H
H
24
Et
O
O
O
H
N
S
N
H
R1
O
Me
R
25–27
20, 25 R = Me, R1 = Et; 21, 27 R = Et, R1 = Ph; 26 R = Me, R1 = Ph
The symmetrical anhydrides method used in peptide synthesis [8] was successfully applied for the
acylation of the hydroxyl group of oximes. Symmetrical anhydrides of N-protected amino acids were obtained
by the condensation of dicyclohexylcarbodiimide (DCC) with a double quantity of the corresponding
N-substituted amino acid in absolute dioxane at 0oC. Treatment of oximes of spirodihydropyranochromenes
16-19 with the obtained symmetrical anhydrides in the presence of catalytic amounts of 4-dimethyl-
aminopyridine (DMAP) leads to the formation of O-aminoacylated derivatives 28-35, modified with residues of
DL-aminobutyric (in 28), trans-4-(aminomethyl)cyclohexanecarboxylic (in 30), and 4-aminobutyric (in 31)
acids, L-2-phenylglycine (in 29, 33), DL-2-norvaline (in 32, 34), and L-phenylalanine (in 35) (Scheme 3).
Derivatives of hydrazones and oximes of spirodihydropyranochromen-2-ones, modified with residues of
amino acids, have been obtained using activated esters and symmetrical anhydrides methods.
EXPERIMENTAL
The progress of reactions and the homogeneity of the obtained compounds was checked by TLC on
Merck 60 F254 plates, eluent was chloroform–methanol, 9:1 or 95:5. Melting points were determined on a
Kofler heating block. The 1H NMR spectra were recorded on Varian VXR 300 (300 MHz) and Varian Mercury
400 (400 MHz) instruments, internal standard was TMS.
157

Sheme 3
O
H
N
Me
Me
O
O
N
R
O
O
R2
Me
O
R1
O
28, 29
O
N
H
N
Me
Me
O
Me
O
30
O
O
N
R
H
N
Me
Me
O
O
N
OH
O
Me
O
R1
Me
O
Ph
N
31
16–19
O
H
N
Ph
O
O
O
Me
32
O
O
H
N
O
N
R
S
O
R2
O
Me
R1
33–35
28 R = H, R1 = Bu, R2 = Et; 29 RR1 = (CH2)4, R2 = Ph; 33 R = H, R1 = Bu, R2 =Ph;
34 R = CH2Ph, R1 = Me, R2 = Pr; 35 RR1 = (CH2)4, R2 = CH2Ph
The synthesis of spiro[(7-hydroxychromane)-2,1'-cyclohexane] (1) was described in [3].
Spirodihydropyranochromen-2-ones 2-7. Conc. H2SO4 (40 ml) was added dropwise with vigorous
stirring to a solution of spirochromane 1 (10.90 g, 50 mmol) and the appropriate ethyl acetoacetate (50 mmol) in
ethanol (20 ml). The reaction mixture was left overnight at room temperature, after which the mixture was
poured into ice water (500 ml). The resulting solid was filtered off and crystallized from 2-propanol.
Data of 1H NMR spectroscopy are given in Tables 1.
Spiro[(4-methyl-7,8-dihydropyrano[3,2-g]chromen-2-one)-8,1'-cyclohexane] (2). Yield 55%;
mp 204-205oC. Found, %: C 75.86; H 7.12. C18H20O3. Calculated, %: C 76.03; H 7.09.
Spiro[(4-ethyl-7,8-dihydropyrano[3,2-g]chromen-2-one)-8,1'-cyclohexane] (3). Yield 63%; mp
155-156°C. Found, %: C 76.32; H 7.29. C19H22O3. Calculated, %: C 76.48; H 7.43.
Spiro[(4-butyl-7,8-dihydropyrano[3,2-g]chromen-2-one)-8,1'-cyclohexane] (4). Yield 68%; mp
117-118°C. Found, %: C 77.32; H 7.95. C21H26O3. Calculated, %: C 77.27; H 8.03.
Spiro[(4-methyl-3-benzyl-7,8-dihydropyrano[3,2-g]chromen-2-one)-8,1'-cyclohexane] (5). Yield 71%;
mp 136-137°C. Found, %: C 79.98; H 7.12. C25H26O3. Calculated, %: C 80.18; H 7.00.
158

Spiro[(2,3,9,10-tetrahydrocyclopenta[c]pyrano[3,2-g]chromen-4-one)-8,1'-cyclohexane] (6). Yield
was 68%; mp 198-199oC. Found, %: C 77.48; H 7.11. C20H22O3. Calculated, %: C 77.39; H 7.14.
Spiro[(1,2,3,4,10,11-hexahydrobenzo[c]pyrano[3,2-g]chromen-5-one)-9,1'-cyclohexane] (7). Yield
65%; mp 154-155°°C. Found, %: C 77.71; H 7.52. C21H24O3. Calculated, %: C 77.75; H 7.46.
Spirodihydropyranochromen-2-thiones 8-13. A mixture of spirodihydropyranochromen-2-one 2-7 (20
mmol) and Lawesson reagent (2.46 g, 11 mmol) in absolute toluene (50 ml) was boiled for 4 h (the progress of
the reaction was checked by TLC). After the end of the reaction the solvent was evaporated, and the oily residue
crystallized from aqueous 2-propanol.
Spiro[(4-methyl-7,8-dihydropyrano[3,2-g]chromen-2-thione)-8,1'-cyclohexane] (8). Yield 86%; mp
181-182°C. Found, %: C 71.84; H 6.81; S 10.79. C18H20O2S. Calculated, %: C 71.94; H 6.71; S 10.67.
Spiro[(4-ethyl-7,8-dihydropyrano[3,2-g]chromen-2-thione)-8,1'-cyclohexane] (9). Yield 90%;
mp 176-177oC. Found, %: C 72.49; H 7.11; S 10.15. C19H22O2S. Calculated, %: C 72.57; H 7.05; S 10.20.
Spiro[(4-butyl-7,8-dihydropyrano[3,2-g]chromen-2-thione)-8,1'-cyclohexane] (10). Yield 93%;
mp 145-146°C. Found, %: C 73.57; H 7.71; S 9.41. C21H26O2S. Calculated, %: C 73.64; H 7.65; S 9.36.
Spiro[(3-benzyl-4-methyl-7,8-dihydropyrano[3,2-g]chromen-2-thione)-8,1'-cyclohexane] (11). Yield
88%; mp 182-183°C. Found, %: C 76.99; H 6.62; S 8.28. C25H26O2S. Calculated, %: C 76.89; H 6.71; S 8.21.
Spiro[(2,3,9,10-tetrahydrocyclopenta[c]pyrano[3,2-g]chromen-4-thione)-8,1'-cyclohexane] (12). Yield
97%; mp 218-219°C. Found, %: C 73.66; H 6.85; S 9.95. C20H22O2S. Calculated, %: C 73.58; H 6.79; S 9.82.
Spiro[(1,2,3,4,10,11-hexahydrobenzo[c]pyrano[3,2-g]chromen-5-thione)-9,1'-cyclohexane]
(13).
Yield 95%; mp 178-179°C. Found, %: C 74.15; H 7.08; S 9.51. C21H24O2S. Calculated, %: C 74.08; H 7.10;
S 9.42.
Hydrazones of Spirodihydropyranochromen-2-ones 14, 15. Hydrazine hydrate (1 ml, 20 mmol) was
added to a solution of thione 8 or 9 (10 mmol) in ethanol (30 ml). The mixture was boiled for 1 h ( the progress
of the reaction was checked by TLC). After the end of the reaction the mixture was cooled to room temperature,
the resulting solid was filtered off, and crystallized from 2-propanol.
Hydrazone of Spiro[(4-methyl-7,8-dihydropyrano[3,2-g]chromen-2-one)-8,1'-cyclohexane] (14).
Yield 94%; mp 200-201°C. Found, %: C 72.38; H 7.35; N 9.51. C18H22N2O2. Calculated, %: C 72.46; H 7.43;
N 9.39.
Hydrazone of Spiro[(4-ethyl-7,8-dihydropyrano[3,2-g]chromen-2-one)-8,1'-cyclohexane] (15).
Yield 86%; mp 169-170°C. Found, %: C 72.92; H 7.69; N 8.91. C19H24N2O2. Calculated, %: C 73.05; H 7.74;
N 8.97.
Oximes of Spirodihydropyranochromen-2-ones 16-19. Hydroxylamine hydrochloride (0.84 g,
12 mmol) was added to a solution of thione 10-13 (6 mmol) in absolute pyridine (10 ml). The mixture was
maintained at 100°C for 6 h (the progress of the reaction was checked by TLC). After the end of the reaction the
mixture was cooled to room temperature, and transferred into 5% acetic acid (100 ml). The resulting solid was
filtered off, and crystallized from 2-propanol.
Oxime of Spiro[(4-butyl-7,8-dihydropyrano[3,2-g]chromen-2-one)-8,1'-cyclohexane] (16). Yield
88%; mp 175-176°C. Found, %: C 73.78; H 8.02; N 4.12. C21H27NO3. Calculated, %: C 73.87; H 7.97; N 4.10.
Oxime of Spiro[(3-benzyl-4-methyl-7,8-dihydropyrano[3,2-g]chromen-2-one)-8,1'-cyclohexane]
(17). Yield 94%; mp 243-244°C. Found, %: C 79.95; H 7.05; N 3.65. C25H27NO3. Calculated, %: C 77.09;
H 6.99; N 3.60.
Oxime of Spiro[(2,3,9,10-tetrahydrocyclopenta[c]pyrano[3,2-g]chromen-4-one)-8,1'-cyclohexane]
(18). Yield 96%; mp 256-257°C. Found, %: C 73.95; H 7.06; N 4.25. C20H23NO3. Calculated, %: C 73.82;
H 7.12; N 4.30.
Oxime of Spiro[(1,2,3,4,10,11-hexahydrobenzo[c]pyrano[3,2-g]chromen-5-one)-9,1'-cyclohexane]
(19). Yield 94%; mp 240-241°C. Found, %: C 74.41; H 7.46; N 4.11. C21H26NO3. Calculated, %: C 74.31;
H 7.42; N 4.13.
159

N-Acylhydrazones of Spirodihydropyranochromen-2-ones 20-27. Diisopropylcarbodiimide (DIC)
(0.52 ml, 3.3 mmol) was added with vigorous stirring and cooling (0°C) to a solution of the appropriate
N-protected amino acid (3.3 mmol) and N-HOSu (0.38 g, 3.3 mmol) in absolute dioxane (20 ml). The reaction
mixture was stirred for 2 h (progress of the reaction was checked by TLC). Hydrazone 14 or 15 (3 mmol) was
added to the resulting active ester. The mixture was stirred vigorously at room temperature for 4-6 h (progress of
the reaction was checked by TLC). After completion of the reaction the mixture was diluted with water (200 ml),
the solid formed was filtered off, and crystallized from 2-propanol.
N-(N-tert-Butyloxycarbonyl-DL-2-aminobutyryl)hydrazone of Spiro[(4-methyl-7,8-dihydropyrano-
1
[3,2-g]chromen-2-one)-8,1'-cyclohexane] (20). Yield 82%; mp 238-239°C. H NMR spectrum (300 MHz,
CDCl3), δ, ppm (J, Hz); 0.97 and 1.00 (3H, two t, J = 7.2, 3"-CH3); 1.20-2.00 (14H, m, H-7,2',3'4',5',6',2"); 1.45
and 1.46 (9H, s, (CH3)2); 2.19 and 2.20 (3H, two s, 4-CH3); 2.77 (2H, m, H-6); 4.11 (1H, m, H-1'''); 5.09 and
5.36 (1H, two m, CONHC); 5.99 and 6.19 (1H, two s, H-3); 6.56 and 6.71 (1H, two s, H-10); 7.03 and 7.06 (1H,
two s, H-5); 8.77 and 9.41 (1H, two s, CONHN). Found, %: C 66.95; H 7.76; N 8.71. C27H37N3O5. Calculated,
%: C 67.06; H 7.71; N 8.69.
N-(N-tert-Butyloxycarbonyl-L-2-phenylglycyl)hydrazone of Spiro[(4-ethyl-7,8-dihydropyrano-[3,2-
1
g]chromen-2-one)-8,1'-cyclohexane] (21). Yield 68%; mp 231-232oC. H NMR spectrum (300 MHz, CDCl3),
δ, ppm (J, Hz): 1.20-1.85 (14H, m, H-7,2',3',4',5'6',1"); 1.45 and 1.46 (9H, s, (CH3)3); 2.56 (2H, q, J = 7.2, H-1");
2.74 (2H, m, H-6); 5.29 (1H, m, H-1'''); 5.90 and 6.22 (1H, d, J = 7.8, CONHC); 5.97 and 6.19 (1H, two s, H-3);
6.51 and 6.53 (1H, two s, H-10); 7.05 and 7.08 (1H, two s, H-5); 7.30-7.53 (5H, m, C6H5); 8.81 and 8.93 (1H,
two s, CONHN). Found, %: C 70.55; H 7.16; N 7.75. C32H39N3O5. Calculated, %: C 70.44; H 7.20; N 7.70.
N-[N-tert-Butyloxycarbonyl-trans-4-aminomethyl)cyclohexanecarbonyl]hydrazone of Spiro[(4-
methyl-7,8-dihydropyrano[3,2-g]chromen-2-one)-8,1′-cyclohexane] (22). Yield 82%; mp 268-269°C.
1H NMR spectrum (300 MHz, DMSO-d6), δ, ppm (J, Hz): 0.95-1.80 (21H, m, H-7,2'3',4',5'6',2",3",4",5",6");
1.39 and 1.41 (9H, s, (CH3)3); 2.17 and 2.19 (3H, two s, 4-CH3); 2.32 (1H, m, H-1"); 2.72-2.81 (4H, m, H-6,4");
6.03 and 6.06 (1H, two s, H-3); 6.59 (1H, m, CONHC); 6.71 and 6.72 (1H, two s, H-10); 7.11 and 7.13 (1H, two
s, H-5); 9.78 and 9 96 (1H, two s, CONHN). Found, %: C 69.15; H 8.16; N 8.71. C31H43N3O5. Calculated, %:
C 69.25; H 8.06; N 8.82.
N-(N-tert-Butyloxycarbonyl-6-aminohexanoyl)hydrazone of Spiro[(4-ethyl-7,8-dihydropyrano-
1
[3,2-g]chromen-2-one)-8,1′-cyclohexane] (23). Yield 72%; mp 185-186oC. H NMR spectrum (300 MHz,
DMSO-d6), δ, ppm (J, Hz): 1.22 (3H, t, J = 7.2, 2"-CH3); 1.25-1.80 (18H, m, H-7,2',3',4',5',6',3''',4''',5'''); 1.38
(9H, s, (CH3)3); 2.57 (4H, m, H-1″,2'''), 2.73 (2H, m, H-6); 2.90 (2H, q, J = 7.2, H-6'''); 5.96 and 6.01 (1H, two s,
H-3); 6.56 (1H, m, CONHC); 6.71 and 6.72 (1H, two s, H-10); 7.14 and 7.17 (1H, two s, H-5); 9.91 and 10.04
(1H, two s, CONHN). Found, %: C 68.65; H 8.14; N 7.95. C30H43N3O5. Calculated, %: C 68.54; H 8.24; N 7.99.
N-(N-Benzyloxycarbonyl-β-alanyl)hydrazone of Spiro[(4-ethyl-7,8-dihydropyrano[3,2-g]chromen-
2-one)-8,1'-cyclohexane] (24). Yield 76%; mp 196-197°C. 1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm (J,
Hz): 1.15-1.20 (3H, m, 2"-CH3); 1.25-1.75 (10H, m, H-2',3',4',5',6'); 1.78 (2H, t, J = 7.2, H-7); 2.46-2.59 (4H, m,
H-1",2'''); 2.72 (2H, m, H-6); 3.28 (2H, m, H-3'''); 5.02 and 5.03 (2H, s, OCH2); 6.01 and 6.07 (1H, two s, H-3);
6.74 and 6.77 (1H, two s, H-10); 7.22 and 7.26 (1H, two s, H-5); 7.28-7.34 (6H, m, CONHC, C6H5); 10.30 and
10.32 (1H, two s, CONHN). Found, %: C 69.65; H 6.74; N 8.15. C30H35N3O5. Calculated, %: C 69.61; H 6.82; N
8.12.
N-[N-(4-Methylbenzenesulfonyl)-DL-2-aminobutyryl]hydrazone of Spiro[(4-methyl-7,8-dihydro-
pyrano[3,2-g]chromen-2-one)-8,1'-cyclohexane] (25). Yield 69%; mp 208-209°C. 1H NMR spectrum
(300 MHz, CDCl3), δ, ppm (J, Hz): 0.88 and 0.99 (3H, t, J = 7.2, 3"-CH3); 1.20-1.90 (12H, m, H-7,2',3',4',5',6');
2.10-2.25 (2H, m, H-2"); 2.20 and 2.22 (3H, two s, 4-CH3); 2.28 and 2.31 (3H, two s, 4'''-CH3); 2.27 (2H, m,
H-6); 3.75 and 4.63 (1H, two m, H-1'''); 5.34 and 5.60 (1H, d, J = 8.4, SO2NH); 5.99 and 6.13 (1H, two s, H-3);
6.74 and 6.77 (1H, two s, H-10); 7.04 and 7.06 (1H, two s, H-5); 7.18 and 7.23 (2H, two d, J = 8.1, H-3'''',5'''');
160

7.72 and 7.77 (2H, two d, J = 8.1, H-2'''',6''''); 8.47 and 9.11 (1H, two s, CONHN). Found, %: C 64.69; H 6.52;
N 7.85; S 5.98. C29H35N3O5S. Calculated, %: C 64.78; H 6.56; N 7.82; S 5.96.
N-[N-(4-Methylbenzenesulfonyl)-L-2-phenylglycyl]hydrazone of Spiro[(4-methyl-7,8-dihydro-
pyrano[3,2-g]chromen-2-one)-8,1'-cyclohexane] (26). Yield 80%; mp 241-242°C. 1H NMR spectrum
(300 MHz, CDCl3), δ, ppm (J, Hz): 1.30-1.85 (12H, m, H-7,2',3',4',5',6'); 2.20 and 2.22 (3H, two s, 4-CH3); 2.30
and 2.33 (3H, two s, 4'''-CH3); 2.76 (2H, t, J = 7.2, H-6); 4.91 and 6.08 (1H, d, J = 8.1, H-2"); 5.91 and 5.94 (1H,
two s, H-3); 6.02 and 6.11 (1H, d, J = 8.4, SO2NH); 6.44 and 6.48 (1H, two s, H-10); 7.03 (1H, s, H-5);
7.12-7.37 (7H, m, H-3'''',5'''', C6H5); 7.65 (2H, d, J = 9.0, H-2'''',6''''); 8.60 and 8.84 (1H, two s, CONHN). Found,
%: C 67.58; H 5.98; N 7.25; S 5.38. C33H35N3O5S. Calculated, %: C 67.67; H 6.02; N 7.17; S 5.47.
N-[N-(4-Methylbenzenesulfonyl)-L-2-phenylglycyl]hydrazone
of
Spiro[(4-ethyl-7,8-dihydro-
pyrano[3,2-g]chromen-2-one)-8,1'-cyclohexane] (27). Yield 77%; mp 209-210°C. 1H NMR spectrum
(300 MHz, DMSO-d6), δ, ppm (J, Hz): 1.19 and 1.22 (3H, two t, J = 7.2, 2″-CH3); 1.30-1.90 (12H, m,
H-7,2',3',4',5',6'); 2.25 and 2.29 (3H, two s, 4'''-CH3); 2.59 (2H, m, H-1"); 2.75 (2H, m, H-6); 5.33 and 5.86 (1H,
d, J = 8.4, H-2"); 5.98 and 6.03 (1H, two s, H-3); 6.65 and 6.72 (1H, two s, H-10); 7.12 and 7.14 (1H, two s,
H-5); 7.16-7.38 (7H, m, H-3'''',5'''',C6H5); 7.56 and 7.59 (2H, two d, J = 9.0, H-2'''',6''''); 8.27 and 8.47 (1H, d,
J = 8.7, SO2NH); 10.37 and 10.40 (1H, two s, CONHN). Found, %: C 68.05; H 6.13; N 7.11; S 5.29.
C34H37N3O5S. Calculated, %: C 68.09; H 6.22; N 7.01; S 5.35.
O-Acyloximes of Spirodihydropyranochromen-2-ones 28-35. Dicyclohexylcarbodiimide (DCC) (0.68
g, 3.3 mmol) was added with vigorous stirring and cooling (0°C) to a solution of the appropriate N-protected
amino acid (6.6 mmol) in absolute dioxane (20 ml). The reaction mixture was stirred for 1 h (progress of the
reaction was checked by TLC). Oxime 16-19 (3 mmol) and DMAP (5 mg) were added to the resulting
symmetrical anhydride. The mixture was stirred vigorously for 8-10 h at room temperature (progress of the
reaction was checked by TLC). The solid dicyclohexylurea was filtered off, and the solvent was removed in
vacuum. The residue was dissolved in ethyl acetate (50 ml) and treated sequentially in a separating funnel twice
with 5% NaHCO3 (50 ml), with water (50 ml), and saturated NaCl solution (50 ml). The organic phase was dried
over anhydrous MgSO4, the solvent was removed in vacuum, and the oily residue was crystallized from
2-propanol.
O-(N-tert-Butyloxycarbonyl-DL-2-aminobutyryl)oxime
of
Spiro[(4-butyl-7,8-dihydropyrano-
1
[3,2-g]chromen-2-one)-8,1′-cyclohexane] (28). Yield 81%; mp 164-165°C. H NMR spectrum (300 MHz,
CDCl3), δ, ppm (J, Hz): 0.96 (3H, t, J = 7.2, 4"-CH3); 1.04 (3H, t, J = 7.2, 3'''-CH3); 1.25-2.00 (18H, m,
H-7,2',3',4',5',6',2",3", 2'''); 1.47 (9H, s, (CH3)3); 2.73 (2H, t, J = 7.2, H-1'''); 2.78 (2H, t, J = 7.2, H-6); 4.52 (1H,
m, H-1'''); 5.20 (1H, d, J = 7.8, NH); 6.19 (1H, s, H-3); 6.75 (1H, s, H-10); 7.14 (1H, s, H-5). Found, %: C 68.49;
H 7.94; N 5.35. C30H42N2O6. Calculated, %: C 68.42; H 8.04; N 5.32.
O-(N-tert-Butyloxycarbonyl-L-2-phenylglycyl)oxime of Spiro[(1,2,3,4,10,11-hexahydrobenzo-
1
[c]pyrano[3,2-g]chromen-5-one)-9,1'-cyclohexane] (29). Yield 70%; mp 161-162°C. H NMR spectrum
(300 MHz, CDCl3), δ, ppm (J, Hz): 1.30-1.80 (16H, m, 2,3,11,2′,3′,4′,5′,6′); 1.45 (9H, s, (CH3)3); 2.33 and 2.44
(2H, two m, H-4); 2.56 (2H, m, H-1); 2.75 (2H, t, J = 7.2, H-11); 5.65 (1H, d, J = 7.2, H-1″); 5.75 (1H, d,
J = 7.8, NH); 6.52 and 6.72 (1H, two s, H-7); 7.02 and 7.07 (1H, two s, H-12); 7.35-7.54 (5H, m, C6H5). Found,
%: C 71.46; H 7.01; N 4.95. C34H40N2O6. Calculated, %: C 71.31; H 7.04; N 4.89.
O-[N-tert-Butyloxycarbonyl-trans-4-(aminomethyl)cyclohexanecarbonyl]oxime of Spiro[(2,3,9,10-
tetrahydrocyclopenta[c]pyrano[3,2-g]chromen-4-one)-8,1'-cyclohexane] (30). Yield 51%; mp 194-195oC. 1H
NMR spectrum (300 MHz, CDCl3), δ, ppm (J, Hz): 0.95-1.80 (21H, m, 11,2′,3′,4′,5′,6′,2″,3″,4″,5″,6″); 1.46 (9H,
s, (CH3)3); 2.15 (2H, m, H-2); 2.49 (1H, m, H-1″); 2.77 (2H, t, J = 7.2, H-10); 2.85 (4H, m, H-3,4″); 3.04 (2H,
m, H-1); 4.65 (1H, m, NH); 6.76 (1H, s, H-6); 6.96 (1H, s, H-11). Found, %: C 70.04; H 7.91; N 5.01.
C33H44N2O6. Calculated, %: C 70.19; H 7.85; N 4.96.
O-(N-tert-Butyloxycarbonyl-4-aminobutyryl)oxime
of
Spiro[(3-benzyl-4-methyl-7,8-dihydro-
pyrano[3,2-g]chromen-2-one)-8,1'-cyclohexane] (31). Yield 72%; mp 153-154°C. 1H NMR spectrum
161

(300 MHz, CDCl3), δ, ppm (J, Hz): 1.25-1.95 (14H, m, H-7,2',3',4',5',6',3''); 1.45 (9H, s, (CH3)3); 2.26 (3H, s,
4-CH3); 2.55 (2H, t, J = 7.2, H-2"); 2.77 (2H, t, J = 7.2, H-6); 3.23 (2H, m, H-4"); 4.01 (2H, s, H-3); 4.59 (1H,
m, NH); 6.74 (1H, s, H-10); 7.15 (1H, s, H-5); 7.16-7.33 (5H, m, C6H5). Found, %: C 70.96; H 7.34; N 4.92.
C34H42N2O6. Calculated, %: C 71.06; H 7.37; N 4.87.
O-(N-Benzyloxycarbonyl-DL-norvalyl)oxime of Spiro[1,2,3,4,10,11-hexahydrobenzo[c]pyrano-
1
[3,2-g]chromen-5-one)-9,1'-cyclohexane] (32). Yield 80%; mp 145-146°C. H NMR spectrum (300 MHz,
CDCl3), δ, ppm (J, Hz): 0.99 (3H, t, J = 7.2, 4"-CH3); 1.27-1.95 (20H, m, 2,3,10,2',3',4',5',6',2",3"); 2.48 (2H, m,
H-4); 2.63 (2H, m, H-1); 2.77 (2H, t, J = 7.2, H-11); 4.66 (1H, m, H-1"'); 5.14 (2H, s, OCH2); 5.42 (1H, d,
J = 7.8, NH); 6.71 (1H, s, H-7); 7.10 (1H, s, H-12); 7.30-7.38 (5H, m, C6H5). Found, %: C 71.19; H 7.11;
N 4.81. C34H42N2O6. Calculated, %: C 71.31; H 7.04; N 4.89.
O-[N-(4-Methylbenzenesulfonyl)-L-2-phenylglycyl]oxime of Spiro[(4-butyl-7,8-dihydropyrano-
1
[3,2-g]chromen-2-one)-8,1'-cyclohexane] (33). Yield 66%; mp 169-170°C. H NMR spectrum (300 MHz,
CDCl3), δ, ppm (J, Hz): 0.94 (3H, t, J = 7.2, 4"-CH3); 1.30-1.90 (16H, m, H-7,2',3',4',5',6',2"3"); 2.32 (3H, s,
4'''-CH3); 2.56 (2H, t, J = 7.2, H-1'''); 2.77 (2H, t, J = 7.2, H-6); 5.30 (1H, d, J = 7.8, H-2'''); 5.81 (1H, d, J = 7.8,
NH); 6.07 (1H, s, H-3); 6.56 (1H, s, H-10); 7.12 (1H, s, H-5); 7.18 (2H, d, J = 8.4, H-3'''',5''''); 7.31-7.40 (5H, m,
C6H5); 7.69 (2H, d, J = 8.4, H-2'''',6''''). Found, %: C 68.85; H 6.35; N 4.51; S 5.05. C36H40N2O6S. Calculated, %:
C 68.77; H 6.41; N 4.46; S 5.10.
O-[N-(4-Methylbenzenesulfonyl)-DL-norvalyl]oxime of Spiro[(3-benzyl-4-methyl-7,8-dihydro-
pyrano[3,2-g]chromen-2-one)-8,1'-cyclohexane] (34). Yield 71%; mp 173-174°C. 1H NMR spectrum
(300 MHz, CDCl3), δ, ppm (J, Hz): 0.94 (3H, t, J = 7.2, 4"-CH3); 1,25-1.90 (16H, m, H-7,2',3',4',5',6′,2'',3");
2.21 (3H, s, 4-CH3); 2.26 (3H, s, 4'''-CH3); 2.78 (2H, t, J = 7.2, H-6); 3.90 (2H, s, H-3); 4.20 (1H, m, H-1"); 5.23
(1H, d, J = 8.4, NH); 6.67 (1H, s, H-10); 7.12-7.28 (8H, m, H-5,3"'' ,5"'', C6H5); 7.70 (2H, d, J = 8.4, H-2"'',6"'').
Found, %: C 69.19; H 6.55; N 4.32, S 5.09. C37H42N2O6S. Calculated, %: C 69.13; H 6.59; N 4.36; S 4 99.
O-[N-(4-Methylbenzenesulfonyl)-L-phenylalanyl]oxime of Spiro[(1,2,3,4,10,11-hexahydrobenzo-
1
[c]pyrano[3,2-g]chromen-5-one)-9,1′-cyclohexane] (35). Yield 73%; mp 198-199oC. H NMR spectrum
(300 MHz, CDCl3), δ, ppm (J, Hz): 1.30-1.90 (16H, m, H-2,3,10,2',3',4',5',6'); 2.32 (3H, s, 4'''-CH3); 2.43 (2H,
m, H-4); 2.62 (2H, m, H-1); 2.78 (2H, t, J = 7.2, H-11); 3.24 (3H, m, H-3''); 4.46 (1H, m, H-2″); 5.20 (1H, d,
J = 8.7, NH); 6.66 (1H, s, H-7); 7.12 (1H, s, H-12); 7.19 (2H, d, J = 8.4, H-3'''',5''''); 7.20-7.30 (5H, m, C6H5);
7.69 (2H, d, J = 8.4, H-2'''',6''''). Found, %: C 69.23; H 6.25; N 4.29; S 4.94. C37H40N2O6S. Calculated, %:
C 69.35; H 6.29; N 4.37; S 5.00.
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