Modified coumarins. 23. Synthesis and structure of cyclohexyldihydroxanthyletin derivatives

Article abstract of DOI:10.1007/s10600-006-0245-9

Cyclohexyldihydroxanthyletin derivatives with S and N in place of the exocyclic O atom were synthesized. The structures of the products were proved by NMR correlation spectroscopy.

Full text of DOI:10.1007/s10600-006-0245-9

Chemistry of Natural Compounds, Vol. 42, No. 6, 2006
MODIFIED COUMARINS. 23. SYNTHESIS AND STRUCTURE
OF CYCLOHEXYLDIHYDROXANTHYLETIN DERIVATIVES
Ya. L. Garazd,1 M. M. Garazd,2 V. A. Turov,1 and V. P. Khilya1
UDC 547.814.5
Cyclohexyldihydroxanthyletin derivatives with S and N in place of the exocyclic O atom were synthesized.
The structures of the products were proved by NMR correlation spectroscopy.
Key words: coumarins, pyranocoumarins, benzopyran-2-thiones, oximes, hydrazones, heteronuclear correlation.
Pyranocoumarinsarecommon in natureandcontain a2,2-dimethylpyran ring annellatedtoabenzopyran-2-onesystem
[1]. Most natural pyranocoumarins are derivatives of the linear pyran xanthyletin or its angular isomer seselin.
The goal of the present work was to modify the dihydropyranocoumarin system at the exocyclic O atom to form
derivatives functionalized at the 2-position with S and N and to establish their structures using NMR correlation spectroscopy.
It is known that coumarins cannot be modified at the exocyclic O atom starting directly with benzopyran-2-one
derivatives. Convenient synthons for synthesizing such compounds are benzopyran-2-thione derivatives. The significantly
higher reactivity of benzopyran-2-thiones compared with benzopyran-2-ones is due to the lower electronegativity of S and the
higher polarizability of the C=S bond.
Cyclohexyldihydroxanthyletin (2)that wasneededfor further transformationswaspreparedbyPechmann condensation
of 2,2-dimethylchroman-7-ol (1) and ethyl-2-oxocyclohexanecarboxylate in the presence of conc. H SO [2].
2
4
H C
3
O
OH
H C
O
O
NNH
2
3
H C
3
H C
3
O
1
5
COOEt
NH NH
2
2
EtOH, H SO
2
4
1'
H C
7
H C
O
O
S
O
O
O
H C
3
O
O
NOH
9
7a
3
3
NH OH
2
H C
3
H C
3
H C
3
10
11
4a
4
12a
11a
12b
12
1
3
2
3
4
Lawesson reagent, the dimer of -methoxyphenylphosphorus sulfide [3], was used for thiation of the exocyclic O atom.
p
Heating 2 with a 10% excess of the reagent in toluene formed 9,9-dimethyl-1,2,3,4,10,11-hexahydrobenzo[ ]pyrano[3,2-
c
]chromen-5-thione (3). Reaction of 3 with hydroxylamine hydrochloride in pyridine gave the oxime 9,9-dimethyl-
g
1,2,3,4,10,11-hexahydrobenzo[ ]pyrano[3,2- ]chromen-5-one (4). Cyclohexyldihydroxanthyletin hydrazone(5)was prepared
c
g
by reaction of 3 with hydrazine in alcohol.
1)TarasShevchenkoKievNational University, 01033, Ukraine, Kiev, ul. Vladimirskaya, 64; 2) InstituteofBioorganic
and Petroleum Chemistry, National Academy of Sciences of Ukraine, 02094, Ukraine, Kiev, ul. Murmanskaya, 1, e-mail:
gmm@i.com.ua. Translated from Khimiya Prirodnykh Soedinenii, No. 6, pp. 531-533, November-December, 2006. Original
article submitted April 18, 2006.
0009-3130/06/4206-0652 ©2006 Springer Science+Business Media, Inc.
652

TABLE 1. PMR and 13C NMR Chemical Shifts of 2-5, ppm
2 (CDCl3)
3 (CDCl3)
4 (DMSO-d6)
5 (DMSO-d6)
C atom
1H
13C
1H
13C
1H
13C
1H
13C
1
2
2.71
25.5
22.1
21.7
24.2
2.75
28.4
22.3
21.2
25.5
2.50
24.2
22.1
2.41
24.3
21.8
1.80
1.80
1.70
1.68
3
1.80
1.80
1.65
22.1
1.61
21.8
4
2.52
2.75
2.22
23.7
2.20
25.5
4a
5
-
120.4
162.7
152.0
104.5
156.5
75.5
-
130.8
197.9
154.5
103.7
156.9
75.7
-
121.8
142.7
151.0
103.0
154.3
75.2
-
119.9
149.5
150.6
103.0
154.7
75.4
-
-
-
-
6a
7
-
-
-
-
6.68
6.83
6.41
6.44
7a
9
-
-
-
-
-
-
-
-
10
11
11a
12
12a
CH3-9
12b
1.84
2.83
-
32.9
1.86
2.85
-
32.3
1.76
2.71
-
32.6
1.75
2.69
-
32.5
22.5
22.3
21.9
21.9
118.1
124.0
113.6
27.2
119.5
123.8
114.8
26.8
116.1
123.9
114.6
27.0
116.5
124.1
114.1
27.0
7.22
-
7.33
-
7.12
-
7.02
-
1.35
-
1.37
-
1.28
-
1.27
-
147.5
142.2
139.9
132.3
H
H
H C
3
O
O
O
H C
3
H
H
H
H
H
H
H
H
H
H
H
H
Scheme 1. Heteronuclear correlations for dihydropyranocoumarins 2.
The compositions of the products were confirmed by elemental analyses and NMR spectroscopy (Table 1). Although
13
the PMR spectra of 2-5 were consistent with the proposed structural formulas, C NMR spectra were measured and
1
13
heteronuclear H— C HMQC and HMBC correlations were found in order to confirm the compositions because the molecular
frameworks were rather complicated.
13
C NMR spectra of 2-5 contained the number of signals corresponding to the structural formulas. However, the
signals were difficult to assign because there were several methylene signals close to each other. Furthermore, signals in the
aromatic region could also be assigned differently. Signals in PMR spectra could be assigned rather reliably based on their
multiplicity and chemical shifts. Those of C atoms directly bonded to protons were assigned unambiguously owing to
correlations through a single chemical bond in the HMQC spectrum. Quaternary atoms could be assigned from correlations
in the HMBC spectrum with protons through 2-3 chemical bonds. Because the molecules contained many protons, signals of
all C atoms could be assigned based on these correlations (Scheme 1).
Thus, thesignalnear 75.5ppmwasassignedtoC-9in the2,2-dimethyldihydropyran ring based on correlations through
two bonds with the signal for C-9 methyl protons, which had chemical shifts of 1.25-1.35 ppm, and with signals for CH -10
2
and CH -11 methylene protons, which resonated near 1.85 and 2.85 ppm, respectively. The C signal at 154-157 ppm was
2
assigned to C-7a based on its correlations with the H-7 singlet, which resonated at 6.4-6.8 ppm, H-12, which gave a singlet
at 7.0-7.2 ppm, and the CH -11 methylene protons. Quaternary C atoms in the pyran-2-one ring were assigned analogously.
2
653

TABLE 2. Characteristic 1H-13C Correlations in HMBC Spectra of 2-5
H atom
C atom
H-1
C-2; C-5 (w); C-12b; C-4a
C-12b
H-2
H-3
C-4a
H-4
C-2; C-5; C-12b; C-4a
C-7a; C-6a; C-11a; C-12a
C-10; 9-CH3; C-9
H-7
9-CH3
H-10
H-11
H-12
9-CH3; C-9; C-11a; C-11
C-9; C-10; C-7a; C-12; C-11a; C-7 (w)
C-7a; C-6a; C-11; C-12b
The signal at 150.0-154.0 ppm was assigned to C-6a based on its correlations through 2-3 bonds with H-7 and H-12; the signal
at 113-115 ppm, to C-12a based on correlations with H-7 and H-12; the signal at 130-147.5 ppm, to C-12b based on correlations
with H-12, CH -1, CH -2, and CH -4. The position of the signal changed greatly from compound to compound because of
2
2
2
conjugation of the C-4a=C-12b double bond to the C-5 substituent. The signal at 119-131 ppm was assigned to C-4a because
it exhibited correlations with CH -4 and CH -3; the signal at 142-198 ppm, to C-5 because of a single correlation with the
2
2
CH -4 protons. Table 2 gives the characteristic correlations for 2-5.
2
Thus, the heteronuclear correlations of 2-5 confirmed that their C skeletons were the same. Additional confirmation
that the annellated cyclohexane ring was angular was the observation of a strong Overhauser effect for CH -1 and CH -11
2
2
methylene protons with saturation of the H-12 signal. This was consistent with these protons being close to each other. This
effect was observed for all studied compounds.
13
The C NMRspectra ofthe synthesized compounds showedthat thepositionsofmost signalswerelargelyindependent
of the type of C-5 substituent. Thus, the chemical shifts of the C atoms in the 2,2-dimethyldihydropyran and benzene rings
changed by less than 2-3 ppm.
In contrast with this, chemical shifts of C atoms in the pyran-2-one ring changed greatly. An extremely interesting
13
feature of the C spectra was the strong dependence of the C-12b chemical shift on the type of C-5 substituent. Thus, whereas
the C-12b chemical shift in starting 2 was 147.5 ppm, it was 132.3 and 129.9 ppm on substitution of the O atom on C-5 by N
in the oxime and hydrazone, respectively. This indicated that the double bond in the pyran-2-one ring was conjugated to the
exocyclic double bond of C-5 and was practicallynonconjugated to the aromatic benzene ring. The location of the C-12b signal
at anomalouslyweakfield mayindicate a significant contribution from a bipolar structurewith localization ofthepositivecharge
on C-12b and the negative charge on the C-5 heteroatom.
EXPERIMENTAL
The course of reactions and purity of products were monitored byTLC on Merck 60 F254 plates using CHCl :CH OH
3
3
13
(9:1) eluent. Melting points were determined on a Kofler block. PMR and C NMR spectra were recorded on a Varian
Mercury-400 spectrometer at working frequency 400 MHz and 100 MHz, respectively, relative to TMS (internal standard).
NOE experiments were performed using the 1D NOESY method with 500 ms mixing time. HMQC spectra were obtained for
128 increments and 32 scans per increment with a spectral range of 4 kHz for protons and 21 kHz for C. The mixing time
corresponded to J = 140 Hz. HMBC spectra were for 400 increments and 32 scans per increment with a spectral range of
13
1
CH
13
2-3
4 kHz for protons and 21 kHz for C. The mixing time corresponded to
J
= 8 Hz. Elemental analyses of all compounds
CH
agreed with those calculated.
The synthesis of 2,2-dimethylchroman (1) has been published [4].
9,9-Dimethyl-1,2,3,4-10,11-hexahydrobenzo[c]pyrano[3,2-g]chromen-5-one (2). Asolution of1(3.56g, 20 mmol)
and ethyl-2-oxocyclohexanecarboxylate (3.2 mL, 20 mmol) in ethanol (10 mL) was stirred vigorously, treated dropwise with
conc. H SO (20 mL), left overnight at room temperature, and poured into icewater (250 mL). The resulting precipitate was
2
4
filtered off and crystallized from propan-2-ol. Yield 4.21 g (74%), mp 145-146°C, C H O .
18 20
3
654

PMR spectrum (400 MHz, CDCl , δ, ppm, J/Hz): 1.35 (6H, s, two CH -9), 1.80 (4H, m, CH -2, CH -3), 1.84 (2H, t,
3
2
2
3
J = 7.2, CH -10), 2.52 (2H, m, CH -4), 2.71 (2H, m, CH -1), 2.83 (2H, t, J = 7.2, CH -11), 6.68 (1H, s, H-7), 7.22 (1H, s, H-12).
2
2
2
2
9,9-Dimethyl-1,2,3,4,10,11-hexahydrobenzo[c]pyrano[3,2-g]chromen-5-thione (3). A mixture of 2 (2.84 g,
10 mmol) and Lawesson reagent (1.23 g, 5.5 mmol) in absolute toluene (20 mL) was boiled for 2 h (course of reaction
monitored byTLC). After the reaction was finished the solvent was evaporated. The oilyproduct was crystallized from aqueous
propan-2-ol. Yield 2.58 g (86%), mp 149-150°C, C H O S.
18 20
2
PMR spectrum (400 MHz, CDCl , δ, ppm, J/Hz): 1.37 (6H, s, two CH -9), 1.80 (4H, m, CH -2, CH -3), 1.86 (2H, t,
3
2
2
3
J = 7.2, CH -10), 2.75 (4H, m, CH -1, CH -4), 2.85 (2H, t, J = 7.2, CH -11), 6.83 (1H, s, H-7), 7.33 (1H, s, H-12).
2
2
2
2
9,9-Dimethyl-1,2,3,4,10,11-hexahydrobenzo[c]pyrano[3,2-g]chromen-5-one Oxime (4). A solution of 3 (0.90 g,
3 mmol) in absolute pyridine (5 mL) was treated with hydroxylamine hydrochloride (0.63 g, 9 mmol). The mixture was held
at 100°C for 6 h (course of reaction monitored by TLC). After the reaction was finished the mixture was cooled to room
temperature and poured intoacetic acid (100 mL, 5%). The resulting precipitate was filtered and crystallized from propan-2-ol.
Yield 0.60 g (67%), mp 222-223°C, C H NO .
18 21
3
PMR spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 1.28 (6H, s, two CH -9), 1.65 (2H, m, CH -3), 1.70 (2H, m,
3
2
6
CH -2), 1.76 (2H, t, J = 7.2, CH -10), 2.22 (2H, m, CH -4), 2.50 (2H, m, CH -1), 2.71 (2H, t, J = 7.2, CH -11), 6.41 (1H, s,
2
2
2
2
2
H-7), 7.12 (1H, s, H-12), 10.05 (1H, s, N–OH).
9,9-Dimethyl-1,2,3,4,10,11-hexahydrobenzo[c]pyrano[3,2-g]chromen-5-one Hydrazone (5). A solution of 3
(0.90 g, 3 mmol) in ethanol (10 mL) was treated with hydrazone hydrate (0.6 mL, 12 mmol). The mixture was boiled for 1 h
(course of reaction monitored by TLC). After the reaction was finished the mixture was cooled to room temperature. The
resulting precipitate was filtered and crystallized from propan-2-ol. Yield 0.65 g (73%), mp 156-157°C, C H N O .
18 22
2 2
PMR spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 1.27 (6H, s, two CH -9), 1.61 (2H, m, CH -3), 1.68 (2H, m,
6
3
2
CH -2), 1.75 (2H, t, J = 7.2, CH -10), 2.20 (2H, m, CH -4), 2.41 (2H, m, CH -1), 2.69 (2H, t, J = 7.2, CH -11), 5.70 (2H, br.s,
2
2
2
2
2
NH ), 6.44 (1H, s, H-7), 7.02 (1H, s, H-12).
2
REFERENCES
1.
2.
3.
4.
R. D. H. Murray, The Naturally Occurring Coumarins, Springer, Vienna and New York (2002).
Ya. L. Garazd, M. M. Garazd, and V. P. Khilya, Khim. Prir. Soedin., 313 (2005).
S. Scheibye, J. Kristensen, and S.-O. Lawesson, Tetrahedron, 35, 1339 (1979).
Ya. L. Garazd, M. M. Garazd, and V. P. Khilya, Khim. Prir. Soedin., 352 (2004).
655