Synthesis of novel condensed binuclear heterocycles based on 1,3- and 1,5-dicarbonyl derivatives of 2,2-dimethyltetrahydropyran

Article abstract of DOI:10.1023/B:COHC.0000023770.12021.66

Treatment of 1,5- and 1,3-dicarbonyl derivatives of 2,2- dimethyltetrahydropyran with a series of binucleophiles gave condensed pyranopyrazole, pyranothiopyrimidine, pyranoisoxazole, and pyranopyridine systems.

Full text of DOI:10.1023/B:COHC.0000023770.12021.66

Chemistry of Heterocyclic Compounds, Vol. 40, No. 1, 2004
SYNTHESIS OF NOVEL CONDENSED
BINUCLEAR HETEROCYCLES BASED ON
1,3- AND 1,5-DICARBONYL DERIVATIVES
OF 2,2-DIMETHYLTETRAHYDROPYRAN
N. V. Zyk1, S. Z. Vatsadze1, M. L. Kostochka1, V. P. Lezina2, and V. G. Vinokurov2
Treatment of 1,5- and 1,3-dicarbonyl derivatives of 2,2-dimethyltetrahydropyran with a series of
binucleophiles gave condensed pyranopyrazole, pyranothiopyrimidine, pyranoisoxazole, and
pyranopyridine systems.
Keywords: 5-acyl-2,2-dimethyltetrahydropyran-4-ones, 2,2-dimethyltetrahydropyran-4-one, pyrano-
isoxazoles, pyranopyrimidines
A number of natural antibiotics with a broad range of activity contain the perhydropyran nucleus, e.g.
streptomycin, kanamycin, and neomycin. The synthetic medicinal substances in the pyran series used in
contemporary medicine are fundamentally benzopyran derivatives. The most important of these is Vitamin E, or
more specifically the group of substances called tocopherols e.g. α-tocopherol, the basis of which constitutes
tocol [1]. With the aim of studying the biological activity of novel pyran derivatives we have been interested in
the possible synthesis of binuclear heterocycles which are condensed at the positions 3 and 4 of the pyran ring.
One possible route for preparing similar structures is the acylation of pyran-4-ones followed by
cyclization with cyanoacetamide to give 3-oxopyrano[3,4-c]pyridine [2]. 2,2-Dimethyltetrahydropyranopyrrole
[3], pyrano[3',4':5,6]pyrido[2,3-d]pyrimidine [4], and pyranoisoxazolidine [5] systems are known. Since the
search for novel, potentially biologically active compounds is a promising goal, the object of this work was the
synthesis of novel, condensed heterocycles based on 1,3- and 1,5-dicarbonyl derivatives of 2,2-dimethylpyran.
In order to prepare the β-diketones we chose the method of acylation of 2,2-dimethyltetrahydropyran-4-
one enamines [1]. The reaction of compound 1 with morpholine gave a mixture of the isomeric enamines 2
and 3.
It had been previously been reported [2] that the result of this reaction was just the single product 2.
1
Detailed analysis of the H NMR spectra of the reaction product showed the presence of the two isomeric
enamines 2 and 3. Evidence for the presence of compound 3 came from two additional triplet signals at 2.5 and
3.80 ppm. The enamines 2 and 3 are formed in the ratio 1:1 but they could not be separated chromatographically
and were used in the subsequent syntheses as the isomeric mixture.
__________________________________________________________________________________________
1
M. V. Lomonosov State University, Moscow 119992, Russia; e-mail: szv@org.chem.msu.ru.
2
Institute of Pharmacology, Russian Academy of Medicinal Science, Moscow 125315; e-mail:
m_kostochka@mail.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 77-81, January,
2004. Original article submitted January 24, 2002.
70
0009-3122/04/4001-0070©2004 Plenum Publishing Corporation

O
N
O
N
O
O
+
+
N
H
O
1
O
O
2
3
The reaction of compounds 2 and 3 with acid chlorides under Stork conditions gave the 1,3-dicarbonyl
compounds 4-7 in 33-56% yields.
O
O
O
O
R
R
+
2, 3
RCOCl
+
NEt3
O
O
4–7
4 R = Me; 5 R = Ph; 6 R = 4-FC6H4; 7 R = 3,4-(MeO)2C6H3
TLC and GLC data for the products 4-7 point to the presence of two compounds in each case but they
were very difficult to separate using preparative GLC. The compounds have very similar retention times on the
column at boiling point. We consider that, as in the case of enamines 2 and 3, the diketones 4-7 exist as a
mixture of two isomers, these also being in the ratio 1:1 according to GLC data. For this reason, a detailed
1
interpretation of the H NMR spectra did not prove possible (it should be noted that each of the isomeric
diketones exists as a mixture of the keto and enol form). The IR spectra of the compounds 4-7 show aromatic
C=C absorption bands at 1580-1630 cm-1 and enol form carbonyl groups at 1640-1670 and 1710-1740 cm-1.
Compound 4 exists almost wholly in the enol form as shown by the presence of a clearly defined C=C
absorption band at 1630 cm-1 and OH at 3300-3500 cm-1 and by the absence of the characteristic absorption
frequency for one of the carbonyl groups. Chromatographic mass spectroscopic analysis of compounds 5 and 6
confirms their composition: for 5 m/z 51, 77, 105, 147, 232 [M]+., for 6 m/z 51, 75, 123, 249, 250 [M]+..
The β-dicarbonyl compounds obtained 4-7 (as the mixture of isomers) underwent heterocyclization with
such binucleophiles as hydrazine hydrate, hydroxylamine hydrochloride, and thiourea. Specific reaction
conditions were chosen for each of the reactions carried out. As a result, we prepared compounds 8, 9.
The 1H NMR spectra of the compounds 8 and 9 show signals for the phenyl substituent and two methyl
groups. The 1H NMR spectrum of compound 8 shows two singlets for the methylene groups in the pyran ring at
2.90 and 4.90 ppm and a signal for the NH group at 7.35 ppm. In the 1H NMR spectrum of compound 9 the two
singlets are observed for the methylenes of the pyran ring at 2.75 and 4.90 ppm.
O
O
O
HN
N
N
Ph
.
Ph
NH2NH2 H2O
.
NH2OH HCl
R
MeCOOH
EtOH
O
O
O
5
9
8
The spectra of the compounds 8,9 show only one of the isomers hence it can be deduced that only the
diketone with less steric hindrance takes part in the reaction.
In the reactions of the diketones 4 with all of the bis nucleophiles used, the products could not be
separated.
71

TABLE 1. Physicochemical Parameters for Compounds 4-7
Found, %
Calculated, %
——————
Com-
pound
Empirical
formula
bp, °С
(mm Hg)
IR spectrum,
Yield, %
37
ν, cm-1
С
H
C9H14O3
63.34
63.52
8.50
8.29
80-115
(11)
1720 (C=O);
1630 (C=C);
4
3300-3500 (OH)
1710, 1680 (C=O);
3300-3510 (OH)
1740, 1640 (C=O);
3300-3500 (OH)
1710, 1670 (C=O);
3400-3510 (OH)
C14H16O3
C14H15FO3
C16H20O5
72.62
72.39
6.70
6.94
138-142 (2)
135-142 (1.7)
175-180 (2)
56
39
5
6*
7
65.41
65.74
7.00
6.90
32.5
_______
* Found: F 7.35%; calculated: F 7.59%.
The reaction of the diketones 7 with hydrazine hydrate in the presence of a catalytic amount of sulfuric
acid gave 3,4-dimethoxybenzoic acid.
The previously known 1,5-dicarbonyl compound 10 [6] has been prepared by the reaction of
benzalacetophenone with 2,2-dimethyltetrahydropyran-4-one as a single isomer. We have found that the
diketone 10 reacts with hydroxylamine hydrochloride in glacial acetic acid and cyclises to the previously
unreported 7,7-dimethyl-2,4-diphenyl-5,8-dihydropyrano[4,3-b]pyridine 11. The anticipated result was not
obtained when carrying out the reaction in alcohol.
1
The H NMR spectrum of the product 11 did not disagree with the proposed structure and the
composition was shown by elemental analysis (see Experimental).
Ph
N
O
O
O
Ph
O
O
.
Ph
KOH, EtOH
Ph
Ph
Ph
NH2OH HCl
1
MeCOOH
10
11
EXPERIMENTAL
Monitoring of the course of the reaction and the purity of the reaction products was carried out using
TLC on Silufol UV-254 plates and by GLC on a Tsvet-152 chromatograph (0.7 m × 3 mm column, liquid phase
SE30/5% on Chromaton-N-AW 0.16-0.20 mm, nitrogen carrier, temperature program 75-300° / 22°C/min).
IR spectra were recorded on a Perkin-Elmer instrument using KBr. Mass spectra were obtained on an HP-5972
1
instrument with an electron ionization energy of 70 eV. H NMR spectra were recorded on a Bruker A-250
(250 MHz) instrument with TMS internal standard. Melting points for the materials were determined on a
Koffler block Boetius apparatus in an open capillary and are uncorrected.
2,2-Dimethyl-4-morpholinodihydropyrans (2, 3). Morpholine (15.26 g, 175.5 mmol) in benzene
(10 ml) was added dropwise to a solution of 2,2-dimethyltetrahydropyran-4-one 1 (15 g, 117 mmol) in benzene
(50 ml) and refluxed in a Dean–Stark apparatus until the calculated amount of water had been produced. The
solvent was distilled off and the residue was distilled in vacuo to give a mixture of compounds 2 and 3
72

(12.15 g); bp 109-112°C (4 mm Hg). Yield 52%. 1H NMR spectrum, δ, ppm: isomer 2: 2.8 (4H, m, CH2–N); 3.7
(4H, t, CH2–O); 1.3 (6H, s, 2CH3); 2.0 (2H, s, 3-H); 4.6 (1H, t, 5-H); 4.2 (2H, m, 6-H); isomer 3: 2.8 (4H, m,
CH2–N); 3.7 (4H, t, CH2–O); 1.3 (6H, s, 2CH3); 2.0 (2H, t, 5-H); 3.8-3.9 (2H, t, 6-H); 4.5 (1H, s, 3-H).
5-Acyl-2,2-dimethyltetrahydropyran-4-ones (5-7) (General Method). The corresponding acid
chloride (54 mmol) in dry benzene (10 ml) was added dropwise with stirring to a solution of the mixture of
enamines 2 and 3 (8.88 g, 45 mmol) and triethylamine (5.45 g, 54 mmol) in dry benzene (60 ml) with the
reaction held at room temperature. The reaction mixture was stirred for a further 2 h, heated to reflux for 30 min,
HCl (18%, 22 ml) added, and heated for a further 1 h. After cooling, the aqueous layer was separated and the
benzene was washed with water to neutral reaction. The aqueous solution was basified with potassium carbonate
to pH ~7 and extracted three times with benzene. The combined benzene fractions were dried over CaCl2,
benzene was distilled off, and the residue was distilled twice in vacuo monitoring the purity of the product by
GLC analysis.
5-Acetyl-2,2-dimethyltetrahydropyran-4-one (4) was prepared similarly but after the addition of
acetyl chloride the mixture was not heated but immediately hydrolyzed with HCl (18%, 22 ml) and then worked
up as described above.
The physicochemical and spectrosopic properties of the compounds 4-7 are given in Table 1.
6,6-Dimethyl-3-phenyl-4,7-dihydro-(2H)-pyrano[4,3-c]pyrazole (8). A mixture of the diketones 5
(0.5 g, 2.1 mmol) and hydrazine hydrate (0.105 g, 2.1 mmol) in alcohol (6.2 ml) was refluxed for 4 h. The
alcohol was evaporated off and the residue was recrystallized from i-PrOH to give compound 8 (300 mg) with
mp 172-175°C. Yield 65.7%. 1H NMR spectrum (CDCl3), δ, ppm: 1.3 (6H, s, 2CH3); 2.9 (2H, s, 7-H); 4.9 (2H,
s, 4-H); 7.3 (1H, s, NH); 7.5-7.9 (5H, m, Ph). Found, %: C 73.31; H 7.25; H 12.35. C14H16N2O. Calculated, %:
C 73.66; H 7.06; N 12.27
6,6-Dimethyl-3-phenyl-4,7-dihydro-(2H)-pyrano[4,3-c]isoxazole (9). A mixture of the diketones 5
(0.5 g, 2.1 mmol), hydroxylamine hydrochloride (0.21 g, 3.1 mmol), and glacial acetic acid (5 ml) was refluxed
for 5 h, poured into water, and taken to neutral reaction. The obtained solution was extracted with benzene,
solvent was distilled off, and the residue was recrystallized from alcohol to give compound 9 (120 mg);
1
mp 95-97°C. Yield 26%. H NMR spectrum (CDCl3), δ, ppm: 1.4 (6H, s, 2CH3); 2.8 (2H, s, 7-H); 4.9 (2H, s,
4-H); 7.4-7.7 (5H, m, Ph). Found, %: C 72.95; H 6.73; N 6.23. C14H15NO2. Calculated, %: C 73.34; H 6.59;
N 6.11.
7,7-Dimethyl-2,4-diphenyl-5,8-dihydropyrano[4,3-b]pyridine (11). A mixture of the 1,5-diketone 10
(1 g, 3 mmol) (obtained according to [6]) and hydroxylamine hydrochloride (0.479 g, 6 mmol) in glacial acetic
acid (10 ml) and alcohol (2 ml) was refluxed for 7 h. The reaction mixture was poured into water, basified to
pH ~8-9, and extracted twice with benzene. The benzene was distilled off and the residue was recrystallized
from i-PrOH. Standing the mother liquor for one week at -5°C gave compound 11 (0.38 g); mp 84-85°C.
1
Yield 40%. H NMR spectrum (CDCl3), δ, ppm: 1.4 (6H, s, 2CH3); 3.0 (2H, s, 8-H); 4.7 (2H, s, 5-H); 7.2-7.9
(11H, m, Ar and Py). Found, %: C 83.90; H 6.76; N 4.21. C22H21NO. Calculated, %: C 83.78; H 6.71; N 4.44.
This work was carried out with the financial support of the Russian fund for basic research (project
No. 99-03-33094a).
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73

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74