A new reaction of the phenylhydrazones of 1,5-diketones. Synthesis of dihydropyran derivatives

Article abstract of DOI:10.1007/s10593-006-0041-2

It was shown that the monophenylhydrazones of 1,5-diketones are converted by reduction with borohydride followed by treatment of the obtained hydrazino alcohols with acidic agents into derivatives of dihydropyran with the elimination of phenylhydrazine as

Full text of DOI:10.1007/s10593-006-0041-2

Chemistry of Heterocyclic Compounds, Vol. 42, No. 1, 2006
A NEW REACTION OF THE PHENYLHYDRAZONES
OF 1,5-DIKETONES. SYNTHESIS OF
DIHYDROPYRAN DERIVATIVES
T. V. Moskovkina
It was shown that the monophenylhydrazones of 1,5-diketones are converted by reduction with
borohydride followed by treatment of the obtained hydrazino alcohols with acidic agents into derivatives
of dihydropyran with the elimination of phenylhydrazine as the respective salt. γ,δ-Unsaturated ketones
were isolated as side products of this reaction. The ways in which these compounds are formed are
discussed.
Keywords: dihydropyrans, 1,5-diketones, monophenylhydrazones, unsaturated ketones, borohydride
reduction, cyclization.
1,5-Diketones and their derivatives are readily obtainable synthons for the synthesis of various
heterocyclic systems. For example, pyridocarbazoles [1], indoloacridines [2], cinnolines [3], and indole
derivatives [4] were obtained from the phenylhydrazones of 1,5-diketones, while a homolog of vibrindole (an
antibiotic of the diindolylmethane series) was synthesized from the bisphenylhydrazone of heptane-2,6-dione
[5].
In the present work it was shown that the monophenylhydrazones 2a-d, obtained from the 1,5-diketones
1a-d, are transformed into derivatives of dihydropyran 4a-d during borohydride reduction followed by treatment
of the reaction mixtures with acidic agents.
R3
R3
R3
R3
R2
R1
R2
R1
R2
R1
R2
R1
3
PhNHNH2
NaBH4
p-TsOH
1
H
Ph
O
Ph
Ph
O O
Ph
NHPh
3a–d
O N
OH
R3
N
1a–d
NHPh
4a–d
R2
R1
2a–d
Ph
O
a R1 = R3 = Ph, R2 = H; b R1 = Ph, R2 = H, R3 = Me;
5a–d
5
4a
5
10b
10a
O
4a
7
c R1 + R2 =
R3 = Ph
,
R3 = Ph; d R1 + R2 =
,
8
8a
10
__________________________________________________________________________________________
Far-East State University, Institute of Chemistry and Applied Ecology, Vladivostok, Russia; e-mail:
innast@imb.dvo.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 26-31, January, 2006.
Original article submitted April 26, 2004.
22
0009-3122/06/4201-0022©2006 Springer Science+Business Media, Inc.

The monophenylhydrazones 2a-d were obtained during the reaction with phenylhydrazine in alcohol
with boiling in the presence of sodium acetate. Compounds 2a-c had been known before [3, 4], while the
hydrazone 2d was obtained for the first time.
The production of the dihydropyrans 4a-d from the phenylhydrazones 2a-d can be realized in one or two
stages, i.e., with or without isolation of the intermediate hydrazono alcohols 3a-d. The latter are produced with
good yields after borohydride reduction of the hydrazones 2a-d in ethyl or isopropyl alcohols and give the
derivatives 4a-d and phenylhydrazine as the salt of the respective acid when treated with p-toluenesulfonic acid
or with absolute alcohol saturated with hydrogen chloride. The yields of the target compounds 4a-d amount to
30-50%.
Their formation can be represented as resulting from cyclization of the hydrazino alcohols followed by
the elimination of phenylhydrazine (path A). We consider path B through hydrolysis of the hydrazone fragment,
subsequent cyclization of the ketols 7a-d, and dehydration of the hydroxytetrahydropyrans 8a-d to be less likely.
In actual fact, the hydrazone groups of the initial compounds 2a-d were not hydrolyzed during the above-
mentioned treatment with acid, as was established by TLC. It can be assumed that such hydrolysis also does not
occur in the hydrazono alcohols 3a-d.
R3
R2
–NH2NHPh
4a–d
R1
O
Ph
A
NHNHPh
6a–d
3a–d
R3
R3
H
B
R2
R1
R2
R1
–H2O
Ph
4a–d
O
OH
Ph
O
OH
7a–d
8a–d
The properties and spectral data of the obtained compounds are given in Table 1. It should be noted that
the IR spectrum of the hydrazone 2c contains an absorption band at 1700 cm-1, confirming that the hydrazone ia
formed at a carbonyl of the phenacyl type. Accordingly, in the IR spectra of the hydrazones 2c,b,d the bands of
the C=O stretching vibrations are at 1670-1678 cm-1. For the hydrazone 2d the choice in favor of the presented
structure was made on the basis of its mass spectrum. In the electron-impact mass spectrum of the previously
unknown hydrazone 2d there is not only a molecular ion peak at 444* but there is also a peak for a fragment ion
at 298, corresponding to removal of the side chain with cleavage of the C–C bond at the β position to the
carbonyl group of the tetralone fragment of the molecule.
The hydrazono alcohols 3a-d do not have bands for the stretching vibrations of the carbonyl group in the
IR spectra, but there are bands for the hydroxyl group at 3580-3600 and also bands for the N–H bonds at 3296-
3340 and the C=N bonds at 1602 cm-1.
In addition to the data from the NMR spectra, given in Table 1, the structure of the dihydropyrans 4a-d
is also confirmed by the data from the IR, mass, and UV spectra. Thus, their IR spectra do not contain bands for
the stretching vibrations of the C=O and O–H groups, but there are bands for the C=C bond at 1645-1652 cm-1.
_______
* Here and subsequently the m/z values for the ion peaks are given.
23

In the UV spectra (isopropyl alcohol–water) absorption maxima are observed at 270 nm. In the mass spectra of
compounds 4a,b,d there are molecular ion peaks at 312, 250, and 338, while in the chemical ionization mass
spectrum of compound 4c there is a peak for the [M+H]+ ion at 321.
1
Features of the H NMR spectra of compounds 4a,b make it possible to put forward certain ideas about
the stereochemistry of these compounds. Thus, in the spectra of 4a,b the signals for the H-6 protons are observed
in the form of a doublet of doublets at 5.06 ppm. The presence of spin–spin coupling constants of the axial–axial
type (J = 10 Hz) demonstrates that this proton has the axial orientation. The vinyl proton H-3 gives a doublet of
doublets at 5.59 and 5.42 ppm (J1 = 4.6 and J2 = 1.2 Hz in the spectrum of compound 4a, and J1 = 4.4 and
J2 = 1.0 Hz in the spectrum of 4b respectively). The small constant probably results from so-called W interaction
with one of the protons at position 5. Stereochemically these compounds then correspond to the formula 9.
R2
H
H
R3
O
H
R1
H
H
9
The unsaturated ketones 5a,d were isolated in this reaction as side products. The structure of the ketones
5a,d was demonstrated by data from the NMR, IR, and mass spectra. For compound 5d it was also proved by 2D
1
1
NMR spectroscopy, i.e., by H, H-COSY, and HMQC experiments, which made it possible to identify all the
spin systems (Table 1). Their mass spectra have molecular ion peaks at the same m/z values as in the spectra of
the corresponding dihydropyrans 4a,d.
These compounds are presumably formed from the corresponding dihydropyrans according to the
scheme given below. This was confirmed by an experiment on the transformation 4a → 5a during treatment with
absolute alcohol saturated with HCl.
R3
H
R2
+
+
H
–
H
+
4a,d
5a,d
R1
O
H
Ph
H
+
The main method for the production of dihydropyran derivatives is diene synthesis from α,β-unsaturated
ketones and various compounds containing a double bond [6-9]. It was also possible to convert certain
compounds containing carbonyl groups at positions 1 and 5 into such derivatives. Thus, the synthesis of
dihydropyrans from ε-keto acids by the action of acetic anhydride is well known [10]. Oxopropylpyrazolones
undergo cyclization during ionic hydrogenation with triethylsilane and trifluoroacetic acid in the presence of
catalytic amounts of boron trifluoride etherate with the formation of substituted 5,6-dihydropyrano[3,2-d]-
pyrazoles [11]. Although the synthesis of dihydropyrans from the 1,5-diketones themselves has not been
described, various triketones of the oxo-1,5-diketone type were converted by ionic or catalytic hydrogenation
over Raney nickel or by borohydride reduction into dihydropyran derivatives containing a keto group conjugated
with the double bond of the dihydropyran ring [11]. At the same time during catalytic hydrogenation over Raney
nickel at 150°C in acetic acid 2-(3-oxo-1,3-diphenylpropyl)tetral-1-one (1d) undergoes reduction of the carbonyl
groups and heterocyclization, leading to the corresponding tetrahydropyran [11].
24

TABLE 1. The Properties of Dihydropyrans 4a-d and Unsaturated Ketones 5a,d
Found, %
Calculated, %
Mass
spectrum,
m/z
——————
Com-
pound
Empirical
formula
mp, °C
Yield, %
C
H
4а
4b
4c
4d
5а
5d
C23H20O
88.56
88.46
86.62
86.40
86.00
86.25
88.54
88.75
88.42
88.46
88.68
88.75
6.27
6.41
7.10
7.20
6.10
6.25
6.28
6.50
6.30
6.41
6.60
6.50
120
100-101
88-90
63-64
78
312 [М]+
250 [М]+
320 [М]+
338 [М]+
312 [М]+
339 [М+H]
66
30
40
50
30
24
C18H18O
C23H20O
C25H22O
C23H20O
C25H22O
64
TABLE 2. The Spectra of Dihydropyrans 4a-d and Unsaturated Ketones
5a,d
IR spectrum,
Com-
pound
1Н NMR spectrum, δ, ppm (J, Hz)
ν, cm-1
4а
4b
4c
4d
1652 (С=С)
1650 (С=С)
1650 (С=С)
1656 (С=С)
5.59 (1H, dd, J1 = 4.6, J2 = 1.2, H-3); 5.06 (1H, dd, J1 = 10.0,
J2 = 2.7, H-6); 3.67 (1H, m, H-4); 2.38 (1H, ddd, J1 = 6.3,
J2 = 10.0, J3 = 13.7, Ha-5); 2.18 (1H,ddt, J1 = 13.7, J2 = 2.7,
J3 = 1.2, He-5)
5.42 (1H, d, J1 = 1.0, J2 = 4.4, H-3); 5.05 (1H, dd, J1 = 2.7,
J2 = 9.5, H-6); 2.42 (1H, ddd, J1 = 3.2, J2 = 6.7, J3 = 13.4, H-4);
2.10 (1H, ddd, J1 = 6.1, J2 = 9.5, J3 = 13.7, Ha-5); 1.83 (1H,
ddt, J1 = 1.2, J2 = 3.7, J3 = 13.7, He-5); 1.17 (3Н, d, J1 = 4.9, СН3)
5.38 (1H, d, J = 3.6, H-3); 4.51 (1H, m, H-8a); 3.71 (2H, m, H-5);
3.53 (1H, dd, J1 = 3.6, J2 = 6.1, H-4); 1.98 (1H, m, H-4а);
1.66 (1H, dd, J1 = 4.1, J2 = 13.7, He-8); 2.05 (1H, dd, J1 = 8.0,
J2 = 13.7, Ha-8); 1.26 ( 3H, s, CH3); 1.38 (3H, s, CH3)
5.47 (1H, d, J = 2.8, H-3); 4.95 (1H, d, J = 2.8, H-10b);
3.45 (1H, dd, J1 = 2.8, J2 = 6.0, H-4); 1.88 (1H, m, H-4a);
3.0 (2H, m, H-6); 2.7 (2H, m, H-5)
5а
1648 (С=С),
1681(СО)
3.51 (2Н, АВ part of АВХ system J1 = 7.0, J2 = 2.2, J3 = 16.7, 2Н-2);
4.31 (1H, m, Н-3); 6.41 (1H, m, Н-4)
5d
1652 (С=С),
1678 (СO)
3.46 (1H, dd, J1 = 7.3, J2 = 16.6, Н-2); 3.64 (1Н, dd, J1 = 7.2,
J2 = 16.6, Н-2); 4.24 (1H, t, J = 7.5, Н-3); 6.35 (1H, br. d,
J = 1.4, Н-5); 2.17 (2H, m, 2Н-6); 2.72 (2H, m, 2Н-7)
The transformation of the monophenylhydrazones of 1,5-dicarbonyl compounds into dihydropyran
derivatives was previously unknown. Thus, we have discovered a new direction for the transformations of these
readily obtainable compounds.
EXPERIMENTAL
1
The H NMR spectra were recorded in deuterochloroform on a Bruker WM-250 instrument (250 MHz)
with TMS as internal standard. The IR spectra were recorded on a Spectrum BX-2 FT-IR System spectrometer
(Perkin-Elmer). The mass spectra were obtained on an LKB 9000S instrument with direct injection into the ion
25

source at ionization potential 70 eV. HPLC-MS was conducted on an Agilent 1100 Series LC/MSD chromato-
mass spectrometer (Hewlett Packard, USA) with an LiChrCART CN column (4 × 250 mm, sorbent grain size
5 µ) with thermostat temperature 40°C and linear gradient elution (30-70% aqueous acetonitrile) at 2 deg/min.
The elution rate was 0.5 ml/min, detection was by the electron absorption spectra (200-300 nm), electrospray
ionization at atmospheric pressure, positive ion recording, ionizer potential 70 eV, potential in ionization
chamber 4 kV, drying gas (nitrogen) rate 6 l/min, spray gas (nitrogen) pressure 50 kg/cm2. The range of recorded
masses was m/z 150-700.
The melting points of the isolated compounds were determined on a Boetius bench. Silica gel L
(Chemapol, former Czechoslovakia) or aluminum oxide was used for column chromatography. The reactions
were monitored and the reaction mixtures were separated by TLC on Sorbfil plates with development in UV
light or with iodine vapor.
Monophenylhydrazones of 1,5-Diketones 2a-d. These compounds were obtained as described in [4].
Compounds 2a-c were previously known [3, 4]. The yield of the monophenylhydrazone 2d was 90%; mp 131°C
(alcohol). Found %: C 84.00; H 6.25; N 6.47. C31H28N2O. Calculated %: C 83.78; H 6.30; N 6.30. IR spectrum
(potassium bromide), ν, cm-1: 1605 (C=N), 1671 (C=O), 3260 (N–H). Mass spectrum (electron impact),
m/z (Irel, %): 444 [M]+ (20); 335 (7); 298 (70); 99 (90); 57 (100).
Reduction of Monophenylhydrazones 2a-d Followed by Heterocyclization. A. To a solution of the
hydrazone 2a-d (1 mmol) in isopropyl alcohol (20 ml) we added NaBH4 (0.152 g, 4 mmol), and we boiled the
mixture for 2 h. The solvent was removed by heating on a water bath, and water (30 ml) and ether (30 ml) were
added to the residue. The ether layer was separated, washed to a neutral reaction with water, dried with
magnesium sulfate, and evaporated. The residue was boiled with a 0.6% solution of p-toluenesulfonic acid in
absolute benzene (10 ml) with a Dean–Stark trap. The solvent was distilled from the reaction mixture, and the
residue was treated with water (20 ml) and ether (20 ml). The ether layer was separated, washed to a neutral
reaction with water, dried with magnesium sulfate, and evaporated. The residue was chromatographed on a
column of aluminum oxide in the 1:50 ethyl acetate–petroleum ether system. 2,4,6-Triphenyl-5,6-dihydropyran
(4a), 4-methyl-2,6-diphenyl-5,6-dihydropyran (4b), 7,7-dimethyl-2,4-diphenyl-4a,7,8,8a-tetrahydro-4H,5H-
pyrano[4,3-b]pyran (4c), 2,4-diphenyl-4a,5,6,10b-tetrahydro-4H-benzo[h]chromene (4d), and (as side products)
the unsaturated ketones 1-oxo-1,3,5-triphenyl-4-pentene (5a) and 1-(1,2-dihydro-3-naphthyl)-1,3-diphenyl-3-
propanone (5d) were obtained (Tables 1 and 2).
B. The reduction was conducted as described above. The hydrazono alcohols 3c,d were crystallized from
alcohol, while the hydrazono alcohols 3a,b were purified by flash column chromatography on aluminum oxide
with gradient elution with ethyl acetate and petroleum ether (1:50 → 1:1) as solvents. The yield of compound 3a
was 88% in the form of an oil. IR spectrum (potassium bromide), ν, cm-1: 1602 (C=N), 3592 (OH), 3300 (NH).
The yield of compound 3c was 93%; mp 110-112°C (alcohol). IR spectrum (potassium bromide), ν, cm-1: 1602
(C=N), 3578 (O–H), 3264 (N–H). Mass spectrum (electron impact), m/z (I, %): 429, [M+H]+. The yield of
compound 3d was 73%; mp 176°C (from alcohol). IR spectrum (potassium bromide), ν, cm-1: 1602 (C=N), 3591
(O–H), 3260 (N–H). Mass spectrum (electron impact), m/z (I, %): 446 [M]+, 428 [M+ - H2O], 298, 167.
The obtained hydrazono alcohols were cyclized as described above. The constants and analytical and
spectral data of the products are given in Tables 1 and 2.
Preparation of the Unsaturated Ketone 5a from the Dihydropyran 4a. A solution of the
dihydropyran 4a (30 mg) in absolute ethanol (2 ml) saturated with HCl was heated for 1 h. The ethanol was
distilled under vacuum, and water (5 ml) and ether (5 ml) were added to the residue. The ether layer was washed
with water and dried with magnesium sulfate. The ether was distilled, and the residue was purified by flash
column chromatography on aluminum oxide in the 1:50 ethyl acetate–petroleum ether system. We obtained
19 mg (65%) of the ketone 5a.
26

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