Some chemical conversions of 3,3,5-trichloro-2-hydroxy- tetrahydropyran

Article abstract of DOI:10.1023/A:1023068608351

A series of chemical conversions of 3,3,5-trichloro-2-hydroxytetrahydropyran has been carried proceeding both with ring opening and with its retention. Alkylation, acylation, and sulfonylation of the hydroxyl group of the initial ring have been carried out.

Full text of DOI:10.1023/A:1023068608351

Chemistry of Heterocyclic Compounds, Vol. 39, No. 1, 2003
SOME CHEMICAL CONVERSIONS
OF 3,3,5-TRICHLORO-2-HYDROXY-
TETRAHYDROPYRAN
K. I. Kobrakov1, V. K. Korolev1, and A. V. Ivanov2
A series of chemical conversions of 3,3,5-trichloro-2-hydroxytetrahydropyran has been carried
proceeding both with ring opening and with its retention. Alkylation, acylation, and sulfonylation of the
hydroxyl group of the initial ring have been carried out.
Keywords: 3,3,5-trichloro-2-hydroxytetrahydropyran, hydrazones, alkylation, acylation, sulfonylation.
We reported in [1.2] the synthesis of 3,3,5-trichloro-2-hydroxytetrahydropyran by the interaction of
chloral with allyl alcohol on heating in acetonitrile in the presence of copper(I) chloride or iron pentacarbonyl.
We showed that the reaction is general for various terminal allyl alcohols [3]. In the present work we report
several chemical conversions of 3,3,5-trichloro-2-hydroxytetrahydropyran (1).
According to data of NMR spectroscopy there is no ring–chain tautomerism in freshly distilled
compound 1 [1]. However since 3,3,5-trichloro-2-hydroxytetrahydropyran is a cyclic hemiacetal, opening of the
pyran ring might be expected in acidic medium. In reality on recording the 1H NMR spectrum in the presence of
strong acids (D2SO4, CF3COOD) the signals at 5.15 and 4.71 ppm, belonging to the proton of the hemiacetal
group, are reduced and in the region of 9 ppm a characteristic singlet appears which indicates opening of the
hemiacetal ring leading to 2,2,4-trichloro-5-hydroxypentanal (2).
Cl
Cl
Cl
OH
Cl
Cl
Cl
H
+
H
OH
O
O
2
1
However attempts to isolate aldehyde 2 lead to regeneration of the initial ring.
By reacting hydropyran 1 with arylhydrazines we successfully synthesized a series of hydrazones of
2,2,4-trichloro-5-hydroxypentanal 3a-e (Table 1).
Cl
Cl
Cl
+
ArNHNH2
H
OH
ArHN
N
2
1
H
3a–e
3 a Ar = 2,4-(NO2)2C6H3; b Ar = 3,5-Cl-Py; c Ar = 4-O2NC6H4; d Ar = Ph; e Ar = 4-MeC6H4
__________________________________________________________________________________________
1
Moscow A. N. Kosygin State Textile University, Moscow 117918, Russia; e-mail:
tom@org.chem.msu.su. 2 Institute of Physiologically Active Substances, Russian Academy of Sciences, Khimki
Moscow Region 141400, Russia. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 69-74,
January, 2003. Original article submitted April 5, 2000.
0009-3122/03/3901-0065$25.00©2003 Plenum Publishing Corporation
65

TABLE 1. Physicochemical Characteristics of Compounds 3a-e
Found, %
Calculated, %
H
IR
——————
Com-
pound
Empirical
formula
spectrum,
mp, °С
Yield, %
νC=N, cm-1
C
N
C11H11Cl3N4O5
C9H9Cl5N3O
34.20
34.26
2.91
2.88
14.49
14.53
163-163.7
163-164
1640
1641
1642
1645
1646
93
74
85
73
69
3a
3b
3c
3d
3e
33.01
2.52
11.47
32.95
2.49
11.53
C11H12Cl3N3O3
C11H13Cl3N2O
C12H15Cl3N2O
38.82
38.79
3.51
3.55
12.35
12.34
159-159.5
147.5-148
157-158
44.63
4.46
9.52
44.70
4.43
9.48
46.51
46.55
4.53
4.48
9.10
9.05
Hydrazones obtained were high-melting crystalline solid substances. Absorption bands were observed in
the IR spectra of compounds 3a-e at 1640-1650 cm-1 characteristic of the C=N double bond of hydrazones.
1
Signals were recorded in the H NMR spectra of compounds 3a-e for the protons of linear
arylhydrazones of 2,2.4-trichloro-5-hydroxyvaleraldehyde at 7.15 (1H, s, CH=N), 2.84 (2H, d, CH2), 4.11 (1H,
m, CH), 3.85 (2H, d, CH2OH), and at 7.92-8.86 ppm for the aromatic fragment. In addition a series of additional
signals were observed in the spectra which were close in chemical shifts to the signals of hydropyran 1. Thus
the signals at 4.94 and 4.65 ppm correspond to the signals of the protons at C(2) of compound 1 (4.78 and
4.14 ppm), the signals at 2.36, 2.67, 2.49, and 2.72 ppm correspond to the signals of protons at C(4) (3.66, 2.59,
and 2.64 ppm), the signals at 4.09 and 3.66 ppm may correspond to the signals of protons at C(5) (3.59 and
3.93 ppm), and the signals at 4.43, 4.28, 3.52, and 2.96 ppm may correspond to the signals of protons at C(6)
(3.75, 3.43, 2.68, and 1.91 ppm) of compound 1. Evidently on dissolving the sample in deuterochloroform an
intramolecular attack of the hydroxyl group oxygen onto the imine carbon atom occurs, which leads to the
formation of 2-(N-aryl)hydrazo-3,3,5-trichlorotetrahydropyrans 4a-e.
Cl
Cl
Cl
NHNHAr
3a–e
O
4a–e
We have therefore shown by spectral and chemical methods that in acid solution compound 1 exists in a
hemiacetal cyclic modification and as linear 2,2,4-trichloro-5-hydroxypentanal.
We have carried out alkylation, acylation, and sulfonation of the hydroxyl group of the initial compound 1.
On reaction with sodium hydride in hexane at 0°C hydropyran 1 was converted into alcoholate 5,
subsequent treatment of which with alkyl halides leads to the formation of ethers 6a-c.
Cl
Cl
Cl
OR
Cl
Cl
Cl
ONa
RHal
NaH
–H2
1
–NaHal
O
6a–c
O
5
An even more convenient means of alkylating compound 1 proved to be reaction in a two-phase
benzene–aqueous NaOH system in the presence of the phase-transfer catalyst triethylbenzylammonium chloride
(TEBAC). This reduced the reaction time significantly and increased the yield of the desired compounds.
The dependence of yields of 2-alkoxytetrahydropyrans 6a-c on the reaction conditions and the
alkylating agent used are given in Table 2.
66

TABLE 2. Yields of 2-Alkoxy-3,3,5-trichlorotetrahydropyrans 6a-c
Found, %
——————
Com- Method of
pound synthesis*
Alkylating
agent
Empirical
formula
bp, °С
Calculated, %
Yield, %
(mm Hg)
C
H
А
B
B
А
B
А
B
А
B
А
B
Methyl iodide
Methyl iodide
Dimethyl sulfate
Ethyl bromide
Ethyl bromide
Ethyl iodide
C6H9Cl3O2
32.76
32.83
4.09 112-113 (0.7)
4.13
56
67
74
47
58
56
69
43
58
50
66
6a
6b
C7H11Cl3O2 35.94
36.00
4.80 118-119 (0.8)
4.75
Ethyl iodide
Propyl bromide
Propyl bromide
Propyl bromide
Propyl bromide
C8H13Cl3O2 38.91
38.82
5.33 134-135 (1.0)
5.29
6c
_______
* Method A is alkylation in hexane in the presence of sodium hydride, B is
alkylation in a water–benzene system in the presence of NaOH and a phase-
transfer catalyst.
The acylation of compound 1 with acid chlorides and anhydrides was carried out by dissolving the
reactants in diethyl ether. Acetyl chloride, acetic anhydride, benzoyl chloride, and 4-nitrobenzoyl chloride were
used as acylating agents and compounds 7a-c (Table 3) were obtained.
Cl
Cl
Cl
OCOR
RCOCl
1
O
7a–c
7 a R = Me, b R = Ph, c R = 4-O2NC6H4
TABLE 3. Physicochemical Characteristics of Compounds 7a-c
Found, %
——————
Com-
pound
Acylating
agent
Empirical
formula
bp, °С
Calculated, %
Yield, %
(mm Hg)
C
H
N
Acetyl chloride
Acetic anhydride
Benzoyl chloride
C7H9Cl3O3
33.94
33.97
3.61
3.67
121-123 (4)
74
82
68
72
7а
C12H11Cl3O3
46.58
46.56
3.60
3.58
152 (1)
—*
7b
7c
4-Nitrobenzoyl
chloride
C12H10Cl3NO5
40.61
2.90
4.00
3.95
40.65
2.84
_______
* mp 43-46°C.
67

TABLE 4. Physicochemical Characteristics of Compounds 8a-c
Found, %
——————
Com-
pound
Empirical
formula
Calculated, %
mp, °С
Yield, %
73
C
H
N
C12H13ClO4S
40.03
40.08
3.70
3.64
64-68
8a
C11H10Cl3NO6S
C11H10Cl3NO6S
33.83
2.59
3.55
3.59
47-50
68-70
62
68
8b
8c
33.82
2.58
33.81
33.82
2.56
2.58
3.61
3.59
The sulfonation of hydropyran 1 was carried out by heating in toluene using p-toluenesulfonyl chloride,
and 2- and 4-nitrobenzenesulfonamide as sulfonating agents. Compounds 8a-c were obtained respectively
(Table 4).
EXPERIMENTAL
The GLC analysis was carried out on a Chrom 5 chromatograph with a flame ionization detector, helium
(30 cm3/min) as carrier gas, glass columns 3500 × 3 mm with 5% of XE 60 on Inerton-Super (0.20-0.25 mm),
1
and thermostat temperature of 200°C. The H NMR spectra were recorded on a Bruker WP 200 (200 MHz)
spectrometer in CDCl3, internal standard was TMS.
2,2,4-Trichloro-5-hydroxypentanal 2,4-Dinitrophenylhydrazone (3a). Solution of 2,4-dinitrophenyl-
hydrazine (2 g, 10 mmol) in alcohol was prepared according to the method of [4]. To the freshly prepared
solution solution of hydropyran 1 (0.205 g, 1 mmol) in alcohol (2 ml) was added. The mixture was stirred and
left overnight. The crystals which precipitated were filtered off and recrystallized from o-xylene. Yield 0.37 g.
1H NMR spectrum, , ppm: linear form, 7.15 (1H, s, CH=N); 2.84 (2H, d, CH2); 4.11 (1H, m, CH); 3.85 (2H, d,
δ
CH2OH); 5.92 (2H, br. s, OH, NH); 8.01, 8.22, 8.96 (3H, m, Ar); cyclic form, 4.94, 4.65 (1H, s, CHON); 3.66,
2.59, 2.64 (2H, dd, CH2); 4.09, 3.66 (1H, m, CHCl); 4.43, 4.28, 3.52, 2.96 (2H, dd, CH2O); 5.92 (1H, br. s, NH);
8.01, 8.22, 8.96 (3H, m, Ar).
2,2,4-Trichloro-5-hydroxypentanal
3,5-Dichloro-2-pyridylhydrazone
(3b).
3,5-Dichloro-2-
pyridylhydrazine (1.79 g, 10 mmol) was dissolved in concentrated H2SO4 (1.5 ml). Water (2 ml) and ethanol
(5 ml) were added to the solution obtained and then solution of compound 1 (0.205 g, 1 mmol) in alcohol (2 ml)
was added. The mixture was stirred and left overnight. The solution was diluted with water (30 ml) and
neutralized to pH 6 with sodium bicarbonate. The precipitated crystals were filtered off, dried, and
1
recrystallized from o-xylene. Yield 0.206 g. H NMR spectrum, , ppm: linear form, 7.15 (1H, s, CH=N); 2.84
δ
(2H, d, CH2); 4.11 (1H, m, CH); 3.85 (2H, d, CH2OH); 5.92 (2H, br. s, OH, NH); 7.75, 8.20 (2H, 2 s, Ar); cyclic
form, 4.94, 4.65 (1H, s, CHON); 3.66, 2.59, 2.64 (2H, dd, CH2); 4.09, 3.66 (1H, m, CHCl); 4.43, 4.28, 3.52,
2.96 (2H, dd, CH2O); 5.92 (1H, br. s, NH); 7.75, 8.20 (2H, 2 s, Ar).
2,2,4-Trichloro-5-hydroxypentanal 4-Nitrophenylhydrazone (3c) was obtained analogously from
1
4-nitrophenylhydrazine (2 g, 13 mmol) and compound 1 (0.205 g, 1 mmol). Yield 0.186 g. H NMR spectrum,
, ppm: linear form, 7.15 (1H, s, CH=N); 2.84 (2H, d, CH2); 4.11 (1H, m, CH); 3.85 (2H, d, CH2OH); 5.92 (2H,
δ
br. s, OH, NH); 7.52, 8.12 (4H, 2 d, Ar); cyclic form, 4.94, 4.65 (1H, s, CHON); 3.66, 2.59, 2.64 (2H, dd, CH2);
4.09, 3.66 (1H, m, CHCl); 4.43, 4.28, 3.52, 2.96 (2H, dd, CH2O); 5.92 (1H, br. s, NH); 7.52, 8.12 (4H, 2 d, Ar).
2,2,4-Trichloro-5-hydroxypentanal Phenylhydrazone (3d). Mixture of phenylhydrazine
hydrochloride (0.4 g, 7 mmol) and compound 1 (0.205 g, 1 mmol) in ethanol (10 ml) was boiled for 8 h. The
solution was cooled and the precipitated solid filtered off. The solid was washed with sodium bicarbonate
68

1
solution, dried, and recrystallized from benzene. Yield 0.127 g. H NMR spectrum, , ppm: linear form, 7.15
δ
(1H, s, CH=N); 2.84 (2H, d, CH2); 4.11 (1H, m, CH); 3.85 (2H, d, CH2OH); 5.92 (2H, br. s, OH, NH); 7.04-7.12
(5H, m, Ar); cyclic form, 4.94, 4.65 (1H, s, CHON); 3.66, 2.59, 2.64 (2H, dd, CH2); 4.09, 3.66 (1H, m, CHCl);
4.43, 4.28, 3.52, 2.96 (2H, dd, CH2O); 5.92 (1H, br. s, NH); 7.04-7.12 (5H, m, Ar).
2,2,4-Trichloro-5-hydroxypentanal 4-Methylphenylhydrazone (3e). Mixture of 4-methylphenyl-
hydrazine (0.4 g, 3 mmol), concentrated HCl (0.2 ml), and compound 1 (0.205 g, 1 mmol) in ethanol (10 ml)
was boiled for 8 h. The solution was cooled, diluted with water (20 ml), the precipitated solid was filtered off,
1
washed with sodium bicarbonate solution, dried, and recrystallized from benzene. Yield 0.129 g. H NMR
spectrum, , ppm: linear form, 7.15 (1H, s, CH=N); 2.84 (2H, d, CH2); 4.11 (1H, m, CH); 3.85 (2H, d, CH2OH);
δ
5.92 (2H, br. s, OH, NH); 7.02, 7.62 (4H, 2 d, Ar); cyclic form, 4.94, 4.65 (1H, s, CHON); 3.66, 2.59, 2.64 (2H,
dd, CH2); 4.09, 3.66 (1H, m, CHCl); 4.43, 4.28, 3.52, 2.96 (2H, dd, CH2O); 5.92 (1H, br. s, NH); 7.02, 7.62 (4H,
2 d, Ar).
2-Alkoxy-3,3,5-trichlorotetrahydropyrans (General Procedure). A. Solution of compound 1 (0.41 g,
2 mmol) in absolute benzene (5 ml) was added with ice-cooling to sodium hydride (0.05 g, 2 mmol) washed
with hexane. The mixture was stirred for 1 h 30 min until hydrogen evolution had finished. The alkylating agent
(2 mmol) was added dropwise with stirring to the obtained suspension of alcoholate. Stirring was stopped after
2 h, the solution was filtered, and benzene evaporated. The residue was distilled in vacuum.
B. Mixture of 40% NaOH solution (5 ml), with a solution of compound 1 (2 mmol), and alkylating agent
(2 mmol) in benzene (5 ml) was stirred for 1 h at 0°C in the presence of TEBAC (0.01 mmol). The benzene
layer was separated, and dried over magnesium sulfate. The solvent was evaporated, and the residue distilled in
vacuum.
1
3,3,5-Trichloro-2-methoxytetrahydropyran (6a). H NMR spectrum, , ppm: 4.67, 4.59 (1H, s,
δ
OCHO); 4.27, 4.30, 4.39, 4.41 (2H, dd, CH2O ring); 4.11, 4.07 (1H, m, CHCl); 2.01, 2.05, 2.32, 2.39 (2H, dd,
CH2); 3.52 (3H, s, CH3).
1
3,3,5-Trichloro-2-ethoxytetrahydropyran (6b). H NMR spectrum, , ppm: 4.86, 4.78 (1H, s,
δ
OCHO); 4.29, 4.32, 4.40, 4.42 (2H, dd, CH2O ring); 4.11, 4.07 (1H, m, CHCl); 2.01, 2.05, 2.32, 2.39 (2H, dd,
CH2 ring); 3.72 (2H, q, CH2O); 1.15 (3H, t, CH3).
1
3,3,5-Trichloro-2-propoxytetrahydropyran (6c). H NMR spectrum, , ppm: 5.06, 4.96 (1H, s,
δ
OCHO); 4.29, 4.32, 4.40, 4.42 (2H, dd, CH2O ring); 4.11, 4.07 (1H, m, CHCl); 2.01, 2.05, 2.32, 2.39 (2H, dd,
CH2); 3.40 (2H, t, CH2O); 1.52 (2H, m, CH2); 0.91 (3H, t, CH3).
2-Acyloxy-3,3,5-trichlorotetrahydropyrans (General Procedure). The acylating agent (10 mmol)
was added to solution of compound 1 (2.05 g, 10 mmol) in ether (10 ml). The mixture was stirred for 1 h at
room temperature, the solvent evaporated, and the residue distilled in vacuum.
1
2-Acetoxy-3,3,5-trichlorotetrahydropyran (7a). H NMR spectrum, , ppm: 5.26, 5.31 (1H, s,
δ
OCHO); 4.42, 4.45, 4.49, 4.54 (2H, dd, CH2O); 4.11, 4.07 (1H, m, CHCl); 2.06, 2.11, 2.45, 2.49 (2H, dd, CH2);
2.01 (3H, s, CH3).
1
2-Benzoyloxy-3,3,5-trichlorotetrahydropyran (7b). H NMR spectrum, , ppm: 7.46-7.84 (5H, m,
δ
C6H5); 5.53, 5.42 (1H, s, OCHO); 4.41, 4.44, 4.49, 4.52 (2H, dd, CH2O); 4.13, 4.09 (1H, m, CHCl); 2.12, 2.16,
2.47, 2.50 (2H, dd, CH2).
3,3,5-Trichloro-2-(4-nitrobenzoyloxy)tetrahydropyran (7c). 4-Nitrobenzoyl chloride (1.85 g) was
added to solution of compound 1 (2.05 g, 10 mmol) in ether (10 ml). The mixture was stirred for 1 h at room
temperature, the solvent evaporated, and the residue recrystallized from hexane. Bright yellow, readily-melting
1
crystals (2.55 g) were obtained. H NMR spectrum, , ppm: 8.03-8.24, (4H, 2 d, C6H4); 5.55, 5.38 (1H, s,
δ
OCHO); 4.42, 4.45, 4.50, 4.52 (2H, dd, CH2O); 4.12, 4.07 (1H, m, CHCl); 2.13, 2.18, 2.49, 2.52 (2H, dd, CH2).
3,3,5-Trichlorotetrahydro-2-pyranyl Sulfonates (General Procedure). Solution of sulfonyl chloride
(1 mmol) in toluene (1 mmol) was added to solution of compound 1 (0.205 g, 1 mmol) in toluene (1.5 ml). The
mixture obtained was heated for 1 h at 85°C, and the solvent evaporated. The residue was recrystallized from
hexane.
69

p
1H NMR spectrum, , ppm: 7.37-7.86
δ
3,3,5-Trichlorotetrahydro-2-pyranyl -Toluenesulfonate (8a).
(4H, dd, C6H4); 5.22, 4.95 (1H, s, OCHO); 4.28, 4.31, 4.36, 4.42 (2H, 2 d, CH2O); 4.10, 4.08 (1H, m, CHCl);
2.06, 2.13, 2.40, 2.43 (2H, dd, CH2); 2.42 (3H, s, CH3).
1
3,3,5-Trichlorotetrahydro-2-pyranyl 2-Nitrobenzenesulfonate (8b). H NMR spectrum, , ppm:
δ
7.91-8.32 (4H, m, C6H4); 5.20, 4.96 (1H, s, OCHO); 4.32, 4.33, 4.39, 4.43 (2H, dd, CH2O); 4.11, 4.05 (1H, m,
CHCl); 2.09, 2.13, 2.36, 2.40 (2H, dd, CH2).
1
3,3,5-Trichlorotetrahydro-2-pyranyl 4-Nitrobenzenesulfonate (8c). H NMR spectrum, , ppm:
8.32-8.87 (4H, dd, C6H4); 5.21, 4.98 (1H, s, OCHO), 4.30, 4.32, 4.37, 4.43 (2H, dd, CH2O); 4.12, 4.07 (1H, m,
δ
CHCl); 2.07, 2.12, 2.39, 2.43 (2H, dd, CH2).
REFERENCES
1.
2.
K. I. Kobrakov, A. V. Ivanov, V. K. Korolev, and A. B. Terent'ev, Khim. Geterotsikl. Soedin., 130
(1998).
T. T. Vasil'eva, A. V. Ivanov, K. I. Kobrakov, K. Laikhia, E. Kolekhmainen, V. K. Korolev,
N. A. Kuz'mina, and A. B. Terent'ev, Izv. Akad. Nauk, Ser. Khim., 187 (1999).
K. I. Kobrakov, V. K. Korolev, and A. V. Ivanov, Khim. Geterotsikl. Soedin., 609 (2002).
Organicum [Russian translation], Vol. 2, Mir, Moscow (1982), p. 71.
3.
4.
70