Synthesis of Aryl-Substituted Propanols, Pentanediols, and Tetrahydropyran

Article abstract of DOI:10.1023/A:1012760303749

Oxidation of N- and C-alkenylanilines with ozone under conditions of alcohol formation was studied. Depending on the structure of the alkenyl moiety, the reaction yields aryl-substituted propanols, pentanediols, or tetrahydropyran.

Full text of DOI:10.1023/A:1012760303749

Russian Journal of Applied Chemistry, Vol. 74, No. 1, 2001, pp. 106 110. Translated from Zhurnal Prikladnoi Khimii, Vol. 74, No. 1,
2001, pp. 103 106.
Original Russian Text Copyright
2001 by Gataullin, Kazhanova, Galeeva, Fatykhov, Spirikhin, Abdrakhmanov.
ORGANIC SYNTHESIS
AND INDUSTRIAL ORGANIC CHEMISTRY
Synthesis of Aryl-Substituted Propanols,
Pentanediols, and Tetrahydropyran
R. R. Gataullin, T. V. Kazhanova, R. I. Galeeva, A. A. Fatykhov,
L. V. Spirikhin, and I. B. Abdrakhmanov
Institute of Organic Chemistry, Ufa Scientific Center, Russian Academy of Sciences, Ufa,
Bashkortostan, Russia
Bashkir State Agricultural University, Ufa, Bashkortostan, Russia
Received June 16, 2000
Abstract Oxidation of N- and C-alkenylanilines with ozone under conditions of alcohol formation was
studied. Depending on the structure of the alkenyl moiety, the reaction yields aryl-substituted propanols, pen-
tanediols, or tetrahydropyran.
Since early 1960s, when the feasibility was dem-
onstrated for preparative synthesis of Claisen rear-
rangement products from N-allylaniline [1, 2], there
has been a great deal of interest in the chemistry of
alkenylanilines. These compounds find extending use
in organic synthesis, including preparation of practi-
cally useful substances. It is known that some N- and
C-alkenylanilines exhibit activity as potato growth
regulators and fungicides against potato phytophthora
infection, inhibit biosynthesis of chitin of flour moth
[3], show a pronounced local anesthetic effect [4], and
are successfully used in synthesis of some valuable
alkaloids [5]. Proceeding with studies [6 8] on trans-
formations of o-alkenylarylamines, we studied oxida-
tion of N- and C-alkenylanilines with ozone.
Previously field tests of the N-ethoxyacetyl analog
of this compound demonstrated its efficiency against
potato phytophthora infection, which was level with
the known antiphytophthora agent Ridomil [ethyl
N-methoxyacetyl-N-(2-methyl-6-ethylphenyl)amino-
butyrate]; the productivity increased by 30%. Pre-
sumably, under the testing conditions involving the
impact of soil, atmospheric oxygen, and sunlight, this
compound could undergo transformations with par-
ticipation of the unsaturated C=C bond of the pentenyl
unit. Oxidation of amine IV with ozone is one of
possible routes to hydroxy derivatives of this sub-
stance. We found that ozonation of IV followed by
treatment with NaBH gives N-methoxyacetyl-N-
4
(1-hydroxyprop-2-yl)aniline in a 35 45% yield.
For example, from aniline (I) by a series of con-
densations we prepared N-methoxyacetyl-N-(2-penten-
4-yl)aniline (IV) in a 68% yield:
When an equimolar amount of ozone is passed
through a solution of IV in cyclohexane methanol,
the reaction does not go to completion, and the ratio
of the initial amine IV and product IVa is 1.5 : 1.
When the similar reaction is performed in methanol,
the ratio of these compounds [scheme (1)], according
O
NH2
O
HN
Cl
Et N
Cl
N
ClCH C Cl
2
1
K CO
3
3
to the H NMR data, varies from 1 : 1 to 1 : 0.7.
2
I
II
In contrast to N-alkenylaniline IV, ozonation in
methanol of pentenylanilines VIa and VIb exhibiting
local anesthetic activity [4] goes to completion; sub-
III
O
(1)
O
sequent treatment of the reaction mixture with NaBH
(1) O
CH3 OCH2C
CH OCH
4
2C
3
4
N
3
N
(2)
NaBH
gives propanols VIIa and VIIb in 50 60% yields
[scheme (2)]. Oxidation of 2-cyclopentenylanilines
VIIIa VIIIc under these conditions yields pentane-
diols IXa IXc in a 60 70% yield [scheme (3)].
MeONa
HO
.
MeOH
MeOH
IV
IVa
1070-4272/01/7401-0106$25.00 2001 MAIK Nauka/Interperiodica

SYNTHESIS OF ARYL-SUBSTITUTED PROPANOLS
107
analysis. The IR spectra of all the products contain a
characteristic absorption band of the OH group at
O
N
1
1
NH2
R2
HN
3400 3600 cm . In the H NMR spectrum of
R1
R1
amine IVa, the methyl protons of the propanol moiety
B
A
Va, Vb
13
give a doublet at 0.96 ppm (J 6.99 Hz). In the
C
NMR spectrum, the signal of the methyl carbon of the
R2
propanol moiety is shifted upfield ( 14.73 ppm) as
C
1
2
compared fo IV. The signals of the C and C atoms
in IVa are observed at 64.45 and 53.62 ppm, respec-
tively.
VIa, VIb
O
N
HN
1
(1) C
(2) D
R1
In the H NMR specrta of amino alcohols VIIa and
(2)
,
VIIb, the methyl groups give a doublet at 1.16 ppm
2"
(J 7.07 Hz). The methine proton H and the methyl-
OH
1
R2
VIIa, VIIb
ene protons H give multiplets at 4.33 and 3.64 ppm.
1"
2"
3"
The signals of the C , C , and C atoms of VIIa
13
and VIIb in the C NMR spectra are observed at 68,
1
2
1
2
where R = H, R = Me (a); R = R = Me (b);
35 37, and 17 18 ppm, respectively.
1
1"
In the H NMR spectra of diols IXa IXc, the H
O
N
5"
and H protons of the pentanediol moiety give sig-
nals at 3.70 and 3.45 ppm, and the signal of OH pro-
tons is observed at 4.80 ppm. In the C NMR spectra
NH2
R3
NH
(1) A
(2) B
R1
R2
R1
R2
13
1"
5"
of IXa IXc, the C and C signals are observed at
2"
67 and 62 ppm, respectively. The signals of the C ,
R3
3"
4"
C , and C atoms are observed at 41 and 28 29 ppm.
VIIIa VIIIc
13
The signals of the benzene carbon atoms in the
C
NMR spectrum of IXc are split owing to coupling
O
with F and give doublets with the coupling constants
OH
N
1
2
5
3
6
NH
R3
of 17 20 (for C , C , C , and C ) and 216 223 Hz
R1
R2
(1) C
(2) D
4
(for the C and C atoms directly bound to F).
,
(3)
OH
The mass spectrum of the tetrahydropyranyl deriv-
+
ative XI contains a molecular peak M (m/z 191).
1
2
3
1
2
3
where R = R = R = H (a); R = Me, R = R = H
EXPERIMENTAL
1
2
3
(b); R = H, R = R = F (c).
1
13
Reagents and conditions: A, ClCH C(O)Cl,
The H and C NMR spectra were taken on a
Bruker AM-300 spectrometer (working frequency 300
2
K CO , 20 C; B, excess piperidine; C, O , MeOH,
2
3
3
0 5 C; D, NaBH , MeOH, 0 5 C.
and 75 MHz, respectively; solvent CDCl ; internal
4
3
reference TMS), and the IR spectra, on a UR-20 spec-
trometer. The product purity was checked by TLC
(Silufol UV-254 plates). The mass spectrum was
obtained with an MKh-1320 spectrometer (70 eV).
The physicochemical characteristics of VIb and VIIa
VIIc are given in [10, 11].
Oxidation of N-acetyl-2-methyl-6-(cyclopent-1-
enyl)aniline (X) [9] unexpectedly gave tetrahydro-
pyran XI (yield 70%):
O
Me
NH
NH
(1) O
(2) NaBH
3
N-(2-Methoxyacetyl)-N-(3-penten-2-yl)aniline
Me
Me
.
4
(4)
(IV) was prepared according to [1]. Yield 90%. R
O
f
MeOH
0 C
0.48 (CH Cl CH OH, 95 : 5), bp 123 C (1 mm Hg).
2
2
3
X
XI
Found, %: C 70.41, H 8.35, N 6.07.
C13H19NO2.
Calculated, %: C 70.59, H 8.60, N 6.33.
The structure of the products was proved by the
1
13
IR and H, C NMR spectra and also by elemental
RUSSIAN JOURNAL OF APPLIED CHEMISTRY Vol. 74 No. 1 2001

108
GATAULLIN et al.
1
1
1
H NMR spectrum (CDCl , , ppm): 0.98 d (3H, J
IR spectrum, , cm : 3280 (NH). H NMR spec-
3
trum (CDCl ), , ppm (J, Hz): 1.49 d (3H, J 6.97,
CH ); 1.70 d (3H, J 6.46, CH ); 2.30 s (3H, CH );
1.50, 1.60, 2.55 (m, 10H, H ); 3.08 s (2H, CH );
3.50 m (1H, CH); 5.35 5.65 m (2H, HC=CH); 7.00 s
(1H, H ); 7.05 d (1H, J 8.79, H ); 7.90 d (1H, H );
9.25 s (1H, NH). C NMR spectrum (CDCl ,
6.61 Hz, CH ), 1.50 d (3H, J 6.35 Hz, CH ), 3.19 s
(3H, OCH ), 3.50 m (2H, CH ), 5.25 5.45 m (3H,
3
3
3
3
3
3
3
2
13
CH, HC=CH), 6.96 7.29 m (5H, ArH). C NMR
spectrum (CDCl , , ppm): 17.46, 17.63 (CH ); 51.39
pip
2
3
3
3
6
5
1
(C ); 56.76 (CH ); 70.58 (CH ); 127.21, 128.28,
3
2
13
,
128.92, 129.81, 130.59, 136.83 (C
(C=O).
, C=C); 167.77
3
arom
ppm): 17.78, 20.03, 21.01 (C
); 23.52, 26.08,
methyl
2"
1
54.97 (C ); 63.03 (C ); 168.78 (C=O); 36.63 (C );
pip
2
N-Chloroacetyl-2-(3-penten-2-yl)-4-methylaniline
(Va). A three-necked flask equipped with a power-
driven stirrer, a reflux condenser, and a dropping fun-
nel was charged with dry K CO and 17.1 g (0.1 mol)
of 2-(3-penten-2-yl)-4-methylaniline in methylene
chloride. A solution of 0.2 mol of freshly distilled
chloroacetyl chloride in 80 ml of CH Cl was slowly
added dropwise with stirring. After reaction comple-
tion, the precipitate was filtered off, 100 ml of water
was added, and the organic layer was washed with a
10% solution of NaHCO until the CO evolution
3
4
1
2
134.75 (C ); 122.62 (C ); 132.22 (C ); 134.11 (C );
3
5
6
127.21 (C ); 135.22 (C ); 127.20 (C ); 137.24 (C ).
2
3
The general procedure of oxidation was as follows.
Through a solution of 10 mmol of IV, IVa, IVb,
VIIIa, VIIIb, or X in 10 ml of methanol at 0 5 C we
passed a calculated amount of an ozone oxygen mix-
ture (controlled with a stopwatch). The mixture was
kept for 5 min at this temperaturem after which 0.6 g
2
2
of NaBH was added at the temperature maintained
4
no higher than 10 15 C. The mixture was allowed to
stand at 20 C for 18 h and then diluted with a 10 : 1
mixture of H O and CH COOH. The product was
extracted with CH Cl , washed with 5% NaHCO and
saturated NH Cl solution, and dried over Na SO .
3
2
ceased and then with two 100-ml portions of water.
The organic solution was dried over MgSO . The sol-
vent was vacuum-evaporated, and the residue was re-
crystallized from benzene. Yield of Va 15.4 g (90%),
4
2
3
2
2
3
4
2
4
1
1
mp 109 C. IR spectrum, , cm : 3275 (NH). H
NMR spectrum, , ppm (J, Hz): 1.35 d (3H, J 7.15,
CH ), 1.66 d (3H, J 7.05, CH ), 2.35 s (3H, CH ),
The solvent was evaporated, and alcohols IVa, VIIa,
VIIb, and IXa IXc or pyran XI was obtained.
3
3
3
N-(2-Methoxyacetyl)-N-(1-hydroxy-2-propyl)ani-
line (IVa). Yield 91%. R = 0.27 (CH Cl CH OH,
1
3.60 m (1H, H ), 4.28 s (2H, CH ), 5.59 m (2H,
2
f
2
2
3
HC=CH), 6.90 (1H, ArH), 6.87 (1H, ArH), 7.85 br.s
(1H, NH). C NMR spectrum (CDCl ), , ppm (J,
Hz): 20.25 (Ia), 35.80 (C ), 42.79 (C Cl), 165.50
95 : 5).
13
3
1
Found, %: C 64.52, H 7.56, N 6.25.
1
2
3
C12H17NO3.
(C=O), 136.70 (C ), 141.80 (C ), 125.55 (C ), 124.49
5
4
6
2
Calculated, %: C 64.57, H 7.62, N 6.28.
(C ), 128.53 (C ), 134.79 (C ), 135.60 (C ), 130.45
3
(C ).
1
H NMR spectrum (CDCl ), , ppm (J, Hz): 0.96 d
(1H, J 6.99, CH ), 3.25 s (3H, CH ), 3.40 m (2H,
3
3
3
Found, %: C 64.00, H 7.16, N 5.98, Cl 15.46.
C12H18NOCl.
Calculated, %: C 63.29, H 7.91, N 6.15, Cl 15.60.
CH ), 3.60 s (2H, CH ), 4.81 m (1H, CH), 7.12 s
2
2
13
(1H, OH), 7.22 7.50 m (5H, ArH). C NMR spec-
1
2
trum (CDCl ), , ppm: 14.73 (C ); 53.62 (C ), 64.45
(C ), 70.93 (C ); 58.97 (C ); 170.25 (C ); 128.42,
129.26, 129.87, 130.59, 137.24 (C ).
3
3
2"
3"
1"
N-[(2-(3-propen-2-yl)-4-methylphenyl)aminocar-
bonylmethyl]piperidine (VIa). Chloroacetylated ani-
line Va (2.3 g, 10 mmol) was dissolved in hot toluene
(20 ml), and 5 ml of piperidine was added. The mix-
ture was refluxed for 4 h. The amine hydrochloride
precipitate was filtered off and washed with 5 ml of
toluene. The filtrate was vacuum-evaporated, and the
residue was recrystallized from a minimal amount of
toluene. Yield of VIa 2.3 g (68%). R 0.48 (CH Cl ).
arom
N-[2-(1-Hydroxy-2-propyl)-4-methylphenyl]-2-
piperidinoacetamide (VIIa). Yield 60%. R 0.36
(CH Cl CH OH, 95 : 5).
f
2
2
3
Found, %: C 70.29, H 8.90, N 9.61.
C17H26N2O2.
Calculated, %: C 70.34, H 8.96, N 9.65.
f
2
2
1
IR spectrum, , cm : 3312 (NH, OH), 1688
Found, %: C 75.56, H 9.28, N 9.27.
C19H28N20.
Calculated, %: C 76.00, H 9.33, N 9.33.
13
(C=O). C NMR spectrum (CDCl ), , ppm: 17.08
(C ), 21.09 (CH ); 23.49, 25.92, 54.86 (C ); 35.71
3
3"
3
pip
RUSSIAN JOURNAL OF APPLIED CHEMISTRY Vol. 74 No. 1 2001

SYNTHESIS OF ARYL-SUBSTITUTED PROPANOLS
109
2"
1"
2
1
(C ), 68.20 (C ), 62.46 (C , CH ); 132.76 (C );
(5H, 2CH , CH), 8.40 s (3H, OH, NH), 6.85 m
(3H, Ar).
2
2
2
3
4
5
136.31 (C ); 127.39 (C ); 135.19 (C ); 127.19 (C );
137.24 (C ), 169.47 (C , C=O).
6
1
N-[2-(1,5-Dihydroxypent-2-yl)-4,5-difluorophen-
yl]-2-piperidinoacetamide (IXc). Yield 59%. R 0.28
f
N-[2-(1-Hydroxy-2-propyl)-4,6-dimethylphenyl]-
(CH Cl CH OH, 90 : 10).
2
2
3
2-piperidinoacetamide (VIIa). Yield 60%. R 0.36
f
(CH Cl CH OH, 90 : 10).
2
2
3
Found, %: C 61.00, H 6.73, F 10.71, N 6.89.
C18H24F2N2O3.
Calculated, %: C 61.02, H 6.78, F 10.73, N 7.91.
Found, %: C 65.01, H 8.38, N 8.36.
C18H28N2O2.
1
1
Calculated, %: C 65.06, H 8.43, N 8.43.
IR spectrum, , cm : 3600 (OH, NH). H NMR
spectrum (CDCl ), , ppm (J, Hz): 6.90 d.d (1H,
3
1
1
IR spectrum, , cm : 3500 (OH, NH). H NMR
6
6
5
6 4
J
11.69, J
8.66, H ), 1.40 3.70 m (23H,
H F
H F
spectrum (CDCl ), , ppm (J, Hz: 1.16 d (3H, J 7.07,
CH ), 1.40 2.60 m (10H, 5CH ), 2.16 s (3H, CH ),
2.24 s (3H, CH ), 3.12 s (2H, CH ), 3.64 m (2H,
CH ), 4.33 m (1H, CH), 6.90 s (1H, OH), 6.96 s (1H,
ArH), 7.03 s (1H, ArH), 8.90 s (1H, NH). C NMR
spectrum (CDCl ), , ppm: 18.00 (C ), 37.38 (C );
3
3
4
3 5
10CH , CH, 2OH), 7.50 d.d (1J, J
7.86, H ), 9.70 s (1H, NH). C NMR spectrum
12.05, J
2
H F
H F
3
2
3
3
13
3
2
(CDCl ), , ppm: 23.14, 25.65, 54.55 (piperidine),
3
2
3"
1"
2"
5"
27.08 (C ); 29.75 (C ); 40.80 (C ); 61.56 (C );
13
1"
1
3
3
4
4
66.26 (C ); 62.08 (C ); 112.44 d (C , J
113.18 d (C ), 130.98 d (C ), 146.50 d.d (C , J
216); 146.59 d.d (C , J
17.55);
3"
2"
C F
3
1
2
2
1
4
4
23.66, 26.26, 55.38 (C ); 62.46 (C ); 170.56 (C );
C F
pip
5
5
5
5 4
223, J
27); 169.81
18.83, 21.24 (C
); 124.81, 128.71, 131.08,
C F
C F
methyl
1
(C ).
135.84, 137.35, 142.83 (C
).
arom
6-Methyl-2-(tetrahydro-2-pyranyl)aniline (XI).
N-[2-(1,5-Dihydroxypent-2-yl)phenyl]-2-piperi-
dinoacetamide (IXa). Yield 63%. R 0.21 (CH Cl
Yield 67%. R 0.30 (CH Cl MeOH 95 : 5).
f
2
2
f
2
2
CH OH, 90 : 10).
3
Found, %: C 75.04, H 8.67, N 7.02.
C12H17NO.
Calculated, %: C 75.39, H 8.90, N 7.33.
Found, %: C 67.48, H 8.70, N 8.71.
C18H28N2O3.
Calculated, %: C 67.50, H 8.75, N 8.75.
1
1
IR spectrum, , cm : 3600 (NH, OH). H NMR
spectrum (CDCl ), , ppm (J, Hz): 1.60 2.30 m (6H,
1
1
3
IR spectrum, , cm : 3600 (OH, NH). H NMR
spectrum (CDCl ), , ppm: 0.86 2.35 m (14H, 7CH ),
6a, b
3CH ), 3.65 d.d.t (2H, J 2.8, J 6.07, J 8.97, H
),
2
1
2
3
3
2
4.10 m (2H, NH ), 4.42 d.d (1H, J 1.95, J 8.11,
2
1
2
3.15 s (2H, CH ), 3.44 3.73 m (5H, 2CH ), 3.44
3.73 m (5H, 2CH , CH), 4.87 s (2H, 2OH), 9.56 s
(1H, NH), 7.07 7.90 m (4H, Ar). C NMR spectrum
2
2
2
4
5
H ), 6.67 t (1H, J 7.49, H ), 6.98 d (1H, H ), 7.02 d
(1H, H ). C NMR spectrum (CDCl ), , ppm: 17.13
(CH ), 23.44 (C ), 25.64 (C ), 29.28 (C ), 68.45 (C ),
79.78 (C ), 117.19 (C ), 122.53 (C ), 124.70 (C ),
2
3
13
13
3
4
5
3
6
3
(CDCl ), , ppm: 23.56, 26.06, 54.98 (piperidine);
3
2
5
3
4
3"
4"
2"
2
27.99 (C ), 30.29 (C ), 41.54 (C ), 61.94 (C ),
5"
1"
4
5
1
6
2
+
62.60 (C ), 67.13 (C ), 123.54 (C ); 125.97 (C );
125.31 (C ), 129.36 (C ), 143.13 (C ). µ , m/z 191.
3
2
1
6
126.78 (C ); 135.48 (C ); 135.85 (C ); 135.94 (C );
1
169.79 (C ).
CONCLUSION
N-[2-(1,5-Dihydroxypent-2-yl)-6-methylphenyl]-
Reduction with sodium borohydride of ozonation
products of o-alkenylanilines is a convenient route to
o-hydroxypropyl-, o-dihydroxypentyl-, and o-tetrahy-
dropyranyl-substituted anilines.
2-piperidinoacetamide (IXb). Yield 66%. R 0.23
f
(CH Cl CH OH, 90 : 10).
2
2
3
Found, %: C 68.21, H 8.93, N 8.35.
C19H30N2O3.
Calculated, %: C 68.26, H 8.98, N 8.38.
REFERENCES
1
1
1. Marcinkiewicz, S., Green, J., and Mamalis, P., Tetra-
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IR spectrum, , cm : 3600 (OH, NH). H NMR
spectrum (CDCl ), , ppm: 0.85 2.30 m (14H, 7CH ),
3
2
2.29 s (3H, CH ), 3.00 s (2H, CH ), 3.45 3.75 m
2. Marcinkiewicz, S., Bull. Acad. Pol. Sci., Ser. Sci.
3
2
RUSSIAN JOURNAL OF APPLIED CHEMISTRY Vol. 74 No. 1 2001

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RUSSIAN JOURNAL OF APPLIED CHEMISTRY Vol. 74 No. 1 2001