Features of catalyzed hydration of 2-(dichloromethyl)-N-[(1R)-1- phenylethyl)]cyclopent-3-ene-1-carboxamides

Article abstract of DOI:10.1134/S107042800905008X

The hydration of gem-dichloromethyl group in 2-(dichloromethyl)-N-[(1R)-1- phenylethyl)]cyclopent-3-ene-1-carboxamides in aqueous acetonitrile catalyzed by AgNO₃, FeCl₃?6H₂O, PdCl₂, and BaO was investigated. The optimum results were obtained at the use of BaO. It was demonstrated, that Pd-catalyzed reactions initiated intermolecular ether formation from the primary hydration products, bicyclic amides.

Full text of DOI:10.1134/S107042800905008X

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2009, Vol. 45, No. 5, pp. 694−697. © Pleiades Publishing, Ltd., 2009.
Original Russian Text © A.M. Gizametdinov, M.S. Miftakhov, 2009, published in Zhurnal Organicheskoi Khimii, 2009, Vol. 45, No. 5, pp. 712−715.
Features of Catalyzed Hydration
of 2-(Dichloromethyl)-N-[(1R)-1-phenylethyl)]cyclopent-3-ene-1-
carboxamides
A. M. Gizametdinov and M. S. Miftakhov
Institute of Organic Chemistry, Ufa Scientific Center, Russian Academy of Sciences, Ufa, 450054 Russia
e-mail: bioreg@anrb.ru
Received June 2, 2008
Abstract—The hydration of gem-dichloromethyl group in 2-(dichloromethyl)-N-[(1R)-1-phenylethyl)]cyclopent-
3-ene-1-carboxamides in aqueous acetonitrile catalyzed byAgNO3, FeCl3·6H2O, PdCl2, and BaO was investigated.
The optimum results were obtained at the use of BaO. It was demonstrated, that Pd-catalyzed reactions initiated
intermolecular ether formation from the primary hydration products, bicyclic amides.
DOI: 10.1134/S107042800905008X
To replace the expensive silver nitrate we attempted
a search for cheaper hydrolysis method of the gem-
dichloromethyl group in compound II. For conversion of
the dihalo-substituted compounds II into aldehydes it was
possible to apply an inexpensive reagent FeCl3·6H2O. In
this case the hydrolysis of compound II also resulted in
the expected compounds III, and the yield and the
duration of the process were comparable to those in the
experiments with AgNO3. At the use in the hydrolysis of
catalytic amounts of PdCl2 alongside with the expected
compounds III quickly formed a product of intermolecular
self-condensation IV. The ether formation was also found
at evaporation of solutions of individual compounds IIIa
and IIIb under reduced pressure and heating to 60°C.
The gem-dichlorocyclobutanone ring of bicycle I is
known to readily undergo opening under the action of
heteronucleophiles [1–3]. In continuation of the research
on the synthesis of chiral cyclopentenes we carried out a
reaction of α,α-dichlorobicyclobutanone (I) with (+)-α-
methylbenzylamine in benzene solution at room tempera-
ture and obtained in a high yield vicinally disubstituted
gem-dichloromethyl derivative of cyclopentene II that
by boiling in aqueous MeCN containing 2.1 equiv of
AgNO3 was converted into a diastereomeric mixture of
bicyclic amides IIIa and IIIb separated by column
chromatography on SiO2. In contrast to amides III dia-
stereomeric amides II failed to be separated on silica gel
(Scheme 1).
Scheme 1.
O
O
Ph, C6H6, 20oC
>95%
N
Ph
H2N
H
Cl
Cl
CHCl2
II
(±)-I
O
O
2.1 equiv AgNO3,
MeCN_H2O, D, 20 h
+
N
Ph
N
Ph
95%
OH
IIIb
OH
IIIa
694

FEATURES OF CATALYZED HYDRATION OF 2-(DICHLOROMETHYL)-N-[(1R)-1-PHENYLETHYL)]...
695
We further demonstrated that the most practical and
efficient reagent for the hydrolysis of amide II was the
barium oxide. The employment of the latter both led to
the formation of exclusively compound III in a high yield
and reduced the reaction time 2.5-fold. In the course of
further experiments we established that the reverse
conversion IV→IIIoccurred quantitatively at boiling ether
IV in aqueous THF in the presence of catalytic amount
of FeCl3·6H2O. Apparently the iron salt played here the
role of a Lewis acid (Scheme 2).
for the reverse hydration reaction IV→III. At the use
of AgNO3 and FeCl3 the acidity of the environment
apparently is on the optimum level, and compound IV
does not accumulate due to the preferable hydration
(IV) → (III).
EXPERIMENTAL
IR spectra were recorded on a spectrophotometer
UR-20 from thin films or mulls in mineral oil. 1H and 13C
NMR spectra were registered on a spectrometer Bruker
AM-300 (at 300 and 75.47 MHz respectively) from
solutions in CDCl3, internal reference TMS. Mass
spectra were taken in ethanol on a Shimadzu LCMS-
2010 instrument, ionizing electrons energy 70 eV. TLC
was performed on Sorbfil plates. The optical rotation was
measured on a polarimeter Perkin-Elmer 241 MC. The
purity of the initial compounds was checked by GLC on
a chromatograph Chrom 5.
The pair of salts Pd(II)–Fe(III) made it possible to
perform effectively the conversions III–IV although the
most well-known examples of the using FeCl3·6H2O and
PdCl2 [4–10] regarded the hydrolysis of the protective
groups. The cause of the different final hydrolysis results
in the presence on the one hand of PdCl2 (formation of
ether IV) andAgNO3, FeCl3, and BaO (formation of III),
on the other hand is as follows. Evidently both the
hydrolysis and etherification in the transitions II→III→IV
are catalyzed by H+ and Lewis acids. Under the same
conditions (MeCN–H2O, boiling) only the PdCl2-catalyzed
reaction gave ether IV. We attribute this fact to the specific
feature of the Pd-system where due to the possible N-
coordination of Pd(II) the intermolecular ether formation
is facilitated, and the acidity of the medium is insufficient
(±)-7,7-Dichlorobicyclo[3.2.0]hept-2-en-6-one
(I). To a stirred solution of 53 g (0.8 mol) of a freshly
distilled cyclopentadiene and 60 g (0.4 mol) of
dichloroacetyl chloride in 400 ml of hexane was added
dropwise within 1.5 h 59 ml of triethylamine in 300 ml of
anhydrous hexane. The reaction mixture was stirred for
Scheme 2.
O
.
1.0 equiv FeCl3 6H2O,
O
O
MeCN_H2O,
N
Ph
Δ, 20 h, 95%
H
+
N
Ph
N
Ph
CHCl2
or 3 equiv BaO
MeCN_H2O,
Δ, 8 h, 94%
OH
IIIb
OH
IIIa
b
II
b
a
a
Ph
N
Ph
N
Ph
Ph
N
N
O
O
O
O
O
O
IVb
IVa
a: 0.1 equiv of PdCl2, MeCN–H2O, Δ, 2 h, 98% or 60°C, 20 mm Hg; b: 0.1 equiv FeCl3·6H2O, THF–H2O, Δ, 5 h, >95%.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 5 2009

GIZAMETDINOV, MIFTAKHOV
696
15 h under argon, the mixture obtained was filtered, the
precipitate was washed on the filter with hexane
(300 ml). The solution was evaporated on a rotary
evaporator, the residue was distilled in a vacuum
collecting the fraction boiling at 49–50°C (0.3 mm Hg).
Yield 59.48 g (84%). Yellow oily fluid. IR spectrum, ν,
cm–1: 1805, 1028, 887, 814, 797, 754, 731, 631. 1H NMR
spectrum, δ, ppm: 2.48–2.88 m (2H, C4H), 4.04–4.22 m
(1H, C5H), 4.32–4.42 m (1H, C1H), 5.78–5.90 m (1H,
C3H), 6.03–6.17 m (1H, C2H). 13C NMR spectrum, δ,
ppm: 35.21 (C4), 58.60 (C1), 59.53 (C5), 88.18 (C7),
128.41, 136.88 (C2, C3), 197.79 (C6). Mass spectrum
(APCI), m/z (Irel, %): 177 (100) [MH, 35Cl]+, 149 (13.3)
[MH – CO]+. Found, %: C 47.23; H 3.09; Cl 39.96.
C7H6OCl2. Calculated, %: C 47.46; H 3.38; Cl 40.11.
a reduced pressure. The residue was subjected to
chromatography on SiO2, eluent petroleum ether–ethyl
acetate, 7:3. We obtained 1.04 g (47%) of yellowish
crystals of compound IIIa and 1.06 g (48%) of colorless
crystals of compound IIIb.
(b) To a solution of 2.3 g (7.7 mmol) of amide II in
35 ml of MeCN was added a solution of 2.1 g (7.7 mmol)
of FeCl3·6H20 in 11 ml of H2O, and the mixture obtained
was stirred at boiling for 20 h (TLC monitoring). After
evaporation of acetonitrile the water phase was extracted
with EtOAc (3 × 35 ml). The combined organic extracts
were dried with MgSO4, the solvent was evaporated under
a reduced pressure. The residue was subjected to
chromatography on SiO2, eluent petroleum ether–ethyl
acetate, 7:3. We obtained 0.88 g (47%) of compound
IIIa and 0.9 g (48%) of compound IIIb.
2-(Dichloromethyl)-N-[(1R)-1-phenylethyl)]-
cyclopent-3-ene-1-carboxamide (II). To a solution of
1.5 g (8.5 mmol) of dichloroketone I in 40 ml of benzene
was added a solution of 1.09 g (9 mmol) of (+)-α-
methylbenzylamine in 10 ml of benzene, and the mixture
was stirred at room temperature for 4 h (TLC monitoring).
The solution was evaporated, the separated precipitate
was washed with hexane to obtain 2.4 g (95%) of a mix-
ture of diastereomers of compound II as yellow crystals.
IR spectrum, ν, cm–1: 3311, 2953, 2852, 1633, 1548, 1446,
1375, 1240, 709, 698. 1H NMR spectrum, δ, ppm: 1.52 d
(3H, CH3, J 6.8 Hz), 2.53–2.73 m (2H, C5H), 3.17 q (1H,
C1H, J 7.8, 8.0 Hz), 3.62–3.74 m (1H, C2H), 5.13 quintet
(1H, CH–Ph, J 6.7, 6.4 Hz), 5.81–5.93 m (2H, NH and
C4H), 5.96–6.08 m (1H, C3H), 6.33 m (1H, CHCl2), 7.35–
7.55 m (5H, Ph). 13C NMR spectrum, δ, ppm: 21.29
(CH3), 36.49 and 36.22 (C5), 46.64 and 46.78 (CH–Ph),
48.70 and 48.86 (C2), 58.95 and 58.49 (C1), 74.34
(CHCl2), 126.3 and 126.13, 127.40 and 127.51, 128.66
and 128.73 (Ph), 128.88 (C4), 133.40 (C3), 142.57 and
142.8 (Ph), 171.07 and 171.02 (C=O). Mass spectrum
(APCI), m/z (Irel, %): 298 (100) [MH, 35Cl]+, 149 (12.5).
Found, %: C 60.05; H 5.42; Cl 23.15; N 4.64.
C15H17Cl2NO. Calculated, %: C 60.40; H 5.70; Cl 23.83;
N 4.70.
(c) To a solution of 1.0 g (3.33 mmol) of the equimolar
mixture of amides II in 20 ml of MeCN was added
a solution of 1.54 g (10 mmol) of BaO in 5 ml of H2O,
and the mixture obtained was stirred at boiling for 20 h
(TLC monitoring). After evaporation of acetonitrile the
water phase was extracted with EtOAc (3×15 ml). The
residue was subjected to chromatography on SiO2, eluent
petroleum ether–ethyl acetate, 7:3. We obtained 377 mg
(46%) of compound IIIa and 385 mg (47%) of compound
IIIb.).
(3aS,6aR)-3-Hydroxy-2-[(1R)-phenylethyl]-
3,3a,6,6a-tetrahydrocyclopenta[c]pyrrol-1(2H)-one
(IIIa), mp 105–107°C, [α]D20 +142.4° (C 0.65, MeOH).
IR spectrum, ν, cm–1: 3232, 2922, 2852, 1647, 1456, 1327,
1290, 1215, 1058, 802, 702. 1H NMR spectrum, δ, ppm:
1.68 d (3H, CH3, J 6.8 Hz), 2.54–2.84 m (2H, C6H),
3.21–3.33 m (1H, C3aH), 3.39 t (1H, C6aH, J 9.08 Hz),
3.73–4.03 br.s (1H, OH), 4.63–4.73 br.s (1H, CH–OH),
5.34 q (1H, CH–Ph, J 7.05 Hz), 5.33–5.49 m (1H, C5H),
5.72–5.84 m (1H, C4H), 7.13–7.35 m (5H, Ph). 13C NMR
spectrum, δ, ppm: 18.66 (CH3), 35.70 (C6), 42.83 (C6a),
49.96 (CH–Ph), 54.17 (C3a), 84.83 (C3), 127.32, 127.43,
128.40 (Ph), 128.61 (C5), 132.30 (C4), 139.79 (Ph),
177.27 (C=O). Mass spectrum (APCI), m/z (Irel, %): 244
(100) [MH]+, 226 (39), 198 (35.3), 177 (13.7), 161 (18.1),
121 (12.8), 93 (13.2), 65 (9.3). Found, %: C 73.28; H 6.36;
N 5.25. C15H17NO2. Calculated, %: C 74.07; H 6.70; N 5.76.
3-Hydroxy-2-[(1R)-phenylethyl]-3,3a,6,6a-tetra-
hydrocyclopenta[c]pyrrol-1(2H)-ones (IIIa) and
(IIIb). (a) To a solution of 2.7 g (9 mmol) of amide II in
40 ml of MeCN was added a solution of 3.21 g (19 mmol)
of AgNO3 in 14 ml of H2O, and the mixture obtained
was stirred at boiling for 20 h (TLC monitoring). After
evaporation of acetonitrile the water phase was extracted
with EtOAc (3 × 40 ml). The combined organic extracts
were dried with MgSO4, the solvent was evaporated under
(3aR,6aS)-3-Hydroxy-2-[(1R)-phenylethyl]-
3,3a,6,6a-tetrahydrocyclopenta[c]pyrrol-1(2H)-one
(IIIb), mp 120–121°C, [α]D20 +37.8° (C 0.8, MeOH). IR
spectrum, ν, cm–1: 3244 (O–H), 2922 (CH3), 2852 (CH3),
1651 (C=O), 1616, 1456 (CH3), 1336 (CH3), 1303, 1273,
1222, 1058, 805, 698. 1H NMR spectrum, δ, ppm: 1.56 d
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FEATURES OF CATALYZED HYDRATION OF 2-(DICHLOROMETHYL)-N-[(1R)-1-PHENYLETHYL)]...
697
1.55 d (3H, CH3 and C'H3, J 6.0 Hz), 2.45–2.9 m
(4H, C6H, C3aH, C6'H, C3a'H, C6aH and C6a'H), 4.66 C
(1H, CH–O and C'H–O), 5.18 q (1H, CH–Ph and C'H–
Ph, J 7.05 Hz), 5.37–5.43 m (1H, C5H and C5'H), 5.78–
5.85 m (1H, C4H and C4'H), 7.22–7.50 m (5H, Ph and
Ph'). 13C NMR spectrum, δ, ppm: 17.01 (C'H3), 17.55
(CH3), 35.43 (C6'), 35.66 (C6), 42.55 (C6a'), 42.82 (C6a),
50.06 (CH–Ph), 50.52 (C'H–Ph), 53.30 (C3a' and C3a),
84.33 (C3), 86.76 (C3'), 127.00, 127.14, 127.23 (Ph and
Ph'), 128.04 (C5), 128.73 (C5'), 132.66 (C4), 133.60 (C4'),
140.87 (Ph'), 141.24 (Ph), 177.26 (C'=O), 177.86 (C=O).
Mass spectrum (APCI), m/z (Irel, %): 469 (73) [MH]+,
246 (37.6), 244 (35.2), 226 (100), 198 (22.3). Found, %:
C 76.55; H 4.43; N 5.64. C30H32N2O3. Calculated, %:
C 76.92; H 4.71; N 5.98.
(3H, CH3, J 5.7 Hz), 2.15–2.35 br.s (1H, OH), 2.54–
2.84 m (2H, C6H), 3.13–3.24 m (1H, C3aH), 3.23 t (1H,
C6aH, J 7.08 Hz), 5.06–5.17 br.s (1H, CH–OH), 5.35 q
(1H, CH–Ph, J 7.05 Hz), 5.59–5.67 m (1H, C5H), 5.75–
5.85 m (1H, C4H), 7.20–7.54 m (5H, Ph). 13C NMR
spectrum, δ, ppm: 17.05 (CH3), 35.64 (C6), 42.85 (C6a),
49.94 (CH–Ph), 53.32 (C3a), 84.38 (C3), 126.96, 127.23,
128.07 (Ph), 128.73 (C5), 132.65 (C4), 141.21 (Ph),
177.35 (C=O). Mass spectrum (APCI), m/z (Irel, %): 244
(100) [MH]+, 226 (43), 198 (33.3), 177 (16.7), 161 (15),
121 (11.7), 93 (16.7), 65 (8.3). Found, %: C 73.97; H 6.63;
N 5.35. C15H17NO2. Calculated, %: C 74.07; H 6.70; N 5.76.
(3aS,6aR,3a'S,6a'R)-3,3'-Oxybis{2-[(1R)-1-
phenylethyl]-3,3a,6,6a-tetrahydrocyclopenta[c]-
pyrrol-1(2H)-one} (IVa). To a solution of 1.5 g (5 mmol)
of amide IIIa in 20 ml of MeCN was added a solution of
89 mg (0.5 mmol) of PdCl2 in 7 ml of H2O, and the mixture
obtained was stirred at boiling for 2 h (TLC monitoring).
The organic solvent was evaporated, the water phase
was extracted with EtOAc (3 × 20 ml). The combined
organic extracts were dried with MgSO4, the solvent was
evaporated under a reduced pressure. The residue was
subjected to chromatography on SiO2, eluent petroleum
ether–ethyl acetate, 1:1. Yield 1.42 g (98%). Orange oily
fluid, [α]D20 +98.4° (C 1.25, CHCl3). IR spectrum, ν, cm–1:
2933, 2922, 2852, 1685, 1418, 1375, 1344, 1288, 1261,
1078. 1H NMR spectrum, δ, ppm: 1.60 d (3H, CH3 and
C'H3, J 6.8 Hz), 2.54–2.84 m (3H, C6H and C3aH, C6'H
and C3a'H), 3.17 t (1H, C6aH and C6a'H, J 7.08 Hz), 4.23 s
(1H, CH–O and C’H–O), 5.16–5.23 m (1H, C5H and
C5'H), 5.32 q (1H, CH–Ph and C'H–Ph, J 7.05 Hz), 5.74–
5.81 m (1H, C4H and C4'H), 7.13–7.35 m (5H, Ph and
Hydrolysis of compound IVa. To a solution of 1.0 g
(2.1 mmol) of compound IVa in 15 ml of THF was added
a solution of 57 mg (0.21 mmol) of FeCl3·6H2O in 5 ml of
H2O, and the mixture obtained was stirred at boiling for
2 h (TLC monitoring). The organic solvent was
evaporated, the water phase was extracted with EtOAc
(3 × 15 ml). The combined organic extracts were dried
with MgSO4, the solvent was evaporated under a reduced
pressure. The residue was subjected to chromatography
on SiO2, eluent petroleum ether–ethyl acetate, 1:1. We
obtained 0.99 g (95%) of compound IIIa.
Hydrolysis of compound IVb. Likewise from 1.2 g
(2.5 mmol) of ether IVb and 68 mg (0.25 mmol) of
FeCl3·6H2O we obtained 1.18 g (95%) of compound IIIb.
REFERENCES
13
Ph'). C NMR spectrum, δ, ppm: 17.90 (C’H3), 18.66
1. Ghosez, L., Montaigne, R., Roussel,A., Vanlierde, H., and
Mollet, P., Tetrahedron Lett., 1966, vol. 7, p. 135.
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and Trost, D.M., Stuttgart–N.-Y.: Thieme, 1994, 260 p.
5. Greene, T.W. and Wuts, P.G.M., Protective Groups in
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p. 3728.
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(CH3), 35.51 (C6'), 35.73 (C6), 42.80 (C6a'), 42.98 (C6a),
48.78 (CH–Ph), 49.82 (C’H–Ph), 54.18 (C3a' and C3a),
84.78 (C3), 86.79 (C3'), 127.35, 127.64, 128.01 (Ph and
Ph'), 128.38 (C5), 128.82 (C5'), 132.33 (C4), 133.12 (C4'),
139.28 (Ph'), 139.81 (Ph), 177.20 (C'=O), 177.27 (C=O).
Mass spectrum (APCI), m/z (Irel, %): 469 (68) [MH]+, 246
(31.6), 244 (32), 226 (100), 198 (28). Found, %: C 76.48;
H 4.36; N 5.55. C30H32N2O3. Calculated, %: C 76.92;
H 4.71; N 5.98.
(3aR,6aS,3a'R,6a'S)-3,3'-Oxybis{2-[(1R)-1-
phenylethyl]-3,3a,6,6a-tetrahydrocyclopenta[c]-
pyrrol-1(2H)-one} (IVb) was similarly prepared from
1.0 g (3.3 mmol) of amide IIIb and 60 mg (0.3 mmol) of
PdCl2. Yield 0.95 g (98%). Orange oily fluid, [α]D20 +69.7°
(C 1.15, CHCl3). IR spectrum, ν, cm–1: 2935, 2922, 2852,
1688, 1418, 1375, 1348, 1292, 1267, 1078. 1H NMR
spectrum, δ, ppm:
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 5 2009