Synthesis of 1-Methoxy-4-(2-morpholinoethyl)-3,3-diphenylpyrrolidin-2-one

Full text of DOI:10.1007/s10593-013-1274-5

Chemistry of Heterocyclic Compounds, Vol. 49, No. 3, June, 2013 (Russian Original Vol. 49, No. 3, March, 2013)
LETTERS TO THE EDITOR
SYNTHESIS OF 1-METHOXY-4-(2-MORPHOLINOETHYL)-
3,3-DIPHENYLPYRROLIDIN-2-ONE
1
1
*
A. Krasikovs and V. Ozola
Keywords: doxapram, lactam, lactone, Mitsunobu reaction.
Doxapram has long been used as an intravenously-administered drug for treatment of acute respiratory
insufficiency [1]. As a part of our research program toward development of novel respiratory stimulants, we
were interested in the synthesis of more potent doxapram analogs. Herein we report a concise synthesis of
N-methoxypyrrolidinone 1.
The key step in the synthesis is transformation of lactone 4 into N-OMe lactam 7, which was elaborated to
the target compound 1 in a straightforward three-step sequence.
The prerequisite lactone 4 was prepared in an iodotetraphenyl-λ5-stibane-catalyzed cycloaddition
reaction between oxirane 3 and diphenyl ketene, generated from acid chloride 2 [2] prior to the cycloaddition
[3]. Transformation of lactone 4 into lactam 7 was achieved in a two-step sequence. Initially, lactone 4 was
converted to O-methylhydroxamic acid 5 in the Me3Al-mediated [4] reaction with H2NOMe·HCl. Because the
hydroxamic acid 5 was unstable and readily cyclized back to lactone 4, it was used in the next step without
purification. Cyclization of compound 5 under Mitsunobu conditions [5] afforded the desired lactam 7 together
with the isomeric O-methyl oxime 6 (ratio 7:6 = 1:3). The ratio of N- vs. O-cyclization products was improved
to 1:1 by substitution of THF and CH2Cl2 by more polar DMF or NMP. Gratifyingly, the isomers could be
separated by chromatography on silica gel. Furthermore, the undesired oxime 6 could be smoothly hydrolyzed
back to the lactone 4 under acidic conditions [6] (81% yield) and reused in the synthesis of lactam 7.
Lactam 7 was elaborated to the target compound 1 in a three-step sequence comprising hydroboration–
oxidation [7] to alcohol 8, followed by conversion to chloride 9 and, finally, alkylation of morpholine [8, 9].
IR spectra were recorded on a Shimadzu IR Prestige21 FTIR spectrometer in thin film. 1H and 13C NMR
spectra were registered on a Varian Mercury 400 instrument (400 and 100 MHz, respectively) in CDCl3, using
1
the residual solvent peak as an internal reference (7.26 ppm for H nuclei, 77.0 ppm for 13C nuclei). High-
resolution mass spectra (ESI) were obtained on a micromass micrOTOF-Q Mass Spectrometer. Elemental
analyses were performed on a Carlo Erba EA 1108 Analyzer. Melting points were determined by using an
OptimMelt automated melting point system and are uncorrected.
______
*To whom correspondence should be addressed, e-mail: vita@osi.lv.
1Latvian Institute of Organic Synthesis, 21 Aizkraukles St., Riga LV-1006, Latvia.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 532-535, February, 2013. Original
article submitted January 2, 2013.
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0009-3122/13/4903-0496©2013 Springer Science+Business Media New York

3,3-Diphenyl-4-vinyldihydrofuran-2(3H)-one O-Methyloxime (6) and 1-Methoxy-3,3-diphenyl-
4-vinylpyrrolidin-2-one (7). A 2 M solution of Me3Al in PhMe (7.77 ml, 15.55 mmol) was added dropwise to a
cooled (0°C) solution of O-methylhydroxylamine hydrochloride (1.30 g, 15.55 mmol) in dry PhMe (18 ml)
under Ar atmosphere. 3,3-Diphenyl-4-vinyldihydrofuran-2(3H)-one (4) (1.37 g. 5.18 mmol) was added, and the
reaction mixture was stirred at 55°C for 20 h. The solvent was evaporated, the residue was dissolved in CH2Cl2
(15 ml) and cooled to 0°C, and saturated aq. NaHCO3 (15 ml) was added. The resulting suspension is stirred at
0°C for 10 min, filtered through Celite, and the Celite pad was washed with CH2Cl2 (10 ml). The layers were
separated, and the water phase was extracted with CH2Cl2 (2×15 ml). The combined organic extracts were washed
with saturated aq. NaHCO3 (40 ml) and dried over Na2SO4. The solvents were evaporated to give 3-hydroxy-
N-methoxy-2,2-diphenylpent-4-enamide (5), which was used in the next step without purification.
Compound 5 was dissolved in NMP (20 ml), cooled to 0°C, and DIAD (0.98 g, 4.85 mmol) and Ph3P
(1.27 g, 4.85 mmol) were added. The reaction mixture was stirred at room temperature for 2 h. Water (20 ml) is
added to the reaction mixture, and the resulting suspension was extracted with t-BuOMe (3×15 ml). Volatiles
were removed under reduced pressure. Purification of the crude mixture by column chromatography (10 to 50%
EtOAc–petroleum ether) afforded pure compounds 6 and 7.
Compound 6. Yield 400 mg (26%), white powder, mp 165-167°C (MeOH), Rf 0.48 (EtOAc–petroleum
ether, 1:3). IR spectrum, ν, cm-1: 1666 (C=N). 1H NMR spectrum, δ, ppm: 3.81 (3H, s, OCH3); 3.94-4.02 (2H,
m, 5-CHA, 4-CH); 4.35-4.43 (1H, m, 5-CHB); 5.13-5.18 (1H, m) and 5.26-5.34 (2H, m, CH=CH2); 7.05-7.10
(2H, m, H Ph); 7.21-7.36 (6H, m, H Ph); 7.46-7.51 (2H, m, H Ph). 13C NMR spectrum, δ, ppm: 49.8; 59.2; 62.5;
71.5; 119.6; 127.0; 127.2; 127.7; 127.8; 128.8; 129.3; 132.7; 140.3; 141.2; 161.1. Found, %: C 77.55; H 6.58; N
4.72. C19H19NO2. Calculated, %: C 77.79; H 6.53; N 4.77.
Compound 7. Yield 410 mg (27%), white powder, mp 115-117°C (MeOH), Rf 0.27 (EtOAc–petroleum
ether, 1:3). IR spectrum, ν, cm-1: 1717 (C=O). 1H NMR spectrum, δ, ppm (J, Hz): 3.31-3.40 (1H, m) and 3.75 (1H,
dd, J = 7.2, J = 8.2, 5-CH2); 3.79-3.90 (1H, m, 4-CH); 3.87 (3H, s, OCH3); 5.07 (1H, dd, J = 1.4, J = 10.0) and 5.24
(1H, dd, J = 1.4, J = 17.2, CH=CH2); 5.36 (1H, ddd, J = 8.0, J = 10.0, J = 17.2, CH=CH2); 6.92-6.98 (2H, m, H Ph);
7.18-7.39 (6H, m, H Ph); 7.63-7.78 (2H, m, H Ph). 13C NMR spectrum, δ, ppm: 43.6; 47.8; 58.1; 62.4; 118.2; 127.0;
127.2; 128.0; 128.1; 128.3; 128.9; 134.9; 140.2; 141.0; 172.0. Found, %: C 77.43; H 6.52; N 4.73. C19H19NO2.
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Calculated, %: C 77.79; H 6.53; N 4.77.
4-(2-Hydroxyethyl)-1-methoxy-3,3-diphenylpyrrolidin-2-one (8). A 1 M solution of BH3 in THF
(2.81 ml) was added to a solution of 1-methoxy-3,3-diphenyl-4-vinyl-pyrrolidin-2-one (7) (0.41 g, 1.40 mmol)
in dry THF (10 ml) at 0°C under Ar atmosphere. The reaction mixture was stirred at room temperature for 4 h,
then cooled to 0°C, and 1 N NaOH (3 ml) and 35% H2O2 (3 ml) were added. The mixture was stirred at room
temperature for 2 h, and then saturated aq. NH4Cl (10 ml) was added. The resulting suspension was extracted
with CH2Cl2 (3×15 ml). The combined organic extracts were washed with saturated aq. NH4Cl (20 ml) and dried
over Na2SO4. Volatiles were evaporated. Purification of the crude product by column chromatography (20 to
90% EtOAc–petroleum ether) afforded product 8. Yield 180 mg (41%), white foam, Rf 0.23 (EtOAc–petroleum
1
ether, 1:1). IR spectrum, ν, cm-1: 1696 (C=O). H NMR spectrum, δ, ppm (J, Hz): 0.79-0.90 (1H, m) and 1.67
(1H, dddd, J = 3.2, J = 5.7, J = 8.3, J = 14.4, CH2CH2OH); 1.40-1.50 (1H, m, OH); 3.15-3.21 (1H, m) and 3.81
(1H, dd, J = 7.0, J = 8.2, 5-CH2); 3.32-3.42 (1H, m, CHAOH); 3.54-3.70 (2H, m, CHBOH, 4-CH); 3.78 (3H, s,
13
OCH3); 6.79-6.87 (2H, m, H Ph), 7.11-7.32 (6H, m, H Ph); 7.48-7.54 (2H, m, H Ph). C NMR spectrum, δ,
ppm: 32.6; 35.2; 48.1; 57.8; 60.4; 62.3; 126.9; 127.3; 128.0; 128.1; 128.5; 128.7; 140.4; 140.8; 172.3. Found,
m/z: 312.1592 [M+H]+. C19H21NO3. Calculated, m/z: 312.1594.
4-(2-Chloroethyl)-1-methoxy-3,3-diphenylpyrrolidin-2-one (9). A mixture of 4-(2-hydroxyethyl)-1-
meth-oxy-3,3-diphenylpyrrolidin-2-one (8) (0.24 g, 0.76 mmol), SOCl2 (3 ml), and DMF (50 µl) was stirred at
room temperature for 20 h. The excess of SOCl2 was removed under reduced pressure. The mixture was cooled
to 0°C and treated with sat. NaHCO3 (15 ml), then extracted with t-BuOMe (3×10 ml). The combined organic
extracts were washed with water (20 ml) and brine (20 ml) and dried over Na2SO4. Volatiles were evaporated.
Purification of the crude product by column chromatography (10 to 35% EtOAc–petroleum ether) afforded
product 9. Yield 210 mg (84%), white powder, mp 123-125°C (MeOH), Rf 0.23 (EtOAc–petroleum ether, 1:3).
1
IR spectrum, ν, cm-1: 1710 (C=O). H NMR spectrum, δ, ppm (J, Hz): 1.11-1.21 (1H, m) and 1.95 (1H, dddd,
J = 3.4, J = 5.3, J = 10.3, J = 14.9, CH2CH2Cl); 3.19-3.25 (1H, m) and 3.88 (1H, dd, J = 7.1, J = 8.1, 5-CH2);
3.45 (1H, ddd, J = 4.3, J = 10.3, J = 11.3, CHACl); 3.51-3.64 (2H, m, CHBCl, 4-CH); 3.87 (3H, s, OCH3); 6.87-
6.91 (2H, m, H Ph); 7.20-7.41 (6H, m, H Ph); 7.57-7.61 (2H, m, H Ph). 13C NMR spectrum, δ, ppm: 32.6; 35.3;
42.7; 47.5; 57.6; 62.4; 127.2; 127.4; 128.2; 128.3; 128.4; 128.6; 140.1; 140.7; 172.2. Found, %: C 68.99;
H 6.07; N 4.21. C19H20ClNO2. Calculated, %: C 69.19; H 6.11; N 4.25.
1-Methoxy-4-(2-morpholinoethyl)-3,3-diphenylpyrrolidin-2-one (1). The reaction mixture of
4-(2-chloroethyl)-1-methoxy-3,3-diphenylpyrrolidin-2-one (9) (118 mg, 0.36 mmol) and morpholine (0.20 ml,
2.27 mmol) in EtOH (5 ml) was heated in a closed vial at 105°C for 48 h. Volatiles were evaporated, and water
(10 ml) was added. The resulting suspension is extracted with EtOAc (3×12 ml). The combined organic extracts
were washed with water (30 ml) and brine (20 ml) and dried over Na2SO4. Purification of the crude product by
column chromatography (50 to 100% EtOAc–petroleum ether) afforded product 1. Yield 100 mg (76%), white
foam, Rf 0.33 (MeOH-CH2Cl2, 1:9). IR spectrum, ν, cm-1: 1706 (C=O). 1H NMR spectrum, δ, ppm (J, Hz): 0.78-
0.90 (1H, m) and 1.57-1.68 (1H, m, CHCH2CH2N); 2.27-2.46 (6H, m, CH2N(CH2)2); 3.19-3.26 (1H, m) and
3.84 (1H, dd, J = 7.0, J = 8.0, 5-CH2); 3.27-3.38 (1H, m, 4-CH); 3.66-3.75 (4H, m, CH2OCH2); 3.86 (3H, s,
13
OCH3); 6.87-6.93 (2H, m, H Ph); 7.18-7.38 (6H, m, H Ph); 7.54-7.59 (2H, m, H Ph). C NMR spectrum, δ,
ppm: 26.8; 36.4; 48.3; 53.9; 56.8; 58.0; 62.3; 66.9; 127.0; 127.3; 128.1 (2C); 128.5; 128.7; 140.5; 140.8; 172.3.
Found, %: C 72.29; H 7.51; N 7.23. C23H28N2O3. Calculated, %: C 72.61; H 7.42; N 7.36.
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