SvMlIETIC COMMUNICATIONS, 29(8), 1277-1286 (1999)

SYNTHESES OF BISOXAZOLIDINES AND MORPHOLONES

Victor Santes," Aurelio Ortiz," Rosa Santillan," Atilano Guti6rrezb and Norberto Farfha*

"Departamento de Quimica, Centro de Investigaci6n y de Estudios Avanzados del IPN, Apdo. Postal 14-740,07000 Mexico D.F., Mexico,

Email Jfarfan@mail.cinvestav.mx. Lab. de RMN, Universidad Aut6noma Metropolitana, Av. Michoach y la

Purfsima dn, Col. Vicentina, 09340 Ixtapalapa, M6xico D. F., Mexico.

Abstract: The preparation of two new bisoxazolidines, two N-(2-hydroxyethy1)- N-alkylglycine derivatives and two morpholones is described. The structure of

(5S,6R)-N-isopropyl-5-methyl-6-phenyl-1,4-oxazin-2-one was established by X- ray crystallographic analysis.

In previous studies we have reported that the reaction of secondary

aminoalcohols with glyoxal provides a route to aminoacids,' oxazino-oxazines and

bisoxazolidines,2 while secondary anilines afford indol derivative^.^ In contrast, the

reaction of primary aminoalcohols with 12-diketones yield heteropropellanes4 and

2-hydroxy-5,6-dihydro-2H-[1,4]-oxazines? or bi(benzothiazoly1) and

benzothiazino-benzothiazine, if o-aminothiophenol is reacted with gy~xa l .~ Recently

we have applied this sequence to the preparation of 1 ,4-piperazines by reaction of

the N,N'-bis-(norephedrine)ethylendiamine derivatives with 1,Zdiketones and

subsequent reduction with dib~rane.~

* To whom correspondence should be addressed

Copyright Q 1999 by Marcel Dekker, Inc.

SANTES ET AL.

In continuing with our interest in this type of reactions we report herein the

condensation of four N-alkylnorephedrines ( la- ld) with glyoxal. The

alkylnorephedrine derivatives (la-lc) were prepared by reaction of (-)-

norephedrine with the corresponding alkylbrornide: while compound I d was

obtained by reaction of pivaloyl chloride with (-)-norephedrine and subsequent

reduction with borane THF?

Unequivocal 'H and I3C spectral assignment for compounds 2a-2d was

achieved by 2D 'H and I3C correlated experiments. Reaction of l a and l b with

glyoxal afforded [5R,5'R,4S,4'S,2R,2'R]-5,5'-diphenyl-4,4'-dimethyl-N,N9-

diethyl-2,2'-bisoxazolidine (2a) and [5R,5'R,4S,4'S,2R,2'S]-5,5'-diphenyl-4,4'-

dimethyl-N,N'-dibenzyl-2,2'-bisoxazolidine (2b), respectively (Scheme I), as

established by NMR experiments. The 'H and "C NMR spectra of 2a show signals

for half of the molecule due the existence of a Cz symmetry axis in the molecule.

Determination of the bisoxazolidine type structure for 2a was based on

measurement of the "C satellite coupling constantsZ for H-2 (k4.53 ppm J,,= 154

Hz, 'JHH=3.66 Hz) and the NOESY spectrum which shows through space

interaction between H-2 and CH3-6, thus allowing to establish the configuration for

C-2 as R. In contrast, the 'H NMR spectrum of 2b shows a different coupling

pattern since the protons at the ring fusion give rise to an AF3 system at 6=4.69

ppm and 4.55 ppm (3JHH=5.6 Hz) for H-2 and H-2,' respectively, thus evidencing

that the new stereogenic centers are different. Complete assignment of the 'H NMR spectra for both compounds was based on the COSY and NOESY experiments. The

NOESY spectrum shows interaction between H-2' and H-2, H-4', H-4, the AB system due to the methylene at the position 7', H-5' and H-5; in addition, H-2

shows interaction with the AB ascribed to H,-7 and H-2', establishing the

configuration at the C2 and C2' ring fusion carbons are R and S, respectively. This

in turn allowed assignment of the I3C NMR spectrum based on the HETCOR

spectrum.

Reaction of compounds l c and I d with glyoxal afforded morpholones 2c

and 2d, respectively (Scheme 1) as evidenced by the "C NMR signal at 6=169.1

and k168.8 ppm for the carbonyl group of 2c and 26, respectively. The 'H NMR

spectra show the characteristic AF3 system for the diastereotopic protons alpha to

BISOXAZOLIDINES AND MORPHOLONES

Scheme 1

the carbonyl group at 6=3.79 and k3.34 ppm for 2c and 6=3.69 and 6=3.54 ppm

for 2d.

The structure of 2d was established by X-ray crystallografic analysis (Figure

1) which shows that the morpholone has a pseudochair conformation, the phenyl

and neopentyl groups occupy pseudoequatorial positions and the methyl group

occupies a pseudoaxial position. Unit cell parameters and basic information about

data collection and structure refinement are summarized in the experimental

section.1° Selected interatomic bond lengths and angles are summarized in the

Table.

Upon standing in ethanoYchoroform solution 2a and 2b hydrolyze to glycine

derivatives 3a and 3b (Scheme 1). The infrarred spectra show the characteristic

bands at 3 196 and 3268 cm" for the OH groups, and the carbonyl groups at 1628

and 1624 cm-I for 3a and 3b, respectively. The 'H NMR spectrum of 3a shows an

AB system for the H-4 methylene group at 6=3.59 ppm and 3.33 ppm ('J,,= 16.1

Hz), while that of 3b is shifted to 6=3.37 ppm and 3.31 ppm ('JH,=17.5 Hz).

Complete 13C spectral assignment was based on HETCOR experiments.

SANTES ET AL.

FIG. Molecular perspective view for morpholone 26.

Table. Selected interatomic bond lengths and angles.

I Interatomic bond lengths (A) for 2d

o(2) - c(2) 1.193(6) N(4) - C(3) 1.427(7) N(4) - C(5) 1.458(6) N(4) - C(14) 1.46 l(6) c(2) - c(3) 1.486(7) c(5) - c(6) 1 .514(6) C(5) - C(13) 1.522(7) C(6) - c(7) 1.49 l(7)

Bond angles (deg) for 26

C(2) - O(1) - C(6) 121.5(4) C(3) - N(4) - C(5) 1 10.9(4)

C(3) - N(4) - C(14) 1 14.3(4) C(5) - N(4) - C(14) 114.8(4)

O(1) - C(2) - O(2) 118.7(5) 0(1) - C(2) - C(3) 119.4(5)

O(2) - C(2) - C(3) 121.9(5) N(4) - C(3) - C(2) 1 16.0(4)

N(4), - C(5) - C(6) 106.8(4) N(4) - C(S) - C(13) 1 13.2(4)

It can be concluded that the reaction of N-alkylnorephedrines leads to

bisoxazolidine type structures when the alkyl substituents are not bulky, however,

bisoxazolidines containing ethyl and benzyl groups slowly hydrolize to the

thermodynamically more stable glycine derivatives. A steric effect is supported by

the fact that bisoxazolidines containing isopropyl and neopentyl groups were not

BISOXAZOLIDINES AND MORPHOLONES 1281

obtained, the major product being the morpholone derivatives which showed good

stability in methanol solution, under the same reaction conditions.

EXPERIMENTAL

'H and I3C NMR spectra were recorded on Jeol Eclipse +400 and Jeol-270

spectrometers. Chemical shifts (ppm) are relative to (CH,),Si. Coupling constants

are quoted in Hz. The HETCOR and COSY standard pulse sequence, which

incorporates quadrature detection in both domains, was used. NOESY experiments

were recorded on a Bruker DMX500. Infrared spectra were recorded on a Perkin

Elmer 16F spectrophotometer. Mass spectra were obtained with an HP 5989A mass

spectrometer. Melting points were obtained on a Gallenkamp MFB-595 apparatus

and are uncorrected. Elemental microanalyses were performed by Oneida Research

Services, Whitesboro, NY 13492. Data for X-ray crystal structure determination of

26 was collected on an Enraf Nonius CAD4 diffractometer, h (MoKa)=0.71069 A,

monochromator: graphite, T= 293 K, / 28 scan, range lo < 8 < 25"

(5R,5'R,4S,4'S,2R,2'R)-N,N'-diethyl-5,5'-diphenyl-4,4'-dimethyl-2,2'-

bisoxazolidine (2a).

To a solution of la (1.0 g, 5.6 rnrnol) in THF (40 rnl) a 40 wt. % solution of

glyoxal in water (0.41 g, 3.90 mrnol) was added and the reaction mixture was

stirred at room temperature for 6 h. The solution was concentrated under vacuum,

ethyl ether was added and the resulting white precipitated was filtered off and dried

to give 2a (1.2 g, 56%); mp 149-151 "C; 'H NMR (399.78 MHz, CDCI,) 6: 7.40

(2H, d, J=7.3 Hz, H-o), 7.33 (2H, t, J=7.3 Hz, H-m), 7.26 (lH, t, J=7.3Hz,

H-p), 5.48 (lH, d, J=2.6 HZ, H-S), 4.53 (lH, s, H-2). 3.47 (lH, dq, J=2.6, 6.6

Hz, H-4), 2.94 (lH, dq, J=7.2, 12.5 Hz, H-7a), 2.36 (lH, dq, J=7.2, 12.5 Hz,

H-7b), 1 .OO (3H, dd, J=7.2 Hz, H-8), 0.74 (3H, d, J=6.6 Hz, H-6) ppm; 13C

NMR (100.54 MHz, CDC13) 6: 140.05 (C-i), 128.02 (C-m), 126.8 (C-p), 126.23

(C-0), 81.93 (C-2), 72.70 (C-5), 54.54 (C-4), 42.1 1 (C-7), 12.26 (C-8), 5.46

(C-6) ppm; MS m/z (%): M+ -C,H, 303 (25), 288 (loo), 273 (27), 243 (24), 165

(41), 136 (43, 91 (13), 65 (31); IR v,(KBr): 3330, 1470, 1450, 1445, 1088, 1034,630,622,590,538,520 cm:' Elemental analysis: Calc.: C, 75.78; H, 8.42;

N, 7.36. Found: C, 75.85; H, 8.49; N, 7.29.

1282 SANTES ET AL.

(5R,5'R,4S,4'S,2R,2'S)-N,N'-dibenzyl-5,5'-diphenyl-4,4'-dimethyl-2,2'-

bisoxazolidine (2b).

To a solution of l b (2.5 g, 10.4 mmol) in ethanol (40 ml) a 40 % wt. solution of

glyoxal in water (0.30 g, 5.18 mmol) was added, the reaction mixture was refluxed

for 2 h and cooled to room temperature. The solvent was removed under vacuum,

ethyl ether was added and the resulting white precipitate was filtered off and dried to

give 2b (1.07 g, 41%); mp 134-135 "C; 'H NMR (270 MHz, CDC13) 6: 7.19-7.49

(20 H, m, H-arom.), 5.40 (lH, d, J 4 . 6 Hz, H-5), 5.04 (lH, d, J 4 . 7 Hz, H-57,

4.69 and 4.55 (2H, AB, Jc5.6 Hz, H-2 and H-2'), 4.49 and 3.84 (2H, AB, J=3.9

HZ, H-7), 4.28 and 3.88 (2H, AB, J=13.8 Hz, H-7'), 3.51 (lH, dq, J 4 . 6 , 6.6

HZ, H-4), 3.21 (lH, dq, J=4.7, 5.6 HZ, H-47, 0.60 (3H, d, J=6.6 Hz, H-6),

0.53 (3H, d, J=5.6 Hz, H-6') ppm; 13C NMR (67.8 MHz, CDC13) 6: 139.9 (C-8),

139.6 (C-12), 138.9 (C-87, 138.5 (C-12'), 129.0, 128.2, 128.1, 127.9, 127.1,

126.8 and 126.1 ( C-10, C-9, C-14, (2-13, C-lo', C-9', C-14' and C-13'), 128.6,

128.0, 127.0 and 126.5 (C-1 1, C-15, C-11' and C-15'), 97.7 (C-2'), 95.1 (C-2),

81.5 (C-5), 80.9 (C-5'), 61.7 (C-4'), 58.7 (C-7'), 57.5 (C-4), 50.9 (C-7), 17.7

(C-6'), 8.7 (C-6) ppm; MS, m/z (%): 254 (3), 253 (33), M'D 252 (100), 225 (3),

224 (15), 120 (3), 118 (6), 92 (3), 91 (34); IR v-(KBr): 3334, 1464, 1034,

1010, 636, 620, 602, 556 cm.-' Elemental analysis: Calc.: C, 80.95; H, 7.14; N,

5.55. Found: C, 80.54; H, 7.24; N, 5.45.

(5S, 6R)- 6-phenyl-5-methyl-N-isopropyl-1,4-oxazin-2-one (2c).

To a solution of l c (1.0 g, 5.2 mrnol) in ethanol (40 ml) a 40 % wt. solution of

glyoxal in water (0.30 g, 5.2 mrnol) was added, the reaction mixture was refluxed

for 2 h and cooled to room temperature. Removal of the solvent under vacuum

yielded morpholone 212 as a yellow oil (1.15 g, 95%); bp 100 "C/300rnrn (dec.); 'H

NMR (270 MHz, CDCl,) 6: 7.25-7.39 (5H, m, H-arom.), 5.60 (lH, d, J=3.1 Hz, H-6), 3.79 and 3.34 (2H, AB, J=18.1 Hz, H-3), 3.40 (lH, dq, J=3.1, 6.6 Hz,

H-5), 2.70 (1 H, heptet, J=6.3 Hz, CH-8), 1.12 (3H, d, J=6.3 Hz, CH3-9), 1.10 (3H, d, J=6.3 Hz, CH3-Y), 0.70 (3H. d, J=6.6 Hz, H-7) ppm; I3C NMR (67.8

MHz, CDC13) 6: 169.1 (C=O), 136.9 (C-i), 128.4 (C-m), 128.0 (C-p), 125.8

(CO), 83.8 (C-6), 52.6 (C-5), 50.8 (CH-8), 48.0 (C-3), 20.7 and 19.5 (CH3-9'

BISOXAZOLIDINES AND MORPHOLONES 1283

and CH3-9), 5.7 (C-7) ppm; MS m/z (%): M', 233 (32), 118 (47), 99 (100),

91(27), 86 (66), 85 (65), 84 (53, 83 (72), 77 (4% 56 (93), 44 (43), 28 (28); IR

v , (film, NaCl): 2972, 1732, 1682 (CO), 1634, 1456, 1258, 1002, 916, 700

cm.-'

(5S, 6R)-6-phenyl-5-methyl-N-neopentyl-1, 4-oxazin-Zone (26). To a solution of I d (1.0 g, 4.5 mmol) in ethanol (40 rnl) a 40% wt. solution of

glyoxal in water (0.26 g, 4.5 mmol) was added and the reaction mixture was

refluxed for 2 h and cooled to room temperature. Removal of the solvent under

vacuum afforded morpholone 2d as a white solid (0.7 g, 63%); mp 106-108 "C;

'H NMR (270 MHz, CDCI,) 6: 7.26-7.39 (SH, m, H-arom.), 5.76 (lH, d, J=3.3

Hz, H-6), 3.69 and 3.54, (2H, AB, J=18.8 Hz, H-3), 3.09 (1 H, dq, J=3.3 Hz,

6.6 HZ, H-5), 2.40 and 2.10 (2H, AB, J=13.8 HZ, CH,-8), 0.93 (9H, S,

CH3-lo), 0.75 (3H, d, J=6.6 Hz, H-7) ppm; I3C NMR (67.8 MHz, CDC1,) 6:

168.8 (C=O), 136.9 (C-i), 128.4 (C-m), 127.9 (C-p), 125.4 (C-o), 83.5 (C-6),

67.1 (CH,-8). 58.1 (C-5), 52.2 (C-3), 33.5 (C-9), 27.7 (CH3-10). 5.3 (C-7) ppm.

MS m/t (%): M', 261 (1 I), 246 (7), 205 (14). 204 (100), 146 (13), 117 (8), 112

(48), 77 (S), 71 (25), 56 (20), 43 (14). 42 (84). 41 (16), 29 (1 l), 28 (5); IR

v ,(KBr): 2976,2950,2918,2864, 1740 (CO), 1380, 1372, 1288, 1258, 1240,

1136, 1004,738,704 cm-'; Elemental analysis: calc.: C, 73.56; H, 8.81; N, 5.36.

Found: C, 73.75; H, 8.98; N, 5.34.

N-ethyl-N-(l-(S)-2-(R)-phenyl-2-hydroxyethyl)glycine (3a).

Compound 2a hydrolyzed in chloroform/methanol solution to give 3a. The same

compound was obtained when l a was heated with glyoxal in ethanol for 8 h, white

solid mp 163-165 "C; 'H NMR (399.78 MHz, DMSO-4) 6: 7.37 (2H, d, J=7.3

Hz, H-o), 7.32 (2H. t, J=7.3 Hz, H-m), 7.22 (lH, t, J=7.3 Hz, H-p), 5.05 (lH,

d, Jz1.8 HZ, H-1), 3.59 and 3.33 (2H, AB, Jz16.1 HZ, H-4), 3.26 (lH, dq,

J=1.8, 6.6 Hz, H-2), 3.00 (2H, m, CH,-7), 1 .O9 (3H, t, J=7.1 Hz, H-8). 0.94

(3H, d, J=6.6 Hz, H-6) ppm; "C NMR (100.54 MHz, DMSO-4) 6: 169.7 (C-5),

1284 SANTES ET AL.

143.7 (C-i), 128.4 (C-m), 127.4 (C-p), 126.4 (C-o), 71.8 (C-1), 63.7 (C-2), 53.2

(C-4), 48.4 (C-7), 11.6 (C-8), 8.4 (C-6) ppm; MS m/z (%): [M+ -H20, 219 (OS)],

192 (0.3), 130 (loo), 105 (8), 85 (20), 77 (30), 58 (46), 56 (82), 28 (18); IR v,,

(KBr): 3196 (OH), 3022,2852,1628 (CO), 1388, 1330, 1062, 1044, 1004, 750,

706 cm:' Elemental analysis: calc.: C, 65.82; H, 8.01; N, 5.90. Found: C, 65.85;

H, 8.03; N, 5.78.

N-benzyl-N-(l-(S)-2-(R)-phenyl-2-hydroxyethyl)glycine (3b).

Compound 2b was allowed to stand in chloroform for three weeks giving 3b as

white solid mp 155-157 "C; 'H NMR (270 MHz, DMSO-d,) 6: 7.26-7.21 ( 1 OH,

m,H-arom),4.81 (lH, d, J=3.9 Hz, H-1), 3.82 and3.73 (2H, AB, J=14.0 Hz,

CH,-7). 3.37 and 3.31 (2H, AB, J=17.5 Hz, H-4), 2.83 (lH, dq, J=3.9, 6.7 Hz,

H-2), 0.92 (3H, d, J=6.7 Hz, H-6) ppm; I3C NMR (67.8 MHz, DMSO-d,) 6:

173.7 (C-5), 145.4 (C-i), 140.1 (C-i'), 129.0, 128.6, 128.2 and 126.6 (C-m,

C-m', C-o' and C-o), 127.3 and (126.9 (C-p' and C-p), 74.2 (C-1), 61.2 (C-2),

55.8 (CH2-7), 52.1 (C-4), 9.9 (C-6) ppm; MS, m/z (%): [M' -H20, 28 1 (1 2)], 192

(47), 147 (43), 91 (87), 56 (loo), 29 (46 ); IR v ,,,(KBr): 3268 (OH), 3064,

2998, 1624 (CO), 1458, 1450, 1390, 1344, 1328, 764, 748 and 704 cm:'

Elemental analysis: calc.: C, 72.24; H, 7.02; N, 4.68. Found: C, 71.87; H, 7.00;

N, 4.62.

Acknowledgment. Financial support from CONACYT is acknowledged.

REFERENCES AND NOTES

Farfhn, N., CuCllar, L., Aceves, J. M. and Contreras, R., Synthesis, 1987,

927.

2, a) Farfh, N., Santillan, R. L., Castillo, D., Cruz, R., Joseph-Nathan, P.

and Daran. J. C., Can. J. Chem., 1992,70, 2664; c) Farfh, N., Santillan,

BISOXAZOLIDINES AND MORPHOLONES 1285

R., Guzmin, J.B., Castillo, B., Ortiz, A., Daran, J. C., Robert, F. and

Halut, S., Tetrahedron, 1994, 50, 9951.

Farfin, N., Hernindez, J. M., Joseph-Nathan, P. and Contreras, R.,

J.Heterocyclic Chem., 1990, 27, 1745.

Ortiz, A., Carrasco, J., Hopfl, H., Santillan, R. and N. Farfh Synth.

Commun., 1998, 28, 1293.

Ortiz, A., Farfh, N., Santillan, R., Rosales, M. J., Garcia-BaCz, E., Daran,

J. C. and Halut, S., Tetrahedron Asymmetry, 1995, 6, 2715.

Farfh, N., Santillan, R., Castillo, B., Carretero, P., Rosales, M. de J.,

Garcia-Bbz, E., Flores-Vela, A., Daran, J. C. and Halut, S., J. Chem.

Res.(S), 1994, 458, ( M ) , 1994, 2521.

Ortiz, A., Farfin, N., Hopfl, H., Santillan, R. and GutiCrrez A.,

Tetrahedron:Asymmetry ,1998 (in press).

Chaloner, P. A., Langadianou, E. and Renuka Perera S. A., J. Chem. Soc.

Perkin Trans. 1, 1991, 273 1.

Tlihuext, H. and Contreras, R., Tetrahedron: Asymmetry, 1992, 3,727.

Crystal data for compound 2d: Colourless crystals, Cl,H,3N02 (M=261.36

gmol-I), crystallized in the orthorrombic space group P 2,2,2,, a=8. 39O(4),

b=10.404(5), c=17.467(4) A, V=1524(1) A? 2=4, pcalcd= 0.70 ~ g m . " A total of

1572 reflections was measured of which 1551 were independent, absorption

correction: DIFABS (rnin: 0.82, max: 1.20), corrections were made for Lorentz and

polarization effects. Solution and refinement: direct methods (SHELXS-86) for

structure solution. Nonhydrogen atoms were refined anisotropically, hydrogen

atoms were found by difference Fourier maps and refined with an overall isotropic

thermal parameter, least squares refinements were carried out by minimizing the

function CW(IF,,I-IF,~)~, where F, and F, are the observed and calculated structure

factors. Unit weight was used. Models reached convergence with

R=X(IIFJ-IFJI)/CIFJ and RW=[ZW(IF,I-IF,~)~IC~(F,,)~]'~ with values R= 0.040,

Rw= 0.037 from 847 reflections with F>3a(F) for 173 variables against IF/,

w= 1 .O, s= 1.87. Largest residual electron density peak / hole in the final difference

map: pmax=0.18, Pmin= -0.36 e - / A3. (CRYSTALS, Program for Refinement of

Crystal Structures, D. J. Watkin, J. R Caruthers, P.V. Betteridge, Univ. Oxford,

version 9, 1994).

1286 SANTES ET AL.

Supplementary Material available: Tables of atomic coordinates, thermal parameters, bond lengths and angles and observed and calculated structure factors have been

deposited at the Cambridge Crystallographic Data Center.

(Received in the USA 06 October 1998)