Studies on the synthesis and dynamic NMR properties of 2-(benzylidene amino)-N-[(R)-2-hydroxy-2-methyl-1-phenylpropyl]acetamide

Article abstract of DOI:10.1007/BF03245877

An efficient method was employed for the preparation of 2-(benzylideneamino)-N-[(R)-2-hydroxy-2-methyl-1-phenylpropyl] acetamide utilizing optically pure (R)-5,5-dimethyl-4-phenyloxazolidin-2-one. This product showed interesting dynamic NMR properties for

Full text of DOI:10.1007/BF03245877

J. Iran. Chem. Soc., Vol. 7, No. 1, March 2010, pp. 185-189.
JOURNAL OF THE
Iranian
Chemical Society
Studies on the Synthesis and Dynamic NMR Properties of
2-(Benzylidene amino)-N-[(R)-2-hydroxy-2-methyl-1-phenylpropyl]acetamide
H.A. Samimia, M. Mamaghania,*, K. Tabatabeiana and H.R. Bijanzadehb
aDepartment of Chemistry, Faculty of Sciences, University of Guilan, P. O. Box 41335-1914, Rasht, Iran
bDepartment of Chemistry, Tarbiat Modaress University, Tehran, Iran
(Received 18 November 2008, Accepted 4 March 2009)
An efficient method was employed for the preparation of 2-(benzylideneamino)-N-[(R)-2-hydroxy-2-methyl-1-phenylpropyl]
acetamide utilizing optically pure (R)-5,5-dimethyl-4-phenyloxazolidin-2-one. This product showed interesting dynamic NMR
properties for the methylene protons adjacent to the azomethine group (ꢀG‡ = 15.1 0.1 kcal mol-1).
Keywords: Chiral azomethine, Azomethine ylide, Dynamic NMR, Chiral auxiliary
INTRODUCTION
such as serine or threonine [10] or using oxiranes [11].
Furthermore, it can be obtained from ꢂ,ꢁ-unsaturated chiral
imides relying on the reaction of 2,3-dihalocarboxylic acid
derivatives with primary amines or ammonia [12], or from
methods using chiral 3-benzoyloxyaminoimides [8a].
In the course of our research program, which was based
on the synthesis and derivatization of heterocyclic compounds
[13], and in a search for a more efficient method for the
synthesis of homochiral aziridine carboxylic acids, our prime
objective was to use optically pure (R)-5,5-dimethyl-4-
phenyloxazolidin-2-one (2) as chiral transferring auxiliary for
the preparation of homochiral aziridine carboxylic acids (8)
(Scheme 1). Interestingly, this approach led us to the
preparation of the chiral azomethine 5.
Auxiliary methodology to transfer chirality, with
predictable stereochemistry in newly formed stereoisomers,
proved to be an indispensable tool in asymmetric synthesis [1].
In this area, the use of enantiomerically pure oxazolidin-2-one
derivatives as chiral auxiliaries in acyl group transformations,
aldol reactions, conjugate addition, alkylation, azidation,
hydroxylation, halogenation, amination and ꢁ-lactam synthesis
has been well demonstrated [2-5]. Currently, Davies et al.
have used SuperQuat 1 (Fig. 1) for the control of the
stereoselectivity of reactions on attached acyl fragments [6]. In
addition, the gem-dimethyl groups in the SuperQuat auxiliary
affect the control of the conformation of the substituents at the
C4 position, thus enhancing the face selective shielding of the
attached acyl fragments [7].
O
O
On the other hand, chiral aziridine carboxylates as useful
intermediates in the synthesis of optically active compounds
have attracted a lot of interest [8,9]. These valuable three-
membered heterocycles are available by enzymatic separation
of the racemic mixtures [9], from ꢁ-hydroxy ꢂ-amino acids
O
NH
R
O
NH
Ph
1
2
*Corresponding author. E-mail: m-chem41@guilan.ac.ir
Fig. 1

Samimi et al.
O
O
O
O
Et3N, DMAP
THF, rt, 12 h
O
N
O
NH
+
Ph
Cl
Ph
Ph
Br2
CHCl3, room temp.
Ph
3
2
O
O
Br
OH
H
Ph
Ph
H
H
N
O
N
NH3
Ph
N
H
H
EtOH, 24 h
77%
H
Br
5
Ph
Ph
O
O
4
diastereomeric
ratio: 3/1
333 K
NH3
EtOH, 24 h
OH
H
O
H
N
O
H
N
N
H
H
N
H
hydrolysis
O
N
Ph
6
Ph
HO2C
Ph
7
8
Ph
Scheme 1
EXPERIMENTAL
General
mmol) and cinnamoyl chloride (1 g, 6 mmol) were added at
room temperature. The reaction mixture was stirred for 12 h
and the progress of the reaction was monitored by TLC
(EtOAc/hexane; 1:5). After completion of the reaction,
diethylether (10 ml) and NaHCO3 (20%) (25 ml) were added.
The organic phase was separated, dried (MgSO4) and the
solvent was evaporated under vacuum. The resultant solid
product was recrystalized from hot EtOH to furnish the
desired product (3) (1.34 g, 4.17 mmol) as white crystals in
72% yield, m.p.: 144-145 °C, [ꢂ]D 25 = +25o [c = 1, CHCl3], IR
(KBr): ꢃmax (cm-1): 3060, 2930, 1771, 1682, 1615, 1450, 752,
Melting points were measured on an Electrothermal 9100
apparatus. IR spectra were determined on a Shimadzo IR-470
1
spectrometer. H NMR spectra were recorded on a 500 MHz
Bruker DRX-500 in CDCl3 as solvent and TMS as internal
standard. Mass spectra were obtained from a GC MS-QP
1100EX Shimadzu instrument. Elemental analyses were done
on a Carlo-Erba EA1110CNNO-S analyzer which agreed with
the calculated values. Preparative thin layer chromatography
was prepared from Merck Kieselgel 60 H, F254, Art No. 7730.
For column chromatography Merk Kieselgel 60, Art No.
107733 was employed. Chemicals were purchased from
Merck and Fluka. All solvents used were dried and distilled
according to standard procedures.
1
690; H NMR (500 MHz, CDCl3, 25 °C): 1.1 (s, 3H), 1.7 (s,
3H), 5.2 (s, 1H), 7.2-7.6 (m, 8H), 7.7 (d, J = 7.2 Hz, 2H), 7.8
(d, J = 15.7 Hz, 1H), 8.1 (d, J = 15.7 Hz, 1H) ppm. Calcd. for
C20H19NO3 (321.37); C, 74.74; H, 5.95; N, 4.35. Found: C,
74.57; H, 6.15; N, 4.27.
Preparation of (R)-5,5-Dimethyl-4-phenyl-3-[(E)-3-
phenylacryloyl] oxazolidin-2-one (3)
To a magnetically stirred solution of (R)-5,5-dimethyl-4-
phenyloxazolidin-2-one (2) (1.0 g, 5.8 mmol) in THF (20 ml),
Et3N (1 ml), dimethylaminopyridine (DMAP) (0.2 g, 1.6
Preparation of (R)-3-(2,3-Dibromo-3-phenylpropa-
noyl)-5,5-dimethyl-4-phenyl oxazolidin-2-one (4)
To a magnetically stirred solution of (3) (0.5 g, 1.6 mmol)
in chloroform (20 ml) a 30% solution of Br2 in chloroform
was added dropwise at room temperature until the bromine
186

Studies on the Synthesis and Dynamic NMR Properties
color no longer discharged. The solvent was evaporated under
according to the Davies protocol [6]. N-Acylation of 2 was
achieved via the reaction of trans-cinnamoyl chloride to afford
the desired acylated auxiliary 3 at room temperature in 72%
yield {[ꢂ]D = +25o (c = 1, CHCl3)}. This product was reacted
with 30% solution of Br2 in chloroform to provide a
diastereomeric mixture of (R)-3-(2,3-dibromo-3-phenyl-
propanoyl)-5,5-dimethyl-4-phenyloxazolidin-2-one (4) in 87%
yield with diastereomeric ratio of 3:1 (determined with 1H
NMR). The diastereomeric mixture was treated with
concentrated NH3 in ethanol at room temperature in order to
furnish the related aziridine products (7), but interestingly, this
vacuum and the residue was recrystallized from a mixture of
petroleum ether/chloroform to provide a diastereomeric
mixture (3/1) of (4) (0.67 g, 1.39 mmol) as white solid in
87%, m.p.: 152-154 °C, IR (KBr): ꢃmax (cm-1): 3050, 2950,
1
1778, 1512, 1615, 1450, 690, 752; H NMR (500 MHz,
CDCl3, 25 °C): (major diastereomer): 1.0 (s, 3H), 1.7 (s, 3H),
5.2 (s, 1H), 5.3 (d, J = 12.9 Hz, 1H), 6.7 (d, J = 12.9 Hz, 1H),
7.4 (m, 10 H) ppm; (minor diastereomer): 1.0 (s, 3H), 1.7 (s,
3H), 5.2 (s, 1H), 5.5 (d, J = 12.5 Hz, 1H), 6.6 (d, J = 12.5 Hz,
1H), 7.4 (m, 10H) ppm; MS m/z 479, 481, 483 (M, M+2,
M+4, <1%), 402 (1.8), 404 (3.57), 406 (1.78), 281 (36.2), 218
(48.1), 190 (15.1), 162 (2.5), 146 (100), 77 (12.5), 58 (16.6);
Calcd. for C20H19Br2NO3 (481.17); C, 49.92; H, 3.98; N, 2.91.
Found: C, 49.83; H, 3.85; N, 3.01.
reaction
gave
2-benzylideneamino-N-[(R)-2-hydroxy-2-
methyl-1-phenylpropyl]acetamide (5) in 77% yield (Scheme
1 ). The formation of azomethine products by ring opening of
aziridine rings which can produce azomethine ylides by
prototropic shift, have been observed before [14].
Preparation of 2-(Benzylideneamino)-N-[(R)-2-
The formation of chiral azomethine product (5) was
visualized by the initial formation of the expected aziridine 7
which underwent in situ, aziridine ring opening and
endocyclic ring cleavage of the oxazolidine-2-one moeity
under the alkaline condition. The structure of the amide 5 was
hydroxy-2-methyl-1-phenylpropyl] acetamide (5)
Concentrated NH3 (0.2 ml) was added dropwise to a
magnetically stirred solution of (R)-3-(2,3-dibromo-3-
phenylpropanoyl)-5,5-dimethyl-4-phenyloxazolidin-2-one (0.5
g, 1 mmol) in EtOH (15 ml) at room temperature. Stirring was
continued at this temperature for 24 h after which the TLC
(EtOAc/hexane; 1:3) examination showed the complete
consumption of the starting dibromo-compound. The solvent
was removed under vacuum and the solid residue was purified
by column chromatography (EtOAc/hexane; 1:5) to furnish 2-
(benzylideneamino)-N-[(R)-2-hydroxy-2-methyl-1-phenyl-
propyl] acetamide (5) (0.24 g, 0.77 mmol) as white crystals in
77% yield, m.p.: 84-86 °C, [ꢂ]D 25 = - 42.9o [c = 1, CHCl3], IR
(KBr): ꢃmax (cm-1): 3400, 3100, 1740, 1710, 1660, 1400, 753,
1
694; H NMR (500 MHz, CDCl3, 25 °C): 0.9 (s, 3H), 1.6 (s,
3H), 1.7 (s, 1H), 4.6 (s, 1H), 5.7 (s, 1H), 6.1 (s, br, 1H), 6.7 (s,
br, 1H), 7.2 (d, J = 6.5 Hz, 2H), 7.4 (m, 6H), 7.7 (dd, J = 2.2,
7.8 Hz, 2H), 8.3 (s, 1H) ppm; MS m/z 295 (23.2, M-15), 294
(100), 293 (73.9), 233 (2.5), 146 (65.2), 118 (4.0), 104 (14.0),
77 (10.1), 59 (56.1); Calcd. for C19H22N2O2 (310.39) C, 73.52;
H, 7.14; N, 9.02. Found: C, 73.37; H, 7.25; N, 9.20.
RESULTS AND DISCUSSION
Fig. 2. Variable temperature 500 MHz 1H NMR spectra of 5 in
Optically pure (R)-5,5-dimethyl-4-phenyloxazolidin-2-one
(2) was readily available from the (R)-phenylglycine
CDCl3.
187

Samimi et al.
1
deduced from its elemental analysis and high-field H NMR
and IR spectral data.
the coalescence temperature kc for the dynamic process in
question was calculated with the help of the Gutowsky-Holm
expression [15] kc = ꢅꢀꢃc/ꢆ2 and the corresponding free
energy of activation was obtained by the Eyring equation [16]
(ꢀG‡ = 15.1 0.1 kcal mol-1).
For further refinement of the structure of the amide 5, a
series of deuterium exchange experiments were carried out in
D2O. The results of this study (Fig. 3) showed that in the
The methylene protons in the amide
5 are
diastreotopic due to the presence of a chiral center in the
molecule which appear as two broad singlets at ꢄ = 6.1 and 6.7
ppm. Interestingly, these two protons showed dynamic
properties and the variable temperature spectra gave the
coalescence temperature 333 K (Fig. 2). The rate constant at
Fig. 3. Deuterium exchange experiment 500 MHz 1H NMR spectra of 5 in CDCl3 a and b at 298 °K,
and c at 328 °K.
188

Studies on the Synthesis and Dynamic NMR Properties
presence of 2 equimolars D2O, the OH proton (ꢄ 1.7 ppm) is
[8]
a) G. Cardillo, S. Casolari, L. Gentilucci, C. Tomasini,
completely removed from the spectra and the intensity of NH
proton (ꢄ = 5.7 ppm) is appreciably decreased (Fig. 3, b).
Exchange of CH2 protons were only observed in the presence
of 4 equimolars of D2O at 328 °K (Fig. 3, c) (signals at ~4.7
and 4.39 ppm in spectra b and c respectively, denote DOH). In
conclusion, we have developed an efficient protocol for the
preparation of chiral azomethine 5 which could be used as an
azomethine ylide precursor for the preparation of highly
substituted chiral five-membered ring nitrogen heterocycles
by1,3-dipolar cycloadditon reaction.
Angew. Chem. Int. Ed. Engl. 35 (1996) 1848; b) D.
Tanner, Angew. Chem. Int. Ed. Engl. 33 (1994) 599; c)
B.F. Bonini, M.G. Fochi, M. Comes-Franchini, A.
Ricci, L. Thijs, B. Zwanenburg, Tetrahedron:
Asymmetry 14 (2003) 3321.
[9]
I. Chervin, A.V. Eremeer, R.G. Kostyanovsky, F.D.
Polyak, Tetrahedron 46 (1990) 6741.
[10] a) O. Ploux, M. Caruso, G. Chassaing, A. Marquet, J.
Org. Chem. 53 (1988) 3154; b) K.J. Shaw, J.R. Luly, H.
Rapoport, J. Org. Chem. 50 (1985) 4515.
[11] J. Legters, L. Thijs, B. Zwanenburg, Reccl. Trav. Chim.
Pays-Bas 111 (1992) 1.
[12] G. Cardillo, L. Gentilucci, C. Tomasini, M.P. Visa
Castejon-Bordas, Tetrahedron: Asymmetry 7 (1996)
755.
ACKNOWLEDGEMENTS
We are thankful to the Research Council of the University
of Guilan for the partial support of this work.
[13] a) M. Mamaghani, N.O. Mahmoodi, A.A. Moghisseh,
L. Pourmohamad, J. Iran. Chem. Soc. 5 (2008) 238; b)
K. Tabatabaeian, M. Mamaghani, N. Mahmoodi, A.
Khorshidi, Tetrahedron Lett. 49 (2008) 1450; c) A.
Badrian, M. Mamaghani, K. Tabatabaeian, H.
Valizadeh, Lett. Org. Chem. 4 (2007) 228; d) K.
Tabatabaeian, M. Mamaghani, N.O. Mahmoodi, A.
Khorshidi, J. Mol. Catal. A 270 (2007) 112; e) K.
Tabatabaeian, M. Mamaghani, N.O. Mahmoodi, A.
Khorshidi, Can. J. Chem. 84 (2006) 1541; f) M.
Mamaghani, K. Tabatabaeian, M. Mirzaeinejad, M.
Nikpassand, J. Iran. Chem. Soc. 3 (2006) 89; g) M.
Mamaghani, M.R. Yazdanbakhsh, A. Badrian, H.
Valizadeh, H.A. Samimi, Lett. Org. Chem. 2 (2005)
721.
REFERENCES
[1]
a) W. Oppolzer, Pure Appl. Chem. 60 (1988) 39; b)
D.A. Evans, Aldrichim. Acta 15 (1982) 23; c) A.
Studer, Synthesis (1996) 793; d) H.U. Blaser, Chem.
Rev. 92 (1992) 935.
[2]
[3]
S.N. Kim, H. Jin, J.G. Jun, Bull. Korean Chem. Soc. 23
(2002) 749.
a) C. Gaul, D. Seebach, Org. Lett. 2 (2000) 1501; b)
D.A. Evans, L.D. Wu, J.J.M. Wiener, J.S. Johnson,
D.H.B. Ripin, J.S. Tedrow, J. Org. Chem. 64 (1999)
6411; c) M.P. Sibi, Aldrichim. Acta 32 (1999) 93.
T. Kotake, S. Rajesh, Y. Hayashi, Y. Mukai, M. Ueda,
T. Kimura, Y. Kiso, Tetrahedron Lett. 45 (2004) 3651.
K. Gillon, S. Cook, C.L. Gibson, A.R. Kennedy, J.
Chem. Soc., Perkin Trans. 1 (2001) 1538.
S.G. Davies, H.J. Sanganee, Tetrahedron: Asymmetry 6
(1995) 671.
[4]
[5]
[6]
[7]
[14] I. Coldham, R. Hufton, Chem. Rev. 105 (2005) 2765.
[15] H.S. Gutowsky, C.H. Holm, J. Chem. Phys. 25 (1956)
1228.
[16] H. Friebolin, Basic One- and Two-Dimensional NMR
S.G. Davies, H.J. Sanganee, P. Szolcsanyl, Tetrahedron
55 (1999) 3337.
Spectroscopy, 4th ed., Wiley-VCH, 2005.
189