An efficient and simple entry to N-substituted β-enamino acid derivatives from 2-alkyl-2-oxazolines and 2-alkyl-2-thiazolines

Article abstract of DOI:10.1021/jo961037y

Reaction of azaenolates of 2-alkyl-oxa(thia)zolines 6 with imidoyl chlorides 7 as electrophiles to furnish masked N-substituted β-enamino acid derivatives 1-2 in 70-90% yield is described. Alternative routes are discussed. Compounds 1-2 generally appear in one tautomeric form, imino or enamino, depending on the nature of the imidoyl chloride. The configuration of the enamino moiety (Z) and the conformation (s-cis) of compounds 1-2 obtained were established by an NMR study and unequivocally set by nuclear Overhauser effect difference experiments. An X-ray structure of compound 1e is also reported, showing a strong intramolecular NH···N hydrogen bond. Ab initio calculations (HF/3-21G and HF/3-21+G) have been carried out on several representative examples (1e, 1p, and 1l) in an attempt to support and provide the correct geometry of these derivatives. Structural considerations among the possible isomers of compounds 1 are discussed. From these studies it was concluded that the theoretical calculations agree with the experimental results. In addition, a very simple one-pot procedure for the preparation of masked N-substituted α-alkylated β-enamino acid derivatives 2 from 6, 7, and different alkyl halides (R³Y) is described.

Full text of DOI:10.1021/jo961037y

J . Org. Chem. 1996, 61, 8849-8859
8849
An Efficien t a n d Sim p le En tr y to N-Su bstitu ted â-En a m in o Acid
Der iva tives fr om 2-Alk yl-2-oxa zolin es a n d 2-Alk yl-2-th ia zolin es†
Santos Fustero,* Antonio Navarro, Dolores D´ıaz, Marta G. de la Torre, and Amparo Asensio
Departamento de Quı´mica Orga´nica, Facultad de Farmacia, Universidad de Valencia, 46100-Burjassot,
Valencia, Spain
Francisco Sanz‡ and M. Liu Gonza´lez‡
Departamento de Termolog´ıa, Facultad de Fı´sicas, Universidad de Valencia,
46100-Burjassot Valencia, Spain
Received J une 3, 1996X
Reaction of azaenolates of 2-alkyl-oxa(thia)zolines 6 with imidoyl chlorides 7 as electrophiles to
furnish masked N-substituted â-enamino acid derivatives 1-2 in 70-90% yield is described.
Alternative routes are discussed. Compounds 1-2 generally appear in one tautomeric form, imino
or enamino, depending on the nature of the imidoyl chloride. The configuration of the enamino
moiety (Z) and the conformation (s-cis) of compounds 1-2 obtained were established by an NMR
study and unequivocally set by nuclear Overhauser effect difference experiments. An X-ray
structure of compound 1e is also reported, showing a strong intramolecular NH‚‚‚N hydrogen bond.
Ab initio calculations (HF/3-21G and HF/3-21+G) have been carried out on several representative
examples (1e, 1p , and 1l) in an attempt to support and provide the correct geometry of these
derivatives. Structural considerations among the possible isomers of compounds 1 are discussed.
From these studies it was concluded that the theoretical calculations agree with the experimental
results. In addition, a very simple one-pot procedure for the preparation of masked N-substituted
R-alkylated â-enamino acid derivatives 2 from 6, 7, and different alkyl halides (R3Y) is described.
In tr od u ction
ration of such compounds.4 Although several attractive
routes to â-amino acids have been recently described,5
the chemoselective reduction of the enaminic function in
â-enamino acid derivatives still remains as one of the
least studied strategies.6 This is probably due to the
difficulty in achieving this selective reduction in an
effective manner and also, in part, because of the high
reactivity of the ester functionality toward a great
number of reducing agents.6,7 A simple way to overcome
this problem would be through the use of protecting
groups to block this functionality. Heterocyclic systems,
such as ∆2-thiazolines, ∆2-imidazolines, and, especially,
∆2-oxazolines, have been extensively used as masked
carboxylic acids.8 The great stability of these hetero-
cycles toward a large variety of reagents, along with the
possibility of introducing chirality into their structure,
Among 1,3-difunctionalized compounds, the â-amino
acid unit is one of the most interesting target structures
due to its pharmacology1 and its utility in several aspects
of synthetic organic chemistry,2 such as chiral auxiliaries,
chiral building blocks, and intermediates in the synthesis
of â-lactams, and because this functionality is found in
several biologically active natural products.3 Therefore,
a great deal of attention has been given, in recent years,
to the development of new methodologies for the prepa-
† This paper is dedicated to Professor Herbert Lehmkuhl on the
occasion of his 70th Birthday.
‡ X-ray Analysis.
X Abstract published in Advance ACS Abstracts, November 15, 1996.
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S0022-3263(96)01037-7 CCC: $12.00 © 1996 American Chemical Society

8850 J . Org. Chem., Vol. 61, No. 25, 1996
Fustero et al.
Ch a r t 1
makes these versatile substrates the protecting groups
of choice for this purpose.
On the other hand, acyclic â-enamino acid derivatives
are well-known as useful starting materials in a variety
of synthetic processes. They have, therefore, recently
been used as building blocks in the synthesis of alkaloids,
mainly through aza-annulation processes,9 and other
biologically active compounds, such as toxins,10 1,4-
dihydropyridines,11 nalidixic acid derivatives,12 â-amino
acids,6e,13 and γ-amino alcohols.14 In addition, they have
proven to be of great utility in asymmetric synthesis15
and also as prodrugs of primary amines.16 Although
simple â-enamino esters are usually synthesized by
condensation of â-keto esters with ammonia or amines,17
other methods have alternatively been developed in order
to ensure the generality and efficiency of such processes.
Nucleophilic addition of alkyl ester enolates to nitriles,18
Michael addition of amines to alkynoates,19 and reaction
of imines with activated carbonic acid derivatives20 are
some of the strategies which, with more or less success,
have been used. In this context, we have recently
reported two new different approaches to â-enamino acid
derivatives. A simple route to masked â-dehydroamino
acids (1-2, R1 ) H, R2 ) alkyl or aryl, R3 ) or * H)
starting from 2-alkyl-2-oxazolines or 2-alkyl-2-thiazolines
and nitriles was initially described (Chart 1).21,22 More
recently, a mild two-step procedure to synthesize â-
enamino esters by reaction of ketimines with 1,1′-
carbonyl diimidazole and subsequent addition of the
corresponding alcohols was developed.23
Sch em e 1
lack of general methods for their preparation, along with
our own interest in the study of their reactivity as
precursors of â-amino acids, we report a new and general
entry to masked N-substituted â-enamino acid deriva-
tives (1-2) (R1 * H) by reacting R-metalated 2-oxa- and
2-thiazolines with imidoyl halides. In addition, alterna-
tive routes are also discussed.
In line with our efforts toward the synthesis of masked
â-dehydroamino acids21 (1-2) and keeping in mind the
(9) (a) Paulvannan, K.; Schwarz, J . B.; Stille, J . R. Tetrahedron Lett.
1993, 34, 215. (b) Paulvannan, K.; Stille, J . R. J . Org. Chem. 1994,
59, 1613. (c) Barta, N. S.; Brode, A.; Stille, J . R. J . Am. Chem. Soc.
1994, 116, 6201. (d) Cook, G. R.; Beholz, L. G.; Stille, J . R. J . Org.
Chem. 1994, 59, 3575.
Resu lts a n d Discu ssion
In order to obtain compounds 1-2 we have considered
three possible alternative strategies, as shown in Scheme
1. Apparently, the most simple access to 1-2 would be,
similar to the synthesis of â-enamino esters, the conden-
sation of â-keto-2-oxazolines (3) with amines (via a,
Scheme 1). However, although the synthesis of â-keto-
2-oxazolines has been described,24 several authors22 have
indicated that such a process leads to a complex mixture
of products and never to the desired enamines 1-2.
Therefore, the other two alternatives (via b and c) were
tested. The second approach (via b) implies the reaction
of azaenolates derived from ketimines with type A
synthons, which may be regarded as masked formyl
groups. We have studied this reaction using meth-
ylketimines, derived from aliphatic and aromatic amines,
and 2-(methylthio)-2-thiazoline (5)25 in different reaction
conditions, and we have found that, in only a few cases
(i.e., R1 ) n-butyl, R2 ) Ar) and always with very low
yields (<20%), the process yielded the target â-dehy-
droaminoacids (1, X ) S, Scheme 2).
(10) Hong, C. Y.; Kishi, Y. J . Am. Chem. Soc. 1992, 114, 7001.
(11) (a) Baindur, N.; Rutledge, A.; Triggle, D. J . J . Med. Chem. 1993,
36, 3743. (b) Poindexter, G. S.; Licause, J . F.; Dolan, P. L.; Foey, M.
A.; Combs, C, M. J . Org. Chem. 1993, 58, 3811. (c) Sausins, A.; Duburs,
G. Heterocycles 1988, 27, 269.
(12) Torii, S.; Okumoto, H.; Xu, L. H. Tetrahedron Lett. 1990, 31,
7175.
(13) (a) Lubell, W. D.; Kitamura, M.; Noyori R. Tetrahedron:
Asymmetry 1991, 2, 543. (b) Lubell, W. D.; Kitamura, M.; Noyori, R.
Tetrahedron: Asymmetry 1991, 2, 543.
(14) Bartoli, G.; Cimarelli, C.; Marcantoni, E.; Palmieri, G.; Petrini,
M. J . Org. Chem. 1994, 59, 5328.
(15) (a) Ando, K.; Yasuda, K.; Tomioca, K.; Koga, K. J . Chem. Soc.
Perkin Trans. 1 1994, 277. (b) Guingant, A.; Hammami, H. Tetrahe-
dron: Asymmetry 1991, 2, 411. (c) Guingant, A. Tetrahedron: Asym-
metry 1991, 2, 415. (d) Huang, P. Q.; Zhou, W. S. Tetrahedron:
Asymmetry 1991, 2, 875. (e) Lee, J .; Oya, S.; Snyder, J . K. Tetrahedron
Lett. 1991, 32, 5899. (f) Ando, K.; Takemasa, Y.; Tokimora, K.; Koga,
K. Tetrahedron 1993, 49, 1579.
(16) Naringrakar, V. H.; Stella, V. J . J . Pharm. Sci. 1990, 79, 138.
(17) (a) Dieckman, W. J ustus Liebigs Ann. Chem. 1901, 27, 317. (b)
Prelog, V.; Szpilfogel, S. Helv. Chim. Acta 1945, 28, 1684. (c) Kloek, J .
A.; Leschinsky, K. L. J . Org. Chem. 1978, 43, 1460. (d) Ferraz, H. M.
C.; Oliveira, E. O.; Payret-Arrua, M. E.; Brandt, C. A. J . Org. Chem.
1995, 60, 7357.
(18) (a) Hannick, S. M.; Kishi, Y. J . Org. Chem. 1983, 48, 3833. (b)
Hiyama, T.; Kobayashi, K. Tetrahedron Lett. 1982, 23, 1597.
(19) (a) Perlmutter, P. In Conjugate Addtion Reactions in Organic
Synthesis; Baldwin, J . E., and Magnus, P. D., Eds.; Pergamon Press:
Oxford, U.K., 1992; Chapter 7, p 352. (b) Cen, W.; Ni, Y.; Shen, Y. J .
Fluorine Chem. 1995, 73, 161.
(20) (a) Barluenga, J .; Pe´rez Carlo´n, R.; Gonza´lez, F. J .; Fustero, S.
Tetrahedron Lett. 1990, 31, 3793. (b) Barluenga, J .; Pe´rez Carlo´n, R.;
Gonza´lez, F. J .; Fustero, S. J . Org. Chem. 1991, 56, 6751. (c) Bartoli,
G.; Cimarelli, C.; Dalpozzo, R.; Palmieri, G. Tetrahedron 1995, 51, 8613.
(21) Fustero, S.; D´ıaz, M. D.; Barluenga, J .; Aguilar, E. Tetrahedron
Lett. 1992, 33, 3801.
(23) Fustero, S.; D´ıaz, M. D.; Pe´rez Carlo´n, R. Tetrahedron Lett.
1993, 34, 725.
(24) (a) Meyers, A. I.; Temple, D. L.; Nolen, R. L.; Mihelich, E. D. J .
Org.Chem. 1974, 39, 2778. (b) Tohda, Y.; Morikawa, M.; Kawashima,
T.; Ariga, M.; Mori, Y. Chem. Lett. 1986, 273. (c) Dixit, A. N.; Reddy,
K. V.; Rakeeb, A.; Deshmukh, A. S.; Rajappa, S.; Ganguly, B.;
Chandrasekhar, J . Tetrahedron 1995, 51, 1437. (d) Castan, F.; De-
nonne, F.; Bigg, D. Synthesis 1993, 1081. (e) Tohda, Y.; Kawashina,
T.; Ariga, M.; Akiyama, R. Bull. Chem. Soc. J pn. 1984, 57, 2329.
(25) Meyers has recently described the synthesis and reactivity in
Pd-mediated cross-coupling reactions of chiral 2-bromo-2-oxazolines,
a very reactive masked formyl group. See: Meyers, A. I.; Novachek,
K. A. Tetrahedron Lett. 1996, 37, 1747.
(22) Separately, Poindexter described the preparation of these
compounds as precursors in the synthesis of 1,4-dihydropyridines.
See: Poindexter, G. S.; Catt, J . D.; Sasse, P. A.; Kercher, M. A.
Heterocycles 1993, 36, 295.

N-Substituted â-Enamino Acid Derivatives
J . Org. Chem., Vol. 61, No. 25, 1996 8851
Sch em e 2
Sch em e 3
These results prompted us to study the third alterna-
tive, which involves, in a similar way, the reaction of
azaenolates, now derived from 2-alkyl-2-oxazolines and
2-alkyl-2-thiazolines (6), with imidoyl carbocation B (via
c, Scheme 1). As the acylimidoyl species B we have used
N-alkyl- and N-arylimidoyl chlorides (7).
Imidoyl halides,26 especially perfluoroalkyl deriva-
tives,27 are promising building blocks in organic synthesis
because of their high reactivity and their participation
in numerous synthetic processes, including the synthesis
of nitrogen heterocycles28 and other interesting fluori-
nated derivatives.29 In addition, they have shown their
utility in several fields of medicinal and agricultural
chemistry.26 N-Alkyl- and N-arylimidoyl chlorides (7)
have been obtained by standard methods, starting either
from amides by treatment with Cl2SO or PCl530 or directly
from carboxylic acids, following the procedure recently
described by Uneyama.26 On some occasions, particularly
for the thermally unstable N-1-phenylethyl derivatives,31
these compounds (7) have been used directly, without
later purification of the crude reaction mixture. No
significant change in the chemical yield of the process
was observed in these cases.
Thus, the treatment of 2-methyl-2-oxa(thia)zolines (6,
1.0 equiv) with lithium diisopropylamide (LDA, 2.0 equiv)
at -78 °C in tetrahydrofuran (THF) for 2 h generated a
slightly yellow solution of the corresponding lithium
azaenolate. Addition of a variety of N-alkyl- or N-
arylimidoyl chlorides (7, 1.0 equiv) to this solution gave,
after standard workup, the corresponding â-dehydroam-
ino acids (1-2) as the only products32 (Scheme 3). Table
1 and Table 2 (entries 2, 4, 6, and 11-13) summarize
the obtained results.
Ta ble 1. N-Su bstitu ted â-En a m in o Acid Der iva tives 1
(R3 ) H) Obta in ed fr om Oxa (th ia )zolin es 6 a n d Im id oyl
Ch lor id es 7
imidoyl chlorides (7)
yield
entry 6a
R1
R2
product (%)c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
6a Ph
6a c-C6H11
6a p-MeOC6H4
6a (()-C6H5(Me)CH
6a Ph
6a p-MeOC6H4
6a p-MeC6H4
6a (()-C6H5(Me)CH
6a p-MeOC6H4
6a p-MeOC6H4
6a p-MeC6H4
6a p-MeC6H4
Ph
Ph
Ph
Ph
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
1q
1r
87
75
72
81
95
87
88
75
85
70
73
70d
75
78
90
80
83
82
75c
78
78
83
72c
90
78
90
p-MeOC6H4
CF3
CF3
CF3
3-pyridyl
i-Pr
Me2CHCH2
t-Bu
6a (S)-(-)-C6H5(Me)CH Ph
6b Ph
6b Ph
Ph
p-MeOC6H4
CF3
3-pyridyl
Me2CHCH2
t-Bu
Ph
CF3
CF3
t-Bu
6b p-MeOC6H4
6b p-MeOC6H4
6b p-MeC6H4
6b p-MeC6H4
6c (()-C6H5(Me)CH
6c p-MeOC6H4
6c p-MeC6H4
6c p-MeC6H4
6d Ph
From Tables 1 and 2 it can be seen that the reaction
works well. High yields are, in general, obtained, and it
does not require the use of an excess of reagents, with
the exception of the base (LDA) for which a 2-fold excess
of LDA is necessary.33 To form the lithium intermediate
1s
1t
1u
1v
1w
1x
1y
1z
p-MeOC6H4
(26) Kantlehner, W.; Mergen, W. W. In Comprehensive Organic
Functional Group Transformations; Katritzky, A. R., Meth-Cohn, O.,
Rees, C, W., Eds.; Pergamon: Tarrytown, NY, 1995; Vol. 5, Chapter
17.
6d (S)-(-)-C6H5(Me)CH Ph
6e (S)-(-)-C6H5(Me)CH Ph
a
6a , 2-Methyl-2-oxazoline; 6b, 2,4,4-trimethyl-2-oxazoline; 6c,
(27) Uneyama, K.; Tamura, K.; Mizukami, H.; Maeda, K.; Watanabe,
H. J . Org. Chem. 1993, 58, 32 and the references cited therein.
(28) (a) Watanabe, H.; Yan, F.; Sakai, T.; Uneyama, K. J . Org. Chem.
1994, 59, 758. (b) Sakamoto, T.; Kikugawa, Y. J . Org. Chem. 1994,
59, 929. (c) Kobayashi, M.; Sadamune, K.; Mizukami, H.; Uneyama,
K. J . Org. Chem. 1994, 59, 1909. (d) Uneyama, K.; Morimoto, O.;
Yamashita, F. Tetrahedron Lett. 1989, 30, 4821.
2-methyl-2-thiazoline; 6d , trans-(4S,5S)-(+)-2-methyl-4-methoxy-
methyl-5-phenyl-2-oxazoline; 6e, cis-(4R,5S)-(+)-2,4-dimethyl-5-
phenyl-2-oxazoline. b Yield after purification. c Only the imino form
was observed. Enamino and imino tautomers were observed (see
ref 36).
d
8, reaction of the product that is initially formed with
the second equivalent of LDA protects it from undesired
reactions and significantly improves the chemical yield
of the process, as has already been postulated in related
systems.29 It is also worth noting that these compounds
appear generally in one tautomeric form, imino (R) or
enamino (â), which depends on the nature of substituents
R1 and R2 (Scheme 3).
(29) Huang, W. S.; Yuan, C. Y. J . Chem. Soc., Perkin Trans. 1 1995,
741.
(30) (a) Ugi, I.; Beck, F.; Fetzer, U. Chem. Ber. 1962, 95, 126. (b)
Appel, R.; Warning, K.; Zienh, K. D. Chem. Ber. 1973, 106, 3450.
(31) The preparation of such compounds, using the thionyl chloride
method, requires purification of the crude reaction by distillation. In
these cases, a partial thermal decomposition affording the correspond-
ing nitriles and alkylhalides has been observed (von Braun reaction).
See: Vaughan, W.; Carlson, D. R. J . Am. Chem. Soc. 1962, 84, 769.
Therefore, the Uneyama method (ref 27) was the only procedure
applied for obtaining these derivatives.
(32) In most instances, small amounts of amides resulting from the
hydrolysis of unreacted imidoyl chlorides (7) were identified in the
crude mixture of the reaction. These byproducts were easily separated
by flash chromatography.
(33) In contrast with other related processes (ref 21), bases, such
as n-butyl lithium, cannot be used in this reaction due to the high
reactivity of the imidoyl halides toward nucleophiles. See also refs 28
and 29.

8852 J . Org. Chem., Vol. 61, No. 25, 1996
Fustero et al.
Ta ble 2. N-Su bstitu ted r-Alk yla ted â-En a m in o Acid Der iva tives 2 (R3 * H), On e-P ot Syn th esis
entry
6a
R1
R2
R3
methodb
product
yield (%)c
1
2
3
4
5
6
7
8
9
10
11
12
13
6a
6f
6a
6f
6a
6f
6a
6b
6a
6b
6f
6f
6f
Ph
Ph
Me
Me
Me
B
A
B
A
B
A
B
B
B
B
A
A
A
2a
90
82
(()-C6H5(Me)CH
p-MeOC6H4
Ph
2b
2c
61d
90
CF3
65d,e
92
p-MeOC6H4
Ph
Ph
Ph
(S)-(-)-C6H5(Me)CH
Ph
p-MeC6H4
3-pyridyl
p-MeOC6H4
p-MeOC6H4
p-MeOC6H4
Ph
n-Bu
Bn
EtO2CCH2
EtO2CCH2
Me
2d
2e
2f
2g
2h
2i
65d
60d
55d
50d
80
p-MeOC6H4
t-Bu
Me
Me
88
2j
70f
6a , 2-Methyl-2-oxazoline; 6b, 2,4,4,-trimethyl-2-oxazoline; 6f, 2-ethyl-2-oxazoline. b method A, Obtained directly from 2-ethyl-2-oxazoline
a
(6f); method B, one-pot reaction from 2-methyl-2-oxazolines (6, R3 ) H), imidoyl halides (7), and alkyl halides (R3Y, MeI, n-BuI, BnBr,
d
and EtO2CCH2Br were used as electrophiles). c Yield after purification. Variable amounts (15-25%) of compounds 1 resulting from the
first step of the reaction of 6 (R3 ) H) and 7 were also identified and by MPLC isolated (see Table 1, entries 4-6, 9, and 17). e Enamino
and imino tautomers (3:1) were observed (see Experimental Section). .fOnly the imino form was observed.
Ch a r t 2
This methodology appears to be general for both the
heterocyclic ring system and the imidoyl halide as shown
in Tables 1 and 2. Of particular interest is its applicabil-
ity to the synthesis of trifluoromethyl derivatives due to
the importance and utility of such compounds in several
fields of organic chemistry.
The structural assignment of compounds 1-2 was
made on the basis of their spectral and analytical data.
The resulting compounds 1-2 were, in most cases,
isolated in the tautomer enaminic form â as seen from
the NMR spectra (Scheme 3). Thus, for example, in the
case of compound 1e (Table 1, entry 5), the 1H NMR
spectrum exhibits characteristic signals at δ 4.89 (s, 1H)
and 10.56 (br s, 1H) corresponding to the vinyl proton in
the HCdC grouping and NH grouping, respectively. This
spectrum is in accordance with the tautomeric form 1eâ,
suggesting also, as consequence of the large shift down-
field of the NH proton, an intramolecular hydrogen bond,
probably between the amino group and the sp2 nitrogen
atom of the oxazoline ring.34
In order to determine the correct stereochemistry of
the enaminic double bond moiety in compounds 1-2 (a 1,
a 2 or b1.1, b1.2, b2.1, b2.2 in Chart 2), 1H NMR NOE-
difference experiments were applied over compound 1e.
This study showed that compound 1e exists predomi-
nantly in the (Z) configuration (a 1 or a 2) in CDCl3
solution. Thus, by irradiation of the vinylic hydrogen at
(Z)-s-trans (a 2). Therefore, a single-crystal X-ray diffrac-
tion analysis was performed for compound 1e. Certain
4.89 ppm, a positive NOE (8.28%) was obtained for the
ortho hydrogens of the p-methoxyphenyl ring at 7.22
selected bond lengths, bond angles, and dihedral angles
ppm. Analogous nuclear Overhauser effect (NOE) en-
of 1e are listed in Table 3, and a plot of the molecular
geometry is given in Figure 1. The crystal structure of
hancements resulted from the saturation of the doublet
at 7.22 ppm. An additional positive NOE (2.48%) with
compound 1e shows that it was in agreement with the
the ortho hydrogens of the phenylamino ring at 6.65 ppm
initially proposed (Z)-s-cis configuration (a 1) and confirms
was also detected, confirming the proposed structure.
the results of previous experiments. (The author has
This experiment, however, did not allow us to distinguish
deposited atomic coordinates for this structure with the
Cambridge Crystallographic Data Centre. The coordi-
between the two possible conformers (Z)-s-cis (a 1) and
nates can be obtained, on request, from the director,
(34) Similar hydrogen bond interactions have been observed for
Cambridge Crystallographic data Centre, 12 Union Road,
Cambridge, CB2 1EZ, UK.) Inspection of the structural
data in Table 3 reveals a strong intramolecular hydrogen
bond between N2-H21 and N1 (N1-H21 2.04 Å) forming
related systems. (a) See, e.g., refs 20c, 21, 22. (b) Chowdhry, M. M.;
Burrows, A. D.; Mingos, D. M.; White, A. J .; Williams, D. J . J . Chem.
Soc., Chem. Commun. 1995, 1521. (c) Dixit, A. N.; Reddy, K. V.;
Deshmukh, A. R.; Rajappa, S.; Ganguly, B.; Chandrasekhar, J .
Tetrahedron 1995, 51, 1437.

N-Substituted â-Enamino Acid Derivatives
J . Org. Chem., Vol. 61, No. 25, 1996 8853
Ta ble 3. Com p a r ison of Selected Ca lcu la ted Bon d Len gth s, Bon d An gles, a n d Dih ed r a l An gles for 1e (a 1) [(Z)-s-cis] a n d
1e (a 2) [(Z)-s-tr a n s] w ith Th ose Exp er im en ta lly Obser ved for 1e (a 1) [(Z)-s-cis]
calculatedb (a 1)
calculatedb (a 2)
observeda (a 1)
HF/3-21G
HF/3-21+G
HF/3-21G
HF/3-21+G
bond lengths (Å)
1.013
1.365
1.350
1.434
N2-H21
N2-C3
0.86(2)
1.011
1.370
1.353
1.433
1.275
1.004
1.374
1.344
1.442
1.003
1.380
1.248
1.441
1.367(3)
1.356(3)
1.441(3)
1.275(3)
C3-C4
C4-C51
C51-N1
C51-O2
N1‚‚‚H21
O2‚‚‚H21
N2-N1
O2-N2
1.270
1.402
1.880
2.679
1.407
1.904
2.689
2.04(2)
1.914
2.740
1.956
2.763
2.747(3)
bond angles (deg)
121.7
122.9
N2-C3-C4
121.3(2)
123.7(2)
127.1(2)
121.9
123.1
128.8
123.5
123.7
126.9
C3-C4-C51
C4-C51-N1
C4-C51-O2
C51-N1‚‚‚H21
C51-O2‚‚‚H21
N1‚‚‚H21-N2
O2‚‚‚H21-N2
126.6
117.5
102.3
134.2
128.3
117.4
103.0
132.0
93.7(7)
96.1
96.1
140.0(1)
136.6
134.8
dihedral angles (deg)
H21-N2-C3-C4
N2-C3-C4-C51
C3-C4-C51-N1
C3-C4-C51-O2
C4-C51-N1‚‚‚H21
C4-C51-O2‚‚‚H21
-3.1(1.5)
-4.7(1)
9.2(4)
-5.7
-2.8
4.7
-5.1
-1.8
3.5
-7.8
-4.3
-6.6
-2.9
5.6
1.0
4.5
0.4
-7.7(4)c
0.0
0.0
a
b
For experimental details see the Experimental Section (X-ray). Estimated standard deviations in parentheses. See computational
methods in the Experimental Section. c Dihedral angle between crystallographic planes.
data for the optimized geometries are shown in Table 3.
As shown in Table 3, there is a good agreement between
the HF/3-21G and the HF/3-21+G geometries for the
compound 1e (a 1 vs a 2) and the experimental geometry
for 1e (a 1). Due to this and also to the large number of
atoms in these types of structures, the other selected
compounds were only optimized with HF/3-21G calcula-
tions. As expected, enamino forms a 1 and a 2 appear to
be more stable than the imino tautomers c and d . The
great stability introduced by the strong hydrogen in-
tramolecular bond between the NH moiety and the N
(sp2) atom in the a 1 structure is reflected in the lower
energy of this structure compared to b1.1, and b1.2, 12.9
(or 11.4 at the HF/3-21+G) and 11.1 kcal mol-1, respec-
tively, and this also justifies the preferred Z stereochem-
istry of the enamino double bond (Table 4).
F igu r e 1. ORTEP diagram of the X-ray crystal structure of
1e showing the intramolecular N2‚‚‚H interaction. Arbitrary
numbering system.
Two conformations, however, are possible for the (Z)
enamino isomer: s-cis (a 1) and s-trans (a 2). Even though,
in general, s-trans conformations are preferred to s-cis
and hydrogen bonding NH‚‚‚O is stronger than NH‚‚‚N,
the most stable conformation is still the s-cis (a 1) with
an Erel of 3.3 and 2.8 kcal mol-1 for 1e and 1p , respec-
tively. This fact can be explained by taking into account
that in the a 1 conformation, a major delocalization of the
π-system occurs, which includes the hydrogen bond and
formation of a six-membered ring.
a six-membered ring. The 7.7° angle between the planes
of the oxazoline ring and the enamino moiety of along
with bond lengths corresponding to the NdC-CdC
grouping suggest the formation of a delocalized π-system
that extends to include the N1‚‚‚H21 bond. The steric
hindrance between the aromatic rings displays the tor-
sion of the phenyl group plane in an angle of 111.3°, as
can be seen in Figure 1.
In order to understand more about the relative stabili-
ties of the representative configurations or conformations
of selected compounds, such as 1e, 1p , and 1l (Table 1),
we began comparative theoretical ab initio molecular
orbital calculations.35 Geometry optimizations were car-
ried out at the HF/3-21G level and additional calculations
of some representative structures, e.g., 1e, have also been
optimized at the HF/3-21+G level. Structures are shown
in Chart 2, and their total and relative energies, in kcal
mol-1, are listed in Table 4. On the basis of the computed
conformational energy differences, the conformer 1e (a 1)
has the strongest intramolecular interaction. Selected
Other tautomeric forms implying the oxazoline ring as
an NH enaminic moeity, i.e., e1, have been also consid-
(35) Frisch, M. J .; Schlegel, H. B.; Gill, P. M. W.; J ohnson, B. G.;
Robb, M. A.; Cheeseman, J . R.; Keith, T.; Petersson, G. A.; Montgomery,
J . A.; Raghavachari, K.; Al-Laham, M. A.; Zakrzewski, V. G.; Ortiz, J .
V.; Foresman, J . B.; Cioslowski, J .; Stefanov, B. B.; Nanayakkara, A.;
Challacombe, N.; Peng, C. Y.; Ayala, P. Y.; Chen, W.; Wong, M. W.;
Andre´s, J . L.; Replogle, E. S.; Gomperts, R.; Mart´ın, R. L.; Fox, D. J .;
Binkley, J . S.; DeFrees, D. J .; Baker, J .; Stewart, J . J . P.; Head-Gordon,
M.; Gonza´lez, C.; Pople, J . A. GAUSSIAN 94, RevisionC.3; Gaussian
Inc.: Pittsburgh, PA, 1995.

8854 J . Org. Chem., Vol. 61, No. 25, 1996
Fustero et al.
Ta ble 4. Ca lcu la ted Tota l (Ha r tr ee) a n d Rela tive En er gies (k ca l m ol-1) of Op tim ized Str u ctu r esa of
Com p ou n d s 1e, 1p , a n d 1l
HF/3-21G//3-21Ga
structure
Etot
Erel
structure
Etot
Erel
1e
1p
a
1 [(Z)-s-cis]
-945.41534
(-945.53485)
[-950.70086]
-945.41011
(-945.52988)
[-950.69437]
-945.39486
(-945.51664)
[-950.68465]
-945.39770
[-950.68749]
-945.39437
-945.39715
[-950.68842]
0.0
(0.0)b
[0.0]c
3.3
a 1 [(Z)-s-cis]
-1128.59989
-1128.59543
-1128.57944
0.0
a 2 [(Z)-s-trans]
b1.1[(E)-s-cis]
a 2 [(Z)-s-trans]
c1 (E)
2.8
(3.1)b
[4.1]c
12.9
12.8
(11.4)b
[10.2]c
11.1
b1.2 [(E′)-s-cis]
[8.4]c
13.2
b2.1 [(E)-s-trans]
b
2.2 [(E′)-s-trans]
11.4
[7.8]c
1l
c1 (E)
c2 (E′)
d 1 (Z)
-945.39187
-945.38987
14.7
16.0
a 1 [(Z)-s-cis]
c1 (E)
-797.98415
[-802.43324]
-797.97795
[-802.44044]
-797.97764
-797.96529
-797.96381
-3.9
[0.9]c
0.0
[0.0]c
0.2
-945.39317
-945.39051
-945.40731
13.9
15.6
5.0
c2 (E′)
d 1 (Z)
d 2 (Z′)
d
2 (Z′)
7.9
8.9
e1
a
b
Full geometries are available in the Supporting Information. Basis set used: HF/3-21+G. c Single-point energies at HF/6-31G*//3-
21G level.
Sch em e 4
ered. This structure would show very similar H and 13C
NMR spectra to that of a 1. However, 1e (e1) is 5.0 kcal
mol-1 higher in energy than 1e (a 1), which confirms, once
again, the experimental results.
1
F igu r e 2. Calculated (3-21G) structure of 1l corresponding
to c1 configuration.
In contrast with the above results, spectral data for
compounds 1-2, in which R1 is a bulky group such as
tert-butyl and R2 an aromatic ring [for instance for
compound 1w (R1 ) t-Bu, R2 ) p-MeC6H4, Table 1, entry
23)], indicated that these derivatives appear generally
in the imino form R36 (Scheme 3, see also Table 1, entries
12 and 19, and Table 2, entry 13). Thus, the most
respectively. Additionally, a small difference of 0.2 kcal
mol-1 between the two isomers corresponding to the
conformers c1 vs c2 was found. Calculations also showed
a significant twisting of the plane that contains the iminic
double bond with respect to the oxazoline ring (Figure
2). The most stable structure for 1l corresponded to the
a 1 configuration, 3.9 kcal mol-1 in respect to c1 , in
contrast with the experimental results (see above). So,
energies were now evaluated with the HF/6-31G*//3-21G
level of theory for 1l and other representative examples
(Table 4). The obtained results for 1l (a 1) showed a
strong intramolecular hydrogen bond in a planar struc-
ture, but now 0.9 kcal mol-1 less stable than 1l (c1).
These facts were consistent with the experimental re-
sults,36 and they can be easily explained if we take into
account the steric hindrance among the bulky tert-butyl
group, the aromatic ring system, and the oxazoline ring,
as shown in Scheme 4.
1
characteristic features of the H NMR spectrum of 1w
were three sets of signals centered at δ 3.13 (t, 2H, J )
4
8.4 Hz), 3.37 (t, 2H, J ) 1.8 Hz), and 4.03 (dt, 2H, J )
4
8.4, and J ) 1.8 Hz). The multiplicity of the signals and
the coupling constants were consistent with the proposed
1w R structure.
In these compounds, however, two main different
isomers, cis-trans (Z-E), are possible (Scheme 4, see also
c1, c2, d 1, and d 2 in Chart 2). Because only one of them
was observed by NMR in the crude reaction mixture, ab
initio calculations for 1l (Table 1, entry 12) were per-
formed in order to establish the correct geometry of these
derivatives. The structural results obtained (Table 4)
indicated that the imino forms c1 (E) and c2 (E′) are 7.9
and 8.9 kcal mol-1 more stable than d 1 (Z) and d 2 (Z′),
On the contrary, no significant energy differences were
observed among these isomers (c1, c2, d 1, and d 2) for
compound 1e, where the steric interactions are dimin-
ished in comparison with 1l (Table 4).
(36) In some cases, i.e.,, for compound 1l, a mixture of enamino (â)
and imino (R) tautomers (â/R ≈ 5/95) was observed by 1H NMR in the
crude mixture of the reaction.

N-Substituted â-Enamino Acid Derivatives
J . Org. Chem., Vol. 61, No. 25, 1996 8855
Sch em e 5
alternative route for the synthesis of these derivatives.
The scope and versatility of these processes are demon-
strated by their use on a wide variety of substrates,
including imidoyl chlorides, oxa- and thiazolines, and
alkyl halides. Further studies related to the reactivity
of 1-2 in reduction reactions are in progress.
Exp er im en ta l Section
Gen er a l Meth od s. All reactions were run under N2
atmosphere. Solvents were dried and distilled upon standard
procedures before use, and THF was distilled, under N2,
immediately prior to use from sodium-potassium alloy and
benzophenone ketyl. Commercial oxazolines and thiazolines
were purchased from Aldrich Co., distilled and stored over 4
Å molecular sieves. (4R,5S)-cis-2,4-Dimethyl-5-phenyloxazo-
line39 and imidoyl chlorides26 were prepared according to the
methods described in the literature. All other reagents were
of the best commercial grade available and were used without
further purification. Diisopropylamine was distilled from
sodium hydride and stored over 4 Å molecular sieves. Thin
layer chromatography (TLC) was performed with UV active
silica gel 60 F254 or neutral aluminum oxide 60 F254, and the
plates were visualized with UV light. Flash column chroma-
tography and medium pressure liquid chromatography (MPLC)
were carried out on silica gel 60 (0.040-0.063 and 0.015-0.040
mm respectively) and basic aluminum oxide (70-290 mesh).
Melting points are uncorrected. Nuclear magnetic resonance
spectra for 1H and 13C were determined on a 200, 250, and
300 MHz spectrometer, in CDCl3, using tetramethylsilane as
an internal standard. Chemical shift values and coupling
constants, J , are reported in δ ppm and in Hz, respectively.
Carbon multiplicities were established by DEPT. Infrared
spectra (cm-1) were obtained on a FT IR spectrometer. Mass
spectral data, low-resolution mass spectroscopy (electron
impact) (LRMS/EI) and high-resolution mass spectroscopy
(HRMS), were obtained at 70 eV by electron impact. Elemen-
tal analyses were performed in the Microanalyses Service CID-
CSIC of Barcelona.
In summary, these findings allow us to assume, due
to the good correlation observed between the calculated
and experimental results for 1e (a 1), the configuration
c1 (E) (Scheme 4 and Figure 2) as the most probable
structure for compounds 1-2 with bulky substituents in
R2.
On the other hand, N-substituted R-alkylated â-enam-
ino acid derivatives 2 (R3 * H) can alternatively be
obtained in a simple one-pot sequential metalation-
alkylation, starting from 2-methyl-2-oxazolines 6 (R3 )
H, X ) O).
It is in this context that we have reported our prelimi-
nary results on the C-alkylation of N-unsubstituted
â-amino-R,â-unsaturated oxazolines 1 (R1 ) R3 ) H) by
a two-step sequence starting from 2-methyl-2-oxazolines
and nitriles.21 In a similar way, several procedures for
the synthesis of R-alkylated â-enamino esters and of
â-dicarbonyl derivatives, resulting from C-alkylation of
4-amino-1-aza-1,3-dienes, have been described.37
As shown in Scheme 5, alkylation products 2 are
formed by treatment of azaenolate 6-Li, generated with
lithium diisopropylamide (2.0 equiv) in THF at -78 °C,
with imidoyl chlorides 7 (1.0 equiv) followed by trapping
of the intermediate azaenolate with the appropriate alkyl
halide R3Y.
Com p u ta tion a l Meth od s. Ab initio calculations were
performed with the GAUSSIAN 9435 series programs. Geom-
etry optimizations were carried out at the HF/3-21G level, and
some representative structures were also fully optimized at
the HF/3-21+G level of theory. In some cases, energies were
evaluated with HF/6-31G*//3-21G level of theory. All the
calculations in this study were performed on a Silicon Graphics
Indigo-Iris, Indigo, or Cray XMP-Unicos supercomputer.
Gen er a l P r oced u r e for th e Syn th esis of N-Su bstitu ted
â-En a m in o-2-oxa (th ia )zolin es 1. Meth od A. To a stirred
solution of diisopropylamine (2.6 mL, 20 mmol) in THF (15mL)
at 0 °C was added butyllithium (2.5 M in hexanes, 8.0 mL, 20
mmol) dropwise. After being stirred for 15 min, the solution
In this way, the N-substituted R-alkylated â-enamino
acid derivatives 2 have been obtained in 50-90% overall
yield after purification by chromatography (Method B,
Table 2). Similar considerations can be made in relation
to this generality, structural assignment, and importance
of the process, as above. Compounds 2 were fully
elucidated on the basis of their 1H and 13C NMR spec-
troscopies and mass spectrometry results (see Experi-
mental Section). Finally, one of the major advantages
of this one-pot reaction is the simplicity and versatility
of the process, along with the accessibility of the starting
materials.
was cooled to -78 °C and 2-methyl-2-oxa(thia)zoline 6 (R3
)
H) (10 mmol) in THF (15mL) was added. The reaction mixture
was stirred for 2 h; then a solution of the desired imidoyl
chloride 7 (10 mmol) in THF (15 mL) was slowly added. When
TLC analysis showed the disappearance of the starting mate-
rial, the reaction was quenched by addition of saturated
ammonium chloride solution. The aqueous layer was extracted
with methylene chloride (3 × 25 mL). The combined organic
layers were washed with brine and dried (Na2SO4), and after
filtration, the solvents were removed under reduced pressure
to furnish the crude product 1. Purification was carried out
as indicated in each case.
2-[(Z)-(2-An ilin o-2-ph en yl)eth en yl]-2-oxazolin e (1a). Re-
crystallization (n-hexane-CHCl3 (5:1)) gave a white solid
(87%): mp 86-88 °C; 1H NMR (250 MHz) 3.92 (t, J ) 8.7,
2H), 4.13 (t, J ) 8.7, 2H), 4.93 (s, 1H), 6.57 (d, J ) 7.3, 2H),
6.78 (t, J ) 7.3, 1H), 6.98 (t, J ) 7.6, 2H), 7.18-7.31 (m, 5H),
10.60 (br s, 1H); 13C NMR (62.8 MHz) 54.36 (t), 65.69 (t), 88.60
(d), 121.63 (d), 122.04 (d), 128.05 (d), 128.33 (d), 128.49 (d),
128.90 (d), 136.52 (s), 141.21 (s), 153.94 (s), 166.16 (s); IR (KBr)
In conclusion, a very simple and efficient method for
the synthesis of masked N-substituted â-enamino acid
derivatives (1-2) has been, for the first time, described.38
The structural assignment for the obtained compounds
was made on the basis of their spectral properties, as well
as X-ray crystallographic analysis, and has been sup-
ported by ab initio calculations at the HF/3-21G and HF/
3-21+G level of theory. This study allowed us to predict
the most probably geometry in compounds 1-2 with
bulky substituents in R2, for which the above mentioned
analytical methods were not completely effective. In
addition, we have studied the reactivity of compounds 1
(R3 ) H) in C-alkylation reactions, which supposes an
(37) (a) Ando, K.; Takemasa, Y.; Tomioka, K.; Koga, K. Tetrahedron
1993, 49, 1579. (b) Barluenga, J .; J ardo´n, J .; Gotor, V. J . Org. Chem.
1985, 50, 802.
(38) To the best of our knowledge, only one example with a similar
structure, obtained by a [2 + 2] cycloaddition reaction of an oxazolinyl
alkylamide with dimethyl fumarate, has been reported. See: Ghose,
S.; Gilchrist, T. L. J . Chem. Soc., Perkin Trans 1, 1991,775.
(39) Meyers, A. I.; Knaus, G.; Kamata, K.; Ford, M. E. J . Am. Chem.
Soc. 1976, 98, 567.

8856 J . Org. Chem., Vol. 61, No. 25, 1996
Fustero et al.
3264, 1628, 1605; HRMS calcd for C17H16N2O 264.1361, found
264.1263; LRMS (EI) m/ z 264 (M+, 37), 263 (M+ - H, 100).
Anal. Calcd for C17H16N2O: C, 77.24; H, 6.11; N, 10.60.
Found: C, 77.30; H, 6.15; N, 10.57.
2-{(Z)-2-(N-1-P h en yleth yla m in o)-3,3,3-tr iflu or op r op e-
n yl}-2-oxa zolin e (1h ). Flash chromatography (n-hexane-
EtOAc (9:1)) on silica gel (Rf ) 0.5) gave 1h (75%) as a clear
yellow oil: 1H NMR (250 MHz) 1.58 (d, J ) 6.8, 3H), 4.04 (t,
J ) 7.5, 2H), 4.22 (t, J ) 7.5, 2H), 4.78 (m, 1H), 5.19 (s, 1H),
7.30-7.40 (m, 5H), 9.21 (br d, 1H); 13C NMR (62.8 MHz) 25.33,
53.92, 54.38, 65.84, 82.80 (q, J C-C-C-F ) 6.8), 120.85 (q, J C-F
) 274.6), 125.37, 126.93, 128.51, 143.30 (q, J C-C-F ) 31.1),
144.86, 165.55; IR(neat) 3442, 1646, 1608; HRMS calcd for
C14H15F3N2O 284.1136 found 234.1138; LRMS (EI) m/ z 284
(M+, 27), 269 (M+ - CH3, 27), 199 (27), 105 (100). Anal. Calcd
for C14H15F3N2O: C, 59.13; H, 5.32; N, 9.86. Found: C, 59.21;
H, 5.39; N, 9.80.
2-{(Z)-[2-(N-p -An isyla m in o)-2-(3-p yr id yl)]et h en yl}-2-
oxa zolin e (1i). MPLC (n-hexane-EtOAc (3:1)) on silica gel
(Rf ) 0.4) gave 1i (85%) as a yellow solid: mp 114-116 °C; 1H
NMR (200 MHz) 3.63 (s, 3H), 3.98 (t, J ) 8.3, 2H), 4.16 (t, J
) 8.3, 2H), 4.88 (s, 1H), 6.59 (s, 4H), 7.09 (m, 1H), 7.50 (m,
1H), 8.44 (m, 1H), 8.54 (d, J ) 2.2, 1H), 10.49 (br s, 1H); 13C
NMR (75 MHz) 55.14 (t), 56.17 (q), 66.64 (t), 88.61 (d), 114.87
(d), 123.76 (d), 125.37 (d), 133.21 (s), 134.49 (s), 136.44 (d),
149.91 (d), 150.56 (d), 152.38 (s), 156.59 (s), 166.93 (s); IR (KBr)
3437, 1617, 1595; LRMS (EI) m/ z 295(M+, 86), 294 (M+ - H,
100). Anal. Calcd for C17H17N3O2: C, 69.12; H, 5.81; N, 14.23.
Found: C, 69.15; H, 5.86; N, 14.20.
2-{(Z)-[2-(N-p -An isyla m in o)-3-m et h yl]-b u t -1-en yl}-2-
oxa zolin e (1j). MPLC (n-hexane-EtOAc (3:1)) on silica gel
(Rf ) 0.3) gave 1j (70%) as a clear yellow oil: 1H NMR (300
MHz) 1.06 (d, J ) 6.6, 6H), 2.79 (m, 1H), 3.80 (s, 3H), 3.95 (t,
J ) 7.5, 2H), 4.18 (t, J ) 7.5, 2H), 4.67 (s, 1H), 6.84 (d, J )
9.0, 2H), 7.03 (d, J ) 9.0, 2H), 10.40 (br s, 1H); 13C NMR (75
MHz) 22.08 (q), 28.07 (d), 54.24 (t), 55.39 (q), 65.28 (t), 77.51
(d), 114.07 (d), 127.58 (d), 132.76 (s), 157.19 (s), 165.30 (s),
167.35 (s); IR (neat) 3390, 1627, 1596, 1507; HRMS calcd for
C15H20N2O2 260.1525, found 260.1517; LRMS (EI) m/ z 260
(M+, 69), 217 (M+ - i-Pr, 100). Anal. Calcd for C15H20N2O2:
C, 69.17; H, 7.75; N, 10.77. Found: C, 69.23; H, 7.81; N, 10.72.
2-{(Z)-[2-(N-p-Tolyla m in o)-4-m eth yl]p en t-1-en yl}-2-ox-
a zolin e (1k ). MPLC (n-hexane-EtOAc (1:1)) on silica gel (Rf
) 0.2) gave 1k (73%) as a clear yellow oil: 1H NMR (250 MHz)
0.73 (d, J ) 6.5, 6H), 1.58 (m, 1H), 2.13 (d, J ) 6.5, 2H), 2.25
(s, 3H), 3.86 (t, J ) 8.6, 2H), 4.08 (t, J ) 8.6, 2H), 4.55 (s, 1H),
6.90 (d, J ) 8.7, 2H), 7.03 (d, J ) 8.7, 2H), 10.40 (br s, 1H);
13C NMR (62.8 MHz) 20.86 (q), 22.29 (q), 26.86 (d), 41.48 (t),
54.27 (t), 65.34 (t), 82.73 (d), 124.81 (d), 129.46 (d), 133.99 (s),
137.74 (s), 156.81 (s), 166.71 (s); IR (neat) 3395, 1629, 1598;
HRMS calcd for C16H22N2O 258.1732, found 258.1727; LRMS
(EI) m/ z 258 (M+, 89), 201 (M+ - t-Bu, 86), 107 (100). Anal.
Calcd for C16H22N2O: C, 74.37; H, 8.59; N, 10.85. Found: C,
74.30; H, 8.52; N, 10.88.
2-[(Z)-(3,3-Dim et h yl-2-N-p -t olylim in o)b u t yl]-2-oxa zo-
lin e (1l). MPLC (n-hexane-EtOAc (3:2)) on silica gel (Rf )
0.4) gave 1l (70%) as a clear yellow oil: 1H NMR (250 MHz)
1.18 (s, 9H), 2.22 (s, 3H), 3.18 (t, 4J ) 1.4, 2H), 3.64 (t, J )
9.0, 2H), 4.05 (t, J ) 9.0, 2H), 6.55 (d, J ) 8.5, 2H), 6.99 (d, J
) 8.5, 2H); 13C NMR (62.8 MHz) 20.63 (q), 27.88 (q), 28.18 (t),
40.64 (s), 54.17 (t), 67.09 (t), 118.64 (d), 129.05 (d), 131.95 (s),
148.25 (s), 163.88 (s), 172.46 (s); HRMS calcd for C16H22N2O
258.1732, found 258.1732; LRMS (EI) m/ z 258 (M+, 19), 201
(M+ - t-Bu, 100). Anal. Calcd for C16H22N2O: C, 74.37; H,
8.59; N, 10.85. Found: C, 74.47; H, 8.67; N, 10.79.
2-[(Z)-(2-Cycloh exyla m in o-2-p h en yl)eth en yl]-2-oxa zo-
lin e (1b). The crude product was purified by flash chroma-
tography (n-hexane-EtOAc (15:1)) on basic aluminum oxide (Rf
) 0.4). Recrystallization (n-hexane-CHCl3 (5:1)) gave 1b (75%)
as a white solid: mp 89-91 °C; 1H NMR (300 MHz) 0.85-
1.80 (m, 10H), 3.10 (m, 1H), 4.00 (t, J ) 8.4, 2H), 4.15 (t, J )
8.4, 2H), 4.54 (s, 1H), 7.37 (s, 5H), 8.70 (br d, 1H); 13C NMR
(75 MHz) 25.43 (t), 26.30 (t), 35.41 (t), 53.25 (d), 55.26 (t), 66.14
(t), 83.53 (d), 128.67 (d), 128.97 (d), 129.39 (d), 138.35 (s),
160.12 (s), 167.48 (s); IR (KBr) 3442, 3164, 1618, 1603; HRMS
calcd for C17H22N2O 270.1654, found 270.1656; LRMS (EI) m/ z
270 (M+, 54), 269 (M+ - H, 100). Anal. Calcd for C17H22N2O:
C, 75.51; H, 8.21; N, 10.37. Found: C, 75.70; H, 8.10; N, 10.40.
2-{(Z)-[2-(N-p -An isyla m in o)-2-p h en yl]et h en yl}-2-ox-
a zolin e (1c). Recrystallization (n-hexane-CHCl3 (4:1)) gave
a white solid (72%): mp 118-120 °C; 1H NMR (250 MHz) 3.69
(s, 3H), 4.00 (t, J ) 7.5, 2H), 4.21 (t, J ) 7.5, 2H), 4.94 (s, 1H),
6.63 (s, 4H), 7.24-7.35 (m, 5H), 10.66 (br s, 1H); 13C NMR
(62.8 MHz) 54.37 (t), 55.21 (q), 65.66 (t), 87.84 (d), 113.71 (d),
121.66 (d), 121.93 (d), 128.51 (d), 129.39 (d), 133.96 (s), 141.46
(s), 153.70 (s), 160.15 (s), 166.25 (s); HRMS calcd for C18H18N2O2
294.1368, found 294.1359; LRMS (EI) m/ z 294 (M+, 38), 293
(M+ - H, 100). Anal. Calcd for C18H18N2O2: C, 73.44; H, 6.17;
N, 9.52. Found: C, 73.50; H, 6.21; N, 9.60.
2-{(Z)-[2-(N-1-P h en yleth yla m in o)-2-p h en yl]eth en yl}-2-
oxa zolin e (1d ). MPLC (n-hexane-EtOAc (3:1)) on silica gel
(Rf ) 0.5) gave 1d (81%) as a yellow oil: 1H NMR (250 MHz)
1.38 (d, J ) 6.8, 3H), 3.93 (t, J ) 7.5, 2H), 4.08 (t, J ) 7.5,
2H), 4.35 (m, 1H), 4.53 (s, 1H), 7.02-7.21 (m, 10H), 9.10 (br
d, 1H); 13C NMR (62.8 MHz) 24.68 (q), 53.91 (t), 54.44 (d), 65.41
(t), 83.95 (d), 125.72 (d), 126.51 (d), 127.89 (d), 127.99 (d),
128.28 (d), 128.57 (d), 138.11 (s), 145.48 (s), 159.32 (s), 166.49
(s); IR (neat) 3250, 1623, 1591; LRMS (EI) m/ z 292 (M+, 47),
291 (49), 277 (42), 207 (100), 105 (73). Anal. Calcd for
C19H20N2O: C, 78.08; H, 6.85; N, 9.59. Found: C, 78.25; H,
6.72; N, 9.65.
2-[(Z)-(2-An ilin o-2-p-m eth oxyp h en yl)eth en yl]-2-oxa zo-
lin e (1e). Recrystallization of the crude product (n-hexane-
CHCl3 (3:1)) gave 1e (95%) as clear yellow crystals: mp 128-
130 °C; 1H NMR (250 MHz) 3.71 (s, 3H), 3.92 (t, J ) 7.5, 2H),
4.13 (t, J ) 7.5, 2H), 4.89 (s, 1H), 6.65 (d, J ) 8.0, 2H), 6.74
(d, J ) 8.0, 2H), 6.81 (t, J ) 8.0, 1H), 6.97 (t, J ) 8.0, 1H),
7.22 (d, J ) 8.0, 3H), 10.56 (br s, 1H); 13C NMR (62.8 MHz)
54.37 (t), 55.21 (q), 65.66 (t), 87.84 (d), 113.72 (d), 121.65 (d),
128.51 (d), 128.76 (d), 129.39 (d), 133.96 (s), 141.46 (s), 153.69
(s), 160.15 (s), 166.25 (s); IR (KBr) 3073, 1623, 1602; HRMS
calcd for C18H18N2O2 294.1368, found 294.1360; LRMS (EI)
m/ z 294 (M+, 39), 293 (M+ - H, 100). Anal. Calcd for
C18H18N2O2: C, 73.44; H, 6.17; N, 9.52. Found: C, 73.40; H,
6.20; N, 9.55.
2-{(Z)-2-(N-p-An isyla m in o)-3,3,3-tr iflu or op r op en yl}-2-
oxa zolin e (1f). Flash chromatography (n-hexane-EtOAc (20:
1)) on silica gel (Rf ) 0.5) furnished 1f (87%) as a yellow oil:
1H NMR (250 MHz) 3.72 (s, 3H), 3.89 (t, J ) 7.5, 2H), 4.15 (t,
J ) 7.5, 2H), 5.21 (s, 1H), 6.75 (d, J ) 9.0, 2H), 7.02 (d, J )
9.0, 2H), 10.15 (br s, 1H); 13C NMR (62.8 MHz) 54.19, 55.34,
66.04, 84.30 (q, J C-C-C-F ) 6.3), 113.82, 120.70 (q, J C-F)275.5),
127.94, 131.71, 143.44 (q, J C-C-F ) 31.3), 157.97, 165.43; IR
(neat) 3411, 1645, 1511; LRMS (EI) m/ z 286 (M+, 86), 217 (M+
- CF3, 100). Anal. Calcd for C13H13F3N2O2: C, 54.53; H, 4.58;
N, 9.79. Found: C, 54.62; H, 4.40; N, 9.82.
(S)-2-{(Z)-[2-(N-1-P h en yleth ylam in o)-2-ph en yl]eth en yl}-
2-oxa zolin e (1m ). MPLC (n-hexane-EtOAc (3:1)) on silica
gel (Rf ) 0.5) gave 1m (75%) as a yellow oil: [R]25 +479.0° (c
D
1
0.80, CH2Cl2); H NMR (250 MHz) 1.38 (d, J ) 6.8, 3H), 3.93
(t, J ) 7.5, 2H), 4.08 (t, J ) 7.5, 2H), 4.35 (m, 1H), 4.53 (s,
1H), 7.02-7.21 (m, 10H), 9.10 (br d, 1H); 13C NMR (62.8 MHz)
24.68 (q), 53.91 (t), 54.44 (d), 65.41 (t), 83.95 (d), 125.72 (d),
126.51 (d), 127.89 (d), 127.99 (d), 128.28 (d), 128.57 (d), 138.11
(s), 145.48 (s), 159.32 (s), 166.49 (s); HRMS calcd for C19H20N2O
292.1576, found 292.1584; LRMS (EI) m/ z 292 (M+, 59), 291
(47), 277 (42), 207 (100), 105 (73). Anal. Calcd for
C19H20N2O: C, 78.08; H, 6.85; N, 9.59. Found: C, 78.21; H,
6.98; N, 9.42.
2-{(Z)-2-(N-p -Tolyla m in o)-3,3,3-t r iflu or op r op en yl}-2-
oxa zolin e (1g). Flash chromatography (n-hexane-EtOAc (15:
1)) on silica gel (Rf ) 0.4) gave 1g (88%) as a clear yellow
solid: mp 46-48 °C; 1H NMR (250 MHz) 2.34 (s, 3H), 4.02 (t,
J ) 7.5, 2H), 4.24 (d, J ) 7.5, 2H), 5.32 (s, 1H), 7.05-7.15 (m,
4H), 10.25 (br s, 1H); 13C NMR (62.8 MHz) 20.92, 54.20, 66.06,
85.06 (q, J C-C-C-F ) 5.8), 120.94 (q, J C-F ) 250.7), 125.72,
129.35, 135.71, 136.48, 142.99 (q, J C-C-F ) 30.9), 165.36; LRMS
(EI) m/ z 270 (M+, 54), 201 (M+ - CF3, 100). Anal. Calcd for
C13H13F3N2O: C, 57.76; H, 4.85; N, 10.37. Found: C, 57.68;
H, 4.84; N, 10.30.
4,4-Dim eth yl-2-[(Z)-(2-a n ilin o-2-p h en yl)eth en yl]-2-ox-
a zolin e (1n ). Flash chromatography (n-hexane-EtOAc (4:

N-Substituted â-Enamino Acid Derivatives
J . Org. Chem., Vol. 61, No. 25, 1996 8857
1)) on silica gel (Rf ) 0.7) furnished 1n (78%) as a yellow
solid: mp 89-91 °C; 1H NMR (200 MHz) 1.34 (s, 6H), 3.89 (s,
2H), 4.92 (s, 1H), 6.67-7.34 (m, 10H), 10.83 (br s, 1H); 13C
NMR (50 MHz) 28.80 (q), 54.60 (s), 77.43 (t), 88.71 (d), 121.56
(d), 122.56 (d), 128.31 (d), 128.83 (d), 129.82 (d), 129.94 (d),
136.66 (s), 142.55 (s), 153.66 (s), 163.54 (s); IR (KBr) 3410,
1660, 1624, 1593; LRMS (EI) m/ z 292 (M+, 95), 291 (M+ - H,
96), 277 (M+ - CH3, 100). Anal. Calcd for C19H20N2O: C,
78.08; H, 6.84; N, 9.58. Found: C, 78.03; H, 6.90; N, 9.50.
4,4-Dim eth yl-2-[(Z)-(2-an ilin o-2-p-m eth oxyph en yl)eth e-
n yl]-2-oxa zolin e (1o). MPLC (n-hexane) on silica gel (Rf )
0.3) gave 1o (90%) as a colorless oil: 1H NMR (250 MHz) 1.32
(s, 6H), 3.77 (s, 3H), 3.88 (s, 2H), 4.89 (s, 1H), 6.65 (d, J ) 8.5,
2H), 6.81 (m, 3H), 7.08 (t, J ) 7.4, 2H), 7.30 (d, J ) 8.5, 2H),
10.61 (br s, 1H); 13C NMR (62.8 MHz) 28.83 (q), 55.13 (q), 66.95
(s), 77.3 (t), 87.88 (d), 113.63 (d), 121.52 (d), 121.73 (d), 128.43
(d), 128.80 (s), 129.31 (d), 141.52 (s), 153.34 (s), 160.00 (s),
163.57 (s); LRMS (EI) m/ z 322 (M+, 94), 321 (M+ - H, 100),
307 (M+ - CH3, 94). Anal. Calcd for C20H22N2O2: C, 74.51;
H, 6.88; N, 8.69. Found: C, 74.20; H, 6.72; N, 8.61.
4,4-Dim et h yl-2-{(Z)-2-(N-p -a n isyla m in o)-3,3,3-t r iflu o-
r op r op en yl}-2-oxa zolin e (1p ). Flash chromatography (n-
hexane-EtOAc (9:1)) on aluminum oxide (Rf ) 0.5) gave 1p
(80%) as a yellow solid. Recrystallization (CHCl3) gave color-
less crystals: mp 50-52 °C; 1H NMR (250 MHz) 1.32 (s, 6H),
3.81 (s, 3H), 3.92 (s, 2H), 5.26 (s, 1H), 6.86 (d, J ) 8.4, 2H),
7.17 (d, J ) 8.4, 2H), 10.23 (br s, 1H); 13C NMR (62.8 MHz)
28.61, 55.27, 67.21, 77.64, 84.55 (q, J C-C-C-F ) 5.3), 113.83,
1669, 1609, 1592, 1570; LRMS (EI) m/ z 308 (M+, 63), 207 (M+
- C3H5NS, 55), 105 (C8H9, 100). Anal. Calcd for C19H20N2S:
C, 73.99; H, 6.54; N, 9.09; S, 10.38. Found: C, 73.97; H, 6.57;
N, 9.08; S, 10.40.
2-{(Z)-2-(N-p-An isyla m in o)-3,3,3-tr iflu or op r op en yl}-2-
th ia zolin e (1u ). Flash chromatography (n-hexane-EtOAc (9:
1)) on aluminum oxide (Rf ) 0.5) gave 1u (78%) as a yellow
oil: 1H NMR (250 MHz) 3.27 (t, J ) 8.0, 2H), 3.79 (s, 3H),
4.33 (t, J ) 8.0, 2H), 5.48 (s, 1H), 6.83 (d, J ) 8.9, 2H), 7.13
(d, J ) 8.9, 2H), 10.56 (br s, 1H); 13C NMR (62.8 MHz) 32.81,
55.37, 64.05, 90.41 (q, J C-C-C-F)6.4), 113.83, 120.67 (q,
J C-F)275.5), 127.80, 131.68, 141.27 (q, J C-C-F)30.3), 157.93,
166.33; IR (neat) 1634; LRMS (EI) m/ z 302 (M+, 17), 232 (M+
- CF3, 100). Anal. Calcd for C13H13N2F3OS: C, 51.64; H, 4.34;
N, 9.27; S, 10.58. Found: C, 51.76; H, 4.42; N, 9.10; S, 10.32.
2-{(Z)-2-(N-p -Tolyla m in o)-3,3,3-t r iflu or op r op en yl}-2-
th ia zolin e (1v). Flash chromatography (n-hexane-EtOAc (9:
1)) on silica gel (Rf ) 0.7) gave 1v (83%) as a yellow oil: 1H
NMR (250 MHz) 2.31 (s, 3H), 3.22 (t, J ) 8.4, 2H), 4.29 (t, J
) 8.4, 2H), 5.51 (s, 1H), 7.01-7.12 (m, 4H), 10.50 (br s, 1H);
13C NMR (62.8 MHz) 20.87, 32.73, 63.96, 91.10 (q, J C-C-C-F
)
6.4), 120.76 (q, J C-F ) 275.7), 125.61, 129.37, 135.69, 136.51,
140.82 (q, J C-C-F ) 31.3), 166.32; IR (neat) 1630; LRMS (EI)
m/ z 286 (M+, 83), 217 (M+ - CF3, 100). Anal. Calcd for
C13H13F3N2S: C, 54.53; H, 4.58; N, 9.79; S, 11.18. Found: C,
54.62; H, 4.51; N, 9.85; S, 11.23.
2-[(Z)-(3,3-Dim eth yl-2-N-p-tolylim in o)bu tyl]-2-th ia zo-
lin e (1w ). MPLC (n-hexane-EtOAc (3:1)) on silica gel (Rf )
0.2) gave 1w (72%) as a yellow oil: 1H NMR (250 MHz) 1.18
(s, 9H), 2.22 (s, 3H), 3.13 (t, J ) 8.4, 2H), 3.37 (t, 4J ) 1.8,
2H), 4.03 (dt, J ) 8.4, 4J ) 1.8, 2H), 6.55 (d, J ) 8.0, 2H), 7.00
(d, J ) 8.0, 2H); 13C NMR (62.8 MHz) 20.76 (q), 28.18 (q), 34.08
(t), 34.21 (t), 40.79 (s), 64.37 (t), 118.73 (d), 129.14 (d), 132.08
(s), 148.39 (s), 166.26 (s), 173.82 (s); HRMS calcd for C16H22N2S
274.1504, found 274.1496; LRMS (EI) m/ z 274 (M+, 26), 217
(M+ - t-Bu, 100). Anal. Calcd for C16H22N2S: C, 70.03; H,
8.09; N, 10.22; S, 11.66. Found: C, 70.12; H, 8.22; N, 10.10;
S, 11.55.
(4S,5S)-4-Meth oxym eth yl-5-p h en yl-2-[(Z)-(2-a n ilin o-2-
p-m eth oxyp h en yl) eth en yl]-2-oxa zolin e (1x). MPLC (n-
hexane-EtOAc (3:1)) on silica gel (Rf ) 0.6) gave 1x (90%) as
a yellow oil: [R]D25 +10.9° (c 1.25, CH2Cl2); 1H NMR (250 MHz)
3.38 (s, 3H), 3.46 (dd, J ) 9.5, 7.3, 1H), 3.63 (dd, J ) 9.9, 4.4,
1H), 3.74 (s, 3H), 4.23 (m, 1H), 4.99 (s, 1H), 5.22 (d, J ) 6.6,
1H), 6.63 (d, J ) 7.3, 2H), 6.74-6.85 (m, 3H), 7.04 (t, J ) 7.3,
2H), 7.25-7.32 (m, 7H), 10.60 (br s, 1H); 13C NMR (62.8 MHz)
54.93 (q), 59.08 (q), 74.19 (d), 74.91 (t), 81.63 (d), 87.28 (d),
113.58 (d), 121.54 (d), 121.91 (d), 125.39 (d), 127.70 (d), 128.39
(d), 128.44 (d), 128.46 (s), 129.27 (d), 141.18 (s), 154.16 (s),
160.03 (s), 165.75 (s); HRMS calcd for C26H26N2O3 414.1943,
found 414.1939; LRMS (EI) m/ z 414 (M+, 52), 369 (M+ - CH2-
OMe, 100). Anal. Calcd for C26H26N2O3: C, 75.33; H, 6.33;
N, 6.76. Found: C, 75.25; H, 6.20; N, 6.68.
120.66 (q, J C-F ) 275.4), 127.95, 131.92, 143.95 (q, J C-C-F
)
30.3), 157.96, 162.79; LRMS (EI) m/ z 314 (M+, 100), 245 (M+
- CF3, 77). Anal. Calcd for C15H17F3N2O: C, 57.30; H, 5.45;
N, 8.92. Found: C, 57.42; H, 5.35; N, 8.90.
4,4-Dim eth yl-2-{(Z)-[2-(N-p-an isylam in o)-2-(3-pyr idyl)]-
eth en yl}-2-oxa zolin e (1q). MPLC (n-hexane-EtOAc (3:2))
on silica gel (Rf ) 0.3) gave 1q (83%) as a yellow solid: mp
70-72 °C; 1H NMR (300 MHz) 1.34 (s, 6H), 3.71 (s, 3H), 3.91
(s, 2H), 4.87 (s, 1H), 6.66 (s, 4H), 7.16 (m, 1H), 7.56 (m, 1H),
8.50 (m, 1H), 8.61 (m, 1H), 10.58 (br s, 1H); 13C NMR (75 MHz)
29.68 (q), 56.21 (q), 67.91 (s), 78.31 (t), 88.73 (d), 114.83 (d),
123.72 (d), 125.37 (d), 133.42 (s), 134.64 (s), 136.43 (d), 149.91
(d), 150.46 (d), 152.09 (s), 156.53 (s), 164.28 (s); LRMS (EI)
m/ z 323 (M+, 89), 322 (M+ - H, 100). Anal. Calcd for
C19H21N3O2: C, 70.55; H, 6.55; N, 13.00. Found: C, 70.57; H,
6.52; N, 13.02.
4,4-Dim eth yl-2-{(Z)-[2-(N-p-tolyla m in o)-4-m eth yl]p en t-
1-en yl}-2-oxa zolin e (1r ). MPLC (n-hexane-EtOAc (20:1))
in silica gel (Rf ) 0.3) gave 1r (82%) as a clear yellow oil: 1H
NMR (250 MHz) 0.75 (d, J ) 6.5, 6H), 1.21 (s, 6H), 1.60 (m,
1H), 2.12 (d, J ) 6.5, 2H), 2.25 (s, 3H), 3.75 (s, 2H), 4.47 (s,
1H), 6.90 (d, J ) 8.3, 2H), 7.03 (d, J ) 8.3, 2H), 10.40 (br s,
1H); 13C NMR (62.8 MHz) 20.77 (q), 22.33 (q), 26.70 (t), 28.76
(q), 41.45 (d), 66.75 (s), 76.99 (t), 82.76 (d), 124.58 (d), 129.39
(d), 133.65 (s), 138.00 (s), 156.24 (s), 163.91 (s); HRMS calcd
for C18H26N2O 286.2045, found 286.2056; LRMS (EI) m/ z 286
(M+, 84), 271 (M+ - Me, 87), 229 (M+ - i-Pr, 100). Anal. Calcd
for C18H26N2O: C, 75.47; H, 9.16; N, 9.79. Found: C, 75.55;
H, 9.02; N, 9.66.
4,4-Dim eth yl-2-[(Z)-(3,3-d im eth yl-2-N-p-tolylim in o)bu -
tyl]-2-oxa zolin e (1s). MPLC (n-hexane-EtOAc (3:1)) on
silica gel (Rf ) 0.3) gave 1s (75%) as a clear yellow oil: 1H
NMR (300 MHz) 1.17 (s, 6H), 1.25 (s, 9H), 2.28 (s, 3H), 3.23
(s, 2H), 3.81 (s, 2H), 6.63 (d, J ) 8.4, 2H), 7.03 (d, J ) 8.4,
2H); 13C NMR (75 MHz) 21.61 (q), 28.82 (q), 28.91 (q), 29.53
(t), 41.67 (s), 67.78 (s), 79.88 (t), 119.74 (d), 130.08 (d), 132.99
(s), 149.21 (s), 162.25 (s), 173.31 (s); HRMS calcd for C18H26N2O
286.2045, found 286.2049; LRMS (EI) m/ z 286 (M+, 24), 229
(M+ - t-Bu, 100). Anal. Calcd for C18H26N2O: C, 75.47; H,
9.16; N, 9.79. Found: C, 75.51; H, 9.11; N, 9.70.
2-{(Z)-[2-(N-1-p h en yleth yla m in o)-2-p h en yl]eth en yl}-2-
th ia zolin e (1t). MPLC (n-hexane-EtOAc (4:1)) on silica gel
(Rf ) 0.4) gave 1t (78%) as a yellow oil: 1H NMR (300 MHz)
1.46 (d, J ) 6.5, 3H), 3.26 (t, J ) 7.5, 2H), 4.37-4.48 (m, 3H),
4.83 (s, 1H), 7.09-7.31 (m, 10H), 9.77 (br d, 1H); 13C NMR
(75 MHz) 25.71 (q), 33.57 (t), 54.78 (d), 65.25 (t), 91.94 (d),
126.56 (d), 127.43 (d), 128.81 (d), 128.87 (d), 129.19 (d), 129.45
(d), 137.55 (s), 146.26 (s), 158.09 (s), 167.37 (s); IR (neat) 3231,
(S)-(4S,5S)-4-Met h oxym et h yl-5-p h en yl-2-{(Z)-[2-(N-1-
p h en yleth yla m in o)-2-p h en yl] eth en yl}-2-oxa zolin e (1y).
MPLC (n-hexane-EtOAc (9:1)) on silica gel (Rf ) 0.4) gave
25
1y (78%) as clear yellow solid: mp 75-76 °C;[R]D +215.8° (c
1
1.00, CH2Cl2); H NMR (250 MHz) 1.33 (d, J ) 6.9, 3H), 3.34
(s, 3H), 3.49 (dd, J ) 9.5, 7.3, 1H), 3.80 (dd, J ) 9.2, 4.4, 1H),
4.30 (m, 1H), 4.32 (m, 1H), 4.66 (s, 1H), 5.16 (d, J ) 5.8, 1H),
7.02-7.30 (m, 15H), 9.08 (br d, 1H); 13C NMR (62.8 MHz) 24.84
(q), 54.21 (d), 59.24 (d), 74.30 (t), 75.42 (d), 81.70 (d), 84.21
(d), 125.54 (d), 126.57 (d), 127.72 (d), 127.92 (d), 128.07 (d),
128.25 (d), 128.31 (d), 128.56 (d), 128.76 (d), 136.98 (s), 141.70
(s), 145.38 (s), 159.98 (s), 166.17 (s); IR (KBr) 3414, 1628, 1603,
1591; HRMS calcd for C27H28N2O2 412.2151, found 412.2141;
LRMS (EI) m/ z 412 (M+, 15), 367 (M+ - CH2OMe, 100). Anal.
Calcd for C27H28N2O2: C, 78.60; H, 6.85; N, 6.79. Found: C,
78.55; H, 6.72; N, 6.66.
(4R,5S)-4-Met h yl-5-p h en yl-(S)-2-{(Z)-[2-(N-1-p h en yl-
eth yla m in o)-2-p h en yl]eth en yl}-2-oxa zolin e (1z). MPLC
(n-hexane-EtOAc (9:1)) on silica gel (Rf ) 0.8) gave 1z (90%)
as a yellow oil:[R]25 +263.1° (c 0.32, CHCl3);1H NMR (250
D
MHz) 0.85 (d, J ) 6.8, 3H), 1.47 (d, J ) 6.8, 3H), 4.45 (m, 1H),
4.61 (m, 1H), 4.76 (s, 1H), 5.53 (d, J ) 9.2, 1H), 7.08-7.36 (m,
15H), 9.25 (br d, J ) 9.8, 1H); 13C NMR (62.8 MHz) 19.26 (q),

8858 J . Org. Chem., Vol. 61, No. 25, 1996
Fustero et al.
25.69 (q), 55.22 (d), 65.54 (d), 82.96 (d), 85.42 (d), 126.60 (d),
126.73 (d), 127.05 (d), 127.37 (d), 127.71 (d), 128.30 (d), 128.81
(d), 128.94 (d), 129.11 (d), 137.97 (s), 138.61 (s), 146.28 (s),
160.69 (s), 165.97 (s); IR (neat) 3379, 1624, 1527; HRMS calcd
for C26H26N2O 282.2045, found 282.2037; LRMS (EI) m/ z 282
(M+, 19), 105 (100). Anal. Calcd for C26H26N2O: C, 81.73; H,
6.86; N, 7.33. Found: C, 81.79; H, 6.79; N, 7.37.
Gen er a l P r oced u r e for th e syn th esis of r-Alk yl N-
su bstitu ted â-en a m in o-2-oxa zolin es 2. Meth od A. Fol-
lowing the general procedure for the synthesis of 1 (R3 ) H)
but in this case the reaction was performed by using 2-ethyl-
2-oxazoline 6f (R3 ) Me) as the starting material.
4,4-Dim et h yl-2-{(Z)-[2-a n ilin o-2-b en zyl-2-(N-p -m et h -
oxyp h en yl)]eth en yl}-2-oxa zolin e (2e). MPLC (n-hexane-
EtOAc (6:1)) on silica gel (Rf ) 0.3) gave 2e (60%) as a white
1
solid: mp 112-113 °C; H NMR (250 MHz) 1.32 (s, 6H), 3.56
(s, 2H), 3.75 (s, 3H), 3.79 (s, 2H), 6.52 (d, J ) 8.0, 2H), 6.76 (d,
J ) 8.0, 3H), 7.00-7.20 (m, 9H), 10.08 (br s, 1H); 13C NMR
(62.8 MHz) 28.78 (q), 33.58 (t), 55.11 (q), 66.91 (s), 77.10 (t),
95.40 (s), 113.67 (d), 120.79 (d), 121.05 (d), 125.16 (d), 127.56
(d), 127.76 (d), 127.92 (d), 128.40 (d), 130.70 (d), 141.95 (s),
143.02 (s), 151.36 (s), 159.47 (s), 165.53 (s); IR (KBr) 3300,
1625, 1593; HRMS calcd for C27H28N2O2 412.2151, found
412.2158; LRMS (EI) m/ z 412 (M+, 100). Anal. Calcd for
C27H28N2O2: C, 78.61; H, 6.84; N, 6.79. Found: C, 78.55; H,
6.79; N, 6.66.
Meth od B. A 2-methyl-2-oxazoline 6a or 6b (R3 ) H, 5
mmol) in THF (20 mL) was deprotonated with LDA [prepared
from butyllithium (2.5M in hexanes, 10 mmol) and diisopro-
pylamine (12 mmol)] at -78 °C, and the desired imidoyl
chloride 7 (5 mmol) in THF (10 mL) was slowly added. When
TLC analysis showed that product 1 was formed (see Table
1), a solution of an alkyl halide (R3Y, 6 mmol) in THF (10 mL)
was added and the mixture was allowed to warm to room
temperature. TLC analysis showed the complete or partial
disappearance of 1 (see Table 2), and when the reaction was
over, usual workup gave the crude product 2. Purification of
the crude product is indicated in each case.
2-[(Z)-(2-An ilin o-1-eth ylacetyl-2-p-m eth oxyph en yl)eth e-
n yl]-2-oxa zolin e (2f). MPLC (n-hexane-EtOAc (3:2)) on
silica gel (Rf ) 0.3) gave 2f (55%) as a clear yellow oil: 1H
NMR (250 MHz) 1.23 (t, J ) 7.1, 3H), 3.14 (s, 2H), 3.77 (s,
3H), 4.03-4.19 (m, 6H), 6.56 (d, J ) 8.6, 2H), 6.80 (m, 3H),
7.00 (t, J ) 7.5, 2H), 7.23 (d, J ) 8.6, 2H), 10.30 (br s, 1H); 13
C
NMR (62.8 MHz) 14.17 (q), 34.52 (t), 54.39 (t), 55.06 (q), 60.28
(t), 65.71 (t), 90.20 (s), 113.76 (d), 121.44 (d), 121.65 (d), 126.92
(s), 128.32 (d), 130.65 (d), 141.30 (s), 152.75 (s), 159.63 (s),
167.35 (s), 173.34 (s); IR (neat) 3444, 1731, 1637, 1596; HRMS
calcd for C22H24N2O4 380.1761, found 380.1740; LRMS (EI)
m/ z 380 (M+, 61), 307 (99), 210 (100). Anal. Calcd for
C22H24N2O4: C, 69.46; H, 6.36; N, 7.36. Found: C, 69.52; H,
6.44; N, 7.29.
2-[(Z)-(2-An ilin o-1-m eth yl-2-p h en yl)eth en yl]-2-oxa zo-
lin e (2a ). Recrystallization (n-hexane-CHCl3 (4:1)) gave a
1
white solid: (90%) mp 102-104 °C; H NMR (250 MHz) 1.69
(s, 3H), 3.99 (t, J ) 8.3, 2H), 4.18 (t, J ) 8.3, 2H), 6.45 (d, J )
5.0, 2H), 6.69 (t, J ) 5.0, 1H), 6.89 (t, J ) 5.0, 2H), 7.18-7.24
(m, 5H), 10.40 (br s, 1H); 13C NMR (62.8 MHz) 14.41 (q), 54.43
(t), 65.60 (t), 92.62 (s), 120.96 (d), 121.18 (d), 128.20 (d), 128.24
(d), 128.36 (d), 129.81 (d), 135.78 (s), 141.89 (s), 150.19 (s),
168.37 (s); IR (KBr) 3264, 1664, 1599, 1495; LRMS (EI) m/ z
278 (M+, 72), 277 (M+ - C5H9NO, 100). Anal. Calcd for
C18H18N2O: C, 77.69; H, 6.47; N, 10.07. Found: C, 77.50; H,
6.61; N, 10.02.
4,4-Dim eth yl-2-[(Z)-(2-a n ilin o-1-eth yla cetyl-2-p-m eth -
oxyp h en yl)eth en yl]-2-oxa zolin e (2g). MPLC (n-hexane-
EtOAc (9:1)) on silica gel (Rf ) 0.3) gave 2g (50%) as a colorless
oil: 1H NMR (250 MHz) 1.22 (t, J ) 7.1, 3H), 1.35 (s, 6H),
3.12 (s, 2H), 3.78 (s, 3H), 3.88 (s, 2H), 4.11 (q, J ) 7.1, 2H),
5.52 (d, J ) 7.5, 2H), 6.83 (m, 3H), 7.00 (t, J ) 7.5, 2H), 7.21
(d, J ) 8.3, 2H), 10.15 (br s, 1H); 13C NMR (62.8 MHz) 14.20
(q), 28.78 (q), 34.40 (t), 55.07 (q), 60.22 (t), 67.12 (t), 77.25 (s),
90.16 (s), 113.77 (d), 121.17 (d), 121.42 (d), 127.02 (d), 128.33
(d), 130.64 (d), 141.52 (s), 152.32 (s), 159.61 (s), 164.78 (s),
173.27 (s); LRMS (EI) m/ z 408 (M+, 80), 407 (M+ - H, 63),
363 (M+ - OEt, 36), 335 (M+ - CO2Et, 82), 321 (M+ - CH2-
CO2Et, 27), 210 (100). Anal. Calcd for C24H28N2O4: C, 70.57;
H, 6.91; N, 6.86. Found: C, 70.42; H, 6.79; N, 6.80.
(S)-2-{(Z)-[1-Met h yl-2-(N-1-p h en ylet h yla m in o)-2-p h e-
n yl]eth en yl}-2-oxa zolin e (2h ). MPLC (n-hexane) in silica
gel (Rf ) 0.3) gave 2h (80%) as a clear yellow oil: [R]25D +381.5°
(c 1.00, CH2Cl2); 1H NMR (250 MHz) 1.35 (d, J ) 6.5, 3H),
1.45 (s, 3H), 3.92 (m, 3H), 4.15 (t, J ) 7.5, 2H), 6.95 (d, J )
8.0, 2H), 7.09-7.35 (m, 8H), 10.70 (br d, 1H); 13C NMR (62.8
MHz) 14.26 (q), 24.95 (q), 54.12 (t), 54.56 (d), 65.34 (t), 87.95
(s), 125.78 (d), 126.29 (d), 127.80 (d), 127.99 (d), 128.17 (d),
128.56 (d), 136.29 (s), 146.33 (s), 155.59 (s), 169.19 (s); IR (neat)
3393, 1617, 1581; HRMS calcd for C20H22N2O 306.1732, found
306.1732; LRMS (EI) m/ z 306 (M+, 68), 291 (M+ - CH3, 86),
201 (M+ - Ph(Me)CH, 100). Anal. Calcd for C20H22N2O: C,
78.39; H, 7.24; N, 9.15. Found: C, 78.51; H, 7.15; N, 9.18.
2-[(Z)-(2-An ilin o-1-m eth yl-2-p-m eth oxyph en yl)eth en yl]-
2-oxa zolin e (2i). Recrystallization (n-hexane-CHCl3 (3:1))
gave a white solid (88%): mp 115-116 °C; 1H NMR (250 MHz)
1.72 (s, 3H), 3.75 (s, 3H), 3.98 (t, J ) 8.9, 2H), 4.17 (t, J ) 8.9,
2H), 6.46 (d, J ) 7.3, 2H), 6.69 (t, J ) 7.3, 1H), 6.77 (d, J )
8.7, 2H), 6.93 (t, J ) 7.3, 2H), 7.15 (t, J ) 7.3, 2H), 10.55 (br
s, 1H); 13C NMR (62.8 MHz) 14.45 (q), 54.40 (t), 55.09 (q), 65.63
(t), 92.56 (s), 113.58 (d), 120.83 (d), 127.921 (d), 128.35 (d),
129.41 (s), 131.05 (d), 142.05 (s), 149.82 (s), 159.30 (s), 168.36
(s); LRMS (EI) m/ z 308 (M+, 42), 307 (M+ - H, 100). Anal.
Calcd for C19H20N2O2: C, 73.99; H, 6.54; N, 9.09. Found: C,
74.05; H, 6.57; N, 9.05.
2-{(Z)-[1-Meth yl-2-(N-1-p h en yleth yla m in o)-2-p h en yl]-
eth en yl}-2-oxa zolin e (2b). MPLC (n-hexane) on silica gel
(Rf ) 0.3) gave 2b (90%) as a clear yellow oil: 1H NMR (250
MHz) 1.35 (d, J ) 6.5, 3H), 1.45 (s, 3H), 3.92 (m, 3H), 4.15 (t,
J ) 7.5, 2H), 6.95 (d, J ) 8.0, 2H), 7.09-7.35 (m, 8H), 10.70
(br d, 1H); 13C NMR (62.8 MHz) 14.26 (q), 24.95 (q), 54.12 (t),
54.56 (d), 65.34 (t), 87.95 (s), 125.78 (d), 126.29 (d), 127.80 (d),
127.99 (d), 128.17 (d), 128.56 (d), 136.29 (s), 146.33 (s), 155.59
(s), 169.19 (s); IR (neat) 3393, 1617, 1581; LRMS (EI) m/ z 306
(M+, 68), 291 (M+ - CH3, 86), 201 (M+ - Ph(Me)CH, 100).
Anal. Calcd for C20H22N2O: C, 78.39; H, 7.24; N, 9.15.
Found: C, 78.41; H, 7.20; N, 9.05.
2-{(Z)-2-(N-p-An isyla m in o)-1-m eth yl-3,3,3-tr iflu or op r o-
p en yl}-2-oxa zolin e (2c). Flash chromatography (n-hexane-
EtOAc (9:1)) on aluminum oxide (Rf ) 0.5) gave 2c (92%) as a
yellow oil: 1H NMR (250 MHz) 2.07 (q, J CH
) 2.5, 3H), 3.86
-F
3
(s, 3H), 3.94 (t, J ) 7.5, 2H), 4.21 (t, J ) 7.5, 2H), 6.80 (d, J )
8.8, 2H), 6.90 (d, J ) 8.8, 2H), 10.12 (br s, 1H); 1H NMR (250
MHz) minor tautomer (imino form) 1.46 (br d, J ) 7.3, 3H),
3.78 (s, 3H); 13C NMR (62.8 MHz) 13.15 (q, J C-C-C-C-F)2.7),
54.33, 55.34, 66.01, 105.62 (q, J C-C-C-F ) 2.8), 114.34, 120.08
(q, J C-F ) 275.5), 124.43, 136.28, 138.15 (q, J C-C-F ) 31.0),
156.05, 166.65; IR (neat) 3137, 1630; LRMS (EI) m/ z 300 (M+,
86), 231 (M+ - CF3, 100), 205 (77). Anal. Calcd for
C14H15N2F3O2: C, 55.98; H, 5.04; N, 9.33. Found: C, 55.72;
H, 5.12; N, 9.22.
2-{(Z)-[1-Bu tyl-2-(N-p-a n isyla m in o)-2-(3-p yr id yl)]eth e-
n yl}-2-oxa zolin e (2d ). MPLC (n-hexane-EtOAc (1:1)) on
silica gel (Rf ) 0.6) gave 2d (65%) as a yellow oil: 1H NMR
(250 MHz) 0.81 (t, J ) 7.8, 3H), 1.21 (m, 2H), 1.40 (m, 2H),
2.20 (t, J ) 7.8, 2H), 3.78 (s, 3H), 4.16 (t, J ) 7.5, 2H), 4.36 (t,
J ) 7.3, 2H), 6.69 (s, 4H), 7.31 (m, 1H), 7.64 (m, 1H), 8.62 (m,
2H), 11.38 (br s, 1H); 13C NMR (62.8 MHz) 13.59 (q), 22.15 (t),
27.74 (t), 33.31 (t), 54.03 (t), 55.02 (q), 65.38 (t), 97.47 (s),
113.58 (d), 122.74 (d), 124.74 (d), 131.63 (s), 133.94 (s), 137.00
(d), 148.38 (s), 148.74 (d), 150.24 (d), 155.17 (s), 167.98 (s); IR
(neat) 1616; HRMS calcd for C21H25N3O2 351.1947, found
351.1935; LRMS (EI) m/ z 351 (M+, 80), 308 (M+ - Pr, 100).
Anal. Calcd for C21H25N3O2: C, 71.76; H, 7.17; N, 11.96.
Found: C, 71.67; H, 7.25; N 11.82.
2-[(Z)-(1,3,3-Tr im et h yl-2-N-p -t olylim in o)b u t yl]-2-ox-
a zolin e (2j). MPLC (n-hexane-EtOAc (9:1)) on silica gel (Rf
) 0.3) gave 2j (70%) as a yellow oil: 1H NMR (200 MHz) 1.18
(s, 9H), 1.35 (d, J ) 7.6, 3H), 2.19 (s, 3H), 3.21-3.62 (m, 3H),
3.93-4.09 (m, 2H), 6.45 (d, J ) 8.0, 2H), 6.96 (d, J ) 8.0, 2H);
13C NMR (50 MHz) 16.89 (q), 20.65 (q), 28.49 (q), 35.63 (d),
41.60 (s), 54.15 (t), 63.04 (t), 118.27 (d), 128.76 (d), 131.44 (s),
147.69 (s), 167.86 (s), 176.25 (s); HRMS calcd for C17H24N2O
272.1889, found 272.1887; LRMS (EI) m/ z 272 (M+, 15), 215

N-Substituted â-Enamino Acid Derivatives
J . Org. Chem., Vol. 61, No. 25, 1996 8859
(M+ - t-Bu, 97), 118 (100). Anal. Calcd for C17H24N2O: C,
74.95; H, 8.89; N, 10.29. Found: C, 74.82; H, 8.79; N, 10.20.
X-r a y An a lysis of 2-[(Z)-(2-a n ilin o-2-p -m eth oxyp h e-
n yl)eth en yl]-2-oxa zolin e (1e). X-ray diffractometer analy-
ses of compound 1e were carried out on a diffractometer
equiped with a graphite monochromator. A single crystal was
selected, obtained by slow evaporation of the solvent from a
hexane/chloroform (6:1) solution, that was mounted on a glass
fiber. The structure of 1e, C18H18N2O2 (Mw 294.356 amu), was
determined from a triclinic crystal with dimensions of 0.19 ×
0.2 × 0.2 mm3 (space group P1h) with unit cell dimensions of a
) 9.07 (1) Å, b ) 9.36 (1) Å, c ) 10.36 (1) Å, R ) 93.35°(2), â
) 112.87°(2), γ ) 100.38°(2), V ) 790.7(3) Å3. It has two
molecules per cell, Dc ) 1.249 g‚cm-3, µ ) 0.8 cm-1, F(000) )
312. The cell dimensions were determined from the setting
angles of 25 reflections with 1° < θ < 25° using MoKR radiation
(λ ) 0.71073 Å). A total of 2887 reflections were measured,
h,k,l values range from (0, 0,-19) to (10,12,19), 1948 of which
were observed with I > 3σ (I) using ω - 2θ step scan technique.
The structure was solved using MULTAN 8240 and refined by
full matrix least-squares methods including positional and
anisotropic thermal parameters for nonhydrogen atoms. Hy-
drogen atoms were introduced at calculated positions and were
isotropically refined. The maximum shift over the error ratio
in the last cycle was less than 0.01. The standard reflections
were monitored every 60 min during data collection and
showed no intensity loss. No correction for absortion was
made. No profile analysis was perfomed on the reflections.
Some double measured reflections were averaged and refined
by full matrix least-squares procedures and give R ) 0.038
and Rw′ ) 0.035.
Ack n ow led gm en t. The authors are grateful to the
Direccio´n General de Investigacio´n Cient´ıfica y Te´cnica
for their financial support of this research (DGICYT,
PB93-0360 and PB94-1313-C02-02) and also the CI-
EMAT (Ministerio de Industria y Energ´ıa) for computer
time. A predoctoral fellowship from the Ministerio de
Educacio´n y Ciencia to D.D. is also gratefully acknowl-
edged. We also thank Prof. Francisco J . Gonza´lez for
assistance in ab initio calculations and for helpful
discussions.
Su p p or tin g In for m a tion Ava ila ble: Copies of 1a -z and
1
2a -j H NMR spectra and optimized structures at the HF/3-
21G level corresponding to compounds 1e, 1p , and 1l (55
pages). This material is contained in libraries on microfiche,
immediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
(40) Main, P.; Fiske, S. J .; Hull, S. E.; Lessinger, L.; Germain, G.;
Declerg, J . P.; Woolfson, M. M. MULTAN 11/ 82, A system of Computer
Programs for the Automatic Solution of Crystal Structures from X-Ray
Diffraction Data; University of York: England, 1982.
J O961037Y