Efficient synthesis of 1-azadienes derived from α-aminoesters. Regioselective preparation of α-dehydroamino acids, vinylglycines, and α-amino acids

Article abstract of DOI:10.1021/jo061140f

(Chemical Equation Presented) An efficient synthesis of 1-azadienes derived from α-aminoesters is achieved through an aza-Wittig reaction of phosphazenes with β,γ-unsaturated α-ketoesters. Regioselective 1,2-reduction of these functionalized 1-azadienes affords vinylglycine derivatives, while conjugative 1,4-reduction gives α-dehydroamino acid compounds. Reduction of both the carbon-carbon and the imine-carbon-nitrogen double bonds leads to the formation of α-amino acid derivatives.

Full text of DOI:10.1021/jo061140f

Efficient Synthesis of 1-Azadienes Derived from r-Aminoesters.
Regioselective Preparation of r-Dehydroamino Acids, Vinylglycines,
and r-Amino Acids
Francisco Palacios,* Javier Vicario, and Domitila Aparicio
Departamento de Qu´ımica Orga´nica I, Facultad de Farmacia, UniVersidad del Pa´ıs Vasco, Apartado 450,
01080 Vitoria-Gasteiz, Spain
francisco.palacios@ehu.es
ReceiVed June 5, 2006
An efficient synthesis of 1-azadienes derived from R-aminoesters is achieved through an aza-Wittig reaction
of phosphazenes with â,γ-unsaturated R-ketoesters. Regioselective 1,2-reduction of these functionalized
1-azadienes affords vinylglycine derivatives, while conjugative 1,4-reduction gives R-dehydroamino acid
compounds. Reduction of both the carbon-carbon and the imine-carbon-nitrogen double bonds leads
to the formation of R-amino acid derivatives.
Introduction
process is difficult and the double nucleophilic addition products
are frequently obtained.5
R,â-Unsaturated imines also called 1-azadienes are a versatile
family of compounds with a wide range of applications in the
field of organic chemistry.1 Besides the well-known aza-Diels-
Alder reaction, 1-azadienes show a very assorted reactivity and
have been extensively used in the synthesis of several natural
products. Recent examples in which 1-azadiene species are
involved in the key step are the synthesis of (+)-abresoline,2a
piericidin A1 and B1,2b ningalin,2c phomazarine,2d or cystoda-
mine.2e Moreover, owing to their ambident electrophilic char-
acter, R,â-unsaturated imines can either undergo 1,23 or
conjugate (1,4)4 nucleophilic addition processes, although
generally, the control on the regioselectivity of the addition
The simplest method for the synthesis of R,â-unsaturated
imines implies condensation of R,â-unsaturated carbonyl com-
pounds with primary amines.6 This method is often complicated
by the Michael addition reaction, especially in the case of R,â-
unsaturated ketones, and the olefination reaction of â-phospho-
(3) Contributions to selective 1,2-addition to R,â-unsaturated imines: (a)
Denmark, S. E.; Stiff, C. M. J. Org. Chem. 2000, 65, 5875-5878. (b) Allin,
S. M.; Button, M. A. C.; Baird, R. D. Synlett 1998, 1117-1119. (c) Qian,
C.; Huang, T. J. Organomet. Chem. 1997, 548, 143-147. (d) Jones, C. A.;
Jones, I. G.; Mulla, M.; North, M.; Sartori, L. J. Chem. Soc., Perkin Trans.
1 1997, 2891-2896. (e) Afarinkia, K.; Cadogan, J. I. G.; Rees, C. W. Synlett
1992, 123.
(4) Recent contributions to selective conjugate addition to R,â-unsaturated
imines: (a) Zheng, J.-C.; Liao, W.-W.; Tang, Y.; Sun, X.-L.; Dai, L.-X. J.
Am. Chem. Soc. 2005, 127, 12222-12223. (b) McMahon, J. P.; Ellman, J.
A. Org. Lett. 2005, 7, 5393-5396. (c) Soeta, T.; Kuriyama, M.; Tomioka,
K. J. Org. Chem. 2005, 70, 297-300. (d) Esquivias, J.; Arraya´s, R. G.;
Carretero, J. C. J. Org. Chem. 2005, 70, 7451-7454. (e) Tomioka, K.;
Shioya, Y.; Nagaoka, Y.; Yamada, K.-i. J. Org. Chem. 2001, 66,
7051-7054.
* To whom correspondence should be addressed. Telephone: (+34) 945
013103. Fax: (+34) 945 013049.
(1) For reviews, see: (a) Jayakumar, S.; Ishar, M. P. S.; Mahajan, M. P.
Tetrahedron 2002, 58, 379-471. (b) Buonora, P.; Olsen, J. C.; Oh, T.
Tetrahedron 2001, 57, 6099-6138. (c) Behforouz, M.; Ahmadian, M.
Tetrahedron 2000, 56, 5259-5288.
(2) (a) Atobe, M.; Yamazaki, N.; Kibayashi, C. Tetrahedron Lett. 2005,
46, 2669-2673. (b) Schnermann, M. J.; Boger, D. L. J. Am. Chem. Soc.
2005, 127, 15704-15705. (c) Boger, D. L.; Soenen, D. R.; Boyce, C. W.;
Hedrick, M. P.; Jin, Q. J. Org. Chem. 2000, 65, 2479-2483. (d) Boger, D.
L.; Hong, J.; Hikota, M.; Ishida, M. J. Am. Chem. Soc. 1999, 121, 2471-
2477. (e) Kitahara, Y.; Tamura, F.; Kubo, A. Tetrahedron Lett. 1997, 38,
4441-4442.
(5) Recent contributions to double addition to R,â-unsaturated imines:
(a) Moonen, K.; Van Meenen, E.; Verwe´e, A.; Stevens, C. V. Angew. Chem.,
Int. Ed. 2005, 44, 7407-7411. (b) Shimizu, M.; Kamiya, M.; Hachiya, I.
Chem. Lett. 2005, 34, 1456-1457. (c) Shimizu, M.; Kurokawa, H.;
Takahashi, A. Lett. Org. Chem. 2004, 1, 353-356. (d) Shimizu, M.; Kamiya,
M.; Hachiya, I. Chem. Lett. 2003, 32, 606-607. (e) Shimizu, M.; Ogawa,
T.; Nishi, T. Tetrahedron Lett. 2001, 42, 5463-5466.
10.1021/jo061140f CCC: $33.50 © 2006 American Chemical Society
Published on Web 09/02/2006
7690
J. Org. Chem. 2006, 71, 7690-7696

1-Azadienes DeriVed from R-Aminoesters
SCHEME 1. Potential Nucleophilic Additions to
â,γ-Unsaturated r-Iminoesters I
selective synthesis of vinylglycines II (Scheme 1, 1,2-addition),
R-dehydro aminoesters III (Scheme 1, 1,4-addition), or saturated
R-aminoesters IV, if the double addition occurs (Scheme 1, 1,2-
and 1,4-additions).
The importance of R-amino acids and their derivatives as buil-
ding blocks of proteins and peptides ensures continued interest
in their chemistry.10 Nonproteogenic R-amino acids are expected
to play key roles in improving the original properties and func-
tions of proteins. Among this family are R-dehydroamino acids.
They show intriguing biological activities,11 have been used to
modify the conformational properties of peptides,12 and also
represent an important family of compounds in organic synthesis
as precursors of R-amino acids, commonly through their enantio-
selective catalytic hydrogenation.13 The most common procedure
for the preparation of R-dehydroamino acids is the â-elimination
of R-amino acid derived alcohols or halides,14a,b although effi-
cient synthesis of R-dehydroamino acids by ring opening of aziri-
dines14c or nucleophilic addition to alkynoates14d has also been
reported.
SCHEME 2. Retrosynthesis of â,γ-Unsaturated
r-Iminoesters I
Continuing with our interest in the design and the chemical
behavior of azadienes, we report here an efficient synthesis of
R-alkoxycarbonyl R,â-unsaturated imines, as well as the syn-
thetic application of these substrates as intermediates for the
preparation of vinylglycine, R-dehydroamino, and R-amino acid
derivatives. Retrosynthetically, we envisaged obtaining goal
products, â,γ-unsaturated R-iminoesters I (Scheme 2), through
the construction of the carbon-carbon (CdC) double bond by
means of the olefination reaction (Wittig-Horner or Wads-
worth-Emmons reaction) of imines or tautomeric enamines
derived from phosphine oxide (R ) C6H5, Scheme 2, route a)
with carbonyl compounds in a similar way to that previously
reported for 1-azadienes.7 Alternative processes could involve
either the formation of the carbon-nitrogen double bond by
means of a simple condensation reaction of amines and the R,â-
unsaturated keto-esters (Scheme 2, route b1) or by the aza-Wittig
reaction of phosphazenes with R,â-unsaturated keto-esters
(Scheme 2, route b2), a strategy widely used for the preparation
of 2-azadienes derived from R- and â-amino acids.9
rated imines or enamines with aldehydes to generate the
conjugated CdC bond is usually a good alternative.7 On the
other hand, the aza-Wittig reaction of phosphazenes with
carbonyl compounds represents an easy method for the con-
struction of imine carbon-nitrogen double bonds in very mild
reaction conditions.8 Moreover, phosphazenes have proved to
be useful building blocks for the synthesis of functionalized
imine compounds such as electronically neutral 2-azadienes,9a
electron-poor 2-azadienes derived from aminophosphorus
derivatives,9b electron-poor 2-azadienes derived from R-9c or
â-amino acids,9d and 3-fluoroalkyl-2-azadienes,9e and these
azadienes have been used also as key intermediates in the
preparation of cyclic compounds.9 In addition, when a carboxylic
substituent is present at the 2 position of the 1-azadiene, the
resulting â,γ-unsaturated R-iminoesters I are R-amino acid
derivatives, which could be excellent starting materials for the
31, 3497-3500. (d) Palacios, F.; Herra´n, E.; Rubiales, G.; Ezpeleta, J. M.
J. Org. Chem. 2002, 67, 2131-2135. (e) Palacios, F.; Alonso, C.; Rubiales,
G.; Villegas, M. Tetrahedron 2005, 61, 2779-2794. (f) Palacios, F.; Pe´rez
de Heredia, I.; Rubiales, G. J. Org. Chem. 1995, 60, 2384-2390.
(10) Barrett, G. C. In Chemistry and Biochemistry of the Amino Acids;
Chapman and Hall: London, 1985.
(11) For reviews about R-dehydroamino acid compounds, see: (a)
RajanBabu, T. V.; Yan, Y.-Y.; Shin, S. Curr. Org. Chem. 2003, 7, 1759-
1770. (b) Drexler, H.-J.; You, J.; Zhang, S.; Fisher, C.; Bauman, W.;
Spannenberg, A.; Heller, D. Org. Process Res. DeV. 2003, 7, 355-361. (c)
Brunner, H. Curr. Org. Chem. 2002, 6, 441-451. (d) Schmidt, U.;
Lieberknecht, A.; Wild, J. Synthesis 1988, 159-172.
(12) (a) Broda, M. A.; Siodłak, D.; Rzeszotarska B. J. Pept. Sci. 2005,
11, 546-555. (b) Mathur, P.; Ramakumar, S.; Chauhan, V. S. Biopolymers
2004, 76, 150-161. (c) Vijayaraghavan, R.; Kumar, P.; Dey, S.; Singh, T.
P. J. Pept. Res. 2003, 62, 63-69.
(13) Some recent contributions to hydrogenation of R-dehydroamino
acids: (a) Hu, X.-P.; Huang, J.-D.; Zeng, Q.-H.; Zheng, Z. Chem. Commun.
2006, 293-295. (b) Zeng, Q.-H.; Hu, X.-P.; Duan, Z.-C.; Liang, X.-M.;
Zheng, Z. J. Org. Chem. 2006, 71, 393-396. (c) Shultz, C. S.; Dreher, S.
D.; Ikemoto, N.; Williams, J. M.; Grabowski, E. J. J.; Krska, S. W.; Sun,
Y.; Dormer, P. G.; DiMichele, L. Org. Lett. 2005, 7, 3405-3408. (d) Hoen,
R.; Van den Berg, M.; Bernsmann, H.; Minnaard, A. J.; De Vries, J. G.;
Feringa, B. L. Org. Lett. 2004, 6, 1433-1436.
(14) (a) Chen, D.; Guo, L.; Liu, J.; Kirtane, S.; Cannon, J. F.; Li, G.
Org. Lett. 2005, 7, 921-924. (b) Stohlmeyer, M. M.; Tanaka, H.; Wandless,
T. J. J. Am. Chem. Soc. 1999, 121, 6100-6101. (c) Davis, F. A.; Liu, H.;
Liang, C.-H.; Reddy, G. V.; Zhang, Y.; Fang, T.; Titus, D. D. J. Org. Chem.
1999, 64, 8929-8935. (d) Trost, B. M.; Dake, G. R. J. Am. Chem. Soc.
1997, 119, 7595-7596.
(6) (a) Pearson, W. H.; Jacobs, V. A. Tetrahedron Lett. 1994, 35, 7001-
7004. (b) Boger, D. L.; Corbett, W. L.; Curran, T. T.; Kasper, A. M. J.
Am. Chem. Soc. 1991, 113, 1713-1729. (c) Teng, M.; Fowler, F. W. J.
Org. Chem. 1990, 55, 5646-5653. (d) Brady, W. T.; Shieh, C. H. J. Org.
Chem. 1983, 48, 2499-2502.
(7) (a) Palacios, F.; Ochoa de Retana, A. M.; Pascual, S.; Oyarzabal, J.
J. Org. Chem. 2004, 69, 8767-8774. (b) Palacios, F.; Pascual, S.; Oyarzabal,
J.; Ochoa de Retana, A. M. Org. Lett. 2002, 4, 769-772. (c) Palacios, F.;
Aparicio, D.; Garc´ıa, J.; Rodr´ıguez, E.; Ferna´ndez-Acebes A. Tetrahedron
2001, 57, 3131-3141. (d) Palacios, F.; Aparicio, D.; Garc´ıa, J.; Rodr´ıguez,
E. Eur. J. Org. Chem. 1998, 1413, 3-1423.
(8) For reviews, see: (a) Palacios, F.; Aparicio, D.; Rubiales, G.; Alonso,
C.; de los Santos, J. M. Curr. Org. Chem. 2006, 10, in press. (b) Fresneda,
P. M.; Molina, P. Synlett 2004, 1-17. (c) Eguchi, S.; Okano, T.; Okawa,
T. Recent Res. DeV. Org. Chem. 1997, 337-345. (d) Wamhoff, H.; Richardt,
G.; Stølben, S. AdV. Heterocycl. Chem. 1995, 64, 159-249. (e) Molina,
P.; Vilaplana, M. J. Synthesis 1994, 1197-1218. (f) Gololobov, Y. G.;
Kasukhin, L. F. Tetrahedron 1992, 48, 1353-1406. (g) Barluenga, J.;
Palacios F. Org. Prep. Proced. Int. 1991, 23, 1-65.
(9) (a) Palacios, F.; Alonso, C.; Amezua, P.; Rubiales, G. J. Org. Chem.
2002, 67, 1941-1946. (b) Palacios, F.; Ochoa de Retana, A. M.; Mart´ınez
de Marigorta, E.; Rodr´ıguez, M.; Pagalday, J. Tetrahedron 2003, 59, 2617-
2623. (c) Barluenga, J.; Ferrero, M.; Palacios, F. Tetrahedron Lett. 1990,
J. Org. Chem, Vol. 71, No. 20, 2006 7691

Palacios et al.
SCHEME 3. Wittig-Horner Reaction of Enamine 1 with p-Nitrobenzaldehyde 3a
Results and Discussion
7 with the loss of ethanol could yield cyclic enamine derived
from 2,5-dihydro-furanone 5 (Scheme 3).
Initially, we explored the preparation of â,γ-unsaturated
R-iminoesters I through the olefination reaction of imines or
tautomeric enamines derived from phosphine oxide (R ) C6H5,
Scheme 2, route a) with carbonyl compounds. Required enamine
phosphine oxide 1 was prepared by a condensation reaction of
the tautomeric keto/enol mixture of phosphine oxide 2 with
p-tolylamine (R1 ) p-CH3-C6H4, Scheme 3). Only the Z-isomer
of enamine 1 (R1 ) p-CH3-C6H4) was obtained. The coupling
The preparative utility of this process for the preparation of
imines 4 is limited due to the low yield and the presence of the
cyclic enamine 5 with concomitant problems for the separation
and purification. For this reason, we explored the preparation
of unsaturated imines 4 by formation of carbon-nitrogen double
bonds from R,â-unsaturated ketones (Scheme 2, routes b1,2).
However, Lewis acid-catalyzed condensation of an amine and
â,γ-unsaturated R-ketoester (Scheme 2, route b1) only gave very
low yield of the â,γ-unsaturated R-iminoester 4, because a
subsequent conjugate addition of a second molecule of amine
to unsaturated derivative took place and 3-amino-2,5-dihydro-
1H-pyrrolin-2-ones were mainly obtained.15 For this reason, the
preparation of unsaturated imines 4 by construction of the
carbon-nitrogen double bonds by aza-Wittig reaction of phos-
phazenes with â,γ-unsaturated R-ketoesters was explored (Scheme
2, route b2). We have already demonstrated the usefulness of
phosphazene species in the selective formation of imine
bonds,9,16 and the increased reactivity of phosphazenes when
aromatic substituents at the phosphorus are replaced by alkyl
substituents.17 Therefore, we thought that an efficient selective
synthesis of â,γ-unsaturated R-iminoesters I could be achieved
by aza-Wittig reaction of the very reactive phosphazenes 9
derived from trimethyl phosphine (Scheme 2, route b2, R )
Me, vide supra) and â,γ-unsaturated R-ketoesters.
3
constant JPC ) 17.5 Hz for the carbonyl group of carboxylic
ester observed in the 13C NMR spectrum is consistent with a
trans-configuration of the carboxylic group toward the phos-
phine oxide group.7 Then, the Wittig-Horner reaction of
enamine-phosphine oxide 1 with aldehyde was studied. Treat-
ment of enamine 1 with NaH in THF and subsequent addi-
tion of p-nitrobenzaldehyde 3a (R2 ) p-NO2-C6H4) afforded
not only the expected functionalized R,â-unsaturated imine 4a
(R1 ) p-CH3-C6H4, R2 ) p-NO2-C6H4) in low yield (38%)
as an anti/syn-mixture of imines (60/40), but also cyclic
R-dehydroamino acid derivative 5 (R1 ) p-CH3-C6H4, R2 )
p-NO2-C6H4; 21%) containing a phosphine oxide group
(Scheme 3). Imine 4a and cyclic enamine 5 were fully
characterized by 1H NMR, 13C NMR, MS, and IR spectroscopy.
Characteristic coupling constants for the vinyl protons of 4a in
the range of 16 Hz are consistent with an E configuration of
the double bond. On the other hand, characteristic signals for 5
â,γ-Unsaturated R-ketoesters, although not commercially avail-
able, can be easily prepared by aldolic or Wittig-type condensa-
tion of aldehydes with the corresponding pyruvate-derived
reagent, as described in the literature.15 Phosphazenes were read-
ily prepared in situ by addition of trimethylphosphine to aryl
azides 8 and, given the instability of P-trialkyl phosphazene
species, N-aryl trimethylphoshazenes 9 were not isolated18 and
were used without purification for the following purposes. The
1
in the H NMR spectrum are the doublet at δ ) 6.65 ppm,
3
with a coupling constant JPH ) 3.1 Hz, corresponding to the
CH proton in the five-membered ring and the singlet δ ) 6.84
ppm, which showed interchange with D2O and was assigned to
the NH group. Whereas the 13C NMR spectrum shows a
characteristic doublet signal at δ ) 81.7 ppm with a coupling
2
constant JPH ) 3.1 Hz for the CH in the five-membered ring,
1
another doublet at δ ) 107.1 with a coupling constant JPC
)
110.3 Hz and a singlet at δ ) 144.1 ppm assigned to the â-
and R-enaminic quaternary carbons, respectively, and a doublet
(15) Palacios, F.; Vicario, J.; Aparicio, D. Eur. J. Org. Chem. 2006,
2843-2850.
3
(16) Some recent contributions: (a) Palacios, F.; Alonso, C.; Rodriguez,
M.; Martinez de Marigorta, E.; Rubiales, G. Eur. J. Org. Chem. 2005, 1795-
1804. (b) Palacios, F.; Alonso, C.; Rubiales, G.; Villegas, M. Tetrahedron
Lett. 2004, 45, 4031-4034. (c) Palacios, F.; Herran, E.; Rubiales, G.
Heterocycles 2002, 58, 89-92. (d) Palacios, F.; Alonso, C.; Rubiales, G.
J. Org. Chem. 1997, 62, 1146-1154.
at δ ) 166.9 with a coupling constant JPC ) 17.5 Hz for the
amide CdO.
Formation of both products could be explained by an initial
addition of the carbanion 6 to aldehyde 3a to give adduct 7.
Olefination reaction with the loss of diphenylphosphine oxide
from this intermediate 7 could give functionalized R,â-unsatur-
ated imine 4a, while intramolecular cyclocondensation of adduct
(17) (a) Cossio, F. P.; Alonso, C.; Lecea, B.; Ayerbe, M.; Rubiales, G.;
Palacios, F. J. Org. Chem. 2006, 71, 2839-2847. (b) Palacios, F.; Herran,
E.; Rubiales, G. J. Org. Chem. 1999, 64, 6239-6246.
7692 J. Org. Chem., Vol. 71, No. 20, 2006

1-Azadienes DeriVed from R-Aminoesters
TABLE 1. 1-Azadienes 1 Obtained by Aza-Wittig Reaction
SCHEME 4. Synthesis of 1-Azadienes 4
entry compd
R1
R2
yield (%) syn/anti
1
2
3
4
5
6
7
8
9
4a
4b
4c
4d
4e
4f
4g
4h
4i
p-Me-C6H4
p-NO2-C6H4
p-NO2-C6H4
p-NO2-C6H4
91a
90a
91a
89b
82b
91b
91b
94b
94b
95b
41/59
38/62
43/57
41/59
43/57
36/64
44/66
42/68
40/60
41/59
p-MeO-C6H4 p-NO2-C6H4
p-Me-C6H4
p-NO2-C6H4
p-Me-C6H4
p-Me-C6H4
p-MeO-C6H4 Me
p-MeO-C6H4 2-furyl
p-NO2-C6H4
p-Me-C6H4
CO2Et
CO2Et
10
4j
p-MeO-C6H4 CO2Et
SCHEME 5. Selective Conjugate (1,4) 1,2 or Total
Reduction of 1-Azadienes 4a
a Isolated yield. b Crude yield.
TABLE 2. r-Dehydroamino Esters 11 Obtained by Selective
Reduction of 1-Azadienes 4 and â,γ-Unsaturated r-Ketoesters 12
entry
compd
R1
R2
yielda (%)
1
2
3
4
5
6
7
11a
11b
11c
11d
11e
12a
12b
p-MeO-C6H4
p-NO2-C6H4
p-Me-C6H4
p-MeO-C6H4
p-MeO-C6H4
p-MeO-C6H4
p-NO2-C6H4
p-NO2-C6H4
CO2Et
CO2Et
CH3
2-furyl
64
75
79
71
69
82
85
p-NO2-C6H4
CO2Et
a Isolated yield.
respective of the double bond (anti-isomer). The same effect
was observed for the R-carboxylic substituent.
a Reagents and conditions: (i) NaBH4, THF, -78 °C; (ii) HCl 3 M,
THF; (iii) NaBH4/TFA, CH3CN, 0 °C; (iv) NaBH4, THF, -30 °C; (v) H2,
Pd-C, MeOH, rt; (vi) CAN, MeCN/H2O.
Azadienes 4 showed in general very low stability because
they yielded the hydrolysis products when most of the common
purification techniques were used. â,γ-Unsaturated R-imi-
noesters 4a-c (R2 ) p-NO2-C6H4; Table 1, entries 1-3) are
solids and allowed workup with water and purification by
crystallization in diethyl ether; however, only workup with water
to get rid of trimethylphosphine oxide was possible for â,γ-
unsaturated R-iminoesters 4d,e (R2 ) p-Me-C6H4; Table 1,
entries 4 and 5), 4f (R2 ) Me; Table 1, entry 6), 4g (R2 )
2-furyl; Table 1, entry 7), or 4h-j (R2 ) CO2Et; Table 1, entries
8-10). Chromatography or distillation of 1-azadienes 4d-j
afforded undesirable side products and, therefore, they were used
without purification in further steps.
CHART 1. 1H and 13C NMR δ Values for syn- and
anti-Imines 4b
This raised the possibility of the selective reduction of
functionalized 1-azadienes 4. Treatment of 1-azadienes 4 derived
from R-amino acids with NaBH4 at -78 °C afforded (Z)-R-
dehydroaminoesters 11 with good yields (Scheme 5, Table 2,
entries 1-5) in a stereoselective fashion. R-Dehydroaminoesters
11 were fully characterized by IR and 1H and 13C NMR
subsequent addition of the â,γ-unsaturated R-ketoester 10 afford-
ed the 1-azadienes derived from R-aminoesters 4 (Scheme 4).
1-Azadienes derived from R-aminoesters 4 were obtained as
syn/anti-mixtures. The configuration of the conjugated double
bond was retained in all the cases. The assignment of the syn-
and anti-isomers was established on the basis of the “steric
1
spectroscopy and CIMS and H NMR-NOE experiments were
performed to determine the configuration of the enaminic bond.
1
The H NMR spectrum of 11a (R1 ) p-MeO-C6H4, R2 )
1
compression” observed in the δ values in H and 13C NMR
p-NO2-C6H4) showed characteristic doublet at δ ) 3.38 ppm
spectra.19 For 1-azadiene 4b (Chart 1, vide infra), if the aromatic
substituent on the nitrogen has a cis-orientation respective of
the conjugated double bond (syn-isomer), the δ values are
3
and triplet at δ ) 6.30 ppm with a coupling constant JHH
)
7.2 Hz, corresponding to the CH2 and the olefinic CH,
respectively. The doublet for the methylene group showed a
NOE effect of 12% with a singlet at δ ) 5.68 ppm, which
underwent interchange with D2O and was, therefore, assigned
to the NH group, whereas the triplet for the methynic proton
showed a NOE effect of 8% with the quadruplet at δ ) 4.27
ppm, corresponding to the CH2 of the ethoxy group. NOE effects
are consistent with a Z configuration of the double bond.
The scope of the reaction is not restricted to aryl 11a (R2 )
p-NO2-C6H4, Table 2, entry 1) or heterocyclic 11e (R2 )
2-furyl, Table 2, entry 5) substituted compounds because
1
smaller in H and 13C NMR than the corresponding δ values
when the substituent of the nitrogen has a trans-orientation
(18) The formation of phosphazene species 9 was evident from the visible
nitrogen gas formation during the addition of trimethylphosphine and was
monitored by NMR when p-nitrophenyl azide was used. The 31P NMR
spectrum showed a clear disappearance of the signal corresponding to
trimethylphosphine at δ ) -61.1 ppm and the appearance of a new signal
at δ ) 14.7 ppm attributed to the phosphazene 9 (R1 ) p-NO2-C6H4).
(19) Knorr, R.; Hintermeyer-Hilpert, M.; Bo¨hrer, P. Chem. Ber. 1990,
123, 1137-1141.
J. Org. Chem, Vol. 71, No. 20, 2006 7693

Palacios et al.
TABLE 3. â,γ-Unsaturated r-Aminoesters 13 and Saturated
r-Aminoesters 14 Obtained by Selective Reduction of 1-Azadienes 4
SCHEME 6. Synthesis of Lactam 17
entry
compd
R1
R2
yielda (%)
1
2
3
4
5
6
7
8
9
13a
13b
13c
13d
13e
14a
14b
14c
14d
14e
p-NO2-C6H4
p-Me-C6H4
p-MeO-C6H4
p-Me-C6H4
p-MeO-C6H4
p-Me-C6H4
p-MeO-C6H4
p-MeO-C6H4
p-MeO-C6H4
p-MeO-C6H4
p-NO2-C6H4
p-NO2-C6H4
p-NO2-C6H4
p-Me-C6H4
CH3
CO2Et
CO2Et
p-NO2-C6H4
CH3
89
85
83
86
81
88,b 82,c 78d
87,b 81c
90,b 92e
88b
10
2-furyl
82b
a Isolated yield. b From 1-azadiene 4 with H2, Pd-C. c From 1-azadiene
4 with NaBH4. d From enaminoester 11 with NaBH4. e From vinylglycines
13 with H2, Pd-C.
oxidation of the parent γ-functionalized R-amino acids,21d-g
oxidation of the â-amino alcohol to R-amino acid,21h isomer-
ization of â-vinylcyclines,21c,i or reduction of the R-iminoester.21j
Then the synthesis of the saturated R-aminoesters 14 was
explored (Scheme 5, vide supra), and the preparation of these
compounds 14 can be achieved by reduction of the R-dehydro-
amino esters 11 with NaBH4 at -30 °C or by catalytic hydro-
genation of the â,γ-unsaturated R-aminoesters 13. Alternatively,
the saturated R-aminoesters 14 can also be prepared directly
from the â,γ-unsaturated R-iminoesters 4 either by reduction
with NaBH4 at -30 °C or by catalytic hydrogenation (Scheme
4, Table 3, entries 6-10). R-Aminoesters 14 were fully charac-
R-dehydroaminoesters 11b,c derived from glutamic esters (R2
) CO2Et, Table 2, entries 2 and 3) or with an alkyl substituent
11d (R2 ) CH3, Table 2, entry 4) can be obtained. Saturated
R-ketoesters 12a,b were also obtained with very good yields
(82-85%) from esters 11a,b by acidic hydrolysis of the
enaminic group with HCl.
Different selectivity on the reduction was observed in acidic
media, because the treatment of 1-azadienes 4 derived from
R-aminoesters with NaBH4 in the presence of trifluoroacetic
acid (TFA) at 0 °C yielded the vinylglycines 13 with very good
yields (Scheme 5, Table 3, entries 1-5). In the presence of a
protic source, the iminium salt is expected to be formed,
activating the 1,2-nucleophilic addition of hydride anion. Full
1
terized on the basis of their H and 13C NMR, IR, and EIMS.
It is noteworthy that this strategy can also be used for the
preparation of vinylglycine derivatives and glutamic ester.
Primary vinylglycine 15 and glutamic ester 16 can also be
obtained in good yields when N-p-methoxyphenyl vinylglycine
13c (R1 ) p-MeO-C6H4, R2 ) p-NO2-C6H4) and glutamic
esters 14b (R1 ) p-MeO-C6H4, R2 ) CO2Et) were used.
N-Deprotection of the N-methoxyphenyl vinylglycine 13c with
cerium ammonium nitrate (CAN) in acetonitrile and water
(Scheme 5) gave vinylglycine 15 in 62% yield. Similarly,
N-deprotection of the N-methoxyphenyl glutamic ester 14b with
CAN afforded glutamic ester 16 (62%).
A special case is the reduction at 25 °C of â,γ-unsaturated
R-aminoester 4h with two carboxylic substituents. The cyclic
lactam 17 derived from glutamic ester was obtained in 73%
yield when the â,γ-unsaturated R-aminoester 4h was treated
with NaBH4 in THF at 25 °C (Scheme 6). No lactam 17 was
observed when glutamic diester 14a was heated in THF, but
the metalation of the saturated R-amino ester 14a with NaH in
THF and subsequent heating of the anion afforded the cyclic
lactam 17. These results suggest that when the reduction of the
â,γ-unsaturated R-aminoester 4h is carried out, first saturated
â,γ-unsaturated R-aminoester 14a is formed and then the
intramolecular attack of the anion to the carbonyl group affords
the cyclic product 17 after the loss of ethanol (Scheme 6).
1
characterization of vinylglycines 13 by H and 13C NMR and
IR spectroscopy and EIMS was performed. The 1H NMR
spectrum of vinylglycine 13b shows a double doublet at δ )
6.53 ppm for one of the olefinic protons with a coupling constant
3JHH ) 15.9 Hz, characteristic for E configuration, with the other
olefinic proton at δ ) 6.86 ppm and a doublet at δ ) 4.75 ppm
corresponding to the CHN. The most characteristic signals in
the 13C NMR spectrum are those corresponding to the alkene
bond at δ ) 130.3 and 130.2 ppm and the CHN at δ ) 59.1
ppm. When the same acidic conditions were tried with the
unstable 1-azadienes derived from glutamate 4h-j, no vinylg-
lycine 13 was obtained, and imine hydrolysis to carbonyl
compounds 10 was observed instead.
Among the R-amino acid family, â,γ-unsaturated R-amino
acids exhibit important biological activity. The simplest member
of this family, R-vinylglycine is a potent inhibitor of several
transaminase and decarboxylase enzymes,20a,b and nature pro-
duces many biologically active molecules bearing substituted
R-vinylglycines in their structure. Rhizobitoxin,20c radiosumin,20d
or (L)-trans-R-methoxyvinylglycine20e constitute some examples
of natural R-vinylglycines. â,γ-Unsaturated R-amino acid
derivatives have been synthesized by deconjugation of dehydro-
R-amino acids,21a,b three-component reaction of alkenyl boronic
acid, amine, and ketoacid,21c formation of the vinylic bond by
Conclusion
(20) (a) Griffith, O. W. J. Biol. Chem. 1983, 258, 1591-1598. (b) Soper,
T. S.; Manning, J. M.; Marcotte, P. A.; Walsh, C. T. J. Biol. Chem. 1977,
252, 1571-1575. (c) Keith, D. D.; de Bernardo, S.; Weigele, M.
Tetrahedron 1975, 31, 2629-2632. (d) Coleman, J. E.; Wright, J. L. C. J.
Nat. Prod. 2001, 64, 668-670. (e) Rando, R. R. Nature 1974, 250, 586-
587.
(21) (a) Alexander, P. A.; Marsden, S. P.; Mun˜oz Subtil, D. M.; Reader,
J. C. Org. Lett. 2005, 7, 5433-5436. (b) Hoppe, I.; Scho¨ellkopf, U. Synthesis
1982, 129-131. (c) Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1997,
119, 445-446. (d) Barton, D. H. R.; Crich, D.; Herve´, Y.; Potier, P.; Thierry,
J. Tetrahedron 1985, 41, 4347-4357. (e) Hanessian, S.; Sahoo, S. P.
The use of aza-Wittig reaction involving phosphazene species
derived from trimethylphosphine constitutes an excellent alter-
Tetrahedron Lett. 1984, 25, 1425-1428. (f) Afzali-Ardakani, A.; Rapoport,
H. J. Org. Chem. 1980, 45, 4817-4820. (g) Pellicciari, R.; Natalini, B.;
Marinozzi, M. Synth. Commun. 1988, 18, 1715-1721. (h) Beaulieu, P. L.;
Duceppe, J.-S.; Johnson, C. J. Org. Chem. 1991, 56, 4196-4204. (i)
Kirihata, M.; Fukuari, M.; Izukawa, T.; Ichimoto, I. Amino Acids 1995, 9,
317-325. (j) Bicknell, A. J.; Burton, G.; Elder, J. S. Tetrahedron Lett.
1988, 29, 3361-3364.
7694 J. Org. Chem., Vol. 71, No. 20, 2006

1-Azadienes DeriVed from R-Aminoesters
3.38 (d, 3JHH ) 7.2 Hz, 2H), 1.31 (t, 3JHH ) 7.2 Hz, 3H). 13C NMR
(75 MHz, CDCl3): δ 165.6, 154.4, 147.4, 140.4, 136.9, 131.8,
129.3, 123.7, 120.6, 119.2, 114.5, 61.7, 55.6, 34.5, 14.2. FTIR (film)
νmax (cm-1): 3371, 1727. CIMS m/z (amu): 357 (M+ + 1, 100).
Elem anal. Calcd (%) for C19H20N2O5: C, 64.04; H, 5.66; N, 7.86.
Found: C, 64.00; H, 5.71; N, 7.82.
native for the construction of the imine carbon-nitrogen double
bond of unsaturated imines derived from R-amino acids,
avoiding the usual regioselectivity problems by the condensation
of R,â-unsaturated carbonylic compounds with amines. A very
efficient regioselective synthesis of electron-poor 1-azadienes
derived from R-amino acids 4 is described. Regioselective
conjugate reduction (1,4-addition) of R,â-unsaturated imines
derived from R-amino acids 4 gives R-dehydroamino acid
derivatives 11, including R-dehydro glutamic ester, while
selective reduction (1,2-addition) of the imine carbon-nitrogen
double bond of functionalized R,â-unsaturated imines 4 led to
the formation of vinylglycine derivatives 13 and 15. Reduction
of both the carbon-carbon and the imine carbon-nitrogen
double bonds of R,â-unsaturated imines 4 afforded R-amino acid
derivatives 14 and 16, as well as cyclic lactam derived from
glutamic ester 17.
Procedure for the Hydrolysis of R-Dehydroamino Esters 11.
To a solution of R-dehydroamino ester 11 (0.5 mmol) in THF (1
mL) was added a 3 M aqueous solution of HCl (1 mL), and the
resulting mixture was refluxed overnight. The reaction was cooled
to rt and neutralized with a saturated aqueous solution of NaHCO3
(10 mL) and extracted with CH2Cl2 (2 × 15 mL), which was dried
over MgSO4 and concentrated under reduced pressure. The crude
residue was purified by chromatography (SiO2, AcOEt/hexanes 1:3).
Ethyl 4-(4-Nitro-phenyl)-2-oxo-butanoate 12a. Compound 12a
was synthesized according to the general procedure with ethyl (E)-
2-p-methoxyphenylamino-4-p-nitrophenyl-3-butenoate 11a (179
mg, 0.5 mmol), affording 103 mg (82%) of 12a as a colorless oil.
Spectroscopic data are in agreement with literature values.22
Representative Example for the Selective 1,2-Reduction of
1-Azadienes 4 with NaBH4 in the Presence of TFA. Synthesis
of Vinylglycines 13: NaBH4 (76 mg, 2 mmol) was slowly added
to a solution of the corresponding 1-azadiene 4 (1 mmol) and TFA
(0.5 mL) in MeCN (3 mL) at 0 °C. The resulting mixture was stirred
at 0 °C for 3 h and was then quenched with an aqueous saturated
solution of NaHCO3 (15 mL), extracted with CH2Cl2 (3 × 20 mL),
dried over MgSO4, and concentrated under reduced pressure. The
crude residue was purified by crystallization from MeOH.
Ethyl (E)-4-p-Nitrophenyl-2-p-nitrophenylamino-3-butenoate
13a. Compound 13a was synthesized according to the general
procedure with ethyl p-nitrophenyl-2-p-nitrophenylimino-(E)-3-
butenoate 4b (369 mg, 1 mmol), affording 391 mg (89%) of 35a
Experimental Section
Representative Example for the Synthesis of 1-Azadienes 4.
To a solution of the corresponding azide 8 (5 mmol) in CH2Cl2
(25 mL) at 0 °C was added a 1 M solution of trimethylphosphine
in toluene (5 mL). The resulting solution was stirred 30 min until
N2 evolution stopped, which indicates the completion of the reaction
and the phosphazene 9 formation, and the corresponding neat â,γ-
unsaturated R-ketoester 10 (5 mmol) was then added. The reaction
was stirred at rt for 30 min and was then washed with water (3 ×
40 mL), dried over MgSO4, and concentrated under reduced
pressure. 1-Azadienes 4d-i were used without any further purifica-
tion in the following steps, and 1-azadienes 4a-c were purified
by crystallization from Et2O.
1
as a yellow solid. Mp 175-176 °C (Et2O). H NMR (300 MHz,
3
3
syn- and anti-Ethyl 4-(p-nitrophenyl)-2-p-nitrophenylimino-
3-(E)-butenoate 4b. Synthesized according to the general procedure
with p-nitrophenyl azide (0.82 g, 5 mmol) and ethyl (E)-4-p-
nitrophenyl-2-oxo-3-butenoate (1.25 g, 5 mmol), affording 1.52 g
(91%) of 4b as a yellow solid (syn/anti ) 38/62). Mp 100-101
°C (Et2O). 1H NMR (300 MHz, CDCl3): δ 8.28 and 8.17 (d, 3JHH
CDCl3): δ 8.19 (d, JHH ) 8.9 Hz, 2H), 8.11 (d, JHH ) 9.2 Hz,
3
3
2H), 7.51 (d, JHH ) 8.9 Hz, 2H), 6.78 (d, JHH ) 14.6 Hz, 1H),
6.62 (d, 3JHH ) 8.9 Hz, 2H), 6.48 (dd, 3JHH ) 14.6 Hz, 3JHH ) 5.2
3
3
Hz, 1H), 5.57 (d, JHH ) 5.1 Hz, 1H), 4.85 (dd, JHH ) 5.1 Hz,
3JHH ) 5.2 Hz, 1H), 4.41-4.22 (m, 2H), 1.36 (t, JHH ) 6.8 Hz,
3
3H). 13C NMR (75 MHz, CDCl3): δ 169.6, 150.9, 147.4, 141.8,
139.2, 131.2, 128.0, 127.4, 126.3, 124.1, 112.2, 62.9, 57.7, 14.2.
FTIR (KBr) νmax (cm-1): 3344, 1728. EIMS m/z (amu): 371 (M+,
87), 298 (100). Elem anal. Calcd for C18H17N3O6: C, 58.22; H,
4.61; N, 11.32. Found: C, 58.17; H, 4.57; N, 11.38.
3
3
) 8.5 Hz, d, JHH ) 8.5 Hz, 2H), 8.23 (d, JHH ) 8.8 Hz, 2H),
3
3
7.71 and 7.51 (d, JHH ) 8.5 Hz, d, JHH ) 8.5 Hz, 2H), 7.60 and
7.36 (d, 3JHH ) 16.6 Hz, d, 3JHH ) 16.3 Hz, 1H), 7.11 and 6.60 (d,
3JHH ) 16.6 Hz, d, JHH ) 16.3 Hz, 1H), 7.02 (d, JHH ) 8.8 Hz,
3
3
2H), 4.49 and 4.14 (q, 3JHH ) 6.9 Hz, q, 3JHH ) 7.0 Hz, 2H), 1.48
Representative Examples for the Total Reduction of 1-Aza-
dienes 4. Synthesis of R-Aminoesters 14. Procedure A: catalytic
hydrogenation of 1-azadienes 4 or vinylglycines 13. A solution of
1-azadiene 4 or vinylglycine 13 (1 mmol) in EtOH (5 mL) with
Pd-C (10%; 53 mg, 0.05 mmol) was stirred overnight under H2
atmosphere at 80 psi. The resulting mixture was filtered through
Celite and concentrated under reduced pressure. The crude residue
was purified by chromatography (SiO2, AcOEt/hexanes 1:3).
Procedure B: reduction of 1-azadienes 4 or R-dehydroamino esters
11 with NaBH4. Over a solution of â,γ-unsaturated 1-azadiene 4
or R-dehydroamino ester 11 (1 mmol) in THF at -30 °C was added
NaBH4 (2 mmol). The resulting mixture was stirred at -30 °C for
3 h, quenched with a saturated aqueous solution of NH4Cl, and
extracted with CH2Cl2, which was dried over MgSO4. The crude
residue was purified by chromatography (SiO2, AcOEt/hexanes 1:3).
Diethyl 2-p-Tolylaminopentanediate 14a. Compound 14a was
synthesized according to the general procedure A with crude ethyl
4-ethoxycarbonyl-2-p-tolylimino-(E)-3-butenoate 4i (289 mg, 1
mmol), affording 258 mg (88%) of 14a as a colorless oil,
synthesized according to the general procedure B with crude ethyl
4-ethoxycarbonyl-2-p-tolylimino-(E)-3-butenoate 4i (289 mg, 1
mmol), affording 0.241 mg (82%) of 14a as a colorless oil, and
synthesized according to the general procedure B with ethyl
3
3
and 1.02 (t, JHH ) 6.9 Hz, t, JHH ) 7.0 Hz, 3H). 13C NMR (75
MHz, CDCl3): δ 163.4 and 162.2, 159.9 and 158.3, 155.3 and
153.9, 148.0, 144.4, 141.5 and 139.6, 140.6, 128.2 and 119.5, 128.0
and 127.8, 124.8 and 124.4, 123.9, 119.7 and 119.3, 65.4 and 62.4,
13.8 and 13.4. FTIR (KBr) νmax (cm-1): 1732, 1600. CIMS m/z
(amu): 370 (M+ + 1, 100). Elem anal. Calcd (%) for C18H15N3O6:
C, 58.54; H, 4.09; N, 11.38. Found: C, 58.50; H, 4.11; N, 11.42.
Representative Example for the Selective 1,4-Reduction of
1-Azadienes 4 with NaBH4. Synthesis of (Z)-R-Dehydroamino
Esters 11: To a suspension of NaBH4 (76 mg, 2 mmol) in THF (3
mL) at -78 °C was added a solution of 1-azadiene 4 (1 mmol) in
THF (2 mL). The reaction was stirred at -78 °C for 12 h and was
then quenched with a saturated aqueous solution of NH4Cl (20 mL).
The mixture was warmed to rt, extracted with CH2Cl2, (3 × 15
mL), dried over MgSO4, and concentrated under reduced pressure.
The crude residue was purified by chromatography (SiO2, AcOEt/
hexanes 1:3).
Ethyl 2-p-Methoxyphenylamino-4-p-nitrophenyl-2-(Z)-buteno-
ate 11a. Synthesized according to the general procedure with ethyl
2-p-methoxyphenylimino-4-p-nitrophenyl-(E)-3-butenoate 4c (354
mg, 1 mmol), affording 232 mg (64%) of 11a as a pale yellow oil.
Rf (AcOEt): 0.87. 1H NMR (300 MHz, CDCl3): δ 8.13 (d, 3JHH
)
9.1 Hz, 2H), 7.28 (d, 3JHH ) 9.1 Hz, 2H), 6.82 (d, 3JHH ) 7.2 Hz,
3
3
2H), 6.76 (d, JHH ) 7.2 Hz, 2H), 6.30 (t, JHH ) 7.2 Hz, 1H),
(22) Dao, D. H.; Okamura, M.; Akasaka, T.; Kawai, Y.; Hida, K.; Ohno,
A. Tetrahedron: Asymmetry 1998, 9, 2725-2737.
3
5.68 (s, 1H), 4.27 (q, JHH ) 7.2 Hz, 2H), 3.78 (s, 3H, CH3O),
J. Org. Chem, Vol. 71, No. 20, 2006 7695

Palacios et al.
4-ethoxycarbonyl-2-p-tolylamino-2-(Z)-butenoate 11c (291 mg, 1
mmol), affording 234 mg (78%) of 14a as a colorless oil. Rf
solution of NH4Cl, extracted with CH2Cl2, dried over MgSO4, and
concentrated under reduced pressure. The crude residue was purified
by chromatography (SiO2, AcOEt/hexanes 1:3), affording 182 mg
(73%) of 17 as a pale yellow oil. Rf (AcOEt): 0.48. 1H NMR (300
MHz, CDCl3): δ 7.33 (d, 3JHH ) 8.1 Hz, 2H), 7.11 (d, 3JHH ) 8.1
1
3
(AcOEt): 0.81. H NMR (300 MHz, CDCl3): δ 6.97 (d, JHH
)
3
8.2 Hz, 2H), 6.54 (d, JHH ) 8.2 Hz, 2H), 4.20-4.09 (m, 5H),
3
3
4.07 (dd, JHH ) 3.2 Hz, JHH ) 7.5 Hz, 1H) 2.49-2.44 (m, 2H),
2.22 (s, 3H), 2.17-2.03 (m, 2H), 1.24 (t, 3JHH ) 7.2 Hz, 3H), 1.23
3
3
Hz, 2H), 4.64 (dd, JHH ) 7.3 Hz, JHH ) 6.1 Hz, 1H), 4.18 (q,
3JHH ) 7.1 Hz, 2H), 2.69 (m, 1H), 2.48 (m, 2H), 2.26 (s, 3H), 2.15
(m, 1H), 1.21 (t, 3JHH ) 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3):
δ 174.2, 171.8, 135.5, 135.3, 129.5, 122.0, 61.9, 61.5, 30.7, 23.1,
20.8, 13.9. FTIR (film) νmax (cm-1) 1735, 1711. EIMS m/z (amu):
247 (M+, 32), 174 (100). Elem anal. Calcd for C14H17NO3: C,
68.00; H, 6.93; N, 5.66. Found: C, 68.01; H, 6.95; N, 5.61.
Pyrrolidinone 17 can also be synthesized in a “one pot” reaction
from 1-azadiene 4i: To a suspension of NaBH4 (75 mg, 2 mmol)
in THF (3 mL) at 0 °C was added a solution of crude diethyl ethyl
4-ethoxycarbonyl-2-p-tolylimino-(E)-3-butenoate 4i (289 mg, 1
mmol) in THF (2 mL). The reaction was stirred at 0 °C for 1 h and
was then refluxed for 12 h. The mixture was washed with H2O,
extracted with CH2Cl2, dried over MgSO4, and concentrated under
reduced pressure, and the crude residue was purified by chroma-
tography (SiO2, AcOEt/hexanes 1:3), affording 173 mg (69%) of
17 as a pale yellow oil.
3
(t, JHH ) 7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 173.7,
172.9, 144.5, 129.8, 127.8, 113.8, 61.2, 60.5, 56.5, 30.5, 28.0, 20.4,
14.2, 14.1. FTIR (film) νmax (cm-1): 3355, 1736. EIMS m/z
(amu): 293 (M+, 100), 220 (90). Elem anal. Calcd for C16H23-
NO4: C, 65.51; H, 7.90; N, 4.77. Found: C, 65.56; H, 7.86; N,
4.74.
Procedure for the Synthesis of Primary Vinylglycine 15. To
a solution of CAN (mg, 1.5 mmol) in water (2 mL) was slowly
added vinylglycine 13c (0.5 mmol) in MeCN (2 mL) at 0 °C. The
mixture was stirred for 1 h, and Na2CO3 was added until pH became
7. The mixture was filtered through Celite, and the filtrate was
extracted with CH2Cl2 (3 × 20 mL), which was dried over MgSO4
and concentrated under reduced pressure. The crude residue was
purified by chromatography (SiO2, AcOEt/hexanes 5:1).
Ethyl 2-Amino-4-(4-nitro-phenyl)-but-3-enoate 15. Synthe-
sized according to the general procedure with ethyl (E)-2-p-
methoxyphenylamino-4-p-nitrophenyl-3-butenoate 13c (178 mg, 0.5
1
mmol), affording 77 mg (62%) of 15 as a yellow oil. H NMR
Acknowledgment. The present work has been supported by
the Direccio´n General de Investigacio´n del Ministerio de Ciencia
y Tecnolog´ıa (MCYT, Madrid DGI, PPQ2003-0910) and by
the Universidad del Pa´ıs Vasco (UPV, GC 2002). J.V. thanks
the Departamento de Educacio´n, Universidades e Investigacio´n
del Gobierno Vasco, for a postdoctoral fellowship.
(300 MHz, CD3OD): δ 8.11 (d, 3JHH ) 8.9 Hz, 2H), 7.24 (d, 3JHH
3
3
) 8.9 Hz, 2H), 6.76 (d, JHH ) 15.8 Hz, 1H), 6.03 (dd, JHH
)
15.8 Hz, 3JHH ) 5.3 Hz, 1H), 4.59 (d, 3JHH ) 5.3 Hz, 1H), 4.12-
4.00 (m, 2H), 1.12 (t, JHH ) 7.2 Hz, 3H). 13C NMR (75 MHz,
3
CD3OD): δ 169.7, 142.50, 138.9, 129.2, 127.2, 124.0, 120.5, 60.5,
58.2, 56.4, 13.4. FTIR (KBr) νmax (cm-1): 3365, 1736. CIMS m/z
(amu): 251 (M+ + 1, 100). Elem anal. Calcd for C12H14N2O4: C,
57.59; H, 5.64; N, 11.19. Found: C, 57.64; H, 5.61; N, 11.23.
Procedure for the Synthesis of 5-Ethoxycarbonyl-1-p-tolyl-
pyrrolidin-2-one 17. To a suspension of NaH (24 mg, 1 mmol) in
THF (3 mL) at 0 °C was added a solution of diethyl 2-p-
tolylaminopentanediate 14a (293 mg, 1 mmol) in THF (2 mL). The
reaction was stirred at 0 °C for 1 h and was then refluxed for 12 h.
The reaction was cooled and quenched with a saturated aqueous
Supporting Information Available: Full characterization and
procedures for the synthesis of enamine 1, the mixture ketone/enol
2, furan-2-one 5, 1-azadienes 4a,c-i, R-dehydroamino esters 11b-
d, R-ketoester 12b, vinylglycines 13b-d, and R-aminoesters 14b-e
and 16. This material is available free of charge via the Internet at
http://pubs.acs.org.
JO061140F
7696 J. Org. Chem., Vol. 71, No. 20, 2006