Synthesis and reactivity of new β-enamino acid derivatives: A simple and general approach to β-enamino esters and thioesters

Article abstract of DOI:10.1021/jo9809480

A new strategy has been developed for the synthesis of several β- enamino acid derivatives. N,N'-Carbonyldiimidazole has been used as C- acylating agent of methyl ketimines, providing a direct and simple route to new β-enamino carbonyl imidazole derivatives 2. These derivatives 2 were cleanly and efficiently transformed into β-enamino esters 4 (X = O) and thioesters 4 (X = S) by reaction with a great variety of alcohols and thiols, including tertiary ones. Alternative and complementary routes to compounds 4 were also investigated. In addition, β-keto esters 6 have been obtained by mild acid hydrolysis of β-enamino esters 4.

Full text of DOI:10.1021/jo9809480

J . Org. Chem. 1998, 63, 8825-8836
8825
Syn th esis a n d Rea ctivity of New â-En a m in o Acid Der iva tives: A
Sim p le a n d Gen er a l Ap p r oa ch to â-En a m in o Ester s a n d Th ioester s
Santos Fustero,* Marta Garc´ıa de la Torre, Viviana J ofre´, Raquel Pe´rez Carlo´n,†
Antonio Navarro, and Antonio Simo´n Fuentes
Departamento de Quı´mica Orga´nica, Facultad de Farmacia, Universidad de Valencia,
46100-Burjassot (Valencia), Spain
J uan Server Carrio´‡
Departamento de Quı´mica Inorga´nica, Facultad de Farmacia, Universidad de Valencia,
46100-Burjassot (Valencia), Spain
Received May 19, 1998
A new strategy has been developed for the synthesis of several â-enamino acid derivatives. N,N′-
Carbonyldiimidazole has been used as C-acylating agent of methyl ketimines, providing a direct
and simple route to new â-enamino carbonyl imidazole derivatives 2. These derivatives 2 were
cleanly and efficiently transformed into â-enamino esters 4 (X ) O) and thioesters 4 (X ) S) by
reaction with a great variety of alcohols and thiols, including tertiary ones. Alternative and
complementary routes to compounds 4 were also investigated. In addition, â-keto esters 6 have
been obtained by mild acid hydrolysis of â-enamino esters 4.
In tr od u ction
esters,5 ester enolate addition to imines,6 enzymatic
resolution of racemates,7 and chemoselective reduction
of â-enamino esters8 are some of the more efficient
methodologies and are used extensively. Due to the
simplicity of the procedure and availability of the starting
materials, the last strategy represents one of the most
convenient and promising approaches for the synthesis
of â-amino acids. Therefore, the development of new and
simple methodologies for the synthesis of â-enamino acid
derivatives is always desirable for access to biologically
important compounds which contain and/or derive from
this structural subunit.9
The study of the synthesis and reactivity of â-amino
acids has been especially an active area of investigation
since in 1991 it was discovered that the anti-cancerous
activity of the diterpene natural taxol mainly depends
on the presence in its framework of an N-benzoyl-(2R,3S)-
3-phenylisoserine moiety.1 Currently, in a more general
context, the increasing interest in this field is based on
obtaining proteinogenic and nonproteinogenic amino
acids and peptide analogues with preestablished confor-
mational properties and biological functions.2,3 In addi-
tion, â-amino acids are useful intermediates for preparing
chiral ligands, chiral buildings blocks, and chiral auxil-
iaries as well as for synthesis of â-lactams.4
(5) See, for example: (a) Pelmutter, P. In Conjugate Addition
Reactions in Organic Synthesis; Baldwin, J . E., Magnus, P. D., Eds.;
Pergamon Press: Oxford, U.K., 1992. (b) Davies, S. G.; Garrido, N.
M.; Ichichara, O.; Walters, I. A. S. J . Chem. Soc., Chem. Commun.
1993, 115. (c) Davies, S. G.; Ichichara, O.; Walters, I. A. S. Synlett
1993, 461. (d) Hawkins, J . M.; Lewis, T. A. J . Org. Chem. 1992, 57,
2114. (e) Hawkins, J . M.; Lewis, T. A. J . Org. Chem. 1994, 59, 649. (f)
Dumas, F.; Mezrhab, B.; d’Angelo, J . J . Org. Chem. 1996, 61, 2293
and references cited therein.
(6) (a) Kleinman, E. F. In Comprehensive Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon Press: New York, 1991; Vol. 2,
Chapter 4.1. (b) Kunz, H.; Schazenbach, D. Angew. Chem., Int. Ed..
Engl. 1989, 28, 1068. (c) Corey, E. J .; Decicco, C. P.; Newbold, R. C.
Tetrahedron Lett. 1991, 32, 5287. (d) Kobayashi, S.; Mitsuharu, A.;
Masaru, Y. Tetrahedron Lett. 1995, 36, 5773. (e) Loh, T.-P.; Wei, L.-L.
Tetrahedron Lett. 1998, 39, 323.
The importance and interest in this class of derivatives
can be shown through the number of procedures recently
developed for their preparation. Asymmetric Michael
addition of amines or lithium amides to R,â-unsaturated
† Current address: Department of Organic Chemistry, University
of Oviedo, Oviedo, Spain.
‡ X-ray analyses.
(1) (a) Total and Semi-Synthetic Approaches to Taxol; Tetrahedron
Symposia in Print 48; Winkler, J . D., Ed.; Elsevier: Oxford, 1992; Vol.
48, p 6953. (b) Nicolaou, K. C..; Dai, W.-M.; Guy, R. K. Angew. Chem.,
Int. Ed. Engl. 1994, 33, 15.
(2) (a) Drey, C. N. C. In Chemistry and Biochemistry of the Amino
Acids; Weinstein, B., Ed.; Dekker: New York, 1976. (b) Drey, C. N. C.
In Chemistry and Biochemistry of the Amino Acids; Barret, G. C., Ed.;
Chapman and Hall: London, 1985; Chapter 3. (c) Griffith, O. W. Annu.
Rev. Biochem. 1986, 55, 855.
(3) (a) Peptide Chemistry: Design and Synthesis of Peptides, Con-
formational Analysis and Biological Functions; Tetrahedron Symposia
in Print 31; Hruby, V. J ., Schwyzer, R., Eds.; Elsevier: Oxford, 1988;
Vol. 44, p 661. For some recent examples, see the following: (b) Li, G.;
J arosinski, M. A.; Hruby, V. Tetrahedron Lett. 1993, 34, 2561. (c)
Giannis, A.; Kolter, T. Angew. Chem., Int. Ed. Engl. 1993, 32, 1244.
(d) Paulvannan, K.; Stille, J . R. Tetrahedron Lett. 1993, 34, 8197. (e)
Robl, J . A.; Cimarusti, M. P.; Simpkins, L. M.; Weller, H. N.; Pan, Y.
Y.; Malley, M.; DiMarco, J . D. J . Am. Chem. Soc. 1994, 116, 2348 and
references therein.
(7) (a) Cardillo, G.; Tolomelli, A.; Tomasini, C. J . Org. Chem. 1996,
61, 8651. (b) Soloshonok, V. A.; Svedas, V. K.; Kukhar, V. P.; Kirilienko,
A. G.; Rybakova, V. A.; Solodenko, V. A.; Fokina, N. A.; Kogut, O. V.;
Galev, I. Y.; Kozlova, E. V.; Shishikina, I. P.; Galunhko, S. V. Synlett
1993, 339. (c) Soloshonok, V. A.; Fokina, N. A.; Rybakova, V. A.;
Shishikina, I. P.; Galunhko, S. V.; Sorochinsky, A. E.; Kukhar, V. P.;
Savchenko, M. V.; Svedas, V. K. Tetrahedron: Asymmetry 1995, 6, 1601.
(d) Soloshonok, V. A.; Soloshonok, I. V.; Kukhar, V. P.; Svedas, V. K.
J . Org. Chem. 1998, 63, 1878.
(8) (a) Melillo, P.; Cvetovich, R.; Ryan, R.; Sletzinger, M. J . Org.
Chem. 1986, 51, 1498. (b) Chiba, T.; Nagatsuma, M.; Nakai, T. Chem.
Lett. 1985, 1343. (c) J olidon, S.; Meul, T. Eur. Pat. Nr. 0144980 A2;
Chem. Abstr. 1987, 105, 43325p. (d) Lubell, W. D.; Kitamura, M.;
Noyori, R. Tetrahedron: Asymmetry 1991, 2, 543. (e) Bartoli, G.;
Cimarelli, C.; Marcantoni, E.; Palmieri, G.; Petrini, M. J . Org. Chem.
1994, 59, 5328. (f) Cimarelli, C.; Palmieri, G. Tetrahedron: Asymmetry
1994, 5, 1455. (g) Palmieri, G.; Cimarelli, C. J . Org. Chem. 1996, 61,
5557. (h) Potin, D.; Dumas, F.; d’Angelo, J . Am. Chem. Soc. 1990, 112,
3483.
(4) (a) Cole, D. Tetrahedron 1994, 50, 9517. (b) J uaristi, E.; Quin-
tana, D.; Escalante, J . Aldrichim. Acta 1994, 27, 3. (c) Cardillo, G.;
Tomasini, C. Chem. Soc. Rev. 1996, 117. (d) Enantioselective Synthesis
of â-Amino acids; J uaristi, E., Ed.; Wiley-VCH: New York, 1997.
10.1021/jo9809480 CCC: $15.00 © 1998 American Chemical Society
Published on Web 11/12/1998

8826 J . Org. Chem., Vol. 63, No. 24, 1998
Fustero et al.
â-Enamino acid derivatives are also valuable and
versatile building blocks in organic synthesis. These
systems have especially been used in asymmetric syn-
thesis of R-10 and â-amino acids,8 in obtaining a wide
number of natural products such as alkaloids, generally
through aza-annulation processes,11 and other biologi-
cally active compounds.12 More recently, they have been
involved in the preparation of conformationally restricted
dipeptides.9 Although several routes for the synthesis
of these derivatives have been reported,13-19 most of them
suffer limitations related usually to their low chemical
yield and/or general applicability. In addition to the
classical condensation reaction between â-keto esters and
amines,13 â-enamino esters have also been obtained in
moderate to good yield by routes involving lithium,
magnesium, and zinc ester or amide enolates with
nitriles,14 tosyl imines,15 imino ethers,16 and imidoyl
halides,17 Michael addition of amines to alkynyl es-
ters,5,12,18 or more recently by reaction of imines with
activated carbonic acid derivatives.19 In this context, we
have developed a simple route to protected N-unsubsti-
tuted and N-substituted â-enamino acid derivatives
starting from 2-alkyl-2-oxa(thia)zolines with nitriles and
imidoyl halides, respectively.20 Alternative approaches
leading to γ-fluorinated â-enamino acid derivatives have
also been described.17b,19,21
imidazole ring and the carbonyl group. In the first case
the significance of this reagent can be shown by the
activation of the carboxylic function, through the forma-
tion of acylimidazolides, which have been extensively
used as intermediates in the preparation of a variety of
carbonylic and carboxylic acid derivatives including pep-
tide synthesis,24 as well as in C-acylation reactions of
methylene active compounds.25 One of the most versatile
and efficient applications of CDI is as a carbonylating
agent. This ability has been mainly used in processes
which imply formation of two carbon-heteroatom bonds.
As examples we can mention the synthesis of chiral
hydantoins,26 isocyanates,27 and unsymmetrically sub-
stituted carbonic acid derivatives24a,28 and, more recently,
the preparation of urea dipeptides.29
In contrast, the utility of CDI in CO transfer reactions
with formation of one or two carbon-carbon bonds has
been less extensively studied and exploited. To the best
of our knowledge only three examples have been reported
related to such processes. In 1979,30 Smith reported a
simple synthesis of tetronic acid derivatives from CDI
and R-hydroxy ketones with moderate yields. Closely
related to this process, Weinreb31 described a second
example of the application of this methodology in the key
step of the synthesis of (+)-actinoboline, an antibiotic
which also shows moderate antitumoral activity. Both
processes proceed via the formation of one C-C bond and
another C-O bond. Finally, Barluenga et al.32 reported,
for the first time, a carbonylating processes with exclu-
sive formation of carbon-carbon bonds. The described
procedure allowed the synthesis of 4(1H)-pyridones from
2-aza-1,3-dienes and CDI, and involves a [5+1] hetero-
cyclization with formation of two new carbonyl-carbon
bonds.
In this paper, we wish to describe a new and simple
method for the synthesis of N-substituted â-enamino
imidazole carbonylic derivatives 2 by reaction of ketimines
1, derived from aliphatic or aromatic amines, with N,N′-
carbonyldiimidazole (CDI).22 In addition, one- and two-
step general procedures for preparing N-substituted
â-enamino esters and thioesters 4 have been developed.
Since its discovery in 1957,23 CDI has been widely used
in organic synthesis as a transfer reagent of both the
In addition, very little is known about the ability of
CDI as transfer reagent of the CO-Im grouping and
simultaneous carbon-carbon bond formation. Therefore,
one of the primary goals of this work was to determine
this behavior by studying its reaction with ketimines.22
(9) Beholz, L. G.; Benovsky, P.; Ward, D. L.; Barta, N. S.; Stille, J .
R. J . Org. Chem. 1997, 62, 1033.
(10) (a) Tomioka, K.; Ando, K.; Takemasa, Y.; Koga, K. J . Am. Chem.
Soc. 1984, 106, 2718. (b) Georg, G. I.; Guan, X.; Kant, J . Tetrahedron
Lett. 1988, 29, 403.
(11) (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
Syn th esis of â-En a m in o Ca r bon yl Im id a zole De-
r iva tives 2. â-Enamino carbonyl imidazole derivatives
(12) (a) Hong, C. Y.; Kishi, Y. J . Am. Chem. Soc. 1992, 114, 7001.
(b) Baindur, N.; Rutledge, A.; Triggle, D. J . J . Med. Chem. 1993, 36,
3743. (c) Poindexter, G. S.; Licause, J . F.; Dolan, P. L.; Foey, M. A.;
Combs, C. M. J . Org. Chem. 1993, 58, 3811. (d) Torii, S.; Okumoto,
H.; Xu, L. H. Tetrahedron Lett. 1990, 31, 7175.
(13) (a) Dieckman, W. Liebigs Ann. Chem. 1901, 27, 317. (b) Prelog,
V.; Szpilfogel, S. Helv. Chim. Acta 1945, 28, 1684. (c) Ferraz, H. M.
C.; Oliveira, E. O.; Payret-Arrua, M. E.; Brandt, C. A. J . Org. Chem.
1995, 60, 7357. (d) Kloek, J . A.; Leschinsky, K. L. J . Org. Chem. 1978,
43, 1460. (e) Soloshonok, V. A.; Kukhar, V. Tetrahedron 1996, 52, 6953.
(14) (a) Hiyama, T.; Kobayashi, K. Tetrahedron Lett. 1982, 23, 1597.
(b) Hannick, S. M.; Kishi, Y. J . Org. Chem. 1983, 48, 3833. (c) Lee, A.
S.-Y.; Cheng, R.-Y. Tetrahedron Lett. 1997, 38, 443.
(15) Fukuyama, T.; Yung, Y. M. Tetrahedron Lett. 1981, 22, 3760.
(16) (a) Celerier, J . P.; Lhommet, R. G. Synthesis 1983, 195. (b)
Celerier, J . P.; Deloisy-Marchalant, E.; Lhommet, R. G.; Maitte, P. Org.
Synth. 1988, 67, 170.
(17) (a) Uneyama, K.; Morimoto, O.; Yamashita, F. Tetrahedron Lett.
1989, 30, 4821. (b) Fustero, S.; Pina, B.; Simo´n-Fuentes, A. Tetrahedron
Lett. 1997, 38, 6771.
(23) (a) Staab, H. A. Liebigs Ann. Chem. 1957, 609. (b) Armstrong,
A. In Encyclopedia of Reagents for Organic Synthesis; Paquette, L. A.,
Ed.; Wiley & Sons: New York, 1995; Vol. 4, p 1006.
(24) (a) Staab, H. A. Angew. Chem. 1962, 74, 407; Angew. Chem.,
Int. Ed. Engl. 1962, 1, 351. (b) Paul, R.; Anderson, G. W. J . Am. Chem.
Soc. 1960, 82, 4596. (c) Kno¨lker, H. J .; El-Alh, A. A. Heterocycles 1993,
36, 1381.
(25) Brooks, D. W.; Lu, L. D.-L.; Masamune, S. Angew. Chem., Int.
Ed. Engl. 1979, 18, 72.
(26) Buntain, I. G.; Suckling, C. J .; Wood, H. C. S. J . Chem. Soc.,
Perkin Trans. 1 1988, 3175.
(27) Staab, H. A.; Benz, W. Liebigs Ann. Chem. 1961, 648.
(28) (a) Walsh, D. A.; Green, J . B.; Franzyshen, S. K.; Nolan, J . C.;
J anni, J . M. J . Med. Chem. 1990, 33, 2028. (b) Ohta, S.; Yamashita,
M.; Nagai, N.; Rawasiki, I.; Maede, K.; Miyano, Y. Heterocycles 1995,
41, 1683 (c) D’Ischia, M.; Prota, G.; Totteveel, R. C.; Westerhof, W.
Synth. Commun. 1987, 17, 1577. (d) Laufer, D. A.; Al-Farhau, E. J .
Org. Chem. 1991, 56, 891. (e) Ohta, S.; Shimabayashi, A.; Aono, M.;
Okamoto, S. Synthesis 1982, 833.
(18) Cen, W.; Ni, Y.; Shen, Y. J . Fluorine Chem. 1995, 73, 161.
(19) Bartoli, G.; Cimarelli, C.; Dalpozzo, R.; Palmieri, G. Tetrahedron
1995, 51, 8613.
(20) (a) Fustero, S.; D´ıaz, M. D.; Barluenga, J .; Aguilar, E. Tetra-
hedron Lett. 1992, 33, 3801. (b) Fustero, S.; Navarro, A.; D´ıaz, D.; G.
de la Torre, M.; Asensio, A.; Sanz, F.; Liu Gonza´lez, M. J . Org. Chem.
1996, 61, 8849.
(29) Zhang, X.; Rodrigues, J .; Evans, L.; Hinkle, B.; Ballantyne, L.;
Pen˜a, M. J . Org. Chem. 1997, 62, 6420.
(30) J erris, P. J .; Wovkulich, P. M.; Smith, A. B., III. Tetrahedron
Lett. 1979, 20, 4517.
(31) (a) Garigipati, R. S.; Tschaen, D. M.; Weinreb, S. M. J . Am.
Chem. Soc. 1985, 107, 7790. (b) Garigipati, R. S.; Tschaen, D. M.;
Weinreb, S. M. J . Am. Chem. Soc. 1990, 112, 3475.
(21) Shen, Y.; Gao, S. J . Fluorine Chem. 1996, 76, 37.
(22) Preliminary communication, see: Fustero, S.; D´ıaz, M. D.; Pe´rez
Carlo´n, R. Tetrahedron Lett. 1993, 34, 725.
(32) (a) Barluenga, J .; Pe´rez, R.; Go´nzalez, F.; Fustero, S. Tetrahe-
dron Lett. 1990, 31, 3793. (b) Barluenga, J .; Go´nzalez, F.; Fustero, S.;
Pe´rez, R. J . Org. Chem. 1991, 56, 675.

New â-Enamino Acid Derivatives
J . Org. Chem., Vol. 63, No. 24, 1998 8827
Ta ble 1. â-En a m in o Ca r bon yl Im id a zol Der iva tives 2 Obta in ed by Rea ction of Ketim in es 1 a n d
N,N′-Ca r bon yld iim id a zole (CDI)
entry
R1
R2
methoda
mp (°C)b
oil
product
yield (%)c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
n-Bu
t-Bu
i-Pr
A
B
A
A
A
B
A
A
A
A
A
A
B
A
A
A
2a
75 (62)
86 (78)
80 (76)
80 (78)
88 (73)
92 (85)
91 (77)
60 (47)
93 (70)
82 (66)
95 (79)
85d,e
n-Bu
n-Bu
n-Bu
oil
oil
oil
2b
2c
2d
c-C3H5
Ph
n-Bu
n-Bu
n-Bu
c-C6H11
c-C6H11
c-C6H11
p-MeOC6H4
2-furyl
2-thiophenyl
Ph
p-EtO2CC6H4
Et
oil
oil
oil
163-165
oil
oil
2e
2f
2g
2h
2i
2j + 2j′
80d (68) f
90 (84)
87 (75)
93 (88)
Ph
Ph
Ph
Ph
146-148
137-139
141-143
2k
2l
2m
p-MeC6H4
17
18
19
20
21
22
23
(CH2)3
A
B
A
A
B
A
A
no reaction
75 (68)
76 (59)
75 (69)
84 (73)
71 (58)
86 (61)
149-151
2n
2o
2p
(()-C6H5(Me)CH
(()-C6H5(Me)CH
i-Pr
Ph
oil
oil
(R)-(+)-C6H5(Me)CH
(S)-(-)-C6H5(Me)CH
i-Pr
i-Pr
96-98
96-98
2q
2r
a
Method A: Ketimine 1 (1.0 equiv), CDI (1.1 equiv), BF3‚OEt2 (1.1 equiv), THF, ∆. Method B: Ketimine 1 (1.0 equiv), LDA (2.0 equiv),
CDI (1.1 equiv), THF, -78 °C to rt. Melting points are uncorrected. c Yields after purification are given in parentheses. Overall yield
b
d
2j + 2j′. e Isolated yield of 2j (43%) and 2j′ (29%). f Isolated yield of 2j (Method B).
2 can be obtained from methyl ketimines 1 and CDI by
different and complementary pathways (Scheme 1).
to a THF solution of ketimine 1 were less efficient and
resulted in a marked decrease in the yield.
We presume that the initial formation of the complex
CDIfBF3 (3) can take place in two different ways; either
via an imidazolium intermediate (3A), as was recently
suggested by Ohta,28b or through coordination of the
boron atom with the carbonyl oxygen (3B) in a similar
way as in the case of carbonyl derivatives (Chart 1).33
Sch em e 1
Ch a r t 1
Thus, the reaction of methyl ketimines with N,N′-
carbonyldiimidazole was first carried out in tetrahydro-
furan (THF) at reflux for several hours (12-24 h) and
required the presence of a Lewis acid, specifically, boron
trifluoride (BF3‚OEt2) as catalyst (molar ratio 1/CDI/BF3‚
OEt2 of 1:1.1:1.1). The process afforded, cleanly, after
standard workup, the corresponding â-enamino carbonyl
imidazole derivatives 2 in good to excellent yields (Method
A, Scheme 1). The results of this study are summarized
in Table 1 (Method A; for Method B see below).
Additionally, we have investigated several aspects of
the reaction conditions closely and have found that
factors such as nature of the reagents, of the solvents,
and particularly of the Lewis acid together with the order
of addition markedly affected the course of the process.
Thus, the highest yields were obtained when THF was
used as solvent, while other solvents such as CH2Cl2,
ether, or toluene gave a dramatic decrease in the amount
of 2 obtained. In the same way, the use of Lewis acids,
with the exception of BF3‚OEt2, such as AlCl3, TiCl4, and
ZnCl2 or an absence of catalyst, completely inhibited the
course of the reaction, with recovery of the unreacted
starting ketimine 1 only.
To determine the preferred structure for the complex
(3A vs 3B, Chart 1), we carried out ab initio calculations
at the HF/6-31G* level of theory.34 The results of this
study showed a marked preference for complex 3A, which
was 12.1 kcal/mol more stable than 3B. In the favored
complex 3A the length of the N-B forming bond is 1.669
Å, a value similar to that calculated for the O-B bond
(1.648 Å) in 3B. A degree of twisting of the imidazole
rings was also observed in each case.
Nevertheless, in both cases the electrophilicity of the
carbonyl carbon was increased, permitting the CDI to
become much more reactive toward ketimines. Thus,
(33) Reetz, M. T.; Hu¨lmann, M.; Massa, W.; Berger, S.; Rademacher,
P.; Heymanns, P. J . Am. Chem. Soc. 1986, 108, 2405.
(34) 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, Revision C.3; Gaussian
Inc.: Pittsburgh, PA, 1995.
We have also observed that the order of addition has
remarkable influence on the chemical yield. Thus, the
best results were obtained when a THF solution of CDI
was allowed to react first with BF3‚OEt2 followed by slow
addition of the corresponding ketimine. In contrast,
reactions carried out by initial addition of the Lewis acid

8828 J . Org. Chem., Vol. 63, No. 24, 1998
Fustero et al.
Sch em e 2
ketimines 1 react through the enamino forms with the
complex CDIfBF3 (3) in an addition-elimination pro-
cess, involving the formation of a new carbon-carbon
bond and loss of an equivalent of imidazole. In all cases,
compounds 2 were isolated in the more stable enamino
tautomeric form 2â (Scheme 2).
Further examination of Table 1 (Method A) reveals
that the reaction is also affected by the substitution
pattern of the ketimine. As shown in Table 1, the
described procedure is rather general as regards the
amine and ketone (R1 and R2 respectively) residues in 1.
However, from experiments carried out within our group,
the process appears to be suitable only for acyclic methyl
ketimines. In contrast, cyclic methyl ketimines (entry
17, Table 1) and other nonmethyl derivatives, for instance
ketimines derived from propiophenone,22 were unreactive
under the same reaction conditions.
One exception to this general behavior is the case of
unsymmetrical alkyl methyl ketimines such as N-(2-
butylidene)cyclohexylamine 1j (entry 12, Table 1). In this
example, two regioisomers 2j and 2j′ resulting from the
competitive addition of 1 to the complex CDIfBF3 by the
CR-methyl or CR-methylene groups respectively, were
obtained in an almost equimolecular mixture (Scheme
3). Both compounds were easily separated by MPLC
few hours (2-4 h) at room temperature and aqueous
workup, â-enamino carbonyl imidazole derivatives 2 were
isolated as the only products and in slightly higher yields
than through Method A (see entries 2, 6, 18, and 21,
Table 1). The process also takes place with total C-C
vs C-N regioselectivity. As in previous reports,17b,19,20b
2 equiv of LDA were necessary in order to increase the
final yield.
Two main advantages are noteworthy in this method.
First, this route is particularly useful for cyclic methyl
ketimines such as 1n (entry 18, Table 1). Thus, whereas
compound 2n was easily obtained in the reaction of
azaenolate of 1n with CDI in 68% isolated yield (Method
B), no reaction was observed using the complex CDIfBF3
(see above, Method A, and entry 17, Table 1).
Another significant difference was in the case of
unsymmetrical alkyl methyl ketimines such as 1j (entry
12, Table 1). In this example it was possible to increase
the regioselectivity of the process in favor of the ther-
modynamically controlled derivative 2j. Thus, if the
azaenolate was generated by slow addition of ketimine
1j to a THF solution of LDA at -10 °C for 1 h, compound
2j was produced in 68% isolated yield along with a small
amount of its regioisomer 2j′ ()5% determined by 1H
NMR of the crude mixture).
Attempts devoted to control the regioselectivity of the
process by formation of the appropriate azaenolate (1j-
Li or 1j′-Li) (Chart 2) using reaction conditions described
Sch em e 3
Ch a r t 2
by Bergbreiter et al.36a were unsuccessful, obtaining in
all cases predominantly (>9:1) the compound 2j corre-
sponding to the thermodynamically controlled azaenol-
ate.36b
chromatography obtaining 2j and 2j′ as pure material
in 43 and 29% yield, respectively (see entry 12, Table 1,
and Experimental Section).
Another characteristic feature of this procedure is the
total C-C vs C-N regioselectivity. In fact, no products
corresponding to the N-acylation have currently been de-
tected being the derivatives 2 the sole isolated products.35
The lack of the reactivity of cyclic methyl ketimines
can be circumvented by using an alternative and comple-
mentary method, in which the key step is the increase
of the nucleophilicity of the starting ketimine through
the formation of the corresponding azaenolate (Method
B, Table 1 and Scheme 1). Thus, the reaction was
accomplished by treatment of ketimines 1 (1.0 equiv) with
LDA (2.0 equiv) in THF at 0 °C, followed by addition, at
-78 °C, of a THF solution of CDI (1.1 equiv). After a
The structures of compounds 2 were supported by
NMR spectroscopy, elemental analysis, and/or high-
resolution mass spectrometry (HRMS). For example, for
2n (entry 18, Table 1) characteristic signals in the 1H
NMR spectrum were observed at δ 5.16 (s, 1H), 7.02 (d,
J ) 1.6 Hz, 1H), 7.40 (d, J ) 1.6 Hz, 1H), 8.09 (s, 1H),
and 9.13 (br s, 1H) which were assigned to the vinylic
proton and the protons from the imidazole ring and NH
group, respectively. Indeed, the carbonyl group appears
at δ 171.2 (CO) in the 13C NMR spectrum. These signals
along with the downfield shift of the NH group suggest
a six-membered intramolecular hydrogen bond -N-H‚
‚‚OdC-, supporting the presence of the tautomeric form
2â, as was mentioned before.
(35) In sharp contrast with these results other carbonic acid
derivatives such as triphosgene [bistrichloromethyl carbonate (BTC)]
afforded in its reaction with ketimines, exclusively, the corresponding
C-N acyl derivatives. Fustero, S.; Garc´ıa de la Torre, M. Unpublished
results.
(36) (a) Smith, J . K.; Bergbreiter, D. E.; Newcomb, M. J . Am. Chem.
Soc. 1983, 105, 4396. (b) Deprotonation experiments were run for
various times (1-4 h) at -78, -10, and 25 °C, respectively.

New â-Enamino Acid Derivatives
J . Org. Chem., Vol. 63, No. 24, 1998 8829
Sch em e 4
Sch em e 5
F igu r e 1. Perspective ORTEP plot of compound 2h showing
the intramolecular O(1)‚‚‚H interaction. Arbitrary numbering
system.
As illustrated in Scheme 5, the reaction of derivatives
2 with alcohols was carried out by using an excess of
alcohol38 in the presence of sodium alkoxide39 in reflux-
ing THF for 6-24 h and provided the corresponding
â-enamino esters 4 (X ) O) (Method C, Table 2) in good
to high yields after aqueous workup and purification of
the crude mixture by recrystallization, flash chromatog-
raphy, or MPLC on silica gel.
The (Z)-s-cis structure 2(â)n was also established by
NOE experiments, as depicted in Chart 3, because an
Ch a r t 3
Table 2 summarizes the â-enamino esters 4 synthe-
sized, the yields and the method used to obtain them (for
explanation see below). As can be seen from Table 2, the
process works well, independently of the nature of the
alcohol, and high yields are generally obtained. Excep-
tions to this trend are related with the steric hindrance
of the starting alcohol. Thus, alcohols containing bulky
groups such as 1-adamantanol (entry 12, Table 2) or tert-
butyl alcohol (entries 1, 8, 9, 18, 19, 23, and 27, Table 2)
showed a tendency for lower ()20%) yields.
Indeed, it is interesting to note that the reaction is
general and applicable to all types of alcohols, including
tertiary ones.28e Thus, simple and reactive primary
alcohols such as methanol or allyl alcohol (entries 2, 3,
21, 25, 26, and 28, Table 2) or others including more
complex structures such as terpenes, geraniol, (+)-
menthol, or (-)-8-phenylmenthol (entries 11, 14, 17, and
29, Table 2), steroids such as 5R-cholestane-3â-ol (entry
16, Table 2), or protected carbohydrates such as 1,2;5,6-
di-O-isopropylidene-R-D-glucofuranose (entry 15, Table 2)
were successfully used.
enhancement of 5.2% (H-4), 8.3% (H-9), and 9.0% (H-12)
in intensity of the signals of pyrrolidine and imidazole
protons, respectively, was observed, upon irradiation of
the vinylic proton (H-6). Furthermore, saturation of the
triplet at δ 2.72 ppm showed a positive NOE (7.5%) with
the vinylic proton at 5.16 ppm.
Finally, the structure and the Z configuration of
compounds 2 were unambiguously confirmed by single-
crystal X-ray diffraction of 2h (entry 10, Table 1), which
was obtained by recrystallization from hexane/chloroform
mixtures, to give pale yellow prismatic crystals.37
A perspective ORTEP plot of 2h is given in Figure 1,
which shows that the aromatic and cyclohexane rings are
almost perpendiculars to the plane of the enamino
carbonyl moiety, with the imidazole ring being coplanar
to the enamino framework. The structure (Figure 1) also
reveals a strong intramolecular interaction between O1
and H100 (O1-H100, 1.91 Å), as was also suggested by
1H NMR.
Syn th esis of â-En a m in o Ester s (4). As mentioned
before â-enamino esters represent an interesting and
useful class of compounds of great importance in organic
synthesis.9-12 To demonstrate the utility of the newly
obtained derivatives 2, we first examined the behavior
of 2 toward heteronucleophiles, particularly alcohols and
thiols (via path a, Scheme 4). Alternative routes (via
paths b and c, Scheme 4) have been also tested.
The (Z)-s-cis configuration shown for â-enamino esters
1
4 was inferred on the basis of their H and 13C NMR and
HRMS data (see Experimental Section). Characteristic
signals of the vinylic proton (δ 4.5-5.1 ppm) and NH
grouping (δ 8.3-10.3 ppm) in the 1H NMR spectra
corroborate the proposed structure.
Alternatively, to simplify the method and to verify the
feasibility of the reaction, we examined the possibility of
obtaining â-enamino esters 4 in a one-pot sequence from
ketimines 1 without isolation of the derivatives 2 (via
path b, Scheme 4). Consequently, when the reaction was
(38) The best results have been obtained with a molar ratio 2/R3-
OH of 1:3 or higher, although for more expensive alcohols such as (-)-
8-phenylmenthol a stoichiometric amount of alcohol could be used
without significant loss in the final chemical yield. However, longer
reaction times were required.
(37) The authors have deposited the atomic coordinates for this
structure with the Cambridge Crystallographic Data Centre. The
coordinates can be obtained on request, from the Director Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ,
U.K.
(39) Although, in general, the use of sodium alkoxide is not neces-
sary, the presence significantly enhanced the rate of the reaction.

8830 J . Org. Chem., Vol. 63, No. 24, 1998
Fustero et al.
Ta ble 2. â-En a m in o Ester s (X ) O) a n d Th ioester s (X ) S) 4 Syn th esized fr om Der iva tives 2 or Ketim in es 1

New â-Enamino Acid Derivatives
J . Org. Chem., Vol. 63, No. 24, 1998 8831
Ta ble 2 (Con tin u ed )
a
Method C: Two-step reaction via 2 and RXH/RX- (1.0-3.0 equiv), THF, reflux. Method D: One-pot reaction from ketimines 1 (1.0
equiv), CDI (1.1 equiv), BF3‚OEt2 (1.1 equiv), and RXH (1.0-3.0 equiv), THF, reflux. Method E: Ketimine 1 (1.0 equiv), LDA (2.0 equiv),
R3OCOIm (1.3 equiv), THF, -78 °C to rt. Method F: Ketimine 1 (1.0 equiv), BF3‚OEt2 (1.1 equiv), R3OCOIm (1.1 equiv), THF, reflux.
b
Melting points are uncorrected. c Yields after purification are given in parentheses.
Sch em e 6
Sch em e 8
carried out by sequential treatment of a THF solution of
the ketimine 1 (or the corresponding lithium azaenolate),
with the complex CDIfBF3 (or CDI) followed by the
appropriate alcohol, the expected compounds 4 were
synthesized successfully (Scheme 6). Optimization of the
reaction conditions and purification of the crude mixture
allowed us to obtain pure derivatives 4 in 40-90% overall
yields (Method D, Table 2).
A third alternative route for obtaining derivatives 4
involved the direct condensation between ketimines 1 and
alkoxy carbonyl imidazole derivatives 5 (via path c,
Scheme 4). We have explored this possibility to examine
the effect of the type of carbonic acid derivative40 (Scheme
7). As in the aforementioned studies, the reaction was
thiols. 2-Propene-1-thiol, R-toluenethiol, and 2-methyl-
2-propanethiol were chosen as representative examples.
The reaction proceeded under similar conditions to those
discussed previously using RS-/RSH as starting hetero-
nucleophile (Scheme 5). The reaction time was shorter
for these compounds and the yields were comparable to
those described for the alcohols. In all cases, the corre-
sponding â-enamino thioesters 4 (X ) S) were obtained
(entries 6, 7, and 20, Table 2). It is worth noting that
the process is also completely regioselective with deriva-
tives 4 (X ) O, S) corresponding to a C-acylation as the
sole identified products.
Finally, â-enamino esters 4 underwent a mild acid
hydrolysis (1 M HCl) leading, in good yields, to the
corresponding â-keto esters 6. Some selected examples
are included in Scheme 8. Because derivatives 6 can be
easily synthesized in a one-pot reaction starting from
ketimines, CDI, and a variety of alcohols, the described
procedure appears as an alternative, versatile, and, in
our opinion, more efficient route to synthesize â-keto
esters41 than the methodology previously developed by
Mander42 which uses alkyl cyanoformates as starting
carbonic acid derivatives.
Sch em e 7
accomplished either through formation of the ketimine
azenolates (Method E, Table 2) or alternatively by acti-
vation of the alkoxy carbonyl imidazole derivatives using
BF3‚OEt2 (Method F, Table 2). In sharp contrast to the
above-mentioned results, the process was found to be
highly dependent on the method used. Thus, whereas
the reaction proceeded smoothly using preformed lithium
azaenolate (Method E, entries 9 and 27, Table 2) showing
no significant differences with respect to Methods C and
D (Table 2), no reaction was observed when the complex
5fBF3 (Method F) was used as starting material (entry
10, Table 2). This inhibition could be explained by the
lower electrophilicity of the carbonyl group in the complex
5fBF3 in comparison with CDIfBF3.
Subsequently, we turned our attention to the reaction
of derivatives 2 with other heteronucleophiles such as
(41) For related reactions of â-keto esters formation from ketones,
see: Mander, L. N. In Encyclopedia of Reagents for Organic Synthesis;
Paquette, L. A., Ed.; Wiley & Sons: New York, 1995; Vol. 4, p 3466
and references cited therein.
(42) (a) Mander, L. N.; Sethi, S. P. Tetrahedron Lett. 1983, 24, 5425.
(b) Mander, L. N.; Sethi, S. P. Org. Synth. 1991, 70, 256.
(40) Other carbonic acid derivatives such as methyl cyanoformate,
diethyl carbonate or benzyl chloroformate have been recently used for
several authors for the synthesis of â-enamino esters in moderate
yields; see: (a) Bennet, R. B.; Cha, J . K. Tetrahedron Lett. 1990, 31,
5437. (b) Reference 19.

8832 J . Org. Chem., Vol. 63, No. 24, 1998
Fustero et al.
for C14H23N3O: 249.1841. Found: 249.1838. Anal. Calcd for
In summary, a new strategy for the synthesis of several
1,3-difunctionalized derivatives, such as â-enamino car-
bonyl imidazoles (2), â-enamino esters, and thioesters (4),
starting from ketimines, N,N′-carbonyldiimidazole, and
alcohols or thiols has been developed. The described
procedure appears to be general and represents an
efficient, simple, and alternative route to â-keto esters
and derivatives.
C
14H23N3O: C, 67.44; H, 9.30; N, 16.85. Found: C, 67.53; H,
9.42; N, 17.00.
(Z)-3-Bu tyla m in o-1-(1H-1-im id a zolyl)-4-m eth yl-2-p en t-
en -1-on e (2b). MPLC (n-hexanes-EtOAc (2:3)) on silica gel
gave a yellow oil (76%): 1H NMR (250 MHz) 0.90 (t, J ) 7.2,
3H), 1.23 (d, J ) 7.2, 6H), 1.42 (m, 2H), 1.65 (m, 2H), 2.80 (m,
1H), 3.31 (q, J ) 6.4, 2H), 5.11 (s, 1H), 7.00 (d, J ) 1.6, 1H),
7.30 (d, J ) 1.6, 1H), 8.16 (s, 1H), 10.12 (br s, 1H); 13C NMR
(62.8 MHz) 13.1 (q), 19.3 (t), 20.4 (q), 28.5 (d), 31.5 (t), 41.8
(t), 76.3 (d), 115.3 (d), 128.9 (d), 134.7 (d), 163.4 (s), 176.4 (s).
HRMS calcd for C13H21N3O: 235.1684. Found: 235.1677.
Anal. Calcd for C13H21N3O: C, 66.35; H, 8.99; N, 17.86.
Found: C, 65.97; H, 9.18; N, 17.93.
(Z)-3-Bu tyla m in o-3-cyclop r op yl-1-(1H-1-im id a zolyl)-2-
p r op en -1-on e (2c). Flash chromatography (EtOAc) on silica
gel gave a yellow oil (78%): 1H NMR (250 MHz) 0.88 (t, J )
7.2, 3H), 1.01-1.03 (m, 5H), 1.45 (m, 2H), 1.68 (m, 2H), 3.52
(q, J ) 6.4, 2H), 4.80 (s, 1H), 7.03 (d, J ) 1.6, 1H), 7.39 (d, J
) 1.6, 1H), 8.10 (s, 1H), 10.12 (br s, 1H); 13C NMR (62.8 MHz)
8.3 (t), 13.3 (q), 14.4 (t), 20.7 (d), 32.6 (t), 43.6 (t), 78.2 (d),
116.4 (d), 130.2 (d), 135.9 (d), 164.6 (s), 172.3 (s); IR (KBr) 3233,
1628, 1587, 1135. HRMS calcd for C13H19N3O: 233.1528.
Found: 233.1529. Anal. Calcd for C13H19N3O: C, 66.92; H,
8.21; N, 18.01. Found: C, 67.21; H, 8.40; N, 18.23.
(Z)-3-Bu tyla m in o-1-(1H-1-im id a zolyl)-3-p h en yl-2-p r o-
p en -1-on e (2d ). MPLC (n-hexanes-EtOAc (1:1)) on silica gel
gave a yellow oil (73%): 1H NMR (250 MHz) 0.82 (t, J ) 7.2,
3H), 1.35 (m, 2H), 1.51 (m, 2H), 3.19 (q, J ) 6.4, 2H), 5.09 (s,
1H), 7.00 (d, J ) 1.6, 1H), 7.30 (d, J ) 1.6, 1H), 7.41 (m, 5H),
8.10 (s, 1H), 9.96 (br s, 1H); 13C NMR (62.8 MHz) 13.1 (q),
19.2 (t), 32.1 (t), 44.3 (t), 83.2 (d), 115.4 (d), 127.0 (d), 128.3
(d), 129.4 (d), 129.5 (d), 134.5 (d), 135.0 (s), 163.1 (s), 168.7
(s). HRMS calcd for C16H19N3O: 269.1528. Found: 269.1529
Anal. Calcd for C16H19N3O: C, 71.35; H, 7.11; N, 15.60.
Found: C, 70.92; H, 7.21; N, 15.48.
(Z )-3-Bu t yla m in o-1-(1H -1-im id a zolyl)-3-(4-m et h oxy-
p h en yl)-2-p r op en -1-on e (2e). MPLC (n-hexanes-EtOAc (1:
1)) on silica gel gave a yellow oil (77%): 1H NMR (250 MHz)
0.82 (t, J ) 7.2, 3H), 1.36 (m, 2H), 1.51 (m, 2H), 3.20 (q, J )
6.4, 2H), 3.81 (s, 3H), 5.06 (s, 1H), 6.91 (d, J ) 8.6, 2H), 6.94
(d, J ) 1.6, 1H), 7.29 (d, J ) 8.6, 2H), 7.38 (d, J ) 1.6, 1H),
8.08 (s, 1H), 9.98 (br s, 1H); 13C NMR (62.8 MHz) 14.3 (q),
20.4 (t), 33.3 (t), 45.5 (t), 56.1 (q), 84.2 (d), 114.7 (d), 116.4 (d),
127.8 (s), 129.7 (d), 130.6 (d), 136.1 (d), 160.0 (s), 165.0 (s),
169.7 (s). HRMS calcd for C17H21N3O2: 299.1633. Found:
299.1627 Anal. Calcd for C17H21N3O2: C, 68.22; H, 7.02; N,
14.04. Found: C, 68.01; H, 7.23; N, 14.14.
(Z)-3-Bu tyla m in o-3-(2-fu r yl)-1-(1H-1-im id a zolyl)-2-p r o-
p en -1-on e (2f). Flash chromatography (cyclohexanes-EtOAc
(1:4)) on silica gel gave a brown oil (47%): 1H NMR (250 MHz)
0.82 (t, J ) 7.2, 3H), 1.45 (m, 2H), 1.64 (m, 2H), 3.53 (q, J )
6.4, 2H), 5.50 (s, 1H), 6.54 (dd, J ) 1.7, 3.4, 1H), 6.82 (d, J )
3.4, 1H), 7.00 (d, J ) 1.6, 1H), 7.41 (d, J ) 1.6, 1H), 7.55 (d, J
) 1.7, 1H), 8.13 (s, 1H), 10.00 (br s, 1H); 13C NMR (62.8 MHz)
14.0 (q), 20.2 (t), 32.6 (t), 45.8 (t), 80.9 (d), 112.3 (d), 115.3 (d),
116.2 (d), 130.1 (d), 135.7 (d), 145.2 (d), 147.4 (s), 156.2 (s),
164.2 (s). HRMS calcd for C14H17N3O2: 259.1320. Found:
259.1315. Anal. Calcd for C14H17N3O2: C, 64.85; H, 6.61; N,
16.20. Found: C, 65.33; H, 6.78; N, 16.41.
(Z)-3-Bu t yla m in o-1-(1H -1-im id a zolyl)-3-(2-t h ien yl)-2-
p r op en -1-on e (2g). Flash chromatography (n-hexanes-
EtOAc (3:1)) on silica gel gave a pale green oil (70%): 1H NMR
(250 MHz) 0.86 (t, J ) 7.2, 3H), 1.33 (m, 2H), 1.48 (m, 2H),
3.32 (q, J ) 6.4, 2H), 5.26 (s, 1H), 7.07 (d, J ) 1.6, 1H), 7.10
(dd, J ) 2.5, 3.7, 1H), 7.22 (d, J ) 2.5, 1H), 7.30 (d, J ) 1.6,
1H), 7.42 (d, J ) 3.7, 1H), 8.07 (s, 1H), 9.98 (br s, 1H); 13C
NMR (62.8 MHz) 13.7 (q), 19.9 (t), 32.6 (t), 45.2 (t), 84.3 (d),
115.8 (d), 127.6 (d), 128.6 (d), 129.4 (d), 130.1 (d), 135.1 (s),
135.5 (d), 161.3 (s), 163.5 (s). HRMS calcd for C14H17N3OS:
275.1092. Found: 275.1094. Anal. Calcd for C14H17N3OS: C,
61.07; H, 6.22; N, 15.26; S, 11.63. Found: C, 61.34; H, 6.30;
N, 15.57; S, 11.70.
Exp er im en ta l Section
Gen er a l Meth od s. All reactions were run under argon
atmosphere. Solvents were dried and distilled upon standard
procedures before use. Commercial N,N′-carbonyldiimidazole
was purchased from Aldrich Co. and stored under argon
atmosphere. Boron trifluoride was distilled and stored under
argon atmosphere. Ketimines were prepared from ketones by
conventional procedures.36a Diisopropilamine was distilled
from sodium hydride and stored over 4 Å molecular sieves.
All other reagents were of the best commercial grade available
and were used without further purification. Thin-layer chro-
matography (TLC) was performed on silica gel 60 F254 plates
and visualized by UV irradiation and/or iodine. Flash column
chromatography and medium-pressure liquid chromatography
(MPLC) were performed using silica gel 60 (0.040-0.063 and
0.015-0.040 mm, respectively). Melting points are uncor-
rected. 1H and 13C NMR spectra were recorded at 250, 300,
and 400 MHz spectrometers, in CDCl3 with tetramethylsilane
as 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 (IR) are reported in cm-1
. Mass spectral data, low-
resolution mass spectroscopy (electron impact) (LRMS/EI)
and high-resolution mass spectroscopy (HRMS), were ob-
tained at 70 eV by electron impact. Elemental analyses
were performed in the Microanalyses Service CID-CSIC of
Barcelona and Microanalytical Service of the University of
Zaragoza.
N-Su bstitu ted â-En a m in o Im id a zole Ca r bon ylic De-
r iva tives 2. Gen er a l P r oced u r e. Meth od A. To a solution
of N,N′-carbonyldiimidazole (2.0 g, 12.3 mmol) in THF (15 mL)
at room temperature was added boron trifluoride (1.52 mL,
12.3 mmol) in THF (5 mL). The resulting mixture was stirred
for 30 min, and then a solution of the desired ketimine 1 (11.2
mmol) in THF (15 mL) was added dropwise. The reaction
mixture was stirred for several hours (12-24) at reflux under
argon atmosphere. The reaction was monitored by TLC. The
reaction was quenched with 3 N NaOH and extracted with
dichloromethane (3 × 25 mL). The organic extracts were
combined, washed with brine and dried over Na2SO4. After
filtration, the solvents were removed under reduced pressure
to provide the crude product 2. Purification was carried out
as indicated in each case.
Meth od B. To a solution of diisopropylamine (2.6 mL, 20
mmol) in 10 mL of THF at 0 °C was dropwise added n-
butyllithium (2.5 M in hexane, 8.0 mL, 20 mmol). After being
stirred for 10 min, ketimine 1 (10.0 mmol) in THF (15 mL)
was added. The resulting mixture was stirred at 0 °C for 30
min. The solution was cooled to -78 °C and N,N′-carbonyl-
diimidazole (1.8 g, 11.0 mmol) in THF (10 mL) was added. The
reaction mixture was stirred at -78 °C for 1 h. The solution
was allowed to warm to room temperature for 2-4 h. The
reaction was quenched by addition of saturated ammonium
chloride solution. Workup of the reaction followed the proce-
dure described in Method A.
(Z)-3-Bu t yla m in o-1-(1H -1-im id a zolyl)-4,4-d im et h yl-2-
p en ten -1-on e (2a ). MPLC (cyclohexanes-EtOAc (1:1)) on
silica gel gave a brown oil (62%): 1H NMR (250 MHz) 0.93 (t,
J ) 7.2, 3H), 1.33 (s, 9H), 1.48 (m, 2H), 1.66 (m, 2H), 3.53 (q,
J ) 6.4, 2H), 5.19 (s, 1H), 7.03 (d, J ) 1.6, 1H), 7.41 (d, J )
1.6, 1H), 8.12 (s, 1H), 10.40 (br s, 1H); 13C NMR (62.8 MHz)
13.7 (q), 19.8 (t), 28.8 (q), 32.5 (t), 36.4 (s), 45.7 (t), 78.6 (d),
115.7 (d), 129.7 (d), 135.3 (d), 163.0 (s), 178.0 (s). HRMS calcd
(Z)-3-Cycloh exyla m in o-1-(1H -1-im id a zolyl)-3-p h en yl-
2-p r op en -1-on e (2h ). Recrystallization (n-hexane-chloro-

New â-Enamino Acid Derivatives
J . Org. Chem., Vol. 63, No. 24, 1998 8833
1
form (3:1)) gave a yellowish solid (66%): mp 163-165 °C; H
NMR (250 MHz) 1.10-1.80 (m, 10H), 3.24 (m, 1H), 5.09 (s,
1H), 7.00 (d, J ) 1.6, 1H), 7.20-7.50 (m, 5H), 7.31 (d, J ) 1.6,
1H), 8.12 (s, 1H), 10.00 (br s, 1H); 13C NMR (62.8 MHz) 24.2
(t), 25.0 (t), 34.1 (t), 53.1 (d), 89.7 (d), 115.7 (d), 127.2 (d), 128.7
(d), 129.8 (d), 129.9 (d), 135.3 (s), 135.4 (d), 163.4 (s), 168.0
(s); IR (KBr) 3241, 1626, 1576, 1209. HRMS calcd for
C18H21N3O: 295.1684. Found: 295.1684. Anal. Calcd for
2-(2-Azolan yliden )-1-(1H-1-im idazolyl)-1-eth an on e (2n ).
Recrystallization (n-hexanes-EtOH (3:1)) gave a yellow solid
(68%): mp 149-151 °C;1H NMR (250 MHz) 2.06 (m, 2H), 2.72
(t, J ) 3.7, 2H), 3.64 (t, J ) 3.7, 2H), 5.16 (s, 1H), 7.02 (d, J )
1.6, 1H), 7.40 (d, J ) 1.6, 1H), 8.09 (s, 1H), 9.13 (br s, 1H); 13
C
NMR (100 MHz) 21.3 (t), 33.1 (t), 47.9 (t), 77.3 (d), 115.8 (d),
129.8 (d), 135.4 (d), 163.6 (s), 171.2 (s). HRMS calcd for
C9H11N3O: 177.0902. Found: 177.0901. Anal. Calcd for
C9H11N3O: C, 61.00; H, 6.26; N, 23.71. Found: C, 60.69; H,
6.21; N, 23.83.
C
18H21N3O: C, 73.19; H, 7.17; N, 14.23. Found: C, 72.73; H,
7.35; N, 14.33.
Eth yl-4-[(Z)-1-cycloh exyla m in o-3-(1H-1-im id a zolyl)-3-
oxo-1-p r op en yl] Ben zoa to (2i). Flash chromatography (n-
hexanes-ether (1:6)) on silica gel gave a yellow oil (79%): 1H
NMR (300 MHz) 1.10-1.90 (m, 10H), 1.46 (t, J ) 7.2, 3H),
3.24 (m, 1H), 4.43 (q, J ) 7.2, 2H), 5.12 (s, 1H), 7.00 (d, J )
1.6, 1H), 7.43 (d, J ) 1.6, 1H), 7.51 (d, J ) 8.7, 2H), 8.12 (s,
1H), 8.15 (d, J ) 8.7, 2H), 10.02 (br s, 1H); 13C NMR (75 MHz)
13.7 (q), 23.6 (t), 24.5 (t), 33.0 (t), 52.6 (d), 60.7 (t), 83.4 (d),
115.2 (d), 126.8 (d), 129.3 (d), 131.2 (d), 134.80 (d), 138.8 (s),
162.9 (s), 165.0 (s), 166.3 (s); LRMS (EI) m/z 367 (M+, 6), 300
(M+ - Im, 100). Anal. Calcd for C21H25N3O3: C, 68.64; H,
6.86; N, 11.44. Found: C, 68.82; H, 6.79; N 11.29.
(()-(Z)-1-(1H-1-Im id a zolyl)-4-m eth yl-3-(1-p h en yleth yl-
a m in o)2-p en ten -1-on e (2o). Flash chromatography (EtOAc)
on silica gel gave a yellow oil (59%): 1H NMR (250 MHz) 0.92
(d, J ) 7.2, 3H), 1.25 (d, J ) 7.2, 3H), 1.65 (d, J ) 7.2, 3H),
2.79 (m, 1H), 4.85 (m, 1H), 5.15 (s, 1H), 7.10-7.40 (m, 5H),
7.14 (d, J ) 1.6, 1H), 7.50 (d, J ) 1.6, 1H), 8.13 (s, 1H), 10.65
(br d, 1H); 13C NMR (62.8 MHz) 21.4 (q), 22.6 (q), 25.6 (d),
30.1 (q), 53.4 (d), 78.7 (d), 116.3 (d), 126.0 (d), 128.3 (d), 129.7
(d), 129.7 (d), 135.60 (d), 144.5 (s), 163.3 (s), 177.2 (s); IR (KBr)
3140, 1629, 1586, 1128. HRMS calcd for C17H21N3O: 283.1684.
Found: 283.1679. Anal. Calcd for C17H21N3O: C, 72.06; H,
7.47; N, 14.86. Found: C, 72.02; H, 7.55; N, 14.80.
(Z)-3-Cycloh exyla m in o-1-(1H-1-im id a zolyl)-2-p en t en -
1-on e (2j). MPLC (EtOAc) gave a yellow oil (43%, method A;
68%, method B): 1H NMR (250 MHz) 1.24 (t, J ) 7.6, 3H),
1.20-1.95 (m, 10H), 2.40 (q, J ) 7.6, 2H), 3.45 (m, 1H), 5.04
(s, 1H), 7.05 (d, J ) 1.6, 1H), 7.42 (d, J ) 1.6, 1H), 8.12 (s,
1H), 10.15 (br d, 1H); 13C NMR (100 MHz) 12.8 (t), 24.4 (t),
25.1 (t), 25.6 (t), 34.0 (q), 51.7 (d), 80.1 (d), 115.7 (d), 129.6 (d),
135.2 (d), 163.7 (s), 170.8 (s); IR (KBr) 3243, 1630, 1590, 1110.
HRMS calcd for C14H21N3O: 247.1684. Found: 247.1686.
Anal. Calcd for C14H21N3O: C, 67.99; H, 8.56; N, 16.99.
Found: C, 68.40; H, 8.62; N, 17.28.
(()-(Z)-1-(1H-1-Im id a zolyl)-3-p h en yl-3-(1-p h en yleth yl-
a m in o)-2-p r op en -1-on e (2p ). MPLC (n-hexanes-EtOAc (3:
1)) on silica gel gave a yellow oil (69%): 1H NMR (250 MHz)
1.60 (d, J ) 7.2, 3H), 4.61 (m, 1H), 5.20 (s, 1H), 7.00 (d, J )
1.6, 1H), 7.10-7.52 (m, 11H), 8.15 (s, 1H), 10.45 (br s, 1H);
13C NMR (62.8 MHz) 24.3 (q), 54.2 (d), 84.5 (d), 115.6 (d), 125.3
(d), 127.2 (d), 127.2 (d), 128.4 (d), 128.6 (d), 129.8 (d), 129.8
(d), 134.8 (s), 135.3 (d), 143.3 (s), 163.5 (s), 168.2 (s). HRMS
calcd for C20H19N3O: 317.1528. Found: 317.1525. Anal.
Calcd for C20H19N3O: C, 75.69; H, 6.03; N, 13.24. Found: C,
76.16; H, 5.85; N, 13.40.
(Z)-3-Cycloh exyla m in o-1-(1H-1-im id a zolyl)-2-m et h yl-
2-bu ten -1-on e (2j′). MPLC (EtOAc) gave a yellow oil (30%,
method A): 1H NMR (250 MHz) 1.38-1.80 (m, 10H), 1.91 (s,
3H), 2.14 (s, 3H), 3.50 (m, 1H), 7.03 (d, J ) 1.6, 1H), 7.21 (d,
J ) 1.6, 1H), 7.89 (s, 1H), 10.80 (br s, 1H); 13C NMR (100 MHz)
15.4 (t), 16.3 (t), 24.3 (q), 25.2 (t), 33.6 (q), 52.4 (d), 88.1 (s),
117.8 (d), 128.4 (d), 136.6 (d), 165.9 (s), 166.8 (s). HRMS calcd
for C14H21N3O: 247.1684. Found: 247.1685. Anal. Calcd for
(R)-(Z)-1-(1H-1-Im id a zolyl)-4-m eth yl-3-(1-p h en yleth yl-
a m in o)2-p en ten -1-on e (2q). Flash chromatography (n-hex-
anes-EtOAc (1:2)) on silica gel gave a white solid (58%): mp
96-98 °C; [R]25 -533.2° (c 0.01, CHCl3); 1H NMR (250 MHz)
D
0.83 (d, J ) 6.9, 3H), 1.15 (d, J ) 6.9, 3H), 1.55 (d, J ) 6.9,
3H), 2.66 (m, 1H), 4.77 (m, 1H), 5.07 (s, 1H), 6.99 (d, J ) 1.6,
1H), 7.19-7.29 (m, 5H), 7.39 (d, J ) 1.6, 1H), 8.09 (s, 1H),
10.55 (br d, 1H); 13C NMR (62.8 MHz) 20.8 (q), 22.0 (q), 24.9
(q), 29.4 (d), 52.7 (d), 78.2 (d), 115.7 (d), 125.3 (d), 127.5 (d),
129.0 (d), 129.9 (d), 135.3 (d), 143.8 (s), 164.5 (s), 176.6 (s).
HRMS calcd for C17H21N3O: 283.1684. Found: 283.1678.
Anal. Calcd for C17H21N3O: C, 72.06; H, 7.47; N, 14.86.
Found: C, 71.88; H, 7.36; N, 14.58.
(S)-(Z)-1-(1H-1-Im id a zolyl)-4-m eth yl-3-(1-p h en yleth yl-
a m in o)2-p en ten -1-on e (2r ). Flash chromatography (n-hex-
anes-EtOAc (1:3)) on silica gel gave a yellow solid (61%): mp
96-98 °C; [R]25D +595.6° (c 0.015, CHCl3); 1H NMR (250 MHz)
0.83 (d, J ) 6.8, 3H), 1.15 (d, J ) 6.9, 3H), 1.55 (d, J ) 6.9,
3H), 2.66 (m, 1H), 4.77 (m, 1H), 5.07 (s, 1H), 6.99 (d, J ) 1.6,
1H), 7.17-7.32 (m, 5H), 7.39 (d, J ) 1.6, 1H), 8.09 (s, 1H),
10.53 (br d, 1H); 13C NMR (62.8 MHz) 20.7 (q), 21.9 (q), 24.8
(q), 29.3 (d), 52.6 (d), 78.1 (d), 115.6 (d), 125.2 (d), 127.5 (d),
128.9 (d), 129.8 (d), 135.2 (d), 143.8 (s), 164.4 (s), 176.56 (s).
HRMS calcd for C17H21N3O: 283.1684. Found: 283.1684.
Anal. Calcd for C17H21N3O: C, 72.06; H, 7.47; N, 14.86.
Found: C, 71.87; H, 7.56; N, 14.61.
N-Su bstitu ted â-En a m in o Ester s a n d Th ioester s (4).
Gen er a l P r oced u r e. Meth od C. To a stirred solution of
â-enamino carbonyl imidazole derivative 2 (10.0 mmol) in 20
mL of dried THF was added an excess of alcohol or thiol (10.0-
30.0 mmol) in the presence of sodium alkoxide or RS-. The
reaction mixture was stirred at reflux under argon atmo-
sphere. The reaction was monitored by TLC. After 6-24 h,
the resulting mixture was quenched with saturated am-
monium chloride solution. The aqueous layer was extracted
with dichloromethane (3 × 25 mL). The combined organic
layers were washed with brine and dried (Na2SO4). After
filtration, the solvents were removed under reduced pressure
to furnish the crude product 4 (X ) O, S). Purification was
carried out as indicated in each case.
C
14H21N3O: C, 67.99; H, 8.56; N, 16.99. Found: C, 67.81; H,
8.41; N, 16.81.
(Z)-3-An ilin o-1-(1H-1-im id a zolyl)-3-p h en yl-2-p r op en -1-
on e (2k ). Recrystallization (n-hexane-chloroform (3:1)) gave
a yellow solid (84%): mp 146-148 °C; 1H NMR (300 MHz) 5.48
(s, 1H), 6.80-7.45 (m, 11H), 7.50 (d, J ) 1.6, 1H), 8.60 (s, 1H),
11.51 (br s, 1H); 13C NMR (75 MHz) 87.8 (d), 115.8 (d), 123.4
(d), 124.3 (d), 128.1 (d), 128.6 (d), 128.7 (d), 130.2 (d), 134.8
(s), 138.5 (s), 163.8 (s), 164.3 (s); IR (KBr) 3200, 1670, 1630,
1600; LRMS (EI) m/z 289 (M+, 8), 222 (M+ - Im, 100). Anal.
Calcd for C18H15N3O: C, 74.72; H, 5.23; N, 14.52. Found: C,
74.33; H, 5.01; N, 14.31.
(Z)-1-(1H-1-Im id a zolyl)-3-(4-m eth yla n ilin o)-3-p h en yl-
2-p r op en -1-on e (2l). Recrystallization (n-hexane-chloroform
(3:1)) gave a yellow solid (75%): mp 137-139 °C; 1H NMR (250
MHz) 2.20 (s, 3H), 5.47 (s, 1H), 6.75 (d, J ) 8.6, 2H), 7.00 (d,
J ) 8.6, 2H), 7.16-7.65 (m, 7H), 8.30 (s, 1H), 11.50 (br s, 1H);
13C NMR (62.8 MHz) 20.1 (q), 88.5 (d), 116.8 (d), 123.6 (d),
128.6 (d), 129.6 (d), 130.8 (d), 130.9 (d), 131.5 (d), 135.2 (d),
136.6 (s), 137.9 (s), 138.8 (s), 164.1 (s), 165.3 (s); LRMS (EI)
m/z 303 (M+, 3), 236 (M+ - Im, 100). Anal. Calcd for
C
19H17N3O: C, 75.24; H, 5.61; N, 13.86. Found: C, 75.01; H,
5.47; N, 13.73.
(Z)-1-(1H-1-Im id a zolyl)-3-p h en yl-3-[(Z)-1-p r op en yla m i-
n o]2-p r op en -1-on e (2m ). Flash chromatography (n-hex-
anes-ether (1:6)) recrystallization (ether) gave a white solid
1
(88%): mp 141-143 °C; H NMR (300 MHz) 1.82 (d, J ) 7.1,
3H), 4.82 (m, 1H), 5.31 (s, 1H), 6.23 (m, 1H), 7.14 (d, J ) 1.6,
1H), 7.58 (m, 6H), 8.21 (s, 1H), 11.80 (br d, 1H); 13C NMR (75
MHz) 11.0 (q), 85.7 (d), 107.9 (d), 116.5 (d), 125.0 (d), 128.0
(d), 128.8 (d), 130.1 (d), 130.3 (d), 133.9 (s), 135.4 (d), 163.2
(s), 163.6 (s); LRMS (EI) m/z 253 (M+, 18), 186 (M+ - Im, 100).
Anal. Calcd for C15H15N3O: C, 71.13; H, 5.97; N, 16.59.
Found: C, 71.12; H, 5.96; N, 16.61.
Meth od D. “On e P ot”. To a stirred solution of N,N′-
carbonyldiimidazole (2.2 g, 14 mmol) in THF (15 mL) was

8834 J . Org. Chem., Vol. 63, No. 24, 1998
Fustero et al.
added boron trifluoride (1.72 mL, 14 mmol) in THF (5 mL) at
room temperature. The resulting solution was stirred at room
temperature for 30 min. Ketimine 1 (12.7 mmol) in THF (15
mL) was added dropwise to the imidazole solution. The
resulting mixture was stirred at reflux for 24 h. Then a
solution of the desired alcohol (12.7-38.1 mmol) in THF (10
mL) was added slowly. The reaction mixture was stirred for
24-48 h. When TLC analyses showed the disappearance of
the â-enamino carbonyl imidazole 2, the reaction was quenched
by addition of 3 N NaOH. The aqueous layer was extracted
with dichloromethane (3 × 25 mL). The combined organic
layers were washed with brine, dried over Na2SO4, and
evaporated under vacuum to afford â-enamino esters deriva-
tives 4.
Meth od E. n-Butyllithium (2.5 M in hexane, 8.0 mL, 20
mmol) was added to a solution of freshly distilled diisopropyl-
amine (2.6 mL, 20 mmol) in 10 mL of THF at 0 °C. After being
stirred for 10 min, ketimine 1 (10.0 mmol) in THF (15 mL)
was added. The solution stirred 30 min at 0 °C and then cooled
at -78 °C. Alkoxy carbonyl imidazole 5 (13.0 mmol) in 5 mL
of THF was added and allowed to stir for 1 h at -78 °C. The
solution was allowed to warm to room temperature. 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 dichloromethane (3 × 25 mL). The combined organic
extracts were washed with brine, then dried (Na2SO4), and
evaporated under vacuum to furnish the crude product 4. The
purification was carried out as indicated in each case.
Meth od F . A solution of boron trifluoride (5.0 mmol, 0.6
mL) in 5 mL of THF was added to a solution of alcoxy carbonyl
imidazole 5 (5.0 mmol) in 15 mL of THF at room temperature
for 30 min. Ketimine 1 (4.5 mmol) in 10 mL of THF was added
dropwise. The solution was heated at reflux for 24 h under
argon atmosphere. The reaction mixture was poured onto
saturated ammonium chloride solution. Work up of the
reaction followed the procedure described in Method E.
ter t-Bu tyl (Z)-3-Bu tylam in o-4-m eth yl-2-pen ten oate (4a).
Flash chromatography (n-hexanes-EtOAc (9:1)) on silica gel
gave a yellow oil (75%): 1H NMR (400 MHz) 0.68 (t, J ) 7.2,
3H), 0.86 (d, J ) 6.8, 6H), 1.13 (m, 2H), 1.20 (s, 9H), 1.31 (m,
2H), 2.40 (m, 1H), 2.95 (q, J ) 6.4, 2H), 4.14 (s, 1H), 8.31 (br
s, 1H); 13C NMR (100 MHz) 13.3 (q), 19.6 (t), 20.9 (q), 28.0 (d),
28.2 (q), 32.3 (t), 41.4 (t), 76.3 (s), 78.4 (d), 170.4 (s), 171.0 (s).
HRMS calcd for C14H27NO2: 241.2041. Found: 241.2041.
Anal. Calcd for C14H27NO2: C, 69.67; H, 11.27; N, 5.80.
Found: C, 69.19; H, 11.09; N, 5.91.
(62.8 MHz) 13.6 (q), 13.9 (q), 17.1 (q), 19.8 (t), 21.0 (d), 21.1
(q), 28.5 (d), 32.3 (t), 41.8 (t), 60.8 (t), 66.7 (d), 75.9 (d), 170.0
(s), 172.1 (s), 172.7 (s). HRMS calcd for C15H27NO4: 285.1940.
Found: 285.1941. Anal. Calcd for C15H27NO4: C, 63.13; H,
9.54; N, 4.91. Found: C, 63.66; H, 9.75; N, 4.98.
Ben zyl (Z)-3-Bu t yla m in o-4-m et h yl-2-p en t en et h ioa t e
(4e). Flash chromatography (n-hexanes-EtOAc (20:1)) on
silica gel gave a yellow oil (78%): 1H NMR (250 MHz) 0.92 (t,
J ) 7.2, 3H), 1.06 (d, J ) 6.8, 6H), 1.37 (m, 2H), 1.52 (m, 2H),
2.59 (m, 1H), 3.17 (q, J ) 6.5, 2H), 4.05 (s, 2H), 4.90 (s, 1H),
7.13-7.30 (m, 5H), 9.47 (br s, 1H); 13C NMR (62.8 MHz) 13.4
(q), 19.6 (t), 20.2 (q), 28.4 (t), 32.0 (t), 32.1 (d), 41.6 (t), 88.0
(d), 126.2 (d), 128.0 (d), 128.4 (d), 139.0 (s), 169.4 (s), 185.1
(s). HRMS calcd for C17H25NOS: 291.1657. Found: 291.1661.
Anal. Calcd for C17H25NOS: C, 70.06; H, 8.65; N, 4.81; S,
14.60. Found: C, 69.87; H, 8.54; N, 4.90; S, 14.53.
Allyl (Z)-3-Bu tyla m in o-4-m eth yl-2-p en ten eth ioa te (4f).
Flash chromatography (n-hexanes-EtOAc (20:1)) on silica gel
gave a yellow oil (86%): 1H NMR (250 MHz) 0.84 (t, J ) 7.2,
3H), 1.04 (d, J ) 6.8, 6H), 1.29 (m, 2H), 1.50 (m, 2H), 2.58 (m,
1H), 3.14 (q, J ) 6.4, 2H), 3.43 (dd, J ) 6.8 and 0.9, 2H), 4.86
(s, 1H), 4.98 (dd, J ) 10.7 and 1.5, 1H), 5.15 (dd, J ) 16.8 and
1.4, 1H), 5.80 (m, 1H), 9.41 (br s, 1H); 13C NMR (62.8 MHz)
13.1 (q), 19.3 (t), 20.5 (q), 27.7 (t), 30.1 (t), 31.8 (d), 41.3 (t),
87.8 (d), 115.5 (t), 134.5 (d), 168.9 (s), 184.8 (s). HRMS calcd
for C13H23NOS: 214.1500. Found: 241.1496. Anal. Calcd for
C
13H23NOS: C, 64.68; H, 9.60; N, 5.80; S, 14.94. Found: C,
64.79; H, 9.48; N, 5.73; S, 14.75.
ter t-Bu tyl (Z)-3-Bu tylam in o-3-ph en yl-2-pr open oate (4g).
MPLC (n-hexanes-EtOAc (10:1)) on silica gel gave a yellow
oil (68%): 1H NMR (250 MHz) 0.76 (t, J ) 7.2, 3H), 1.23 (m,
2H), 1.45 (m, 2H), 1.50 (s, 9H), 2.95 (q, J ) 6.4, 2H), 4.41 (s,
1H), 7.28 (m, 5H), 8.32 (br s, 1H); 13C NMR (62.8 MHz) 14.0
(q), 20.1 (t), 28.9 (q), 33.4 (t), 44.5 (t), 78.5 (s), 87.0 (d), 128.1
(d), 128.4 (d), 129.1 (d), 137.3 (s), 164.5 (s), 171.1 (s); IR (KBr)
3276, 3056, 1645, 1609, 1593, 1141. HRMS calcd for C17H25
NO2: 275.1885. Found: 275.1874. Anal. Calcd for C17H25
-
-
NO2: C, 74.14; H, 9.15; N, 5.09. Found: C, 74.35; H, 9.23; N,
5.30.
(1R,2S,5R)-2-Isop r op yl-5-m eth ylcycloh exyl (Z)-3-Bu -
tyla m in o-3-p h en yl-2-p r op en oa te (4h ). Flash chromatog-
raphy (n-hexanes-EtOAc (10:1)) on silica gel gave a yellow
oil (80%): [R]25D -3.9° (c 0.0025, CH2Cl2); 1H NMR (250 MHz)
0.70 (t, J ) 7.2, 3H), 0.74 (d, J ) 7.0, 3H), 0.78 (d, J ) 7.0,
3H), 0.86 (d, J ) 7.0, 3H), 0.96-1.97 (m, 9H), 1.35 (m, 2H),
1.50 (m, 2H), 2.92 (q, J ) 6.4, 2H), 4.46 (s, 1H), 4.62 (dt, J )
10.7, 4.3, 1H), 7.15-7.27 (m, 5H), 8.47 (br t, 1H); 13C NMR
(62.8 MHz) 13.6 (q), 16.5 (q), 19.7 (t), 20.7 (q), 22.0 (q), 23.5
(t), 26.1 (d), 31.3 (d), 32.9 (t), 34.3 (t), 41.4 (t), 44.2 (t), 47.1
(d), 71.8 (d), 85.2 (d), 127.67 (d), 128.4 (d), 128.9 (d), 136.3 (s),
164.6 (s), 170.0 (s). HRMS calcd for C23H35NO2: 357.2668.
Found: 357.2667. Anal. Calcd for C23H35NO2: C, 77.31; H,
9.80; N, 3.92. Found: C, 77.73; H, 10.00; N, 3.98.
1-Ad a m a n tyl (Z)-3-Bu tyla m in o-3-p h en yl-2-p r op en oa te
(4i). MPLC (n-hexanes-EtOAc (20:1)) on silica gel gave a pale
green oil (50%): 1H NMR (250 MHz) 0.82 (t, J ) 7.2, 3H), 1.31
(m, 2H), 1.45 (m, 2H), 1.64-2.17 (m, 15H), 3.05 (q, J ) 6.4,
2H), 4.48 (s, 1H), 7.31-7.38 (m, 5H), 8.45 (br t, 1H); 13C NMR
(62.8 MHz) 13.9 (q), 20.0 (t), 31.0 (d), 33.4 (t), 36.6 (t), 42.1 (t),
44.5 (t), 78.6 (s), 87.0 (d), 128.0 (d), 128.3 (d), 129.0 (d), 136.8
(s), 164.6 (s), 170.5 (s); IR (KBr) 3274, 3055, 1686, 1640, 1609,
1173. HRMS calcd for C23H31NO2: 353.2354. Found: 353.2354.
Anal. Calcd for C23H31NO2: C, 78.18; H, 8.78; N, 3.96.
Found: C, 78.53; H, 8.91; N, 3.93.
Meth yl (Z)-3-Bu tyla m in o-4-m eth yl-2-p en ten oa te (4b).
Flash chromatography (n-hexanes-EtOAc (9:1)) on silica gel
gave a yellow oil (88%): 1H NMR (400 MHz) 0.91 (t, J ) 7.4,
3H), 1.06 (d, J ) 7.2, 6H), 1.30 (m, 2H), 1.56 (m, 2H), 2.65 (m,
1H), 3.14 (q, J ) 6.5, 2H), 3.53 (s, 3H), 4.41 (s, 1H), 8.31 (br s,
1H); 13C NMR (100 MHz) 13.3 (q), 19.6 (t), 20.9 (q), 28.1 (d),
32.2 (t), 41.4 (t), 49.2 (q), 76.4 (d), 171.2 (s), 171.3 (s). HRMS
calcd for C11H21NO2: 199.1572. Found: 199.1571. Anal.
Calcd for C11H21NO2: C, 66.30; H, 10.62; N, 7.03. Found: C,
66.19; H, 10.69; N, 7.13.
2,2,2-Tr iflu or oet h yl (Z)-Bu t yla m in o-4-m et h yl-2-p en -
ten oa te (4c). MPLC (n-hexanes-EtOAc (15:1)) on silica gel
gave a colorless oil (65%): 1H NMR (400 MHz) 0.95 (t, J )
7.2, 3H), 1.23 (d, J ) 6.9, 6H), 1.46 (m, 2H), 1.58 (m, 2H), 2.68
(m, 1H), 3.22 (q, J ) 6.4, 2H), 4.41 (q, J ) 8.8, 2H), 4.55 (s,
1H), 8.65 (br t, 1H); 13C NMR (100 MHz) 13.6 (q), 19.9 (t), 21.1
(q), 28.7 (d), 32.4 (t), 41.9 (t), 58.5 (q, J C-C-F ) 34.9), 75.2 (d),
123.7 (s, J C-F ) 276.1), 158.8 (s), 173.6 (s). HRMS calcd for
(2S)-5-Oxo-2-a zola n yl (Z)-3-Bu t yla m in o-3-p h en yl-2-
p r op en oa te (4j). Flash chromatography (n-hexanes-EtOAc
C
C
12H20NO2F3: 267.1446. Found: 267.1436. Anal. Calcd for
12H20NO2F3: C, 55.17; H, 7.66; N, 5.36. Found: C, 54.79; H,
(1:3)) on silica gel gave a yellow solid (75%): [R]25 -3.18° (c
D
1
7.49; N, 5.33.
0.0017, CHCl3); mp 70-72 °C; H NMR (250 MHz) 0.77 (t, J
(S)-1-Eth yloxyca r bon yleth yl (Z)-3-Bu tyla m in o-4-m eth -
yl-2-p en t en oa t e (4d ). MPLC (n-hexanes-EtOAc (8:1)) on
silica gel gave a yellow oil (85%): [R]25D -59.78° (c 0.0136, CH2-
Cl2); 1H NMR (250 MHz) 0.90 (t, J ) 7.2, 3H), 1.12 (d, J ) 6.8,
6H), 1.28 (t, J ) 7.2, 3H), 1.50 (d, J ) 7.0, 3H), 1.48 (m, 2H),
1.57 (m, 2H), 2.65 (m, 1H), 3.20 (q, J ) 6.4, 2H), 4.22 (m, 2H),
4.59 (s, 1H), 5.04 (q, J ) 7.0, 1H), 8.63 (br s, 1H); 13C NMR
) 7.2, 3H), 1.23 (m, 2H), 1.39 (m, 2H), 1.81 (m, 1H), 2.21 (m,
1H), 2.30 (m, 2H), 3.00 (q, J ) 6.4, 2H), 3.85 (m, 2H), 4.13 (m,
1H), 4.47 (s, 1H), 5.96 (br s, 1H), 7.20-7.35 (m, 5H), 8.50 (br
t, 1H); 13C NMR (62.8 MHz) 13.6 (q), 19.7 (t), 23.3 (t), 29.6 (t),
32.9 (t), 44.3 (t), 53.4 (d), 65.4 (t), 83.4 (d), 127.7 (d), 128.35
(d), 129.2 (d), 135.9 (s), 165.9 (s), 169.8 (s), 177.9 (s). HRMS
calcd for C18H24N2O3: 316.1786. Found: 316.1783. Anal.

New â-Enamino Acid Derivatives
J . Org. Chem., Vol. 63, No. 24, 1998 8835
Calcd for C18H24N2O3: C, 68.33; H, 7.65; N, 8.85. Found: C,
68.19; H, 7.53; N, 8.72.
95.8 (d), 127.6 (d), 128.3 (d), 129.1 (d), 136.1 (s), 161.0 (s), 189.0
(s). HRMS calcd for C19H27NOS: 317.1813. Found: 317.1813.
Anal. Calcd for C19H27NOS: C, 71.88; H, 8.57; N, 4.41; S,
10.10. Found: C, 71.57; H, 8.69; N, 4.53; S, 9.98.
(2E)-3,7-Dim et h yl-2,6-oct a d ien yl (Z)-3-Bu t yla m in o-3-
p h en yl-2-p r op en oa te (4k ). MPLC (n-hexanes-EtOAc (10:
1)) on silica gel gave a yellow oil (80%): 1H NMR (250 MHz)
0.83 (t, J ) 7.2, 3H), 1.31 (m, 2H), 1.46 (m, 2H), 1.59 (s, 3H),
1.67 (s, 3H), 1.71 (s, 3H), 2.00-2.07 (m, 4H), 3.05 (q, J ) 6.4,
2H), 4.59 (s, 1H), 4.63 (d, J ) 7.0, 2H), 5.11 (br t, 1H), 5.40 (br
t, 1H), 7.34-7.39 (m, 5H), 8.45 (br t, 1H); 13C NMR (62.8 MHz)
13.6 (q), 16.4 (q), 17.6 (q), 19.7 (t), 25.6 (q), 26.3 (t), 33.0 (t),
39.6 (t), 44.2 (t), 59.7 (t), 84.7 (d), 119.3 (d), 123.8 (d), 127.7
(d), 128.2 (d), 128.99 (d), 131.6 (s), 136.3 (s), 140.9 (s), 164.5
(s), 170.4 (s); IR (KBr) 3279, 3055, 1645, 1609, 1593, 1167,
1145. HRMS calcd for C23H33NO2: 355.2511. Found: 355.2506.
Anal. Calcd for C23H33NO2: C, 77.70; H, 9.36; N, 3.94.
Found: C, 77.42; H, 9.10; N, 3.81.
Meth yl (Z)-3-An ilin o-3-p h en yl-2-p r op en oa te (4q). Re-
crystallization (n-hexane) gave an orange solid (94%): mp 84-
86 °C; 1H NMR (300 MHz) 3.81 (s, 3H), 5.00 (s, 1H), 6.70-
7.12 (m, 5H), 7.39 (m, 5H), 10.30 (br s, 1H); 13C NMR (75 MHz)
50.5 (q), 90.6 (d), 122.1 (d), 122.9 (d), 128.1 (d), 128.3 (d), 128.5
(d), 129.3 (d), 135.8 (s), 140.2 (s), 159.1 (s), 170.3 (s); LRMS
(EI) m/z 253 (M+, 73), 193 (100). Anal. Calcd for C16H15NO2:
C, 75.87; H, 5.97; N, 5.53. Found: C, 75.67; H, 5.81; N, 5.33.
Isop r op yl (Z)-3-An ilin o-3-p h en yl-2-p r op en oa t e (4r ).
Flash chromatography (n-hexanes-ether (3:1)) on silica gel
gave a yellow solid (71%): mp 82-84 °C; 1H NMR (300 MHz)
1.32 (d, J ) 7.2, 6H), 5.00 (s, 1H), 5.15 (m, 1H), 6.65-7.10 (m,
5H), 7.32 (m, 5H), 10.38 (br s, 1H); 13C NMR (75 MHz) 22.0
(q), 66.2 (d), 91.7 (d), 121.9 (d), 122.7 (d), 128.0 (d), 128.2 (d),
128.4 (d), 129.2 (d), 135.9 (s), 140.3 (s), 158.7 (s), 169.5 (s);
LRMS (EI) m/z 281 (M+, 50), 194 (100). Anal. Calcd for
C18H19NO2: C, 76.84; H, 6.81; N, 4.98. Found: C, 77.04; H,
6.81; N, 5.20.
1,2:5,6-Di-O-isop r op ilyd en -r-D-glu cofu r a n os-3-O-yl (Z)-
3-Bu tyla m in o-3-p h en yl-2-p r op en oa te (4l). Flash chroma-
tography (n-hexanes-EtOAc (2:1)) on silica gel gave a yellow
oil (82%): [R]25 -18.55° (c 0.0076, CH2Cl2); 1H NMR (250
D
MHz) 0.84 (t, J ) 7.2, 3H), 1.28 (m, 2H), 1.29 (s, 3H), 1.30 (s,
3H), 1.37 (s, 3H), 1.48 (m, 2H), 1.52 (s, 3H), 3.08 (q, J ) 6.4,
2H), 4.05 (d, J ) 5.4, 2H), 4.32 (m, 2H), 4.54 (s, 1H), 4.58 (d,
J ) 3.7, 1H), 5.24 (d, J ) 2.8, 1H), 5.87 (d, J ) 3.7, 1H), 7.37
(m, 5H), 8.75 (br t, 1H); 13C NMR (62.8 MHz) 13.5 (q), 19.6 (t),
25.2 (q), 26.1 (q), 26.6 (q), 32.8 (t), 44.2 (t), 66.4 (t), 72.7 (d),
74.6 (d), 79.56 (d), 83.5 (d), 83.6 (d), 104.9 (d), 108.8 (s), 111.8
(s), 127.5 (d), 128.3 (d), 129.2 (d), 135.8 (s), 165.9 (s), 168.7 (s).
HRMS calcd for C25H35NO7: 461.2413. Found: 461.2413.
Anal. Calcd for C25H35NO7: C, 65.06; H, 7.64; N, 3.03.
Found: C, 65.45; H, 7.49; N, 2.89.
ter t-Bu tyl (Z)-3-An ilin o-3-p h en yl-2-p r op en oa te (4s).
Flash chromatography (n-hexanes-ether (5:1)) on silica gel
gave a yellow oil (75%): 1H NMR (300 MHz) 1.55 (s, 9H), 4.98
(s, 1H), 6.62-7.01 (m, 5H), 7.30 (m, 5H), 10.25 (br s, 1H); 13
C
NMR (75 MHz) 28.4 (q), 79.2 (s), 93.1 (d), 121.9 (d), 122.5 (d),
128.0 (d), 128.2 (d), 128.4 (d), 129.1 (d), 136.0 (s), 140.5 (s),
158.1 (s), 169.9 (s); LRMS (EI) m/z 295 (M+, 21), 193 (100).
Anal. Calcd for C19H21NO2: C, 77.26; H, 7.17; N, 4.74.
Found: C, 76.88; H, 6.93; N, 4.79.
5r-Ch olesta n -3-â-yl (Z)-3-Bu tyla m in o-3-p h en yl-2-p r o-
Ben zyl (Z)-3-An ilin o-3-p h en yl-2-p r op en oa te (4t). Flash
chromatography (n-hexanes-ether (1:2)) on silica gel gave a
yellow solid (84%): mp 70-72 °C; 1H NMR (300 MHz) 5.10 (s,
1H), 5.23 (s, 2H), 6.72-7.45 (m, 15H), 10.30 (br s, 1H); 13C
NMR (75 MHz) 64.9 (t), 90.1 (d), 122.2 (d), 127.8 (d), 128.1
(d), 128.3 (d), 128.4 (d), 128.5 (d), 129.4 (d), 137.1 (s), 138.0
(s), 140.1 (s), 159.9 (s), 170.0 (s). HRMS calcd for C22H19NO2:
329.1415. Found: 329.1408. Anal. Calcd for C22H19NO2: C,
80.22; H, 5.81; N, 4.25. Found: C, 80.20; H, 5.88; N, 4.63.
Meth yl 2-(2-Azola n ylid en )a ceta te (4u ). Flash chroma-
tography (n-hexanes-EtOAc (3:1)) on silica gel gave a white
p en oa te (4m ). Flash chromatography (n-hexane-EtOAc (15:
1)) on silica gel gave a yellow oil (74%): [R]25 +13.6° (c 0.01,
D
1
CH2Cl2); H NMR (250 MHz) 0.65 (s, 3H), 0.72 (s, 3H), 0.85
(d, J ) 6.4, 3H), 0.65-2.06 (m, 42H), 3.03 (q, J ) 6.4, 2H),
4.52 (s, 1H), 7.35 (m, 5H), 8.56 (br t, 1H); 13C NMR (62.8 MHz)
12.0 (t), 12.2 (q), 13.6 (q), 18.6 (q), 19.7 (s), 21.2 (t), 22.5 (d),
22.8 (d), 23.8 (t), 24.2 (t), 27.9 (d), 27.9 (t), 28.2 (t), 28.6 (t),
32.0 (t), 33.0 (t), 34.5 (t), 35.4 (q), 35.7 (d), 36.1 (t), 36.9 (t),
40.0 (t), 42.5 (s), 44.2 (t), 44.8 (d), 54.2 (d), 56.2 (d), 56.4 (d),
71.7 (d), 85.4 (d), 127.7 (d), 128.1 (d), 128.9 (d), 136.4 (s), 164.8
(s), 170.0 (s). HRMS calcd for C40H63NO2: 589.4858. Found:
589.4848. Anal. Calcd for C40H63NO2: C, 81.49; H, 10.69; N,
2.37. Found: C, 81.58; H, 10.60; N, 2.42.
(1R,2S,5R)-5-Meth yl-2-(1-m eth yl-1-p h en yleth yl)cyclo-
h exyl (Z)-3-Bu tylam in o-3-ph en yl-2-pr open oate (4n ). Flash
chromatography (n-hexanes-EtOAc (5:1)) on silica gel gave a
yellow oil (71%): [R]25D +44.6° (c 0.012, CHCl3); 1H NMR (250
MHz) 0.78 (t, J ) 7.2, 3H), 0.81 (m, 3H), 0.80-0.95 (m, 4H),
1.23 (s, 3H), 1.29 (s, 3H), 1.36-1.21 (m, 6H), 1.37-1.45 (m,
2H), 2.96 (q, J ) 6.4, 2H), 4.14 (s, 1H), 4.74 (dt, J ) 7.5, 4.2,
1H), 7.02-7.33 (m, 10H), 8.43 (br t, 1H); 13C NMR (62.8 MHz)
13.7 (q), 19.8 (t), 21.8 (d), 25.0 (q), 27.0 (t), 28.2 (q), 31.3 (d),
33.0 (t), 34.6 (t), 40.1 (t), 42.3 (t), 44.3 (t), 50.8 (d), 72.6 (d),
85.7 (d), 124.8 (d), 125.5 (d), 127.7 (d), 128.1 (d), 128.9 (d), 136.3
(s), 151.4 (s), 164.5 (s), 169.5 (s). HRMS calcd for C29H39NO2:
433.2980. Found: 433.3004. Anal. Calcd for C29H39NO2: C,
80.33; H, 9.06; N, 3.23. Found: C, 80.01; H, 8.79; N, 3.19.
ter t-Bu t yl (Z)-3-Cycloh exyla m in o-3-p h en yl-2-p r op e-
n oa te (4o). Recrystallization (cyclohexane-chloroform) gave
a white solid (58%): mp 118-120 °C; 1H NMR (400 MHz)
1.00-1.80 (m, 10H), 1.49 (s, 9H), 3.00 (m, 1H), 4.46 (s, 1H),
7.35 (m, 5H), 8.40 (br d, 1H); 13C NMR (100 MHz) 24.8 (t),
25.3 (t), 28.7 (q), 34.6 (t), 52.6 (d), 78.2 (s), 87.4 (d), 127.7 (d),
128.2 (d), 128.8 (d), 137.0 (s), 163.5 (s); 170.2 (s). HRMS calcd
for C19H27NO2: 301.2041. Found: 301.2046. Anal. Calcd for
1
solid (50%): mp 95-97 °C; H NMR (250 MHz) 2.15 (m, 2H),
2.74 (t, J ) 7.7, 2H), 3.68 (t, J ) 6.6, 2H), 3.79 (s, 3H), 4.68 (s,
1H), 8.10 (br s, 1H); 13C NMR (62.8 MHz) 21.6 (t), 31.8 (t),
46.7 (q), 49.4 (t), 75.6 (d), 166.1 (s), 170.4 (s). HRMS calcd for
C7H11NO2: 141.0789. Found: 141.0788. Anal. Calcd for
C7H11NO2: C, 59.56; H, 7.85; N, 9.92. Found: C, 59.87; H,
7.74; N, 9.87.
Allyl (Z)-3-P h en yl-3-(1-p h en ylet h yla m in o)-2-p r op e-
n oa te (4v). Flash chromatography (n-hexanes-EtOAc (9:1))
on silica gel gave an orange oil (76%): 1H NMR (300 MHz)
1.50 (d, J ) 7.2, 3H), 4.43 (m, 1H), 4.70 (m, 2H), 4.71 (s, 1H),
5.22 (dq, J ) 10.4, 1.4, 1H), 5.31 (dq, J ) 17.2, 1.5, 1H), 6.00
(m, 1H), 7.10-7.40 (m, 10H), 8.92 (br d, 1H); 13C NMR (75
MHz) 24.3 (q), 53.6 (d), 63.3 (t), 86.1 (d), 116.9 (t), 125.3 (d),
126.6 (d), 127.4 (d), 127.9 (d), 128.2 (d), 128.9 (d), 133.1 (d),
136.0 (s), 144.5 (s), 164.3 (s), 169.6 (s); IR (KBr) 3280, 1657,
1613, 1594, 1479; LRMS (EI) m/z 307 (M+, 15), 105 (100). Anal.
Calcd for C20H21NO2: C, 78.15; H, 6.89; N, 4.56. Found: C,
77.71; H, 6.68; N, 4.41.
ter t-Bu tyl (Z)-4,4-Dim eth yl-3-(1-p h en yleth yla m in o)-2-
p en ten oa te (4w ). Flash chromatography (n-hexanes-EtOAc
(10:1)) on silica gel gave a yellow oil (75%):1H NMR (250 MHz)
1.45 (d, J ) 6.9, 3H), 1.51 (s, 9H), 4.40 (m, 1H), 4.56 (s, 1H),
7.06-7.30 (m, 10H), 8.79 (br d, 1H); 13C NMR (62.8 MHz) 24.5
(q), 28.6 (q), 53.7 (d), 78.4 (s), 88.9 (d), 125.7 (d), 126.7 (d),
127.7 (d), 128.0 (d), 128.3 (d), 128.8 (d), 136.6 (s), 145.0 (s),
163.5 (s), 170.1 (s). HRMS calcd for C21H25NO2: 323.1885.
Found: 323.1880. Anal. Calcd for C21H25NO2: C, 75.21; H,
9.63; N, 4.62. Found: C, 74.79; H, 9.50; N, 4.39.
C
19H27NO2: C, 75.71; H, 9.03; N, 4.65. Found: C, 75.97; H,
9.21; N, 4.81.
ter t-Bu tyl (Z)-3-Cycloh exylam in o-3-ph en yl-2-pr open eth -
ioa t e (4p ). Flash chromatography (n-hexanes-EtOAc (20:
1)) on silica gel gave a yellow solid (70%): mp 124-126 °C;1H
NMR (250 MHz) 1.01-1.73 (m, 10H), 1.45 (s, 9H), 3.02 (m,
1H), 4.81 (s, 1H), 7.20-7.34 (m, 5H), 9.20 (br d, 1H); 13C NMR
(62.8 MHz) 24.7 (t), 25.2 (t), 30.6 (q), 34.5 (t), 46.7 (s), 52.9 (d),
(R)-Meth yl (Z)-4-Meth yl-3-(1-ph en yleth ylam in o)-2-pen -
ten oa te (4x). Flash chromatography (n-hexanes-EtOAc (4:
1)) on silica gel gave a yellow oil (68%): [R]25 -420.0° (c
D
0.00705, CHCl3); 1H NMR (250 MHz) 0.74 (d, J ) 6.8, 3H),

8836 J . Org. Chem., Vol. 63, No. 24, 1998
Fustero et al.
1.07 (d, J ) 6.8, 3H), 1.47 (d, J ) 6.8, 3H), 2.45 (m, 1H), 3.61
(s, 3H), 4.50 (s, 1H), 4.68 (m, 1H), 7.16-7.29 (m, 5H), 9.08 (br
d, 1H); 13C NMR (62.8 MHz) 20.8 (q), 22.5 (q), 25.2 (q), 28.9
(d), 50.0 (d), 52.0 (q), 78.3 (d), 125.4 (d), 127.0 (d), 128.7 (d),
145.3 (s), 171.7 (s), 171.7 (s). HRMS calcd for C15H21NO2:
247.1572. Found: 247.1572. Anal. Calcd for C15H21NO2: C,
72.84; H, 8.56; N, 5.66. Found: C, 72.39; H, 8.77; N, 5.67.
(R)-(1R,2S,5R)-2-Isop r op yl-5-m eth ylcycloh exyl (Z)-4-
Meth yl-3-(1-p h en yleth yla m in o)-2-p en ten oa te (4y). Flash
hydrogen atoms anisotropically refined using the XRAY76
system,44 hydrogen atoms placed at calculated positions and
included as fixed contributors with a common isotropic tem-
perature factor, 121 refined parameters. In the final stages
an empirical weighting scheme was chosen as to give no trends
in ∆F vs ω∆2F and vs sin θ/λ using the program PESOS,45
R ) 0.065, Rw ) 0.069, geometrical calculations with PARST.46
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,
PB94-1313-C02-02 and PB97-0760-C02-01) and also the
CIEMAT (Ministerio de Industria y Energ´ıa) for com-
puter time. A predoctoral fellowship from the Fundacio´n
Ramo´n Areces to M.G.T. is also gratefully acknowl-
edged. We also thank Prof. Amparo Asensio for as-
sistance in ab initio calculations and for helpful discus-
sions.
chromatography (n-hexanes-EtOAc (10:1)) on silica gel gave
1
a yellow oil (75%): [R]25 -357.0° (c 0.010, CHCl3); H NMR
D
(250 MHz) 0.72 (d, J ) 6.8, 6H), 0.85(d, J ) 6.8, 6H), 1.05 (d,
J ) 6.8, 3H), 1.45 (d, J ) 6.8, 3H), 0.67-1.93 (m, 10H), 2.43
(m, 1H), 4.44 (s, 1H), 4.57 (dt, J ) 10.7, 4.2, 1H), 7.15-7.29
(m, 5H), 9.06 (br d, 1H); 13C NMR (62.8 MHz) 16.5 (q), 20.8
(q), 22.1 (d), 22.5 (q), 23.6 (t), 25.3 (q), 26.1 (t), 28.9 (d), 31.5
(q), 34.5 (d), 41.6 (t), 47.3 (q), 52.0 (d), 71.8 (d), 79.4 (d), 125.4
(d), 127.0 (d), 128.7 (d), 145.5 (s), 171.1 (s), 171.4 (s). HRMS
calcd for C24H37NO2: 371.2824. Found: 371.2828. Anal.
Calcd for C24H37NO2: C, 77.84; H, 9.73; N, 3.78. Found: C,
78.30; H, 9.70; N, 3.89.
Su p p or tin g In for m a tion Ava ila ble: General procedure,
spectroscopical (1H and 13C NMR and HRMS) and analytical
data for products 6, tables of atomic coordinates, bond angles
and distances, anisotropic thermal parameters (Tables 3-7)
for 2h , and optimized structures at the HF/6-31G* level for
complexes 3A and 3B (9 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.
(S)-Eth yl (Z)-4-Meth yl-3-(1-p h en yleth yla m in o)-2-p en -
ten oa te (4z). Flash chromatography (n-hexanes-EtOAc (4:
1)) on silica gel gave a yellow oil (64%): [R]25D +43.8° (c 0.017,
CHCl3); 1H NMR (250 MHz) 0.73 (d, J ) 6.8, 3H), 1.06 (d, J )
6.8, 3H), 1.20 (t, J ) 7.0, 3H), 1.45 (d, J ) 6.8, 3H), 2.44 (m,
1H), 4.06 (q, J ) 7.0, 2H), 4.47 (s, 1H), 4.62 (m, 1H), 7.15-
7.28 (m, 5H), 9.06 (br d, 1H); 13C NMR (62.8 MHz) 14.6 (q),
20.8 (q), 22.4 (q), 25.1 (t), 28.8 (q), 51.9 (d), 58.3 (d), 78.7 (d),
125.3 (d), 126.9 (d), 128.6 (d), 145.3 (s), 171.4 (s), 171.7 (s).
HRMS calcd for C16H23NO2: 261.1729. Found: 261.1736.
Anal. Calcd for C16H23NO2: C, 73.56; H, 8.81; N, 5.36.
Found: C, 73.29; H, 8.69; N, 5.51.
J O9809480
(43) Altomare, A.; Burla, M. C.; Camalli, M.; Cascasano, G.; Gia-
covazzo, G.; Guagliardi, A.; Polidori, G. J . Appl. Crystallogr. 1994, 27,
435.
X-r a y An a lysis of (Z)-3-Cycloh exyla m in o-1-(1H-1-im id -
a zolyl)-3-p h en yl-2-p r op en -1-on e (2h ).
C18N3OH21, M )
(44) Stewart, J . M.; Machin, P. A.; Dickinson, C. W.; Ammon, H.
L.; Heck, H.; Flack, H. The X-ray 76 System; Technical report TR-446;
Computer Science Center, University of Maryland: College Park,
Maryland, 1976.
(45) Mart´ınez-Ripoll, M.; Cano, F. H. PESOS Computer Program;
Instituto Rocasolano, CSIC: Madrid, Spain, 1975.
(46) Nardelli, M. Comput. Chem. 1983, 7, 95.
294.4, pale yellow prismatic crystal, orthorhombic Pmnb, a )
9.143(1) Å, b ) 10.798(1) Å, c )17.171(1) Å, V ) 1695.2(3) Å3,
Z ) 4, F(000) ) 628, Mo KR radiation (λ ) 0.7107 Å), µ ) 0.73
cm-1, Dc ) 1.15 g cm-3, Enraf-Nonius CAD4 diffractometer:
1590 independent reflections, 801 observed with I > 2σ(I).
Solution by direct methods with the program SIR92,43 non-