Efficient and general synthesis of 5-(alkoxycarbonyl)methylene-3-oxazolines by palladium-catalyzed oxidative carbonylation of prop-2-ynylamides

Article abstract of DOI:10.1021/jo0200217

A variety of prop-2-ynylamides have been carbonylated under oxidative conditions to give oxazolines, oxazolines with chelating groups, and bisoxazolines bearing an (alkoxycarbonyl)methylene chain at the 5 position in good yields. The cyclization-alkoxycarbonylation process was carried out in alcoholic media at 50-70°C and under 24 bar pressure of 3:1 carbon monoxide/air in the presence of catalytic amounts of 10% Pd/C or PdI₂ in conjunction with KI. Cyclization occurred by anti attack of an oxygen function on the palladium-coordinated triple bond, followed by stereospecific alkoxycarbonylation, strictly resulting in E-stereochemistry. The structures of representative oxazolines and bisoxazolines have been determined by X-ray diffraction analysis.

Full text of DOI:10.1021/jo0200217

4450
J . Org. Chem. 2002, 67, 4450-4457
Efficien t a n d Gen er a l Syn th esis of
5-(Alk oxyca r bon yl)m eth ylen e-3-oxa zolin es by P a lla d iu m -Ca ta lyzed
Oxid a tive Ca r bon yla tion of P r op -2-yn yla m id es
Alessia Bacchi,† Mirco Costa,*,‡ Bartolo Gabriele,§ Giancarlo Pelizzi,† and Giuseppe Salerno|
Dipartimento di Chimica Generale, Analitica e Chimica Fisica, Universita` di Parma, Parco Area delle
Scienze 17, 43100 Parma, Italy, Dipartimento di Chimica Organica e Industriale, Universita` di Parma,
Parco Area delle Scienze 17, 43100 Parma, Italy, Dipartimento di Scienze Farmaceutiche, Universita`
della Calabria, 87036 Arcavacata di Rende, Cosenza, Italy, and Dipartimento di Chimica, Universita`
della Calabria, 87036 Arcavacata di Rende, Cosenza, Italy
mirco.costa@unipr.it
Received J anuary 8, 2002
A variety of prop-2-ynylamides have been carbonylated under oxidative conditions to give oxazolines,
oxazolines with chelating groups, and bisoxazolines bearing an (alkoxycarbonyl)methylene chain
at the 5 position in good yields. The cyclization-alkoxycarbonylation process was carried out in
alcoholic media at 50-70 °C and under 24 bar pressure of 3:1 carbon monoxide/air in the presence
of catalytic amounts of 10% Pd/C or PdI2 in conjunction with KI. Cyclization occurred by anti attack
of an oxygen function on the palladium-coordinated triple bond, followed by stereospecific
alkoxycarbonylation, strictly resulting in E-stereochemistry. The structures of representative
oxazolines and bisoxazolines have been determined by X-ray diffraction analysis.
In tr od u ction
We now give a full account of the PdI2- or Pd/C-KI-
catalyzed oxidative cyclization-alkoxycarbonylation of
2-ynylamides to obtain 5-[(alkoxycarbonyl)methylene]-
oxazolines in good yields according to eq 1. Oxazolines
are a very interesting class of heterocyclic compounds
with many important applications in the field of metal
complex-catalyzed organic syntheses9 and polymers.10
Moreover, a variety of molecules containing the oxazoline
ring display a wide range of biological activities.11
The usefulness and peculiar activity of the PdI2-KI
(or Pd/C-KI) catalytic system in the oxidative carbony-
lation of alkynes was reported by us some years ago.1
Oxidative PdI2-KI- or Pd/C-KI-catalyzed cyclocarbony-
lation-alkoxycarbonylation or cyclization-alkoxycarbo-
nylation of acetylenic compounds bearing a suitably
placed nucleophilic group has allowed the direct synthesis
of new heterocyclic derivatives such as functionalized â-
and γ-lactones,2 â- and γ-lactams,3 nitrogen heterocycles,4
pyrrole-3,4-diacetic acid and esters,5 furans,6 thiophenes,7
and tetrahydrofurans8 starting from readily available
substrates. Formation of oxazolines by oxidative carbo-
nylation of 2-ynylamides has only been disclosed in a
preliminary communication.3
† Dipartimento di Chimica Generale, Analitica e Chimica Fisica,
Universita` di Parma.
Resu lts a n d Discu ssion
‡ Dipartimento di Chimica Organica e Industriale, Universita` di
Parma.
We shall consider the synthesis of oxazolines, oxazo-
lines with chelating groups, and bisoxazolines.
§ Dipartimento di Scienze Farmaceutiche, Universita` della Calabria.
| Dipartimento di Chimica, Universita` della Calabria.
(1) Gabriele, B.; Costa, M.; Salerno, G.; Chiusoli, G. P. J . Chem. Soc.,
Chem. Commun. 1992, 1007-1008. Gabriele, B.; Costa, M.; Salerno,
G.; Chiusoli, G. P. J . Chem. Soc., Perkin Trans. 1 1994, 83-87.
(2) Gabriele, B.; Costa, M.; Salerno, G.; Chiusoli, G. P. J . Chem. Soc.,
Chem. Commun. 1994, 1429-1430. Gabriele, B.; Salerno, G.; De
Pascali, F.; Costa, M.; Chiusoli, G. P. J . Chem. Soc., Perkin Trans. 1
1997, 147-154.
(3) Bonardi, A.; Costa, M.; Gabriele, B.; Salerno, G.; Chiusoli, G. P.
Tetrahedron Lett. 1995, 36, 7495-7498.
(4) Bacchi, A.; Chiusoli, G. P.; Costa, M.; Sani, C.; Gabriele, B.;
Salerno, G. J . Organomet. Chem. 1998, 562, 35-43.
(5) Chiusoli, G. P.; Costa, M.; Reverberi, S. Synthesis 1989, 262-
265.
(9) Foche, F.; Schulz, E.; Tommasino, M. L.; Lamaire, M. Chem. Rev.
2000, 100, 2159-2231. J ohnson, J . S.; Evans, D. A. Acc. Chem. Res.
2000, 33, 325-335. Gomez, M.; Muller, G.; Rocamora, M. Coord. Chem.
Rev. 1999, 195, 769-835. Tomooka, K.; Komine, N.; Nokai, T.
Tetrahedron Lett. 1998, 39, 5513-5516. Takacs, J . M.; Quincy, D. A.;
Shay, W.; J ones, B. E.; Ross, C. R. Tetrahedron: Asymmetry 1997, 8,
3079-3087. Yoo, S.; Roberson, M.; Reichel, F.; Hazell, R. G.; J ørgensen,
K. A. J . Org. Chem. 1999, 64, 6677-6687. Zenner, J . M.; Larock, R. J .
Org. Chem. 1999, 64, 7312-7322. Castro, J .; Moyano, A.; Perica`s, M.
A.; Riera, A.; Alvarez-Larena, A.; Piniella, J . F. J . Am. Chem. Soc. 2000,
122, 7944-7952. Brunner, H.; Sto¨riko, R.; Nuber, B. Tetrahedron:
Asymmetry 1998, 9, 407-422.
(6) Gabriele, B.; Salerno, G.; De Pascali, F.; Tomasi Sciano`, G.; Costa,
M.; Chiusoli, G. P. Tetrahedron Lett. 1997, 38, 6877-6880. Gabriele,
B.; Salerno, G., De Pascali, F.; Costa, M.; Chiusoli, G. P. J . Org. Chem.
1999, 64, 7693-7699.
(10) Carter, N. G. Green Chem. 2001, G40-44; Onimura, K.;
Tsutsumi, H.; Oishi, T. Chem. Lett. 1998, 791-792; Puts, R. D.; Sogah,
D. Y. Macromol. 1997, 30, 6826-6836. Tsukamoto, A. (Teijin Ltd.
J apan) J P 2001048965 A2 20 Feb 2001. Weber, M.; Muelhaupt, R. Ger.
Offen. DE 19739686A1, 11 Mar. 1999 (BASF A.-G. Germany). On-
imura, K.; Tsutsumi, H.; Oishi, T. Polym. Bull. 1997, 39, 437-444.
Deviney, M. L.; Kampa, J . J . U.S. Pat. 5644006A 1 J ul 1997 (Southwest
Research Institute, USA).
(7) Fazio, A.; Gabriele, B.; Salerno, G.; Destri, S. Tetrahedron 1999,
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P. J . Organomet. Chem. 2000, 593-594, 409-415.
10.1021/jo0200217 CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/11/2002

Synthesis of 5-(Alkoxycarbonyl)methylene-3-oxazolines
Sch em e 1
J . Org. Chem., Vol. 67, No. 13, 2002 4451
Sch em e 2
Syn th esis of Oxa zolin es. N-(1,1-Dimethylprop-2-
ynyl)amides 1 (1a , R ) Me; 1b, R ) Ph; 3.0 mequiv) were
caused to react at 55-60 °C under a 3:1 CO/air initial
pressure of 24 bar in the presence of 10% Pd/C or PdI2
(0.03 mequiv) and KI (0.45 mequiv) in MeOH (20 mL)
for 30 h. (E)-5-[(Methoxycarbonyl)methylene]oxazolines
2 were formed as the main products through a cycliza-
tion-methoxycarbonylation process (65 and 83% GLC
yield, respectively, eq 2).
The molecule 4b, shown in Figure S2 (Supporting
Information), is symmetric with respect to the C1-O1
carbonyl group, which belongs to a crystallographic 2-fold
axis; the two ligand arms are reciprocally syn in relation
to the carbonyl group. Each of the two molecular arms
is completely planar, and the carbonylic substituent is
in a position anti to the heterocyclic oxygen relative to
the C2-C3 double bond (O2-C3-C2-C1 ) 178.6(1)°).
However, the overall molecular planarity is slightly
perturbed by the mutual repulsion between the two syn
C-H groups adjacent to the carbonyl. The two molecular
arms are planar, but the molecule is folded by 23° around
the C1-C2 single bond due to H‚‚‚H intramolecular
repulsion. The molecular structure of 2b (Figure S1,
Supporting Information) corresponds to a single arm of
compound 4b, with a methoxy terminal group at C1.
Similarly to compound 4b, the molecular skeleton is
remarkably planar. The carboxy substituent at C1 is in
an anti position relative to O2 (O2-C3-C2-C1 ) 178.5-
(2)°); the bond distances and angles show a perfect
agreement with those observed for the oxazoline ring of
4b, as reported in Table S1 (Supporting Information).
These are the first examples in the crystallographic
literature12 of an oxazolinic system containing an exocy-
clic double bond at C3.
The (E) configuration of the (methoxycarbonyl)meth-
ylene moiety in 2b was supported by its X-ray structure
(Figure S1, Supporting Information). The (E) configura-
tion for 2a was assigned by comparison of the chemical
shift of the olefinic proton in 2a with that of the same
proton in 2b.
Small amounts of (Z)-5-[(methoxycarbonyl)methylene]-
oxazolines 3 (7-8%) were also detected in the reaction
mixtures. Their formation was due to a subsequent
isomerization of 2 as checked through low conversion
reactions. Moreover, an 8% yield of (E,E)-1,3-bis(4,4-
dimethyl-2-phenyl-4H-oxazol-5-ylidene)propan-2-one 4b,
whose structure was proved by X-ray analysis (Figure
S2, Supporting Information), was obtained in the case
of 1b. The yield of product 4b could be increased by
carrying out the reaction in more concentrated solutions.
For example, when 5 mL of MeOH instead of 20 mL was
used under the above-mentioned conditions, 4b was
obtained as the main product (43%), together with its E,Z
isomer 5b (7% yield) and 2b (30% yield).
The E configuration in compounds 2 is in agreement
with an anti 5-exo-dig attack of oxygen on the triple bond
coordinated to Pd(II) with formation of an (E)-vinylpal-
ladium intermediate I, followed by stereospecific meth-
oxycarbonylation to give 2 and Pd(0). Reoxidation of the
latter according to the usual mechanism regenerates the
catalytically active Pd(II) species1 (Scheme 1, anionic
iodide ligands are omitted for clarity).
The obtainment of the ketonic derivative 4b can be
interpreted as involving a bis-vinylpalladium intermedi-
ate II, formed by disproportionation of complex I,13 which
undergoes carbon monoxide insertion, followed by reduc-
tive elimination to give 4b and Pd(0), according to
Scheme 2.
(11) For some recent examples, see: Bosc, J . J .; J arry, C.; Martinez,
B.; Molimard, M. J . Pharmacol. 2001, 53, 923-927. Gasch, C.; Pradera,
M. A.; Salameh, B. A. B.; Molina, J . L.; Fuentes, J . Tetrahedron:
Asymmetry 2001, 12, 1267-1277. Wong, W. C.; Sun, W.; Cui, W.; Chen,
Y.; Forray, C.; Vaysse, P. J .-J .; Branchek, T. A.; Gluchowski, C. J . Med.
Chem. 2000, 43, 1699-1704. Hirashima, A.; Shinkai, K.; Pan, C. P.;
Kuwano, E.; Taniguchi, E.; Eto, M. Pestic. Sci. 1999, 55, 119-128.
Hirashima, A.; Pan, C. P.; Tomita, J .; Kuwano, E.; Taniguchi, E.; Eto,
M. Pestic. Biochem. Phys. 1997, 58, 219-228. Hirashima, A.; Tomita,
J .; Pan, C. P.; Taniguchi, E.; Eto, M. Biorg. Med. Chem. 1997, 5, 2121-
2128. Hirashima, A.; Pan, C. P.; Katafuchi, Y.; Taniguchi, E.; Eto, M.
J . Pestic. Sci. 1997, 22, 74-74. Hirashima, A.; Pan, C. P.; Katafuchi,
Y.; Taniguchi, E.; Eto, M. J . Pestic. Sci. 1996, 21, 419-424. Camoutsis,
C. J . Heterocycl. Chem. 1996, 33, 539-557. Uchida, C.; Ogawa, S.
Bioorg. Med. Chem. 1996, 4, 275-281.
It is noteworthy that, as we already reported,4 under
the above-mentioned conditions N-(1,1-dimethylprop-2-
(12) Allen, F. H.; Kennard, O.; Taylor, R. Acc. Chem. Res. 1983, 16,
146-153.
(13) Gabriele, B.; Salerno, G.; Costa, M.; Chiusoli, G. P. J . Orga-
nomet. Chem. 1995, 503, 21-28.

4452 J . Org. Chem., Vol. 67, No. 13, 2002
Bacchi et al.
Sch em e 3
Sch em e 4
ynyl)ureas afforded two types of products simulta-
neously: oxazoline derivatives 2 and cyclic ureas 6
containing E- or Z-(methoxycarbonyl)methylene chains,
respectively, depending on whether the cyclization was
initiated by oxygen or nitrogen attack on the triple bond.
The obtainment of 6 can be interpreted as involving the
formation of an intermediate III resulting from the
reaction between PdI2 and the -NHR′ moiety of the urea.
Intermediate III then inserts the triple bond through a
syn 5-exo-dig-type attack, which leads to a (Z)-vinylpal-
ladium intermediate IV. Methoxycarbonylation of the
latter affords 6 (Scheme 3). In agreement with the
mechanism shown in Scheme 3, bulky and electron-
withdrawing groups in N-bonded R′ substituent favored
the formation of product 2 with respect to 6.4
fundamental role for the success of the reaction.
The presence of different functional groups is compat-
ible with the cyclization-alkoxycarbonylation reaction.
Thus, carbonylation of N-(1,1-dimethylprop-2-ynyl)acryl-
amide 1e (2.5 mmol) under the above-mentioned condi-
tions of CO/air pressure in the presence of 10% Pd-C
(0.05 mmol) and KI (0.75 mmol) in MeOH (15 mL) at 50
°C for 24 h gave the expected product 2e in 57% yield
together with a 27% of oxazoline 9e, clearly deriving from
methanol addition to the vinyl group of 2e. Small
amounts of the dimethoxyfuranone derivative 10e (13%),
corresponding to oxidative dimethoxycarbonylation of the
triple bond,1 were also detected in the reaction mixture
(eq 4).
The X-ray structure of cyclic urea 6c (R′ ) H) supports
the assigned stereochemistry for the (methoxycarbonyl)-
methylene chain (Figure S3, Supporting Information).
The molecule has a rigid molecular structure, with
torsion angles planar within 5°, apart from those involv-
ing methyl groups C6 and C7. The configuration of the
methoxycarbonyl group around the C2-C3 double bond
is opposite to the one observed for all the oxazoline
compounds, being syn relative to N2, which takes the
place of O2 in the heterocyclic system (N2-C3-C2-C1
) 0(1)°). The analysis of the bonding geometry within
the ring (Table S1, Supporting Information) shows that
the structural asymmetry of the ring is reflected in a
different distribution of the bond strength among similar
bonds, evidenced in particular by the remarkably diverse
behavior of the two N atoms.
The presence of geminal alkyl groups R to the triple
bond is a necessary requisite for directing the catalytic
process toward the formation of cyclization products, as
shown by the results obtained in the case of an R-unsub-
stituted substrate such as N-(prop-2-ynyl)benzamide 1d .
Carbonylation of this compound under the usual condi-
tions afforded maleic diester 7d (deriving from oxidative
dialkoxycarbonylation of the triple bond)1 as the main
product (69% yield) and only modest amounts (14%) of
oxazole 8d (apparently deriving from isomerization of the
initially formed 5-(methoxycarbonyl)methyleneoxazoline
derivative) (eq 3). The gem-dialkyl effect14 thus plays a
Analogously, ethyl 3-(1,1-dimethylprop-2-ynylcarbam-
oyl)acrylate 1f reacted under the usual conditions (in
ethanol instead of methanol) to give oxazoline 2f in good
(14) Sammes, P. G.; Weller, D. J . Synthesis 1995, 1205-1222 and
references therein.

Synthesis of 5-(Alkoxycarbonyl)methylene-3-oxazolines
Sch em e 5
J . Org. Chem., Vol. 67, No. 13, 2002 4453
Sch em e 6
yield (75%), as well as small amounts of its Z isomer 3f
(9%) and dimethoxyfuranone 10f (7%, eq 5). No ethanol
addition to the vinyl group was observed in this case.
ing E oxazoline 2h in 77% yield (eq 7).
The X-ray analysis of a single crystal confirmed the E
structure of the oxazoline-bonded methoxycarbonylm-
ethylene group (Figure S4, Supporting Information).
The introduction of a p-chloropyridin-2-yl group in
place of the phenyl at C5 (Figure S4, Supporting Infor-
mation) does not result in any significant change in the
molecular structure of oxazoline 2h (anti, O2-C3-C2-
C1 ) -178.2(2)°) with respect to compounds 4b and 2b,
as shown by the comparison of bonding geometry in Table
S1 (Supporting Information). The presence of substitu-
ents on the terminal pyridinyl causes a perturbation of
the molecular planarity, obtained by rotation of the
aromatic ring around the C5-C6 bond (O2-C5-C6-N2
) 13.6(3)°).
Syn th esis of Bisoxa zolin es. The oxidative cycliza-
tion-alkoxycarbonylation reaction was also extended to
the synthesis of bisoxazolines from several acetylenic
diamides. Thus, N,N′-bis(1,1-dimethylprop-2-ynyl)tereph-
thalamide 11i (1.79 mmol) was reacted in MeOH (10 mL)
with CO/air (18/6 bar) in the presence of 10% Pd-C (0.06
mmol) and KI (0.09 mmol) at 55 °C for 30 h: (E,E)-
bisoxazoline 12i was formed as the main product (69%)
together with its (E,Z)-isomer 13i (2%). Two byproducts
14i and 15i, both deriving from cyclization-methoxy-
carbonylation of one of the two propynyl groups and
dimethoxycarbonylation of the other one, were formed
in small yield (7% and 6% respectively) (eq 8, Scheme
4). Compound 15i is the ring chain tautomer of 14i.1
Analogously, bisoxazoline 12j was obtained as the main
product (51%) starting from 2,2-dimethylmalonic acid
(1,1-dimethylprop-2-ynyl) amide 11j (eq 9, Scheme 5).
Two additional carbonylation products 14j and 15j, both
deriving from cyclization-methoxycarbonylation of one
of the two propynyl groups and dimethoxycarbonylation
Syn th esis of Oxa zolin es w ith Ch ela tin g Gr ou p s.
To exploit the synthetic potentiality of our methodology,
we also prepared some (1,1-dimethylprop-2-ynyl)amides
of organic acids bearing a suitably placed coordinating
atom and (1,1-dimethylprop-2-ynyl)amides of bibasic
organic acids. Oxidative carbonylation of such substrates
could in fact afford new chelating monooxazoline or
bisoxazoline ligands by a very simple approach. Accord-
ingly, carbonylation of the pyridine-2-carboxylic acid (1,1-
dimethylprop-2-ynyl)amide 1g (3.0 mmol) carried out
under CO (21 atm) and air (7 atm) in MeOH in the
presence of 10% Pd/C (0.06 mmol) and KI (0.9 mmol) at
70 °C for 30 h led to (E)-(4,4-dimethyl-2-pyridin-2-yl-4H-
oxazol-5-ylidene)acetic acid methyl ester 2g in 83% yield
(eq 6).
Carbonylation of the 4-chloropyridine-2-carboxylic acid
(1,1-dimethylprop-2-ynyl)amide 1h led to the correspond

4454 J . Org. Chem., Vol. 67, No. 13, 2002
Bacchi et al.
K2CO3. MeOH and EtOH were dried over 4A molecular sieves.
Reactions were analytically monitored by GLC with an instru-
ment equipped with a flame ionization detector and a elec-
tronic peak area integrator. A 5% methylsilicone (30 m × 0.25
mm) capillary column was used with helium as the carrier gas.
All yields were determined gas chromatographically using the
internal standard method unless otherwise specified. Thin-
layer chromatography (TLC) was performed on silica gel coated
aluminum plates. Gravity-flow liquid chromatography was
carried out on silica gel (0.063-0.200 mm); solvent mixtures
were prepared by volume. Melting points are uncorrected.
Elemental analyses were performed at our analytical labora-
tory. IR spectra were obtained with a FT-IR spectrometer.
Mass spectra (m/z relative intensity) were taken at 70 eV
ionizing voltage. 1H NMR and 13C NMR spectra were taken
in CDCl3 at room temperature and recorded at 300 and 75
MHz, respectively. Chemical shifts and coupling constants (J )
are given in ppm (δ) and in Hz, respectively.
of the other one, were also formed in moderate yields
(20% and 13%, respectively). Compound 15j is the ring
chain tautomer of 14j.1
Carbonylation of pyridine-2,6-dicarboxylic acid (1,1-
dimethylprop-2-ynyl)amide 11k carried out under the
same conditions led to the formation of bisoxazoline 12k
(56% yield) and maleic diester derivative 14k (9%) as
shown in eq 10 (Scheme 6).
A cyclohexane ring was also chosen as a linkage
between the two oxazoline rings. Oxidative carbonylation
of trans-cyclohexane-1,2-dicarboxylic acid (1,1-dimethyl-
prop-2-ynyl)amide 11l led to the expected bisoxazoline
derivative 12l in 66% yield (eq 11), whose structure was
confirmed by X-ray analysis (Figure S5, Supporting
Information).
Single-crystal X-ray diffraction analyses were carried out
at room temperature by Siemens AED (4b, 2b, 2h , 12l) and
Enraf-Nonius CAD4 (6c) diffractometers. Graphite-monochro-
mated Cu KR (λ ) 1.541 78 Å) radiation was used for all
compounds apart from 2h , which was analyzed using Mo KR
radiation (λ ) 0.710 69 Å). Relevant details concerning data
collection and structure refinements are listed in Table S2
(Supporting Information). Crystals were stable during data
collection. The intensity data were processed with a peak
profile analysis procedure and corrected for Lorentz and
polarization effects. The phase problem was solved by direct
methods using SIR97.15 Full-matrix least-squares refinements
were carried out by SHELXL9716 on F2, using all measured
merged data.
Anisotropic thermal displacement parameters were refined
for all non-hydrogen atoms. Hydrogen atoms were partly
located on difference Fourier maps, and partly introduced in
idealized positions, riding on their carrier atoms. Where
appropriate, extinction was accounted for as implemented in
the refinement program. Programs PARST9717 and ZORTEP18
were used for analyzing and drawing the molecular structures.
Use was made of the packages of the Cambridge Structural
Database (release October 2000). All the calculations were
performed on a Digital Alpha 255 workstation at the Centro
di Studio per la Strutturistica Diffrattometrica del C.N.R. in
Parma.
Table S1 (Supporting Information) lists the main geometric
features obtained by the diffraction analysis. Crystallographic
data (excluding structure factors) for the structures in this
paper have been deposited with the Cambridge Crystal-
lographic Data Centre as supplementary publication numbers
CCDC 185162-185166. Copies of the data can be obtained,
free of charge, on application to CCDC, 12 Union Road,
Cambridge, CB2 1EZ, UK [fax: +44(0)-1223-336033; e-mail:
deposit@ccdc.cam.ac.uk].
In compound 12l (Figure S5, Supporting Information),
the terminal aromatic at C5 is replaced by a cyclohexyl
moiety, which in turn carries a second oxazoline arm. The
two oxazoline rings are anti and axial (C5-C6-C7-C19
) -162(1)°). The two molecular halves are rotated in a
trans arrangement, with a pseudo-2-fold axis bisecting
the C9-C10 and C6-C7 bonds. The double bonds C2-
C3 and C16-C17 both have a trans geometry with
respect to the methoxycarbonyl substituent and endocy-
clic oxygen, as reported for the above derivatives. To get
information on the effect of replacing the 5-aryl substitu-
ent with an aliphatic group on the molecular geometry
of the heterocyclic system, the structures of the 5-aryl
derivatives 4b, 2b, 2h , and 6c have been compared with
that of 12l (Table S1, Supporting Information). Even if
a thorough comparison is biased by the high standard
deviations associated to bonding parameters for 12l, it
can be seen that the removal of the aromatic substituent
at C5 causes the elongation of the C-N and the shorten-
ing of the C-O bond, with a concomitant significant
strengthening of the exocyxlic CdC bond and a weaken-
ing of the C-Me single bond. This is in agreement with
electron density delocalization in the oxazoline system.
In conclusion, we have developed a new synthetic route
to oxazoline and bisoxazoline derivatives containing the
(alkoxycarbonyl)methylene moiety by oxidative cycliza-
tion-alkoxycarbonylation of readily available 2-ynyl-
amides. The compounds reported here are not readily
obtainable by other methods and offer a wide range of
potential applications.
N-(1,1-Dimethylprop-2-ynyl)acetamide 1a was prepared
from acetic anhydride and acetylenic amine.19 Benzamides 1b
and 1d , acrylamide 1e, picolinamides 1g and 1h , terephthalic
diamide 11i, 2,2-dimethylmalonamide 11j, and pyridine-2,6-
dicarboxylic acid (1,1-dimethylprop-2-ynyl) amide 11k were
prepared causing the respective acid chloride to react with
acetylenic amines according to the procedures reported in the
literature.20 Ethyl 3-(1,1-dimethylprop-2-ynlyncarbamoyl)acry-
(15) Altomare, A.; Cascarano, G.; Giacovazzo, C.; Guagliardi, A.;
Burla, M. C.; Polidori, G.; Camalli, M. J . Appl. Crystallogr. 1994, 27,
435.
(16) Sheldrick, G. M. SHELXL97. Program for structure refinement.
University of Goettingen, Germany, 1997.
(17) Nardelli, M. PARST97, updated version of PARST95. J . Appl.
Crystallogr. 1995, 28, 659.
(18) Zsolnai, L.; Pritzkow, H. ZORTEP. ORTEP original program
modified for PC. University of Heidelberg, Germany, 1994.
(19) Chiu, S. K.; Dube, M.; Keifer, L.; Szilgyi, S.; Timberlake, J . W.
J . Org. Chem. 1978, 43, 61-65.
(20) Brunner, H.; Spetel, G. J . Organomet. Chem. 1978, 160, 149-
158. Furniss, B. S.; Hannaford, A. J .; Smith, P. W. G.; Tatchell, A. R.
Vogel’s Textbook of Practical Organic Chemistry, 5th ed.; Longmann
Scientific & Tecnical: Essex, U.K., 1991; p 708.
Exp er im en ta l Section
Ma ter ia ls a n d Gen er a l Meth od s. Solvents and chemicals
were reagent grade and were used without further purifica-
tions except for 1,1-dimethylprop-2-ynylamine and prop-2-
ynylamine, which were distilled from K2CO3 and stored over

Synthesis of 5-(Alkoxycarbonyl)methylene-3-oxazolines
J . Org. Chem., Vol. 67, No. 13, 2002 4455
late 1f and bis(1,1-dimethylprop-2-ynyl)-1,2-cyclohexyldicar-
boxamide 11l were obtained by transforming the corresponding
carboxylic group into amide through reaction with N-hydrox-
ysuccinimide and subsequently with acetylenic amine accord-
ing to a procedure reported in the literature.21 The pure amides
were recovered by crystallization from suitable solvents. 1H
and 13C NMR, IR, and mass spectra confirmed the assigned
structures.
N-(1,1-Dim eth ylpr op-2-yn yl)ben zam ide (1b): white solid;
mp 152-153 °C; IR (KBr) ν cm-1 3335 (s), 3266 (s), 2116 (w),
1642 (s), 1544 (s); 1H NMR (CDCl3) δ 1.76 (s, 6 H, 2 CH3), 2.36
(s, 1 H, tCH), 6.23 (s, 1 H, NH), 7.38-7.48 (m, 3 H aromatic),
7.72-7.77 (m, 2 H aromatic); MS m/z 187 (M+, 20), 186 (22),
105 (100), 77 (28). Anal. Calcd for C12H13NO: C, 76.98; H, 7.00;
N, 7.48. Found: C, 76.97; H, 6.99; N, 7.46.
N-(P r op -2-yn yl)ben za m id e (1d ): white solid; mp 111-112
°C; IR (KBr) ν cm-1 3325 (s), 3270 (s), 2110 (w), 1645 (s), 1541
(s); 1H NMR (CDCl3) δ 2.22 (t, J ) 2.5, 1 H, tCH), 4.18 (dd, J
) 5.3, 2.5, 2 H, NCH2), 7.12 (bs, 1 H, NH), 7.34-7.47 (m, 3 H
aromatic), 7.74-7.83 (m, 2 H aromatic); MS m/z 159 (M+, 27),
158 (47), 105 (100), 77 (28). Anal. Calcd for C10H9NO: C, 75.45;
H, 5.70; N, 8.80. Found: C, 75.43; H, 5.71; N, 8.78.
N-(1,1-Dim eth ylpr op-2-yn yl)acr ylam ide (1e): white solid;
mp 65-67 °C; IR (KBr) ν cm-1 3328 (s), 3267 (s), 2111 (w),
1640 (s), 1610 (m); 1H NMR (CDCl3) δ 1.69 (s, 6 H, 2 CH3),
2.35 (s, 1 H, tCH), 5.62 (dd, J ) 10.2, 1.4, 1 H, dCHH), 5.70
(bs, 1 H, NH), 6.04 (dd, J ) 16.9, 10.2, 1 H, dCH(CO)), 6.29
(dd, J ) 16.9, 1.4, 1 H, dCHH); MS m/z 137 (M+, 8), 136 (47),
122 (22), 68 (100). Anal. Calcd for C8H11NO: C, 70.04; H, 8.08;
N, 10.21. Found: C, 70.01; H, 8.07; N, 10.19.
138(100). Anal. Calcd for C15H22N2O2: C, 68.67; H, 8.45; N,
10.68. Found: C, 68.63; H, 8.44; N, 10.67.
P yr id in e-2,6-d ica r boxylic a cid (1,1-d im eth ylp r op -2-
yn yl)a m id e (11k ): white solid; mp 130-132 °C; IR (KBr) ν
1
cm-1 3306 (s), 3270 (s), 2115 (w), 1654 (s), 1544 (s); H NMR
(CDCl3) δ 1.81 (s, 12 H, 4 CH3), 2.41 (s, 2 H, 2 tCH), 7.81 (s,
2 H, 2 NH), 8.02 (t, J ) 2.6, 1 H aromatic at C-4), 8.34 (d, J )
2.6, 2 H aromatic at C-3 and C-5); MS m/z 297 (M+, 10), 282
(20), 216 (100), 149 (70), 121 (65). Anal. Calcd for C17H19N3O2:
C, 68.67; H, 6.44; N, 14.13. Found: C, 68.64; H, 6.44; N, 14.11.
tr a n s-Cycloh exa n e-1,2-d ica r boxylic a cid (1,1-d im eth -
ylp r op -2-yn yl)a m id e (11l): white solid; mp 195-197 °C; IR
(KBr) ν cm-1 3386 (s), 3288 (s), 2115 (w), 1652 (s), 1540 (s); 1H
NMR (CDCl3) δ 1.11-1.37 (m, 4 H, 4 CH), 1.58 (s, 6 H, 2 CH3),
1.59 (s, 6 H, 2 CH3), 1.71-1.95 (m, 4 H, 4 CH), 2.24-2.28 (m,
2 H, 2 CH(CO)) 2.70 (s, 2 H, 2 tCH), 5.81 (bs, 2 H, 2 NH); 13
C
NMR (CDCl3) δ 24.8, 28.7, 28.9, 29.0, 47.2, 47.3, 69.0, 87.1,
174.0; MS m/z 302 M+, 1), 154 (100), 67 (80). Anal. Calcd for
C
18H26N2O2: C, 71.49; H, 8.67; N, 9.26. Found: C, 71.46; H,
8.66; N, 9.24.
Gen er a l P r oced u r e for th e Oxid a tive Cycliza tion -
Alk oxyca r bon yla tion Rea ction s of N-P r op -2-yn yla m id es.
All reactions were carried out in a 125 mL stainless steel
autoclave with a magnetic stirring. In a typical experiment,
the autoclave was charged under air with 1,1-dimethylprop-
2-ynylbenzamide (0.561 g, 3 mmol), 10% Pd-C (0.032 g, 0.03
mmol), and KI (0.075 g, 0.45 mmol) in methanol (20 mL). The
autoclave was pressurized with air (6 atm) and CO (up to 24
atm) and heated under stirring for the required time. Different
conditions are indicated in the text. At the end of the reaction,
the alcohol was eliminated under vacuum, the residue was
recovered with CH2Cl2 and filtered to remove KI, and the solid
catalyst and the solution was checked by GC/MSD (if necessary
an internal standard was added).
(E)-2,4,4-Tr im et h yl-4H -oxa zol-5-ylid en ea cet ic Acid
Meth yl Ester (2a ). The reaction was carried out as described
in the general procedure starting from 1a (0.375 g, 3.0 mmol)
at 55 °C for 30 h. Chromatography with n-hexane/EtOAc (8/
2) gave 2a (0.326 g, 59%) as colorless oil: IR (neat) ν cm-1
1720 (s), 1691 (m), 1449 (m), 1264 (s), 1166 (s); 1H NMR
(CDCl3) δ 1.61 (s, 6 H, (CH3)2CN), 2.09 (s, 3 H, CH3Cd), 3.69
(s, 3 H, CO2CH3), 5.61 (s, 1 H, dCH); MS m/z 183 (M+, 9), 168
(6), 69 (100), 59 (12). Anal. Calcd for C9H13NO3: C, 59.00; H,
7.15; N, 7.65. Found: C, 58.97; H, 7.18; N, 7.62.
Eth yl 3-(1,1-d im eth ylp r op -2-yn ylca r ba m oyl)a cr yla te
(1f): white solid; mp 64-65 °C; IR (KBr) ν cm-1 3308 (s), 3180
(s), 2111 (w), 1652 (s), 1601 (m); 1H NMR (CDCl3) δ 1.28 (t, J
) 7.1, 3 H, CO2CH2CH3), 1.67 (s, 6 H, (CH3)2CN), 2.35 (s, 1 H,
tCH), 4.21 (q, J ) 7.1, 2 H, CO2CH2CH3), 6.32 (bs, 1 H, NH),
6.78 (d, J ) 15.4, 1 H, dCH), 6.90 (d, J ) 15.4, 1 H, dCH); 13
C
NMR (CDCl3) δ 14.0, 28.7, 47.9, 61.1, 69.6, 86.4, 130.4, 136.6,
162.5, 165.6; MS m/z 209 (M+, 13), 194 (15), 127 (100), 68 (70).
Anal. Calcd for C11H15NO3: C, 63.14; H, 7.23; N, 6.69. Found:
C, 63.11; H, 7.21; N, 6.67.
P yr id in e-2-ca r boxylic a cid (1,1-d im eth ylp r op -2-yn yl)-
a m id e (1g): white solid; mp 56-57 °C; IR (KBr) ν cm-1 3324
1
(s), 3238 (s), 2128 (w), 1675 (s), 1558 (s); H NMR (CDCl3) δ
1.74 (s, 6 H, 2 CH3), 2.37 (s, 1 H, tCH), 7.31-7.47 (m, 1 H
aromatic at C-5), 7.82 (td, J ) 7.8, 1.7, 1 H aromatic at C-4),
8.13 (s, 1 H, NH), 8.18 (ddd, J ) 7.8, 1.2, 0.9, 1 H aromatic at
C-3), 8.50 (ddd, J ) 4.7, 1.7, 0.9, 1 H aromatic at C-6); MS
m/z 188 (M+, 30), 173 (100), 106 (80), 78 (65). Anal. Calcd for
(Z)-2,4,4-Tr im et h yl-4H -oxa zol-5-ylid en ea cet ic Acid
Meth yl Ester (3a ). Chromatography with n-hexane/EtOAc
(8/2) gave 3a (0.032 g, 5%) as colorless oil: IR (neat) ν cm-1
1720 (s), 1690 (m), 1265 (s), 1165 (s); 1H NMR (CDCl3) δ 1.48
(s, 6 H, (CH3)2CN), 1.99 (s, 3 H, CH3Cd), 3.73 (s, 3 H, CO2-
CH3), 5.09 (s, 1 H, dCH); MS m/z 183 (M+, 17), 141 (48), 69
(100), 59 (12). Anal. Calcd for C9H13NO3: C, 59.00; H, 7.15;
N, 7.65. Found: C, 58.95; H, 7.18; N, 7.61.
C
11H12N2O: C, 70.19; H, 6.43; N, 14.88. Found: C, 70.17; H,
6.44; N, 14.87.
4-Ch lor op yr id in e-2-ca r boxylic a cid (1,1-d im eth ylp r op -
2-yn yl)a m id e (1h ): pink solid from n-hexane; mp 101-102
°C; IR (KBr) ν cm-1 3376 (s), 3276 (s), 2129 (w), 1685 (s), 1579
(s); 1H NMR (CDCl3) δ 1.75 (s, 6 H, 2 CH3), 2.37 (s, 1 H, t
CH), 7.40 (dd, J ) 5.2, 2.1, 1 H aromatic at C-5), 8.11 (s, 1 H,
NH), 8.18 (dd, J ) 2.1, 0.6, 1 H aromatic at C-3), 8.40 (dd, J
) 5.2, 0.6, 1 H aromatic at C-6); MS m/z 222 (M+, 20), 207
(70), 112 (100). Anal. Calcd for C11H11N2ClO: C, 59.33; H, 4.98;
N, 12.58. Found: C, 59.31; H, 4.98; N, 12.59.
N,N′-Bis(1,1-dim eth ylpr op-2-yn yl)ter eph th alam ide (11i):
white solid; mp 248-251 °C; IR (KBr) ν cm-1 3318 (s), 3287
(s), 2120 (w), 1645 (s), 1541 (s); 1H NMR (DMSO-d6) δ 1.62 (s,
12 H, 4 CH3), 3.10 (s, 2 H, 2 tCH), 7.88 (s, 4 H aromatic),
8.33 (s, 2 H, 2 NH); MS m/z (CI) 298 [(M + 2)+, 90], 296 (M+,
100). Anal. Calcd for C18H20N2O2: C, 72.95; H, 6.80; N, 9.45.
Found: C, 72.92; H, 6.80; N, 9.44.
(E)-4,4-Dim et h yl-2-p h en yl-4H -oxa zol-5-ylid en ea cet ic
Acid Meth yl Ester (2b). The reaction was carried out as
described above for the synthesis of compounds 2a and 3a .
Chromatography with n-hexane/EtOAc (8/2) gave 2b (0.566
g, 77%) as a white solid: mp 85-86 °C; IR (KBr) ν cm-1 1720
1
(s), 1673 (s), 1661 (s), 1648 (s), 1075 (s); H NMR (CDCl3) δ
1.74 (s, 6 H, 2 CH3), 3.70 (s, 3 H, CO2CH3), 5.79 (s, 1 H, d
CH), 7.44-7.54 (m, 3 H aromatic), 7.96-8.00 (m, 2 H aro-
matic); 13C NMR (CDCl3) δ 24.6, 50.9, 72.8, 93.8, 125.8, 128.0,
128.6, 131.8, 157.7, 166.4, 178.0; MS m/z 245 (M+, 10), 230
(15), 217 (40), 69 (100), 59 (16). Anal. Calcd for C14H15NO3:
C, 68.56; H, 6.16; N, 5.71. Found: C, 68.53; H, 6.15; N, 5.67.
(Z)-4,4-Dim et h yl-2-p h en yl-4H -oxa zol-5-ylid en ea cet ic
Acid Meth yl Ester (3b). Chromatography with n-hexane/
EtOAc (8/2) gave 3b (0.032 g, 5%) as a white solid: mp 77-78
1
°C; IR (KBr) ν cm-1 1720 (s), 1673 (s), 1661 (s), 1648 (s); H
N,N′-Bis(1,1-dim eth ylpr op-2-yn yl)-2,2-dim eth ylm alon a-
m id e (11j): pale yellow solid; mp 131-132 °C; IR (KBr) ν cm-1
3417 (s), 3276 (s), 2104 (w), 1673 (s), 1545 (s); 1H NMR (CDCl3)
δ 1.40 (s, 6 H, (CH3)2C(CO)), 1.58 (s, 12 H, 2 (CH3)2CN), 2.29
(s, 2 H, 2 tCH), 6.48 (bs, 2 H, 2 NH); MS m/z 262 (M+, 1),
NMR (CDCl3) δ 1.77 (s, 6 H, 2 CH3), 3.77 (s, 3 H, CO2CH3),
5.19 (s, 1 H, dCH), 7.43-7.53 (m, 3 H aromatic), 8.05-8.08
(m, 2 H aromatic); MS m/z 245 (M+, 9), 230 (21), 145 (67), 104
(100), 77 (32), 69 (95), 59 (12). Anal. Calcd for C14H15NO3: C,
68.56; H, 6.16; N, 5.71. Found: C, 68.52; H, 6.14; N, 5.66.
(E ,E )-1,3-B is -(4,4-d im e t h y l-2-p h e n y l-4H -o x a zo l-5-
ylid en e)p r op a n -2-on e (4b). The reaction was carried out as
(21) Corradini, R.; Marchelli, R.; Palla, G. Chromatographia 1994,
38, 173-176.

4456 J . Org. Chem., Vol. 67, No. 13, 2002
Bacchi et al.
described above for the synthesis of compound 2a , except in a
more concentrated methanol solution (5 mL instead of 20 mL).
Chromatography with n-hexane/EtOAc (7/3) gave 4b (0.228
g, 38%) as a white solid: mp 241-244 °C; IR (KBr) ν cm-1
1685 (m), 1580 (s), 1449 (s); 1H NMR (CDCl3) δ 1.78 (s, 12 H,
4 CH3), 6.22 (s, 2 H, 2 dCH), 7.43-7.56 (m, 6 H aromatic),7.97-
8.00 (m, 4 H aromatic); 13C NMR (CDCl3) δ 24.2, 73.2, 104.3,
126.0, 127.1, 128.4, 131.8, 157.9, 177.2, 183.5; MS m/z 400 (M+,
2), 145 (100), 104 (39), 77 (10), 69 (23). Anal. Calcd for
170 (46), 55 (49). Anal. Calcd for C12H17NO5: C, 56.46; H, 6.71;
N, 5.49. Found: C, 56.41; H, 6.69; N, 5.45.
(E)-3-[(E)-(5-Eth oxyca r bon yl)m eth ylen e-4,4-d im eth yl-
4,5-d ih yd r ooxa zol-2-yl]a cr ylic Acid Eth yl Ester (2f). The
reaction was carried out as described above for the synthesis
of compound 2a . Chromatography with n-hexane/EtOAc (8/2)
gave 2f (0.548 g, 61%) as a white solid: mp 81-82 °C; IR (KBr)
ν cm-1 1724 (s), 1662 (m), 1045 (s); 1H NMR (CDCl3) δ 1.27 (t,
J ) 7.1, 3 H, CO2CH2CH3), 1.30 (t, J ) 7.1, 3 H, CO2CH2CH3),
1.66 (s, 6 H, (CH3)2CN), 4.15 (q, J ) 7.1, 2 H, CO2CH2CH3),
4.25 (q, J ) 7.1, 2 H, CO2CH2CH3), 5.68 (s, 1 H, EtO2CCHd
CO), 6.65 (d, J ) 15.9, 1 H, CHdCHCO2Et), 7.08 (d, J ) 15.9,
1 H, CHdCHCO2Et); 13C NMR (CDCl3) δ 14.0, 14.1, 24.5, 59.9,
61.2, 73.0, 95.1, 128.6, 130.7, 156.0, 164.8, 165.8, 176.5; MS
m/z 281 (M+, 10), 266 (30), 180 (100), 69 (35), 59 (28). Anal.
Calcd for C14H19NO5: C, 59,78; H, 6.81; N, 4.98. Found: C,
59.74; H, 6.80; N, 4.93.
C
25H24N2O3: C, 74.98; H, 6.04; N, 7.00. Found: C, 74.95; H,
6.05; N, 6.96.
(E ,Z)-1,3-B is (4,4-d im e t h y l-2-p h e n y l-4H -o x a zo l-5-
ylid en e)p r op a n -2-on e (5b): The reaction was carried out
as described above for the synthesis of compound 4b. Chro-
matography with n-hexane/EtOAc (7/3) gave 5b (0.030 g, 5%)
as a white solid: mp 221-223 °C; IR (KBr) ν cm-1 1685 (m),
1645 (s), 1583 (s); 1H NMR (CDCl3) δ 1.52 (s, 6 H, 2 CH3), 1.81
(s, 6 H, 2 CH3), 5.49 (s, 1 H, dCH), 6.68 (s, 1 H, dCH), 7.45-
7.57 (m, 6 H aromatic), 7.99-8.12 (m, 4 H aromatic); 13C NMR
(CDCl3) δ 24.2, 28.7, 72.4, 73.2, 102.3, 102.7, 125.8, 126.1,
128.0, 128.4, 128.5, 128.6, 131.9, 132.2, 159.5, 159.7, 171.5,
172.0, 185.8; MS m/z 400 (M+, absent), 145 (100), 104 (45), 77
(24), 69 (16). Anal. Calcd for C25H24N2O3: C, 74.98; H, 6.04;
N, 7.00. Found: C, 74.93; H, 6.05; N, 6.94.
(Z)-3-[(E)-(5-Eth oxyca r bon yl)m eth ylen e-4,4-d im eth yl-
4,5-dih ydr ooxazol-2-yl]acr ylic Acid Eth yl Ester (3f). Chro-
matography with n-hexane/EtOAc (8/2) gave 3f (0.042 g, 5%)
as a pale yellow deliquescent solid: IR (neat) ν cm-1 1724 (s),
1
1688 (s), 1161 (s); H NMR (CDCl3) δ 1.31 (t, J ) 7.1, 6 H, 2
CO2CH2CH3), 1.43 (s, 6 H, (CH3)2CN), 4.21 (q, J ) 7.1, 2 H,
CO2CH2CH3), 4.26 (q, J ) 7.1, 2 H, CO2CH2CH3), 5.15 (s, 1 H,
EtO2CCHdCO), 6.87 (d, J ) 15.8, 1 H, CHdCHCO2Et), 7.15
(d, J ) 15.8, 1 H, CHdCHCO2Et); MS m/z 281 (M+, 10), 266
(25), 180 (100), 69 (95), 59 (45). Anal. Calcd for C14H19NO5:
C, 59,78; H, 6.81; N, 4.98. Found: C, 59.72; H, 6.78; N, 4.93.
(E)-3-[1-(5,5-Diet h oxy-2-oxo-2,5-d ih yd r ofu r a n -3-yl)-1-
m et h ylet h ylca r b a m oyl]a cr ylic Acid E t h yl E st er (10f).
Chromatography with n-hexane/EtOAc (8/2) gave 10f (0.043
g, 4%) as a pale yellow oil: IR (neat) ν cm-1 3350 (s), 1750 (s),
1720 (s), 1645 (s), 1541 (s); 1H NMR (CDCl3) δ 1.22 (t, J ) 7.1,
6 H, 2 OCH2CH3), 1.29 (t, J ) 7.1, 3 H, OCH2CH3), 1.64 (s, 6
H, (CH3)2CN), 3.70 (q, J ) 7.1, 2 H, OCH2), 3.73 (q, J ) 7.1, 2
H, OCH2), 4.21 (q, J ) 7.1, 2 H, OCH2), 6.37 (bs, 1 H, NH),
6.68 (d, J ) 15.3, 1 H, CHdCHCO2Et), 6.70 (s, 1 H, dCHC-
(OEt)2), 6.88 (d, J ) 15.3, 1 H, CHdCHCO2Et); MS m/z 355
(M+, absent), 282 (100), 186 (50). Anal. Calcd for C17H25NO7:
C, 57,46; H, 7.09; N, 3.94. Found: C, 57.42; H, 7.08; N, 3.88.
(E)-(4,4-Dim eth yl-2-p yr id in -2-yl-4H-oxa zol-5-ylid en e)-
a cetic Acid Meth yl Ester (2g). The reaction was carried out
as described above for the synthesis of compound 2a . Chro-
matography with n-hexane/EtOAc (7/3) gave 2g (0.539 g, 73%)
as a white solid: mp 126-127 °C; IR (KBr) ν cm-1 1720 (s),
1672 (m), 1439 (s); 1H NMR (CDCl3) δ 1.75 (s, 6 H, (CH3)2-
CN), 3.72 (s, 3 H, CO2CH3), 5.87 (s, 1 H, dCH), 7.42-7.48 (m,
1 H aromatic at C-5), 7.83 (td, J ) 5.9, 1.3, 1 H aromatic at
C-4), 8.07 (d,t J ) 5.9, 0.8, 1 H aromatic at C-3), 8.77 (ddd, J
) 3.6, 1.3, 0.8, 1 H aromatic at C-6); MS m/z 246 (M+, 10),
231 (15), 105 (100), 69 (75), 59 (15). Anal. Calcd for
2-(Ben zoyla m in om eth yl)m a leic Acid Dim eth yl Ester
(7d ). The reaction was carried out as described above for the
synthesis of compound 2a . Chromatography with n-hexane/
EtOAc (7/3) gave 7d (0.498 g, 60%) as a colorless oil: IR (neat)
1
ν cm-1 3325 (s), 1721 (s), 1640 (s), 1552 (s); H NMR (CDCl3)
δ 3.72 (s, 3 H, CO2CH3), 3.81 (s, 3 H, CO2CH3), 4.32 (dd, J )
6.0, 1.5, 2 H, CH2), 6.12 (t, J ) 1.5, 1 H, dCH), 6.75 (bt, 1 H,
NH), 7.38-7.50 (m, 3 H aromatic), 7.73-7.78 (m, 2 H aro-
matic); MS m/z 277 (M+, 2), 105 (100), 77 (28), 59 (6). Anal.
Calcd for C14H15NO5: C, 60.65; H, 5.45; N, 5.05. Found: C,
60.60; H, 5.40; N, 4.99.
(2-P h en yloxa zol-5-yl)a cet ic Acid Met h yl E st er (8d ).
Chromatography with n-hexane/EtOAc (7/3) gave 8d (0.061
g, 9%) as a white solid: mp 56-57 °C; IR (film) ν cm-1 1740
1
(s), 1645 (s), 1167 (s); H NMR (CDCl3) δ 3.74 (s, 3 H, CO2-
CH3), 3.79 (s, 2 H, CH2), 7.06 (s, 1 H on oxazole ring), 7.40-
7.43 (m, 3 H on phenyl ring), 7.97-8.01 (m, 2 H on phenyl
ring); MS m/z 217 (M+, 21), 158 (100), 104 (18), 77 (15), 59 (8).
Anal. Calcd for C12H11NO3: C, 66.35; H, 5.10; N, 6.45. Found:
C, 66.31; H, 5.06; N, 6.41.
(E)-(4,4-Dim et h yl-2-vin yl-4H -oxa zol-5-ylid en e)a cet ic
Acid Meth yl Ester (2e). The reaction was carried out as
described in the general procedure starting from 1e (0.343 g,
2.5 mmol), 10% Pd-C (0.053 g, 0.05 mmol), and KI (0.125 g,
0.75 mmol) at 50 °C for 24 h. Chromatography with n-hexane/
EtOAc (8/2) gave 2e (0.244 g, 50%) as a white solid: mp 46-
1
47 °C; IR (neat) ν cm-1 1718 (s), 1651 (m), 1264 (s); H NMR
C
13H14N2O3: C, 63.40; H, 5.73; N, 11.38. Found: C, 63.36; H,
(CDCl3) δ 1.65 (s, 6 H, (CH3)2CN), 3.68 (s, 3 H, CO2CH3), 5.68
(s, 1 H, dCH), 5.81 (d, J ) 11.0, 1 H, dCHH), 6.14 (d, J )
17.3, 1 H, dCHH), 6.29 (dd, J ) 11.0, 17.3, 1 H, CHdCH2);
MS m/z 195 (M+, 17), 180 (14), 167 (18), 69 (100), 59 (8). Anal.
Calcd for C10H13NO3: C, 61.53; H, 6.71; N, 7.17. Found: C,
61.49; H, 6.70; N, 7.13.
5.69; N, 11.34.
(E)-[2-(4-Ch lor op yr id in -2-yl)-4,4-d im et h yl-4H -oxa zol-
5-ylid en e]a cetic Acid Meth yl Ester (2h ). The reaction was
carried out as described above for the synthesis of compound
2a . Chromatography with n-hexane/EtOAc (7/3) gave 2h (0.588
g, 70%) as a white solid: mp 143-145 °C; IR (KBr) ν cm-1
1719 (s), 1648 (s); 1H NMR (CDCl3) δ 1.75 (s, 6 H, (CH3)2CN),
3.71 (s, 3 H, CO2CH3), 5.87 (s, 1 H, dCH), 7.45 (dd, J ) 6.0,
2.0, 1 H aromatic at C-5), 8.09 (dd, J ) 2.0, 0.5, 1 H aromatic
at C-3), 8.64 (dd, J ) 6.0, 0.5, 1 H aromatic at C-6); MS m/z
280 (M+, 5), 265 (10), 141 (95), 69 (100), 59 (20). Anal. Calcd
for C13H13ClN2O3: C, 55.62; H, 4.67; N, 9.98. Found: C, 55.57;
H, 4.66; N, 9.93.
(E,E)-1,4-Bis[(5-m et h oxyca r b on ylm et h ylen e)-4,4-d i-
m eth yl-4,5-d ih yd r ooxa zol-2-yl]ben zen e (12i). The reaction
was carried out as described above in the general procedure
starting from 11i (1.79 mmol) in the presence of 10% Pd-C
(0.06 mmol) and KI (0.09 mmol) in MeOH (10 mL). Chroma-
tography with n-hexane/EtOAc (7/3) gave 12i (0.742 g, 60%)
as a white solid: mp 192-194 °C; IR (KBr) ν cm-1 1720 (s),
1678 (s), 1653 (s); 1H NMR (CDCl3) δ: 1.75 (s, 12 H, 2 (CH3)2-
CN), 3.72 (s, 6 H, 2 CO2CH3), 5.80 (s, 2 H, 2 dCH), 8.05 (s, 4
H aromatic); 13C NMR (CDCl3) δ 24.7, 51.2, 73.1, 94.5, 128.3,
(E)-[2-(2-Meth oxyeth yl)-4,4-dim eth yl-4H-oxazol-5-ylide-
n e]a cetic Acid Meth yl Ester (9e). Chromatography with
n-hexane/EtOAc (8/2) gave 9e (0.108 g, 19%) as colorless oil:
IR (neat) ν cm-1 1719 (s), 1655 (s), 1245 (s); 1H NMR (CDCl3)
δ 1.62 (s, 6 H, (CH3)2CN), 2.67 (t, J ) 6.8, 2 H, CH2CH2OCH3),
3.35 (s, 3 H, OCH3), 3.68 (s, 3 H, CO2CH3), 3.69 (t, J ) 6.8, 2
H, CH2OCH3), 5.62 (s, 1 H, dCH); MS m/z 227 (M+, 3), 212
(5), 141 (64), 69 (100), 59 (12). Anal. Calcd for C11H17NO4: C,
58.14; H, 7.54; N, 6.16. Found: C, 58.10; H, 7.51; N, 6.12.
N-[1-(5,5-Dim et h oxy-2-oxo-2,5-d ih yd r ofu r a n -3-yl)-1-
m eth yleth yl]a cr yla m id e (10e). Chromatography with n-
hexane/EtOAc (8/2) gave 10e (0.051 g, 8%) as colorless oil: IR
1
(neat) ν cm-1 3351 (s), 1750 (s), 1645 (s); H NMR (CDCl3) δ
1.64 (s, 6 H, (CH3)2CN), 3.45 (s, 6 H, 2 OCH3), 5.60 (dd, J )
10.2, 1.2, 1 H, dCHH), 5.84 (bs, 1 H, NH), 6.05 (dd, J ) 16.9,
1.2, 1 H, dCHH), 6.19 (dd, J ) 16.9, 10.2, 1 H, CHdCH2) 6.68
(s, 1 H, dCHC(OMe)2); MS m/z 255 (M+, 1), 224 (17), 196 (100),

Synthesis of 5-(Alkoxycarbonyl)methylene-3-oxazolines
J . Org. Chem., Vol. 67, No. 13, 2002 4457
129.0, 157.2, 166.4, 177.7; MS m/z 412 (M+, 11), 397 (56), 384
(100), 312 (76), 141 (62), 69 (96), 59 (17). Anal. Calcd for
(E)-[2-[1-[1-(5,5-Dim eth oxy)-2-oxo-2,5-d ih yd r ofu r a n -3-
yl)-1-m eth yleth ylcar bam oyl]-1-m eth yleth yl]-4,4-dim eth yl-
4H-oxa zol-5-ylid en e]a cetic Acid Meth yl Ester (15j). Chro-
matography with n-hexane/EtOAc (7/3) gave 15j (0.118 g, 9%)
as a white solid: mp 135-136 °C; IR (neat) ν cm-1 3351 (s),
C
22H24N2O6: C, 64.07; H, 5.87; N, 6.79. Found: C, 64.02; H,
5.85; N, 6.74.
(E ,Z)-1,4-Bis[(5-m e t h oxyca r b on ylm e t h yle n e -4,4-d i-
m eth yl-4,5-d ih yd r ooxa zol-2-yl]ben zen e (13i). Chromatog-
raphy with n-hexane/EtOAc (7/3) gave 13i (0.012 g, 1%) as a
white solid: mp 180-182 °C; IR (KBr) ν cm-1 1719 (s), 1706
(s), 1677 (s), 1653 (s); 1H NMR (CDCl3) δ 1.50 (s, 6 H, (CH3)2-
CN), 1.75 (s, 6 H, (CH3)2CN), 3.73 (s, 3 H, CO2CH3), 3.78 (s, 3
H, CO2CH3), 5.23 (s, 1 H, dCH), 5.81 (s, 1 H, dCH), 8.05-
8.08 (m, 2 H, aromatic), 8.15-8.18 (m, 2 H aromatic); 13C NMR
(CDCl3) δ 24.7, 28.6, 51.2, 51.3, 72.7, 73.1, 90.6, 94.5, 128.3,
128.6, 128.9, 129.3, 157.2, 158.9, 165.0, 166.5, 174.4, 177.7;
MS m/z 412 (M+, 4), 397 (14), 141 (59), 69 (100), 59 (16). Anal.
Calcd for C22H24N2O6: C, 64.07; H, 5.87; N, 6.79. Found: C,
64.01; H, 5.85; N, 6.71.
(Z)-2-[1-[4-(E)-(5-Met h oxyca r b on ylm et h ylen e-4,4-d i-
methyl-4,5-dihydrooxazol-2-yl)benzoylamino]-1-methylethyl]-
m a leic Acid Dim eth yl Ester (14i). Chromatography with
n-hexane/EtOAc (7/3) gave 14i (0.071 g, 5%) as a white solid:
mp 93-95 °C; IR (KBr) ν cm-1 1723 (s), 1653 (s), 1104 (s); 1H
NMR (CDCl3) δ 1.72 (s, 6 H, (CH3)2CN), 1.73 (s, 6 H, (CH3)2-
CN), 3.71 (s, 3 H, CO2CH3), 3.72 (s, 3 H, CO2CH3), 3.77 (s, 3
H, CO2CH3), 5.79 (s, 1 H, dCH), 6.05 (s, 1 H, dCH), 6.45 (bs,
1 H, NH), 7.79 (d, J ) 8.3, 2 H aromatic), 8.01 (d, J ) 8.3, 2
H aromatic); 13C NMR (CDCl3) δ 24.7, 26.7, 51.2, 51.9, 51.5,
73.1, 94.5, 118.4, 127.0, 128.4, 128.7, 137.6, 154.2, 157.1, 165.1,
166.4, 168.4, 177.7; MS m/z 472 (M+, 7), 413 (68), 272 (66),
130 (100), 69 (47), 59 (11). Anal. Calcd for C24H28N2O8: C,
61.01; H, 5.97; N, 5.93. Found: C, 60.98; H, 5.95; N, 5.87.
(E)-[2-[4-[1-(5,5-Dim et h oxy-2-oxo-2,5-d ih yd r ofu r a n -3-
yl)-1-m eth yleth ylca r ba m oyl]p h en yl]-4,4-d im eth yl-4H-ox-
a zol-5-ylid en e]a cetic Acid Meth yl Ester (15i). Chroma-
tography with n-hexane/EtOAc (7/3) gave 15i (0.089 g, 6%) as
a white solid: mp 83-85 °C; IR (KBr) ν cm-1 1773 (s), 1722
(s), 1301 (s), 1105 (s); 1H NMR (CDCl3) δ 1.71 (s, 6 H, (CH3)2-
CN), 1.72 (s, 6 H, (CH3)2CN), 3.44 (s, 6 H, C(OCH3)2), 3.70 (s,
3 H, CO2CH3), 5.78 (s, 1 H, dCHCO2Me), 6.54 (bs, 1 H, NH),
6.73 (s, 1 H, dCHC(OMe)2), 7.73-7.77 (m, 2 H aromatic),
7.95-7.98 (m, 2 H, aromatic); 13C NMR (CDCl3) δ: 24.7, 26.6,
51.1, 51.3, 51.9, 73.1, 94.4, 118.3, 127.1, 128.3, 137.9, 140.6,
142.1, 157.1, 158.9, 166.3, 166.4, 166.9, 177.7; MS m/z 472 (M+,
absent), 413 (47), 272 (51), 130 (100), 69 (48), 59 (9). Anal.
Calcd for C24H28N2O8: C, 61.01; H, 5.97; N, 5.93. Found: C,
60.97; H, 5.95; N, 5.88.
1
1750 (s), 1720 (s); H NMR (CDCl3) δ 1.42 (s, 6 H, (CH3)2C),
1.54 (s, 6 H, (CH3)2CN), 1.64 (s, 6 H, (CH3)2CN), 3.40 (s, 6 H,
2 OCH3), 3.68 (s, 3 H, CO2CH3), 5.64 (s, H, dCHCO2Me), 6.60
(s, 1 H, dCHC(OMe)2), 7.19 (bs, 1 H, NH); MS m/z 438 (M+,
absent), 211 (100), 143 (80), 69 (27), 59 (7). Anal. Calcd for
C
21H30N2O8: C, 57.52; H, 6.90; N, 6.39. Found: C, 57.48; H,
6.87; N, 6.36.
(E)-[2-[6-(5-Meth oxyca r bon ylm eth ylen e-4,4-d im eth yl-
4,5-d ih yd r ooxa zol-2-yl)p yr id in -2-yl]-4,4-d im eth yl-4H-ox-
a zol-5-ylid en e]a cetic Acid Meth yl Ester (12k ). The reac-
tion was carried out as described above for the synthesis of
compound 2a . Chromatography with n-hexane/EtOAc (7/3)
gave 12k (0.595 g, 48%) as a white solid: mp 130-131 °C; IR
(KBr) ν cm-1 1728 (s), 1437 (s); 1H NMR (CDCl3) δ 1.76 (s, 12
H, 2 (CH3)2CN), 3.73 (s, 6 H, 2 CO2CH3), 5.92 (s, 2 H, 2 dCH),
7.98 (t, J ) 7.8 Hz, 1 H aromatic at C-4), 8.28 (d, J ) 7.8 Hz,
2 H aromatic at C-3 and C-5); MS m/z 413 (M+, 38), 385 (40),
353 (100), 141 (50), 59 (8). Anal. Calcd for C21H23N3O6: C,
61.01; H, 5.61; N, 10.16. Found: C, 60.97; H, 5.58; N, 10.13.
(Z)-2-[1-[[6-(E)-(5-Met h oxyca r b on ylm et h ylen e-4,4-d i-
methyl-4,5-dihydrooxazol-2-yl)pyridine-2-carbonyl]amino]-1-
m eth yleth yl]m a leic Acid Dim eth yl Ester (14k ). Chroma-
tography with n-hexane/EtOAc (7/3) gave 14k (0.071 g, 5%)
as a white solid: mp 146-147 °C; IR (KBr) ν cm-1 3391 (m),
1722 (s), 1683 (s); 1H NMR (CDCl3) δ: 1.71 (s, 6 H, (CH3)2-
CN), 1.75 (s, 6 H, (CH3)2CN), 3.67 (s, 3 H, CO2CH3), 3.71 (s, 3
H, CO2CH3), 3.76 (s, 3 H, CO2CH3), 5.84 (s, 1 H, dCH), 6.01
(s, 1 H, dCH), 7.96 (t, J ) 7.9, aromatic at C-4), 8.18 (d, J )
7.9, 1 H aromatic at C-3 or C-5), 8.29 (d, J ) 7.9, 1 H aromatic
at C-5 or C-3), 8.33 (bs, 1H, NH); MS (CI): m/z 474 [(M + 1)+,
100]. Anal. Calcd for C23H27N3O8: C, 58.35; H, 5.75; N, 8.87.
Found: C, 58.33; H, 5.74; N, 8.84.
(E,E)-tr a n s-[2-[2-(5-Met h oxyca r b on ylm et h ylen e-4,4-
dim eth yl-4,5-dih ydr ooxazol-2-yl)cycloh exyl]-4,4-dim eth yl-
4H-oxa zol-5-ylid en e]a cetic Acid Meth yl Ester (12l). The
reaction was carried out as described above for the synthesis
of compound 2a . Chromatography with n-hexane/EtOAc (8/2)
gave 12l (0.740 g, 59%) as a white solid: mp 118-120 °C; IR
(KBr) ν cm-1 1722 (s), 1659 (m); 1H NMR (CDCl3) δ 1.28-1.36
(m, 4 H, 4 CH), 1.54 (s, 12 H, 2 (CH3)2CN), 1.49-1.56 (m, 4 H,
4 CH), 2.05-2.08 (m, 2 H, 2 CH), 3.67 (s, 6 H, 2 CO2CH3),
5.63 (s, 2 H, 2 dCH); MS m/z 418 (M+, 1), 83 (30), 69 (100), 59
(13). Anal. Calcd for C22H30N2O6: C, 63.14; H, 7.23; N, 6.69.
Found: C, 63.09; H, 7.19; N, 6.64.
(E,E)-[2-[1-(5-Meth oxycar bon ylm eth ylen e-4,4-dim eth yl-
4,5-d ih yd r ooxa zol-2-yl)-1-m eth yleth yl]-4,4-d im eth yl-4H-
oxa zol-5-ylid en e]a cetic Acid Meth yl Ester (12j). The
reaction was carried out as described above for the synthesis
of compound 2a . Chromatography with n-hexane/EtOAc (7/3)
gave 12j (0.500 g, 45%) as a white solid: mp 89-90 °C; IR
1
(KBr) ν cm-1 1720 (s), 1689 (s), 1068 (s); H NMR (CDCl3) δ
Ack n ow led gm en t. Financial support from the Min-
istero dell’Universita` e della Ricerca Scientifica e Tec-
nologica is gratefully acknowledged (Progetto d’Interesse
Nazionale PIN MM03027791). The facilities of Centro
Interfacolta` di Misure (Universita` di Parma) were used
for recording NMR and mass spectra. The X-ray dif-
fraction experiments were carried out at the Centro di
Studio per la Strutturistica Diffrattometrica del CNR
in Parma.
1.56 (s, 6 H, (CH3)2C), 1.61 (s, 12 H, 2 (CH3)2CN), 3.67 (s, 6 H,
2 CO2CH3), 5.59 (s, 2 H, 2 dCH); 13C NMR (CDCl3) δ:23.3,
24.3, 37.9, 51.0, 72.6, 94.0, 162.0, 166.3, 177.9; MS m/z 378
(M+, 1), 335 (15), 142 (100), 69 (75), 59 (12). Anal. Calcd for
C
19H26N2O6: C, 60.31; H, 6.92; N, 7.40. Found: C, 60.26; H,
6.90; N, 7.35.
(Z)-2-[1-[2-(E)-(5-Met h oxyca r b on ylm et h ylen e-4,4-d i-
methyl-4,5-dihydrooxazol-2-yl)-2-methylpropionylamino]-1-
m eth yleth yl]m a leic Acid Dim eth yl Ester (14j). Chroma-
tography with n-hexane/EtOAc (7/3) gave 14j (0.197 g, 15%)
as a colorless oil: IR (neat) ν cm-1 3378 (m), 1723 (s), 1671
(s), 1075 (s); 1H NMR (CDCl3) δ 1.46 (s, 6 H, (CH3)2C), 1.54 (s,
6 H, (CH3)2CN), 1.64 (s, 6 H, (CH3)2CN), 3.68 (s, 3 H, CO2-
CH3), 3.70 (s, 3 H, CO2CH3), 3.78 (s, 3 H, CO2CH3), 5.67 (s, H,
dCH), 5.93 (s, 1 H, dCH), 7.23 (bs, 1 H, NH); MS m/z 438
(M+, absent), 211 (100), 143 (80), 69 (25), 59 (9). Anal. Calcd
for C21H30N2O8: C, 57.52; H, 6.90; N, 6.39. Found: C, 57.47;
H, 6.88; N, 6.35.
Su p p or tin g In for m a tion Ava ila ble: X-ray structural
information for 2b, 4b, 2h , 12l, and 6c is collected in the
Tables S1 and S2. The structures of 2b, 4b, 2h , 12l, and 6c
are shown in Figures S1-S5, respectively. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O0200217