Heterocyclic derivative syntheses by palladium-catalyzed oxidative cyclization-alkoxycarbonylation of substituted γ-oxoalkynes

Article abstract of DOI:10.1021/jo050155v

4-Yn-1-ones containing different substituents, prop-2-ynyl α-ketoesters, and prop-2-ynyl α-ketoamides have been caused to react catalytically under oxidative carbonylation conditions to give tetrahydrofuran, dioxolane and oxazoline, dihydropyridinone, and

Full text of DOI:10.1021/jo050155v

Heterocyclic Derivative Syntheses by Palladium-Catalyzed
Oxidative Cyclization-Alkoxycarbonylation of Substituted
γ-Oxoalkynes
Alessia Bacchi,† Mirco Costa,*,‡ Nicola Della Ca`,‡ Bartolo Gabriele,§ Giuseppe Salerno,| and
Silvia Cassoni‡
Dipartimento di Chimica Generale ed Inorganica, Chimica Analitica e Chimica Fisica, Universita` di
Parma, Parco Area delle Scienze 17/A, 43100 Parma, Italy, Dipartimento di Chimica Organica e
Industriale, Universita` di Parma, Parco Area delle Scienze 17/A, 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 January 25, 2005
4-Yn-1-ones containing different substituents, prop-2-ynyl R-ketoesters, and prop-2-ynyl R-ketoa-
mides have been caused to react catalytically under oxidative carbonylation conditions to give
tetrahydrofuran, dioxolane and oxazoline, dihydropyridinone, and tetrahydropyridinedione deriva-
tives in satisfactory yields. Reactions were carried out in MeOH or MeCN/MeOH mixtures at 65-
100 °C in the presence of catalytic amounts of PdI2 in conjunction with KI under 32 bar (at 25 °C)
of a 3:1 mixture of CO and air. Anti and syn 5-exo-dig cyclization modes account for the formation
of different products. It has been found that cyclopentenone, dihydropyridinone, and tetrahydro-
pyridinedione derivatives, formed when the reaction is carried out at higher temperature and for
a longer time, can also be selectively obtained through an acid treatment of tetrahydrofuran and
oxazoline derivatives involving an unusual rearrangement. The structures of 6-methoxy-2,2-
dimethyl-3-oxo-5-phenyl-2,3-dihydropyridine-4-carboxylic acid methyl ester and 2,2,5-trimethyl-
3,6-dioxo-1,2,3,6-tetrahydropyridine-4-carboxylic acid methyl ester have been confirmed by X-ray
diffraction analysis.
Introduction
useful to promote heterocyclization reactions with high
selectivity under mild conditions.2 An especially impor-
tant application of Pd-catalysis concerns the synthesis
of heterocyclic carbonyl compounds through heterocyclo-
carbonylation or heterocyclization-alkoxycarbonylation
of unsaturated substrates bearing a nucleophilic function
Transition-metal-catalyzed annulation reactions rep-
resent an effective and straightforward methodology for
the synthesis of heterocyclic compounds, which has
brought significant results during the past years.1 Pal-
ladium catalysis, in particular, has proven to be very
(1) For a recent review, see: Nakamura, I.; Yamamoto, Y. Chem.
Rev. 2004, 104, 2127-2198.
(2) (a) Li, J. J.; Gribble, G. W. Palladium in Heterocyclic Chemistry;
Pergamon: Oxford, 2000. (b) Zeni, G.; Larock, R. C. Chem. Rev. 2004,
104, 2285-2309. For a recent account on PdI2-catalyzed synthesis of
heterocycles, see: (c) Gabriele, B.; Salerno, G.; Costa, M. Synlett 2004,
2468-2483.
† Dipartimento di Chimica Generale e Inorganica, Chimica Analitica
e Chimica Fisica, Universita` di Parma.
‡ Dipartimento di Chimica Organica e Industriale, Universita` di
Parma.
§ Dipartimento di Scienze Farmaceutiche, Universita` della Calabria.
| Dipartimento di Chimica, Universita` della Calabria.
10.1021/jo050155v CCC: $30.25 © 2005 American Chemical Society
Published on Web 05/19/2005
J. Org. Chem. 2005, 70, 4971-4979
4971

Bacchi et al.
in appropriate position.3 The catalytic system based on
PdI2 or 10% Pd-C in conjunction with an excess of KI
has proven to be particularly effective to promote this
kind of reaction in the presence of oxygen as an oxidant.3a,4
In particular, some time ago we described the synthesis
of (E)-5-(alkoxycarbonyl)methylene-3-oxazolines from prop-
2-ynylamides promoted by the above-mentioned pal-
ladium catalytic system (PdI2 + KI or Pd/C + KI)5 (eq
1).
SCHEME 2
situ by R3OH attack on the carbonyl group of 3, followed
by alkoxycarbonylation (Scheme 2). The presence of
substituents on the triple bond (R1) and at the carbonyl
group (R2) played a key role in the selectivity of the
process toward the formation of a five- or six-membered
ring.
We have now extended our investigations on hetero-
cyclic ring formation by means of PdI2-catalyzed oxidative
cyclization-alkoxycarbonylation reactions to aliphatic
acetylenic ketones. The Pd-catalyzed oxidative carbony-
lation of 4-yn-1-ones, to give 2-methoxy-5-[(methoxycar-
bonyl)methylene]tetrahydrofurans as the main products,
using (MeCN)2PdCl2 as catalyst and 1,4-benzoquinone as
oxidant has been reported recently.7 Under the applied
mild conditions, the reactions of 4-yn-1-ones afforded
cyclic ketals either as single diastereomers, sometimes
together with a methoxyacrylate derivative, or as a
diastereomeric mixture.
In this case, intramolecular anti nucleophilic attack of
oxygen to the triple bond coordinated to Pd(II) was
followed by alkoxycarbonylation, so the overall process
corresponded to 5-exo-dig cyclization-alkoxycarbonyla-
tion (Scheme 1; in this and in the following schemes
anionic iodide ligands are omitted for clarity).
SCHEME 1
The presence of geminal groups R to the triple bond
was a necessary requisite for directing the catalytic
process toward the formation of cyclization products.
More recently we reported the direct synthesis of benzo-
[c]pyran derivatives 4 and 1,3-dihydroisobenzofuran
derivatives 5 by Pd-catalyzed oxidative cyclization-
alkoxycarbonylation of 2-alkynylbenzaldehydes or 2-
alkynylphenyl ketones 3 (eq 2).6
We caused 4-yn-1-ones containing different substitu-
ents, prop-2-ynyl R-ketoesters, and prop-2-ynyl R-ketoa-
mides to react catalytically under oxidative carbonylation
conditions with our catalytic system, PdI2-KI. Here we
report the results of our investigations, which allowed
us to compare the activity of our catalytic system with
7
the one based on (MeCN)2PdCl2 and to discover rear-
rangement processes leading to different classes of
heterocyclic derivatives.
Results and Discussion
Oxidative Carbonylation of 4-Yn-1-ones. The oxi-
dative carbonylation reactions of 4-yn-1-ones 6 were
carried out at 65-100 °C for 24-36 h in a mixture of
MeOH/MeCN (0.4/5.0 v/v) and under a CO-air pressure
of 24/8 bar measured at room temperature, in the
presence of PdI2 (3.3 mol %) and KI (KI/PdI2 molar ratio
) 10). The reaction led to the formation of 2-methoxy-
5-[(methoxycarbonyl)methylene]tetrahydrofurans 7 and
7′ in moderate to good yields and fair diastereoselectivity
The reaction proceeded through 6-endo-dig or 5-exo-
dig intramolecular attack on the triple bond coordinated
to Pd(II) by the nucleophilic oxygen atom generated in
(3) For recent reviews, see: (a) Gabriele, B.; Salerno, G.; Costa, M.;
Chiusoli, G. P. Curr. Org. Chem. 2004, 8, 919-946. (b) Alonso, F.;
Beletskaya, I.; Yus, M. Chem. Rev. 2004, 104, 3079-3159. (c) Vizer,
S. A.; Yerzhanov, K. B.; Al Quntar, A. A. A.; Vembitsky, V. M.
Tetrahedron 2004, 60, 5499-5538.
(4) (a) Gabriele, B.; Costa, M.; Salerno, G.; Chiusoli, G. P. J. Chem.
Soc., Chem. Commun. 1992, 1007-1008. (b) Gabriele, B.; Costa, M.;
Salerno, G.; Chiusoli, G. P. J. Chem. Soc., Perkin Trans. 1 1994, 83-
87.
(5) Bacchi, A.; Costa, M.; Gabriele, B.; Pelizzi, G.; Salerno, G. J. Org.
Chem. 2002, 67, 4450-4457.
(6) Bacchi, A.; Costa, M.; Della Ca`, N.; Fabbricatore, M.; Fazio, A.;
Gabriele, B.; Nasi, C.; Salerno, G. Eur. J. Org. Chem. 2004, 574-585.
4972 J. Org. Chem., Vol. 70, No. 13, 2005

Pd-Catalyzed Oxidative Cyclization-Alkoxycarbonylation
TABLE 1. Synthesis of 2-Methoxy-5-
rearrangement product, 3-ethyl-2-methyl-5-oxocyclopent-
1-ene-1,3-dicarboxylic acid dimethyl ester 8b, was also
formed as coproduct (entry 4).
[(methoxycarbonyl)methylene]tetrahydrofurans 7 and 7′
by Oxidative Carbonylation of 4-Yn-1-ones 6 (2.0 mmol)a
As already reported in the literature,7 product 8b was
also obtained by acid treatment of 7b. A plausible
mechanism for its formation is shown in Scheme 4.
T
t
conv 6 yield 7 yield 7′
entry
6
R1 R2
R3
(°C) (h) (%)b (%)c (%)c
1
2
3
4d
5
6
7
8
9
6a Me
6a Me
H
H
CO2Me 70 36
CO2Me 100 36
55
97
72
89
90
90
96
88
66
98
33 11
55 (39) 27 (13)
6b Me Et CO2Me 65 36
6b Me Et CO2Me 100 24
6c Me Bn CO2Et 100 36
65 (54)
41 (30)
74 (62)
85 (73)
89 (78)
77 (65)
39
3
8
6
3
0
SCHEME 4
6d Me Et COMe
6e (CH2)4 CO2Me 70 36
6f Ph 70 36
6g Ph Me CO2Et 100 36
70 36
H
H
21
10e 6g Ph Me CO2Et 100 36
61 (46) 30 (14)
a In MeCN/MeOH (5.0/0.4 mL/mL) mixture, in the presence of
PdI2 (3.3 mol %) and KI (KI/PdI2 molar ratio ) 10), under 32 bar
(at 25 °C) of a 3:1 mixture of CO and air. b Based on starting 6,
by GLC. c GLC yield (isolated yield) based on 6. d The reaction also
led to the formation of 3-ethyl-2-methyl-5-oxocyclopent-1-ene-1,3-
dicarboxylic acid dimethyl ester 8b (32% GLC yield, 21% isolated).
e The ratio of the mixture MeCN/MeOH was 4.5/1.0 mL/mL.
The diastereoselectivity of the cyclization products is
controlled by the presence of neighboring groups in the
R position to the ketonic CO. On the other hand their
presence is not necessary for the cyclization to occur, as
shown by the formation of compound 7f (yield 77%, entry
8).
SCHEME 3
Some differences should now be pointed out between
the behavior of our catalytic system (PdI2/KI) and the one
previously used,7 (MeCN)2PdCl2, in the oxidative carbo-
nylation of 6. The latter catalyst allowed the reaction to
be carried out under milder conditions (0 °C and atmo-
spheric pressure of CO) but required a stoichiometric
amount of an organic reoxidant (1,4-benzoquinone) be-
cause, contrary to the PdI2/KI system, air was not active
for Pd(0) reoxidation. On the other hand no significant
difference in diastereoselectivity was observed for the
carbonylation reaction of the common substrates 6a, 6b,
and 6e using the two catalytic systems, under appropri-
ate reaction conditions. Other substrates 6, used in this
work, however, showed a good stereoselectivity toward
isomers 7.
As regards the mechanism, Kato et al.7 suggested that
a cyclic oxonium intermediate plays a key role in control-
ling the diastereoselectivity of the reaction and enabling
the formation of a not negligible amount of acyclic
methoxyacrylate derivative in addition to the desired
cyclic ketal. In our case, the intermediacy of the cyclic
oxonium ion in the reaction mechanism cannot be ex-
cluded even if the formation of an acyclic methoxyacrylate
derivative did not occur. This different behavior could
tentatively be attributed to the presence, in our catalytic
system, of I- ions, which may cause a greater steric
hindrance than the Cl- ones, thus preventing the attack
of MeOH to the olefinic carbon of vinyl palladium
intermediate (Scheme 3a). An alternative to the forma-
tion of a cyclic oxonium ion could be MeOH addition to
the keto group in a concerted fashion with carbonyl
oxygen attack on the PdI2-activated alkyne to give the
ketal intermediate directly as shown in Scheme 3b.
Oxidative Carbonylation of 4-Ynones Bearing an
r-Amido Group. In sharp contrast with 4-yn-1-ones
bearing an ester group at the R position (Table 1, entries
(eq 3 and Table 1). In some cases, only the most abundant
diastereoisomer 7 was isolated, and its stereochemistry
was determined by 2D NOESY NMR experiments. It is
interesting to note that, in contrast to the reaction of
2-alkynylbenzaldehydes or 2-alkynylphenyl ketones 3
carried out under analogous conditions,6 4-ynones 6
underwent 5-exo-dig cyclization exclusively (Scheme 3)
Diastereoselectivity toward 7 was moderate when R2
) H (entries 1 and 2) or when R1 ) Ph (entries 9 and
10), whereas it was higher when both R1 and R2 were
alkyl groups (entries 3-7). For example, carbonylation
of 2-acetyl-2-ethylpent-4-ynoic acid methyl ester 6b,
carried out at 65 °C for 36 h, led to a 65% GLC yield of
7b and only 3% of 7′b at 72% substrate conversion (entry
3). Interestingly, when the same reaction was carried out
at 100 °C, its conversion reached 89% after 24 h, but the
diastereoselectivity was lower; moreover, in this case, a
(7) Kato, K.; Yamamoto, Y.; Akita, H. Tetrahedron Lett. 2002, 43,
4915-4917.
J. Org. Chem, Vol. 70, No. 13, 2005 4973

Bacchi et al.
TABLE 2. Synthesis of 2-Methoxy-5-
1-7 and 9 and 10), the oxidative carbonylation of 4-yn-
1-ones bearing an R-amido group selectively afforded a
γ-lactam derivative resulting from nucleophilic attack of
amide nitrogen on the activated triple bond. For example,
the reaction of 2-acetyl-2-ethyl-pent-4-ynoic acid pheny-
lamide 6h, carried out under the same conditions re-
ported in Table 1, afforded the two geometric isomers
(E:Z ) 1:20) of (4-acetyl-4-ethyl-5-oxo-1-phenyl-pyrroli-
din-2-ylidene) acetic acid methyl ester 9h (total yield
87%) (eq 4, Scheme 5). Acid treatment with HCl (0.22 M
[(methoxycarbonyl)methylene]dioxolanes 11 by
Oxidative Carbonylation of Prop-2-ynyl-r-ketoesters 10
(2.0 mmol)a
T
(°C)
t
(h)
conv 10
yield 11
entry
10
R
(%)b
(%)c
12
13
10a
10b
Me
Ph
65
65
30
24
99
99
75 (61)
70 (58)
a In MeOH (5.6 mL), in the presence of PdI2 (3.3 mol %) and KI
(KI/PdI2 molar ratio ) 10), under 32 bar (at 25 °C) of a 3:1 mixture
of CO and air. b Based on starting 10, by GLC. c GLC yield
(isolated yield) based on 10.
TABLE 3. Cyclization-Alkoxycarbonylation Reactions
of Prop-2-ynyl-r-ketoamides 12 (2.0 mmol)a
T
t
conv 12 yield 13 yield 14 yield 15
entry 12 R1 R2 (°C) (h)
(%)b
(%)c
(%)c
(%)bc
14 12a Me Me 75 16
15 12a Me Me 75 40
16 12b Ph Me 75 16
17 12b Ph Me 75 40
100
100
98
85 (74)
8 (5)
52 (43) 39 (30)
81 (70) 14 (8)
67 (59) 30 (23)
6 (3)
100
a In MeCN/MeOH (5.0/0.5 mL/mL) mixture, in the presence of
PdI2 (3.33 mol %) and KI (KI/PdI2 molar ratio ) 10), under 32 bar
SCHEME 5
°
(at 25 C) of a 3:1 mixture of CO and air. b Based on starting 12,
by GLC. c GLC yield (isolated yield) based on 12.
group) nor products deriving from a subsequent rear-
rangement of 11 were observed under these conditions.
In particular acid treatment of 11 (10% HCl in dry MeOH
or 0.22 M HCl in dioxane/water ) 4/1 v/v) at room
temperature, led to its complete decomposition without
formation of new products.
In contrast to 10, the PdI2/KI-catalyzed oxidative
carbonylation of prop-2-ynyl-R-ketoamides 12 with MeOH
as the nucleophile led to a mixture of different cyclization
products 13, 14, and 15 (eq 6 and Table 3). The structures
in dioxane/water ) 4/1 v/v) at room temperature for 15-
20 min caused the practically complete isomerization of
9h(Z) into 9h(E).
Oxidative Carbonylation of Prop-2-ynyl r-Keto-
esters and r-Ketoamides. The observation (Scheme 4)
that a C-O to C-C rearrangement could take place
under the carbonylation conditions prompted us to study
the behavior of acetylenic substrates containing an
R-dicarbonyl functionality, which could lead in one step
to highly functionalized five- or six-membered rings. We
thus applied our methodology to prop-2-ynyl R-ketoesters
10 and R-ketoamides 12.
Under conditions similar to those previously used for
4-yn-1-ones 6, but in MeOH as the only solvent, prop-2-
ynyl R-ketoesters 10 selectively afforded 2-methoxy-5-
(alkoxycarbonyl)methylene-[1,3]dioxolane derivatives 11,
resulting from MeOH attack on the ester carbonyl group
followed by 5-exo-dig cyclization and methoxycarbonyla-
tion, in good yields (eq 5 and Table 2). The addition of
of products 14b and 15a were confirmed by X-ray
diffraction analysis (see Supporting Information).
Interestingly, no six-membered products were formed
using propan-1-ol in place of MeOH as the nucleophile
under similar conditions; for example, the reaction of
N-(1,1-dimethylprop-2-ynyl)-2-oxopropionamide 12a, car-
ried out under the same conditions reported in entry 15
but at 70 °C and with 1.0 mL of PrOH, afforded oxazoline
13′a as the sole product in 92% GLC yield (81% isolated)
at total substrate conversion (eq 7).
MeCN to MeOH depressed the yield of the reaction.
Neither products deriving from 6-exo-dig cyclization
(ensuing from MeOH attack on the ketonic carbonyl
4974 J. Org. Chem., Vol. 70, No. 13, 2005

Pd-Catalyzed Oxidative Cyclization-Alkoxycarbonylation
SCHEME 6
SCHEME 7
Formation of oxazolines 13a,b and 13′a corresponded
to the usual alkoxylation-5-exo-dig cyclization-alkoxy-
carbonylation sequence, followed in this case by a final
ROH elimination from the 2-alkoxyoxazolidine interme-
diate, with formation of a CdN double bond (Scheme 6).
On the other hand, six-membered compounds 14a,b
and 15a derived from subsequent transformations of
13a,b, as shown by experiments carried out at different
reaction times (compare entries 14 and 16 with entries
15 and 17, respectively). These unusual rearrangements
also occurred under acidic conditions. For example, when
pure oxazolines 13a,b (1.0 mmol) were treated with a
10% solution of HCl in anhydrous MeOH (10 mL) at room
temperature, a fast conversion (15-20 min) of 13a,b into
6-methoxy-3-oxo-2,3-dihydropyridines 14a,b was ob-
served in almost quantitative yield (eq 8).
13a,b 10% HCl/MeOH8 14a,b (96-92%)
(8)
added with a solution of HCl (0.22 M in dioxane/water
4/1 v/v, 15 mL) and the resulting mixture was let to react
at room temperature. After 0.5 h, 15a or 15b was formed
as the sole product in 71% and 69% yield, respectively
(eq 11) of isolated product. Thus, this procedure offers a
convenient method for the one-pot synthesis of new 3,6-
dioxo-pyridine derivatives starting from very simple and
readily available substrates.
rt
On the other hand, the reaction of pure 13a,b and 13′a
(1.0 mmol) with HCl (0.22 M in dioxane/water 4/1 v/v,
10 mL) at room temperature for 15-20 min led to the
formation of 3,6-dioxo-1,2,3,6-tetrahydro-pyridines 15a,b
and 15′a in 92-96% yields (eq 9). Products 14a,b could
also be converted into 15a,b under analogous conditions
(eq 10).
1) CO, O2, MeOH
PdI2/KI
10 % HCl
13a,a′,b dioxane/H O, rt8 15a,a′,b (92-96%)
(9)
12a,b
8 15a,b (71%, 69%)
(11)
2
2) H+
10 % HCl
14a,b dioxane/H O, rt8 15a,b (92-95%)
(10)
That geminal groups R to the triple bond direct the
process toward cyclization8 was clearly shown using
2-oxo-N-prop-2-ynylpropionamide 16 bearing an R-un-
substituted triple bond. The oxidative carbonylation of
this substrate, carried out under the usual conditions at
70 °C for 40 h, afforded maleic diester 17 as the main
product (78% yield, 68% isolated, deriving from triple
bond dicarbonylation)4 together with small amounts
(13%, 8% isolated yield) of (2-acetyloxazol-5-yl)acetic acid
methyl ester 18, clearly resulting from aromatization of
the initially formed oxazoline derivative (eq 12).
2
A likely mechanism for these transformations is shown
in Scheme 7. In anhydrous MeOH, a reversible MeOH
addition to the CdN double bond of 13 with formation of
a 2-alkoxyoxazolidine intermediate takes place (path a),
followed by cleavage of the endocyclic C-O bond and
C-C bond formation through nucleophilic attack of the
enolic â-carbon to the carbonyl group; elimination of
water then gives 14. A similar sequence of steps, with
H2O instead of MeOH as the initial nucleophile, accounts
for the formation of 15 from 13 in aqueous dioxane (path
b). In the latter medium, conversion of 14 into 15 is easily
explained by addition of H2O to the CdN double bond
followed by MeOH elimination (path c).
We have ascertained that is also possible to directly
convert products 13a,b into 3,6-dioxo-1,2,3,6-tetrahydro-
pyridines 15a,b by Pd-catalyzed carbonylation followed
by one-pot acid-catalyzed ring enlargement. Thus, the
carbonylation mixture deriving from 12a or 12b was
J. Org. Chem, Vol. 70, No. 13, 2005 4975

Bacchi et al.
stainless steel autoclave. In a typical experiment, the autoclave
was charged in the presence of air with PdI2 (24.0 mg, 6.7 ×
10-2 mmol), KI (111.0 mg, 0.7 mmol), and a solution of 6 (2.0
mmol) in MeCN/MeOH or pure MeOH as the solvent. The
autoclave was pressurized at room temperature with CO (24
bar) and air (up to 32 bar) and stirred at the required
temperature for the required time (see Tables 1-3 for the
solvent, temperature, reaction time, and product yield for each
substrate). After cooling, the autoclave was degassed and
opened. The crude reaction mixture was filtered, the solvent
was evaporated under vacuum and products were isolated by
column chromatography (SiO2): 7a (4:1 hexane/AcOEt, 191
mg, 39%); 7′a (4:1 hexane/AcOEt, 63 mg, 13%); 7b (4:1 hexane/
AcOEt, 249 mg, 65%); 7c (3:2 hexane/AcOEt, 432 mg, 62%);
7d (4:1 hexane/AcOEt, 347 mg, 73%); 7e (4:1 hexane/AcOEt,
443 mg, 78%);7f (10:1 hexane/AcOEt, 322 mg, 65%); 7g (10:1
hexane/AcOEt, 307 mg, 46%); 7′g (10:1 hexane/AcOEt, 94 mg,
14%); 8b (10:1 hexane/AcOEt, 101 mg, 21%); 9h(Z) (6:1 hexane/
AcOEt, 427 mg, 71%); 11a (10:1 hexane/AcOEt, 298 mg, 61%);
11b (10:1 hexane/AcOEt, 355 mg, 58%); 11b (10:1 hexane/
AcOEt, 312 mg, 74%); 13′a (10:1 hexane/AcOEt, 387 mg, 81%);
13b (10:1 hexane/AcOEt, 382 mg, 70%); 14a (10:1 hexane/
AcOEt, 23 mg, 5%); 14b (10:1 hexane/AcOEt, 46 mg, 8%); 17
(1:1 hexane/AcOEt, 330 mg, 68%); 18 (4:1 CH2Cl2/AcOEt, 30
mg, 8%).
Conclusions
In summary, we have found a simple and efficient
route for the synthesis of new heterocyclic compounds
starting from readily available acetylenic derivatives.
The catalytic system, based on PdI2 with an excess of
KI in the presence of oxygen as oxidant, has proven to
be particularly effective in promoting the oxidative
cyclization-alkoxycarbonylation of 4-yn-1-ones, prop-2-
ynyl R-ketoesters, and R-ketoamides to give different
heterocyclic carbonyl compounds under mild conditions.
Interestingly, in the case of prop-2-ynyl R-ketoamides,
the oxidative carbonylation gave a mixture of five-
membered and six-membered heterocycles, the latter
deriving from an unusual rearrangement of the initially
formed five-membered compounds. This rearrangement
was acid-catalyzed, so the substrates could be conve-
niently converted in high yields into new 3,6-dioxo-
1,2,3,6-tetrahydro-pyridine derivatives through a two-
step, one-pot procedure corresponding to carbonylation
followed by acid-catalyzed rearrangement.
Acid-Promoted Isomerization of 9h(Z) into 9h(E).
Treatment with HCl in Anhydrous Methanol. A mixture
of pure (Z)-(4-Acetyl-4-ethyl-5-oxo-1-phenyl-pyrrolidin-2-ylidene)-
acetic acid methyl ester 9h(Z). Next, (1.0 mmol) in HCl (10%
weight in dry methanol, 10 mL) was stirred at room temper-
ature for 20 min. The solution was neutralized with Na2CO3
and then filtered. The solvent was eliminated under reduced
pressure and (E)-(4-acetyl-4-ethyl-5-oxo-1-phenyl-pyrrolidin-
2-ylidene)-acetic acid methyl ester 9h(E) (287 mg, 95%) was
recovered as pure product.
Typical Procedure for the Acid-Catalyzed Rearrange-
ment of Oxazolines 13a, 13b, 13′a, and 6-Methoxy-3-oxo-
2,3-dihydropyridines 14a, 14b. Treatment with HCl in
Anhydrous Methanol. A mixture of pure oxazoline 13a or
13b (1.0 mmol) in HCl (10% weight in dry methanol, 10 mL)
was stirred at room temperature for 20 min. The solution was
neutralized with Na2CO3 and then filtered. The solvent was
eliminated under reduced pressure and 6-methoxy-3-oxo-2,3-
dihydropyridines 14a or 14b were recovered as pure products
in 96% or 92% yield, respectively.
Treatment with HCl in Dioxane/Water. A mixture of
pure oxazolines 13a, 13′a, 13b, or 6-methoxy-3-oxo-2,3-di-
hydropyridines 14a and 14b (1.0 mmol) respectively in HCl
(0.22 M in dioxane/water 4/1 v/v, 10 mL) was stirred at room
temperature for 15-20 min. The solution was neutralized with
Na2CO3 and then extracted several times with Et2O. The
collected organic layers were dried over Na2SO4 and filtered,
and the solvent was eliminated by rotatory evaporation. The
3,6-dioxo-1,2,3,6-tetrahydro-pyridines 15a, 15′a, and 15b,
respectively, were recovered as pure products in yields ranging
from 92% to 96%: 15a (203 mg, 96%); 15′a (222 mg, 93%);
15b (251 mg, 92%).
Typical Procedure for the Acid-Catalyzed Rearrange-
ment of Crude Carbonylation Mixture of 12a or 12b. A
solution of HCl (0.22 M in dioxane/water 4/1 v/v, 15 mL) was
slowly added to the crude reaction mixture deriving from
carbonylation of 12a,b, and the resulting mixture was stirred
at room temperature for 0.5 h. The mixture was extracted
several times with Et2O and the collected organic layers were
dried over Na2SO4. After filtration and elimination of the
solvent by rotatory evaporation, 3,6-dioxo-1,2,3,6-tetrahydro-
pyridine 15a was purified by column chromatography (SiO2)
using hexane/AcOEt 10/1 as eluent (300 mg, 71% yield based
on 12a). An analogous procedure was used for the crude
mixture of the oxidative carbonylation of 12b, to obtain pure
15b by column chromatography (SiO2) using hexane/AcOEt
10/1 as eluent (370 mg, 68% yield).
Experimental Section
Preparation of Substrates. Methyl acetoacetate, methyl
2-ethylacetoacetate, 3-ethyl-2,4-pentanedione, ethyl 2-benzyl-
acetoacetate, methyl cyclohexanone-2-carboxylate, ethyl ben-
zoyl acetate, acetoacetanilide, oxalyl chloride, methyl sulfoxide,
4-pentyn-1-ol, R,R-dichloromethyl methyl ether, pyruvic acid,
benzoylformic acid, prop-2-ynylamine, N-methylprop-2-yny-
lamine, 2-methyl-3-butyn-2-ol, bromoethane, and iodomethane
were commercially available and were used without further
purification. 1,1-Dimethylprop-2-ynylamine,9 substrates 6a,10
6b,11 6c,11 6d,11 6e,11 6f,12 6g,11 and 6h11 were prepared
according to the procedures reported in the literature. Alky-
lations of ethyl benzoyl acetate and acetoacetanilide were
carried out according to a reported procedure13 using EtBr or
MeI as alkylating agents of the respective sodium enolates.
Propynyl esters, secondary propynylamides of pyruvic or
benzoylformic acids were prepared through standard proce-
dures14 starting from the respective acid chlorides obtained
according a preparation reported in the literature.15 The
substrates were purified by column chromatography using
suitable eluents. 1H, 13C NMR, IR, mass spectra, and elemental
analyses confirmed the assigned structures (see Supporting
Information).
Typical Procedure for the Oxidative Cyclization-
Alkoxycarbonylation of 4-Yn-1-ones 6a-g, 2-Acetyl-2-
ethylpent-4-ynoic Acid Phenylamide 6h, Prop-2-ynyl
r-Ketoesters 10a,b, Prop-2-ynyl r-Ketoamides 12a,b, and
2-Oxo-N-prop-2-ynylpropionamide 16, and Separation of
Products. All carbonylations were carried out in a 45 mL
(8) For a review on the gem-dialkyl effect on cyclizations, see:
Sammes, P. G.; Weller, D. J. Synthesis 1995, 1205-1222.
(9) (a) Straziota, M. Ger. Offen Appl. DE 2530003, 1976; Chem.
Abstr. 1976, 84, 135100n. (b) Foschi, C.; Carrillo, G.; Colombo, M. Ger.
Offen Appl. DE 2600706, 1976; Chem. Abstr. 1976, 85, 142612e.
(10) Cruciani, P.; Stammler, R.; Aubert, C.; Malacria, M. J. Org.
Chem. 1996, 61, 2699-2708.
(11) Polo, E.; Bellabarba, R. M.; Prini, G.; Traverso, O.; Green, M.
L. H. J. Organomet. Chem. 1999, 577, 211-218.
(12) Adams, T. C.; Dupont, A. C.; Carter, J. P.; Kachur, J. F.;
Guzewska, M. E.; Rzeszotarski, W. J.; Farmer, S. G.; Noronha-Blob,
L.; Kaiser, C. J. Med. Chem. 1991, 34, 1585-1593.
(13) Searles, A. L.; Lindwall, H. G. J. Am. Chem. Soc. 1946, 68, 988-
990.
(14) Furniss, B. S.; Hannaford, A. J.; Smith, P. W. G.; Tatchell, A.
R. Vogel’s Textbook of Practical Organic Chemistry, 5th ed.; Longmann
Scientific & Techical; Essex, U.K., 1991; pp 698, 708.
(15) Ottenheijm, H. C. J.; de Man, J. H. M. Synthesis 1975, 163-
164.
4976 J. Org. Chem., Vol. 70, No. 13, 2005

Pd-Catalyzed Oxidative Cyclization-Alkoxycarbonylation
Characterization of Products. All products were fully
characterized by IR, 1H NMR and 13C spectroscopies, MS
spectrometry, elemental analysis, and in the case of 14b and
15a, also by X-ray diffraction analysis (see Supporting Infor-
mation). Melting points are uncorrected. 1H NMR and 13C
NMR spectra were recorded in CDCl3 solutions at 300 and 75
MHz, respectively, with Me4Si as internal standard. Chemical
shifts and coupling constants (J) are given in ppm (δ) and in
Hz, respectively. IR spectra were taken on a FT-IR spectrom-
eter. Mass spectra were obtained at 70 eV on a GC-MS
apparatus. Microanalyses were performed at our analytical
laboratory.
The stereochemistry of 7g and 7′g was attributed on the
basis of 1H NMR chemical shifts of the protons of geminal CH3
(R2) and CO2CH2CH3 (R3) groups, respectively. The CH3
protons or alternatively the CO2CH2CH3 group ones suffer
from the induced field generated by the ring current when the
B0 field is perpendicular to the plane of the vicinal phenyl ring
(R1). The geometry of the system is such that the protons in
question are situated “inside” the diamagnetic circulation of
electrons, undergoing an average higher-field shift. Thus it is
possible to distinguish the two configurations when the phenyl
and the vicinal CH3 groups are on the same side [δ 0.86 (s)
CH3, 1.27 (t) OCH2CH3, 3.10 (s) OCH3, 4.15-4.26 (m) OCH2-
CH3] or when they are on the opposite side [δ 0.77 (t)
OCH2CH3, 1.47 (s) CH3, 3.09 (s) OCH3, 3.44-3.70 (m) OCH2-
CH3], the absorption of the OCH3 protons being shifted at
higher field of about the same value for both diastereoisomers.
2-Methoxy-5-methoxycarbonylmethylene-2-methyl-
tetrahydrofuran-3-carboxylic Acid Methyl Ester 7a. Pale
yellow oil. IR (film) νmax cm-1 3015 (w), 2956 (m), 1740 (s), 1719
(s), 1438 (m), 1360 (m), 1326 (m), 1265 (m), 1154 (m); 1H NMR
δH 5.33 (t, 1 H, J ) 1.9), 3.74 (s, 3 H), 3.67 (s, 3 H), 3.50-3.47
(m, 1 H), 3.27 (s, 3 H), 3.37-3.23 (m, 2 H), 1.71 (s, 3 H); MS
m/z 244 (M+, 3), 212 (60), 181 (100), 153 (55), 111 (33), 69 (25),
59 (21). Anal. Calcd for C11H16O6: C, 54.09; H, 6.60. Found C,
53.96; H, 6.56.
2-Methoxy-5-methoxycarbonylmethylene-2-methyl-
tetrahydrofuran-3-carboxylic Acid Methyl Ester 7′a. Pale
yellow oil, impure of 7a. IR (film) νmax cm-1 3015 (w), 2956
(m), 1740 (s), 1719 (s), 1438 (m), 1360 (m), 1326 (m), 1265 (m),
1154 (m); 1H NMR δH 5.36 (t, 1 H, J ) 1.8), 3.72 (s, 3 H), 3.66
(s, 3 H), 3.36-3.33 (m, 1 H), 3.31 (s, 3 H), 3.34-3.20 (m, 2 H),
1.49 (s, 3 H); MS m/z 244 (M+, 4), 213 (80), 181 (100), 171 (38),
153 (78), 111 (70), 85 (37), 59 (30). Anal. Calcd for C11H16O6:
C, 54.09; H, 6.60. Found C, 53.93; H, 6.54.
60.2, 50.6, 49.8, 38.7, 34.8, 15.0, 13.9; MS m/z 348 (M+, 1),
317 (5), 316 (10), 285 (5), 257 (10), 243 (10), 225 (90), 197 (5),
179 (5), 165 (5), 141 (5), 115 (5), 91 (100), 69 (5), 59 (5). Anal.
Calcd for C19H24O6: C, 65.50; H, 6.94. Found: C, 65.42; H,
7.00.
(4-Acetyl-4-ethyl-5-methoxy-5-methyldihydrofuran-2-
ylidene)acetic Acid Methyl Ester 7d. Pale yellow oil. IR
(film) νmax cm-1 2972 (m), 1711 (s), 1654 (s), 1462 (m), 1437
(s), 1360 (s), 1284 (m), 1138 (s); 1H NMR δH 5.34 (dd, 1 H, J )
2.4, 1.3), 3.69 (s, 3 H), 3.52 (ddd, 1 H, J ) 18.3, 2.3, 1.6), 3.44
(dd, 1 H, J ) 18.3, 1.3), 3.25 (s, 3 H), 2.19 (s, 3 H), 1.94 (qdd,
1 H, J ) 13.5, 7.4, 1.6), 1.59 (s, 3 H), 1.30 (qd, 1 H, J ) 13.5,
7.4), 0.81 (t, 3 H, J ) 7.4) (the stereochemistry of the
substituents of the ring was confirmed by a 2D NOESY
experiment); 13C NMR δC 206.2, 172.9, 168.4, 112.17, 92.0,
63.9, 50.7, 49.5, 35.3, 28.8, 25.8, 15.5, 8.6; MS m/z 256 (M+,
1), 241 (1), 225 (10), 195 (5), 182 (100), 167 (30), 151 (20), 139
(10), 123 (20), 113 (50), 101 (40), 79 (10), 69 (15), 55 (15). Anal.
Calcd for C13H20O5: C, 60.92; H, 7.87. Found: C, 60.84; H,
7.92.
7a-Methoxy-2-methoxycarbonylmethylenehexahydro-
benzofuran-3a-carboxylic Acid Methyl Ester 7e. Colorless
oil. IR (film) νmax cm-1 2948 (s), 1759 (s), 1652 (s), 1462 (m),
1435 (s), 1368 (s), 1360 (s), 1330 (m), 1292 (m), 1277 (s), 1237
(s), 1188 (m), 1156 (m), 1124 (s), 1105 (s), 1079 (m), 1040 (s),
1
994 (s); H NMR δH 5.34 (dd, 1 H, J ) 2.3, 1.0), 3.65 (s, 3 H),
3.61 (s, 3 H), 3.46 (dd, 1 H, J ) 18.0, 2.3), 3.18 (s, 3 H), 3.17
(d, broad, 1 H, J ) 18.0), 2.26 (d, broad, 1 H, J ) 13.3), 1.87-
1.58 (m, 4 H), 1.44 (d, broad, 1 H, J ) 13.3), 1.33-1.15 (m, 2
H); 13C NMR δC 172.7, 171.6, 168.1, 109.1, 93.1, 53.1, 51.7,
50.6, 48.9, 40.3, 33.7, 26.8, 21.4, 20.6; MS m/z 284 (M+, 2),
252 (23), 237 (2), 221 (30), 194 (13), 193 (100), 168 (63), 153
(19), 137 (45), 109 (24), 101 (11), 91 (15), 69 (15), 55 (10). Anal.
Calcd for C14H20O6: C, 59.14; H, 7.09. Found: C, 59.05; H,
7.16.
(5-Methoxy-5-phenyl-dihydrofuran-2-ylidene)acetic
Acid Methyl Ester 7f. Pale yellow oil. IR (film) νmax cm-1 2993
(w), 2945 (m), 2834 (w), 1745 (w), 1708 (s), 1650 (s), 1434 (s),
1359 (s), 1324 (m), 1269 (m), 1245 (m), 1189 (m), 1115 (s), 1041
1
(s), 972 (s), 700 (s); H NMR δH 7.46-7.31 (m, 5 H), 5.54 (dd,
1 H, J ) 1.8, 1.5), 3.69 (s, 3 H), 3.40-3.29 (m, 1 H), 3.26-3.13
(m, 1 H), 3.11 (s, 3 H), 2.53-2.45 (m, 1 H), 2.08-1.97 (m, 1
H); 13C NMR δC 175.4, 168.5, 138.5, 128.5, 128.4, 125.7, 112.6,
91.4, 50.9, 50.6, 38.1, 29.8; MS m/z 248 (M+, 19), 230 (3), 216
(47), 201 (23), 187 (4), 185 (10), 159 (40), 147 (100), 129 (17),
115 (33), 101 (54), 91 (10), 77 (56), 69 (25). Anal. Calcd for
C14H16O4: C, 67.73; H, 6.50. Found: C, 67.65; H, 6.55.
3-Ethyl-2-methoxy-5-methoxycarbonylmethylene-2-
methyltetrahydrofuran-3-carboxylic Acid Methyl Ester
7b. Pale yellow oil. IR (film) νmax cm-1 2953 (s), 2884 (m), 2841
(m), 1750 (s), 1710 (s), 1646 (s), 1436 (s), 1360 (s), 1244 (s); 1H
NMR δH 5.28 (dd, 1 H, J ) 2.3, 1.3), 3.67 (s, 3 H), 3.64 (s, 3
H), 3.52 (ddd, 1 H, J ) 18.6, 2.3, 1.4), 3.36 (dd, 1 H, J ) 18.6,
1.3), 3.20 (s, 3 H), 1.91 (qdd, 1 H, J ) 13.3, 7.3, 1.4), 1.53 (s,
3 H), 1.24 (qd, 1 H, J ) 13.3, 7.3), 0.79 (t, 3 H, J 7.3) (the
stereochemistry of the substituents of the ring was confirmed
by a 2D NOESY experiment); 13C NMR δC 172.9, 171.4, 168.2,
111.8, 92.2, 59.8, 51.9, 50.6, 49.6, 35.2, 25.9, 14.9, 8.8; MS m/z
272 (M+, 1), 257 (1), 225 (1), 208 (50), 180 (90), 154 (5), 149
(100), 135 (20), 121 (30), 93 (35), 77 (30), 59 (30), 53 (20). Anal.
Calcd for C13H20O6: C, 57.34; H, 7.40. Found: C, 57.26; H,
7.43.
2-Methoxy-5-methoxycarbonylmethylene-3-methyl-2-
phenyltetrahydrofuran-3-carboxylic Acid Ethyl Ester
7g. Colorless oil; IR (film) νmax cm-1 2981 (m), 2946 (m), 1736
(s), 1732 (s), 1712 (s), 1450 (m), 1436 (m), 1360 (s), 1301 (m),
1273 (m), 1125 (s), 1039 (s), 983 (s); 1H NMR δH 7.50-7.47
(m, 2 H), 7.39-7.36 (m, 3 H), 5.54 (dd, 1 H, J ) 2.4, 1.3), 4.26-
4.15 (m, 2 H) 3.94 (dd, 1 H, J ) 18.3, 2.4), 3.70 (s, 3 H), 3.34
(dd, 1 H, J ) 18.3, 1.3), 3.10 (s, 3 H), 1.27 (t, 3 H, J ) 7.1),
0.86 (s, 3 H); 13C NMR δC 172.6, 171.2, 168.3, 133.5, 129.0,
128.2, 127.7, 113.3, 92.8, 61.1, 55.6, 51.3, 50.9, 40.3, 22.0, 14.0;
MS m/z 334 (M+, 1), 319 (2), 302 (45), 289 (15), 271 (8), 229
(100), 137 (15), 105 (15), 77 (9). Anal. Calcd for C18H22O6: C,
64.66; H, 6.63. Found: C, 64.59; H, 6.67.
2-Methoxy-5-methoxycarbonylmethylene-3-methyl-2-
phenyltetrahydrofuran-3-carboxylic Acid Ethyl Ester
7′g. Colorless oil. IR (film) νmax cm-1 2982 (m), 2946 (m), 1737
(s), 1732 (s), 1712 (s), 1450 (m), 1436 (m), 1360 (s), 1299 (m),
1211 (m), 1125 (s), 1039 (s), 983 (s); 1H NMR δH 7.50-7.46
(m, 2 H), 7.37-7.31 (m, 3 H), 5.52 (dd, 1 H, J ) 2.3, 1.3), 3.81
(dd, 1 H, J ) 17.8, 1.3), 3.68 (s, 3 H), 3.70-3.44 (m, 2 H) 3.09
(s, 3 H), 2.59 (dd, 1 H, J ) 17.8, 2.3), 1.47 (s, 3 H) 0.77 (t, 3 H,
J ) 7.1); 13C NMR δC 173.7, 172.3, 168.5, 134.4, 129.0, 128.1,
126.7, 111.8, 91.5, 60.9, 57.4, 50.8, 50.7, 41.4, 16.3, 13.3; MS
m/z 334 (M+, 1), 319 (2), 302 (45), 289 (15), 271 (8), 229 (100),
3-Benzyl-2-methoxy-5-methoxycarbonylmethylene-2-
methyltetrahydrofuran-3-carboxylic Acid Ethyl Ester
7c. Pale yellow oil. IR (film) νmax cm-1 2981 (s), 2945 (s), 2832
1
(m), 1744 (s), 1713 (s), 1654 (s), 1598 (m), 1437 (s); H NMR
δH 7.26-7.23 (m, 3 H), 7.02-6.98 (m, 2 H), 5.40 (dd, 1 H, J )
2.3, 1.3), 4.21-4.09 (m, 2 H) 3.68 (s, 3 H), 3.41 (d, 1 H, J )
18.0, 1.3), 3.38 (d, 1 H, J ) 12.9), 3.36 (dd, 1 H, J ) 18.0, 2.3),
3.27 (s, 3 H), 2.38 (d, 1 H, J ) 12.9), 1.70 (s, 3 H), 1.20 (t, 3 H,
J ) 7.2) (the stereochemistry of the substituents of the ring
was confirmed by a 2D NOESY experiment); 13C NMR δC
172.4, 170.5, 168.0, 135.6, 129.8, 128.4, 127.0, 111.7, 92.6, 60.9,
J. Org. Chem, Vol. 70, No. 13, 2005 4977

Bacchi et al.
137 (15), 105 (15), 77 (9). Anal. Calcd for C18H22O6: C, 64.66;
H, 6.63. Found: C, 64.60; H, 6.68.
21.9, 10.2; MS m/z 239 (M+, 5), 224 (5), 198 (30), 180 (35), 154
(10), 128 (100), 111 (60), 87 (20), 83 (40), 69 (100), 59 (90).
Anal. Calcd for C12H17NO4: C, 60.24; H, 7.16; N, 5.85. Found:
C, 60.16; H, 7.10; N, 5.79.
3-Ethyl-2-methyl-5-oxocyclopent-1-ene-1,3-dicarboxy-
lic Acid Dimethyl Ester 8b. Colorless oil. IR (film) νmax cm-1
2955 (m), 1713 (s), 1632 (s), 1435 (m), 1328 (m), 1233 (s), 1018
(2-Benzoyl-4,4-dimethyl-4H-oxazol-5-ylidene)acetic Acid
Methyl Ester 13b. Pale yellow oil. IR (film) νmax cm-1 2974
(w), 1716 (m), 1664 (s), 1596 (m), 1578 (m), 1353 (m), 1200
1
(m); H NMR δH 3.80 (s, 3 H), 3.67 (s, 3 H), 2.90 (d, 1 H, J )
18.6), 2.36 (d, 1 H, J ) 18.6), 2.24 (s, 3 H), 2.14-2.04 (m, 1 H),
1.81-1.70 (m, 1 H), 0.77 (t, 3 H, J ) 7.4); 13C NMR δC 200.4,
182.6, 172.4, 163.1, 133.2, 56.9, 52.8, 52.0, 43.6, 27.1, 15.2, 8.4;
MS m/z 240 (M+, 10), 225 (1), 212 (35), 208 (50), 181 (55), 180
(92), 154 (5), 149 (100), 135 (15), 121 (27), 107 (5), 93 (32), 77
(20), 59 (28). Anal. Calcd for C12H16O5: C, 59.99; H, 6.71.
Found: C, 59.90; H, 6.75.
1
(m), 1171 (m), 1101 (m); H NMR δH 8.31 (dd, 2 H, J ) 7.3,
1.4), 7.64 (td, 1 H, J ) 7.3, 1.4), 7.49 (t, 2 H, J ) 7.3), 5.84 (s,
1 H), 3.71 (s, 3 H), 1.79 (s, 6 H); 13C NMR δC 181.1, 175.8,
166.2, 153.4, 134.7, 134.1, 130.7, 128.6, 95.8, 74.4, 51.3, 24.4;
MS m/z 273 (M+, 1), 186 (4), 142 (3), 105 (100), 77 (40), 69
(10), 59 (1), 51 (10). Anal. Calcd for C15H15NO4: C, 65.92; H,
5.53; N, 5.13. Found: C, 65.84; H, 5.55; N, 5.08.
(Z)-(4-Acetyl-4-ethyl-5-oxo-1-phenylpyrrolidin-2-yl-
idene)acetic Acid Methyl Ester 9h (Z). Pale yellow oil. IR
(film) νmax cm-1 2971 (m), 1714 (s), 1650 (s), 1594 (m), 1434
(m), 1360 (m), 1124 (s), 1071 (s); 1H NMR δH 7.31 (t, 2 H, J )
7.8), 7.14-7.06 (m, 3 H), 5.55 (t, 1 H, J ) 2.0), 4.00 (dd, 1H, J
) 19.3, 2.0), 3.68 (s, 3 H), 3.04 (dd, 1H, J ) 19.3, 2.0), 2.42 (s,
3 H), 2.21-2.01 (m, 2 H), 0.96 (t, 3 H, J ) 7.4); 13C NMR δC
203.0, 168.0, 167.1, 156.5, 144.6, 128.7, 125.0, 122.5, 95.4, 60.5,
51.2, 33.4, 29.3, 25.1, 8.8; MS m/z 301 (M+, 38), 273 (100), 259
(66), 241 (49), 226 (50), 212 (34), 198 (65), 158 (88), 144 (49),
104 (48), 77 (89), 59 (5). Anal. Calcd for C17H19NO4: C, 67.76;
H, 6.36; N, 4.65. Found: C, 67.66; H, 6.40; N, 4.60.
(E)-(4-Acetyl-4-ethyl-5-oxo-1-phenylpyrrolidin-2-yl-
idene)acetic Acid Methyl Ester 9h (E). Pale yellow oil. IR
(film) νmax cm-1 2969 (m), 1736 (s), 1710 (s), 1628 (s), 1596
(w), 1496 (m), 1437 (m), 1400 (m), 1346 (m), 1167 (s), 1145 (s);
1H NMR δH 7.53-7.41 (m, 3 H), 7.16-7.13 (m, 2 H), 5.04 (t, 1
H, J ) 2.0), 4.06 (dd, 1 H, J ) 19.4, 2.0), 3.67 (s, 3 H), 3.17
(dd, 1 H, J ) 19.4, 2.0), 2.39 (s, 3 H), 2.17-2.08 (m, 2 H), 0.98
(t, 3 H, J ) 7.5); 13C NMR δC 203.2, 174.6, 167.4, 158.0, 133.6,
129.9, 129.3, 127.4, 93.8, 61.7, 50.9, 32.1, 28.5, 26.0, 8.7; MS
m/z 301 (M+, 6), 270 (8), 258 (100), 244 (33), 226 (47), 200 (19),
77 (18). Anal. Calcd for C17H19NO4: C, 67.76; H, 6.36; N, 4.65.
Found: C, 67.69; H, 6.38; N, 4.60.
(2-Acetyl-2-methoxy-5,5-dimethyl-[1,3]dioxolan-4-yl-
idene)acetic Acid Methyl Ester 11a. Colorless oil. IR (film)
νmax cm-1 2986 (m), 1748 (s), 1719 (s), 1655 (s), 1438 (m), 1384
(s), 1359 (s), 1206 (s), 1128 (s), 1049 (s); 1H NMR δH 5.44 (s, 1
H), 3.64 (s, 3 H), 3.37 (s, 3 H), 2.25 (s, 3 H), 1.79 (s, 3 H), 1.63
(s, 3 H); 13C NMR δC 197.7, 172.5, 166.2, 117.1, 90.0, 86.3, 50.9,
49.2, 24.8, 24.3; MS m/z 244 (M+, absent), 213 (3), 201 (95),
169 (16), 143 (47), 125 (60), 111 (40), 84 (25), 69 (100), 59 (32).
Anal. Calcd for C11H16O6: C, 54.09; H, 6.60. Found: C, 54.00;
H, 6.65.
(2-Benzoyl-2-methoxy-5,5-dimethyl-[1,3]dioxolan-4-
ylidene)acetic Acid Methyl Ester 11b. Colorless oil. IR
(film) νmax cm-1 2984 (w), 2949 (w), 1713 (s), 1659 (s), 1384
(m), 1360 (m), 1133 (s); 1H NMR δH 8.12 (dd, 2 H, J ) 7.5,
1.4), 7.59 (td, 1 H, J ) 7.5, 1.4), 7.46 (td, 2 H, J ) 7.5, 1.4),
5.55 (s, 1 H), 3.67 (s, 3 H), 3.49 (s, 3 H), 1.88 (s, 3 H), 1.62 (s,
3 H); 13C NMR δC 188.9, 172.3, 166.3, 133.7, 132.3, 130.5,
128.2, 90.3, 86.5, 51.0, 49.3, 24.9, 24.8; MS m/z 306 (M+,
absent), 275 (1), 247 (5), 201 (100), 169 (20), 142 (20), 125 (40),
105 (57), 77 (30), 69 (29), 59 (12). Anal. Calcd for C16H18O6:
C, 62.74; H, 5.92. Found: C, 62.63; H, 5.95.
6-Methoxy-2,2,5-trimethyl-3-oxo-2,3-dihydropyridine-
4-carboxylic Acid Methyl Ester 14a. Colorless oil. IR (film)
νmax cm-1 2979 (m), 2951 (m), 1745 (s), 1659 (s), 1627 (s), 1439
(m), 1346 (s), 1259 (s), 1067 (s); 1H NMR δH 3.75 (s, 3 H), 3.65
(s, 3 H), 1.96 (s, 3 H), 1.24 (s, 6 H); 13C NMR δC 201.7, 164.9,
154.3, 140.4, 134.0, 64.6, 53.1, 52.1, 27.5, 15.2; MS m/z 225
(M+, 6), 210 (18), 193 (100), 178 (98), 150 (46), 138 (26), 84
(30), 67 (58), 59 (8), 56 (24). Anal. Calcd for C11H15NO4: C,
58.66; H, 6.71; N, 6.22. Found: C, 58.60; H, 6.75; N, 6.14.
6-Methoxy-2,2-dimethyl-3-oxo-5-phenyl-2,3-dihydro-
pyridine-4-carboxylic Acid Methyl Ester 14b. Pale yellow
solid, mp 94-95 °C. IR (KBr) νmax cm-1 2920 (w), 1738 (m),
1
1650 (s), 1613 (m), 1428 (w), 1292 (m), 1019 (m); H NMR δH
7.34-7.41 (m, 5 H), 3.73 (s, 3 H), 3.58 (s, 3 H), 1.47 (s, 6 H);
13C NMR δC 202.5, 164.7, 153.4, 141.1, 134.6, 132.1, 129.5,
128.5, 128.0, 65.1, 53.6, 52.3, 28.1; MS m/z 272 ((M-15)+, 2),
255 (100), 240 (95), 212 (15), 200 (20), 156 (7), 129 (55), 115
(10), 84 (20), 75 (10), 56 (20). Anal. Calcd for C16H17NO4: C,
66.89; H, 5.96; N, 4.88. Found: C, 66.79; H, 6.03; N, 4.81.
2,2,5-Trimethyl-3,6-dioxo-1,2,3,6-tetrahydropyridine-
4-carboxylic Acid Methyl Ester 15a. Colorless solid, mp 121
°C; IR (KBr) νmax cm-1 3200 (m), 3086 (w), 1741 (s), 1685 (m),
1
1670 (s), 1623 (m), 1332 (s), 1208 (m); H NMR δH 7.93 (s, 1
H), 3.84 (s, 3 H), 2.08 (s, 3 H), 1.43 (s, 6 H); 13C NMR δC 193.9,
164.5, 161,7, 146.5, 135.7, 61.8, 52.6, 27.9, 15.3; MS m/z 211
(M+, 15), 196 (4), 180 (20), 154 (75), 126 (35), 96 (70), 67 (100).
Anal. Calcd for C10H13NO4: C, 56.86; H, 6.20; N, 6.63. Found:
C, 56.80; H, 6.25; N, 6.58.
2,2,5-Trimethyl-3,6-dioxo-1,2,3,6-tetrahydropyridine-
4-carboxylic Acid Propyl Ester 15′a. Pale yellow oil. IR
(film) νmax cm-1 3445 (s), 2974 (w), 2928 (w), 1733 (s), 1675
(s), 1634 (s), 1237 (m), 1210 (m); 1H NMR δH 6.31 (s, 1 H),
4.28 (t, 2 H, J ) 6.7), 2.16 (s, 3 H), 1.79-1.69 (m, 2 H), 1.49 (s,
6 H), 0.99 (t, 3 H, J ) 7.5); 13C NMR δC 193.5, 164.1, 161,3,
146.2, 136.1, 67.6, 62.0, 28.3, 21.9, 15.2, 10.2; MS m/z 239 (M+,
12), 196 (12), 182 (18), 181 (16), 140 (10), 112 (20), 67 (19).
Anal. Calcd for C12H17NO4: C, 60.24; H, 7.16; N, 5.85. Found:
C, 60.16; H, 7.18; N, 5.79.
2,2-Dimethyl-3,6-dioxo-5-phenyl-1,2,3,6-tetrahydro-
pyridine-4-carboxylic Acid Methyl Ester 15b. Colorless
oil. IR (film) νmax cm-1 3242 (m), 2919 (m), 1738 (s), 1732 (s),
1682 (s), 1614 (m), 1434 (m), 1171 (m), 1333 (m), 1165 (m); 1H
NMR δH 7.41-7.43 (m, 5 H), 6.32 (s, broad, 1 H), 3.64 (s, 3 H),
1.57 (s, 6 H); 13C NMR δC 194.8, 164.3, 160.5, 146.7, 135.8,
131.7, 130.2, 129.0, 128.1, 62.3, 52.6, 28.3; MS m/z 273 (M+,
4), 241 (5), 216 (50), 201 (10), 188 (30), 173 (4), 160 (40), 129
(100), 102 (60), 75 (20), 51 (10). Anal. Calcd for C15H15NO4:
C, 65.92; H, 5.53; N, 5.13. Found: C, 65.85; H, 5.56; N, 5.05.
2-[(2-Oxopropionylamino)methyl]but-2-enedioic Acid
Dimethyl Ester 17. Colorless oil. IR (film) νmax cm-1 3364
(m), 3009 (w), 2957 (m), 1726 (s), 1686 (s), 1526 (m), 1438 (m),
1271 (s), 1174 (m); 1H NMR δH 7.44 (s, 1 H), 6.00 (t, 1 H, J )
6.1), 4.10 (d, 2 H, J ) 6.1), 3.74 (s, 3 H), 3.66 (s, 3 H), 2.39 (s,
3 H); 13C NMR δC 196.2, 166.5, 165.4, 160.2, 129.8, 123.3, 52.5,
51.9, 40.9, 24.2; MS m/z 243 (M+, 1), 212 (5), 200 (40), 172
(10), 168 (100), 142 (40), 126 (20), 98 (20), 59 (30). Anal. Calcd
for C10H13NO6: C, 49.38; H, 5.39; N, 5.76. Found: C, 49.32;
H, 5.41; N, 5.70.
(2-Acetyl-4,4-dimethyl-4H-oxazol-5-ylidene)acetic Acid
Methyl Ester 13a. Pale yellow oil. IR (film) νmax cm-1 2975
(w), 2942 (w), 1721 (s), 1669 (s), 1350 (m), 1166 (m), 1078 (s);
1H NMR δH 5.78 (s, 1 H), 3.70 (s, 3 H), 2.56 (s, 3 H), 1.71 (s, 6
H); 13C NMR δC 188.4, 176.3, 166.0, 154.3, 96.0, 73.8, 51.2,
26.7, 24.2; MS m/z 211 (M+, 16), 180 (15), 168 (17), 141 (56),
110 (33), 84 (31), 69 (100), 59 (16). Anal. Calcd for C10H13NO4:
C, 56.86; H, 6.20; N, 6.63. Found: C, 56.80; H, 6.18; N, 6.57.
(2-Acetyl-4,4-dimethyl-4H-oxazol-5-ylidene)acetic Acid
Propyl Ester 13′a. Pale yellow oil. IR (film) νmax cm-1 2975
(m), 2940 (m), 1721 (s), 1668 (s), 1461 (m), 1350 (m), 1166 (s),
1075 (s); 1H NMR δH 5.74 (s, 1 H), 4.02 (t, 2 H, J 6.7), 2.52 (s,
3 H), 1.67 (s, 6 H) 1.67-1.59 (m, 2 H), 0.91 (t, 3 H, J 7.5); 13
C
NMR δC 188.4, 176.0, 165,7, 154.3, 96.5, 73.7, 65.7, 26.7, 24.3,
4978 J. Org. Chem., Vol. 70, No. 13, 2005

Pd-Catalyzed Oxidative Cyclization-Alkoxycarbonylation
(2-Acetyloxazol-5-yl)acetic Acid Methyl Ester 18. Col-
orless oil. IR (film) νmax cm-1 2957 (m), 2918 (m), 2851 (m),
1740 (vs), 1704 (s), 1508 (m), 1232 (m), 1120 (m); 1H NMR δH
7.21 (t, 1 H, J ) 0.7), 3.82 (d, 2 H, J ) 0.7), 3.75 (s, 3 H), 2.65
(s, 3 H); 13C NMR δC 185.5, 167.8, 157.7, 148.6, 127.4, 52.6,
31.5, 26.3; MS m/z 183 (M+, 100), 168 (5), 141 (15), 139 (10),
124 (60), 109 (10), 97 (10), 82 (90), 68 (15), 59 (30), 52 (5). Anal.
Calcd for C8H9NO4: C, 52.46; H, 4.95; N, 7.65. Found: C,
52.45; H, 5.01; N, 7.58.
zionale PIN MM03027791). The facilities of Centro
Interfacolta` di Misure (Universita` di Parma) were used
for recording NMR spectra.
Supporting Information Available: Structures of 14b
and 15a (Figures S1 and S2, respectively); X-ray structural
information for 14b and 15a (Tables S1 and S2); spectroscopic
characterization of 6b-h, 10a,b, 12a,b, and 16 substrates;
crystallographic data for 14b and 15a in CIF format. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. Financial support from the
Ministero dell’Universita` e della Ricerca Scientifica e
Tecnologica is aknowledged (Progetto d’Interesse Na-
JO050155V
J. Org. Chem, Vol. 70, No. 13, 2005 4979