Preparation of α- and β-substituted alanine derivatives by α-amidoalkylation or Michael addition reactions under heterogeneous catalysis assisted by microwave irradiation

Article abstract of DOI:10.1016/S0040-4020(01)00461-6

Silica-supported Lewis acids are useful catalysts in conjunction with microwave irradiation for the synthesis of a range of alanine derivatives. Reaction of methyl α-acetamidoacrylate (1) with different heterocycles, such as furan (2), pyrrole (3), N-benzylpyrrole (4), indole (5) and pyrazole (6) and the carbocycle 1,3,5-trihydroxybenzene (7), led to several α-amino acid precursors.

Full text of DOI:10.1016/S0040-4020(01)00461-6

TETRAHEDRON
Pergamon
Tetrahedron 57 22001) 5421±5428
Preparation of a- and b-substituted alanine derivatives by
a-amidoalkylation or Michael addition reactions under
heterogeneous catalysis assisted by microwave irradiation
a,p
Antonio de la Hoz, Angel Dõaz-Ortiz, Marõa Victoria Gomez, Jose Antonio Mayoral,
a
a
b
Â
Â
Â
Â
Andres Moreno, Ana Marõa Sanchez-Migallon and Ester Vazquez
a,p
a
a
Â
Â
Â
Â
Â
a
 Â
Facultad de Quõmica, Departamento de Quõmica Organica, Universidad de Castilla-La Mancha, Campus Universitario,
13071 Ciudad Real, Spain
bICMA-Facultad de Ciencias, Universidad de Zaragoza-CSIC, Pedro Cerbuna 12, E-50009 Zaragoza, Spain
Received 18 January 2001; revised 26 March 2001; accepted 24 April 2001
AbstractÐSilica-supported Lewis acids are useful catalysts in conjunction with microwave irradiation for the synthesis of a range of alanine
derivatives. Reaction of methyl a-acetamidoacrylate 21) with different heterocycles, such as furan 22), pyrrole 23), N-benzylpyrrole 24),
indole 25) and pyrazole 26) and the carbocycle 1,3,5-trihydroxybenzene 27), led to several a-amino acid precursors. q 2001 Elsevier Science
Ltd. All rights reserved.
1. Introduction
reactions. On the other hand, enamides such as methyl
a-acetamidoacrylate can act as a-amidoalkylation reagents,
most often after protonation at the terminal carbon atom.8
The development and application of new and practical
methods for the preparation of structurally diverse amino
acid derivatives is of fundamental importance due to the
widespread use of these compounds in practically all areas
of the physical and life sciences. Thus, non-naturally occur-
ring amino acid derivatives constitute an increasingly
important resource for new chemotherapeutic agents that
include antibacterial compounds and enzyme inhibitors.1
Some b-dialkylamino-a-alanines and b-2heteroaryl)-a-
alanines are non-proteinogenic amino acids that are widely
found in nature.2 Moreover, aromatic amino acids, such as
phenylglycine and arylglycine analogues, have found
applications in the synthesis of penicillin and cephalosporin
antibiotics.3
Here we would like to describe the ability of methyl
a-acetamidoacrylate 21) to act as an electrophile in Lewis
acid catalyzed a-acetamidoalkylation reactions with hetero-
cycles such as furan, pyrrole, N-benzylpyrrole, indole and
pyrazole to afford 2-methylglycine analogues. The results
obtained depend very much on the reaction conditions and
the Lewis acid used as the catalyst and a comparative study
of the in¯uence of the catalyst on the yield of the a-amino
acid precursors will be showed.
The reactions were performed using homogeneous catalysis,
although in these cases long reaction times were required.
For this reason, we found it of interest to study the reaction
of methyl a-acetamidoacrylate with different heterocycles
and carbocycles using heterogeneous catalysis assisted by
microwave irradiation under solvent-free conditions. In all
cases, the catalysts were obtained by treatment of silica with
ZnCl2 [Si2Zn)],9 Et2AlCl [Si2Al)]10 or TiCl4 [Si2Ti)].11 The
most important objectives of this work were:
N-Acyl-a,b-didehydroamino acids have proven to be useful
intermediates in the asymmetric and non-asymmetric
synthesis of a-amino acids.4 The potential value of the
N-acyl-a,b-dehydroamino acid esters in synthetic chemistry
is derived mainly from their ready availability and the
intrinsic reactivity of their double bonds due to the presence
both of acylamino and ester groups, which facilitate the
nucleophilic attack at the a and b positions. In particular,
alanine derivatives are known to behave as dienophiles,5
dipolarophiles6 and electrophiles7 in Michael-type
1. To try to decrease the reaction times.
2. To avoid the use of the polluting homogeneous catalysts
commonly used.
3. To study the chemo- and regioselectivity of the reaction
2competition between a-amidoalkylation, Michael
addition and Diels±Alder cycloaddition was observed).
4. To determine the reactivity of these alanine derivatives
with aromatic systems.
Keywords: microwave irradiation; amino acid; nucleophile.
Corresponding authors. Tel.: 134-926295300; fax: 134-926295318;
e-mail: adlh@qino-cr.uclm.es
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020201)00461-6

5422
A. de la Hoz et al. / Tetrahedron 57 62001) 5421±5428
NHCOCH3
CO2CH3
MW
CO2CH3
+
+
C
CH2
CO2CH3
X
X
NHCOCH3
CH
Si(M)
X
CH3
NHCOCH3
2: X = O
3: X = NH
1
Scheme 1.
The process described here, because of its procedural
simplicity and the use of readily available chemicals,
appears to be a promising and useful route to a wide variety
of aromatic a-amino acids with potential therapeutic
action.12
or carbocycles, such as 2±8, under microwave irradiation
within 10±30 min to afford the a- and/or b-substituted
alanine derivatives 9±13, 15±17. This method provides
access to aryl-substituted amino acid derivatives as well
as to amino acids containing a b-tertiary carbon. The
reactions were usually performed at atmospheric pressure
in a focused microwave reactor with the exception of the
reactions involving furan. In these cases, owing to the low
boiling point of furan, a hermetically sealed Te¯on vessel in
a domestic oven or a modi®ed Fisher±Porter reaction vessel
2. Results and discussion
Methyl a-acetamidoacrylate 21) reacted with heterocycles
Table 1. Reactions of heterocyclic or carbocyclic derivatives with methyl a-acetamidoacrylate 21) using silica-supported Lewis acids as catalysts
Entry
Heterocycle 2molar ratio)a
Furan 22) 210:1)
Catalystb
Reaction conditions
Products
Yield 2%)
1
2
3
Si2Zn)
Si2Al)
Si2Ti)
15 min 150 W 508C
15 min 150 W 508C
15 min 150 W 508C
9: ,3
9: 16
9: 18
CO2CH3
C
O
NHCOCH3
CH3
9
4
5
Pyrrole 23) 26:1)
Si2Zn)
Si2Al)
Si2Ti)
Si2Zn)
15 min 270 W 1008C
25 min 150 W 708C
30 min 120 W 808C
15 min 1008C
11: 70
10: 51111: 12
10: 32111: 27
11: 14
CO2CH3
C
N
NHCOCH3
6
CH3
10
7c
H
+
CH2
CO2CH3
CH
N
11
NHCOCH3
H
8
9
10
N-Benzyl-pyrrole 24) 21:2)
Si2Zn)
Si2Al)
Si22Ti)
15 min 285 W 1008C
10 min 240 W 708C
15 min 240 W 608C
12: ,3
12: 26
12: 44
CO2CH3
C
NHCOCH3
N
CH3
CH2Ph
12
11
12
13
14
15c
Si2Zn)
Si2Al)
Si2Ti)
Si2Al)d
Si2Al)d
15 min 270 W 1008C
15 min 150 W 708C
15 min 150 W 708C
15 min 90 W 508C
15 min 508C
14: 37
NHCOCH3
CH3
13: 39114: 54
13: 18114: 22
13: 50114: 23
13: 12
C
CO2CH3
+
CH3
Indole 25) 21:1)
CH3O2C
N
N
N
H
H
13
14
H
16
17
18
19
Pyrazole 26) 21:1)
Si2Zn)
Si2Al)
Si2Ti)
Si2Al)e
10 min 240 W 808C
10 min 240 W 808C
10 min 240 W 808C
10 min 210 W 808C
15116:,3
15: 17116: 24
15: 7116: 6
15: 7116: 41
N
N
+
N
N
CO2CH3
CH2 CH
CH3
C CO2CH3
NHCOCH3
NHCOCH3
O
16
15
20
1,3,5-Trihydroxy-benzene
27) 21:3)
Si2Zn)
15 min 285W 1008C
HO
17: 41
17
O
21
22
Si2Al)
Si2Ti)
10 min 240W 608C
10 min 240W 60 8C
17: 37
17: 46
CH3
OH
NHCOCH3
23
1,3,5-Trimethoxy-benzene
28) 21:3)
Si2Zn)
20 min 240W 1108C
18: 91
CO2CH3
H
OCH3
24
25
Si2Al)
Si2Ti)
Si2Zn)
15 min 270W 1108C
15 min 270W 1108C
20 min 1108C
18: 23
18: 32
18: ,3
18
H
OCH3
CH3O
26c
a
Molar ratio of heterocyclic or benzene derivative±methyl a-acetamidoacrylate.
0.5 g of Si2M) was used as catalyst.
Thermal heating.
In this reaction, a molar ratio indole±methyl a-acetamidoacrylate of 1:2 was used.
In this reaction a molar ratio pyrazole±methyl a-acetamidoacrylate of 2:1 was used.
b
c
d
e

A. de la Hoz et al. / Tetrahedron 57 62001) 5421±5428
5423
in a focused microwave reactor were used. The internal
pressure in these reactions was always less than 3 bars.
when the reaction was performed at 508C and an increase in
the amount of N-acetyl-a,b-didehydroalanine methyl ester
used, under the same conditions, led to a 50% yield of the
a-amidoalkylation product 213), which was the main
product 2entry 14). When we used similar conditions
under thermal heating the yield decreased to 12%, a fact
that demonstrates the activation of microwave irradiation.
Our study began with furan and pyrrole 2Scheme 1) and was
later extended to include other heterocyclic and carbocyclic
systems. Molar ratios and temperatures were optimised and
Table 1 shows the best results for each heterocyclic
compound.
We performed the reaction with pyrazole under similar
conditions 2Table 1, entries 16±19) and in these cases addi-
tion at N-1 was observed. The selectivity depended on the
reaction conditions and the Lewis acid used as a catalyst,
although a mixture of a-amidoalkylation and Michael
addition products was always obtained.
Reactions involving furan were performed in a focused
microwave reactor 2entries 1±3). Under these conditions,
although nearly complete conversions were observed, yields
were low because both reagents can decompose; furan by
ring opening and the alanine derivative by polymerization.
This decomposition has previously been observed in
reactions of 1 with cyclopentadiene.5b Reducing the amount
of catalyst did not overcome this decomposition. The use
of small, closed Te¯on vessels to avoid the evaporation of
furan in a multimode microwave oven allowed us to
increase the temperature, although yields were not improved
under these conditions 2data not shown). Under classical
conditions at room temperature, using Si2Ti) as the catalyst,
a yield of only 22% was obtained after 24 h.
The competition between a-amidoalkylation and Michael
addition reactions can be considered according to an
enamine±imine equilibrium, which is activated by the
presence of the Lewis acid 2Scheme 3).
According to Scheme 3, the reaction of a good nucleophile
with the electrophile, non-activated by co-ordination to an
acid centre, takes place in the b-position. This behaviour is
observed for heterocycles bearing suf®ciently acidic NH
groups which are able to react with aluminium and titanium
Lewis acids to form a good nucleophile in an irreversible
way 2Scheme 4). For this reason, the Michael type reaction
is not observed with the Zn-catalyst.
In reactions with pyrrole both a-amidoalkylation and
Michael addition took place. Catalysts such as Si2Ti) or
Si2Al) favoured the a-amidoalkylation product 2entries 5
and 6) while the use of Si2Zn) exclusively gave the Michael
addition product in 70% yield 2entry 4). On using classical
heating, i.e. in an oil bath under similar reaction conditions
2time and temperature), product 11 was obtained in only
14% yield. However, with N-benzylpyrrole the only reac-
tion observed was a-amidoalkylation. The best catalyst was
Si2Ti) 2entry 10), whereas Si2Zn) gave no reaction even at
1008C and Si2Al) gave only a low yield that did not increase
with time 2entries 8 and 9, respectively).
This equilibrium it is not possible in furan or N-substituted
pyrrole derivatives due to the absence of NH, consequently
only a-amidoalkylation is observed 2Scheme 5).
O
COOCH3
MX
n
C
OCH3
CH3
N+ (MX )-
This reaction was extended to other benzocondensed hetero-
cycles including indole 25) and azoles such as pyrazole 26)
with the aim of obtaining tryptophan derivatives and b- and
a-21-pyrazolyl)alanine derivatives as synthetic precursors
of anticonvulsant agents.13
n
NH COCH3
COCH3
Nu
Nu
Reactions with indole 2Table 1, entries 11±15) afforded the
bisindolyl derivative 214) as the main product. This product
was obtained by elimination of acetamide and reaction with
a second equivalent of indole 2Scheme 2). The assistance of
the indole system in the elimination of acetamide controls
the formation of the symmetric dimer.
CH3
COOCH3
Nu CH2 CH
Nu
C
COOCH3
NHCOCH3
NHCOCH3
Scheme 3.
Product 14 predominates upon using a molar ratio of 1:1 and
it was the only product obtained when Si2Zn) was used
2entry 11). However, the best yields were obtained with
Si2Al). Elimination of acetamide occurred to a lesser extent
N+
MX
MX
n
N
n
N
(MX )-
N
n
N
H
N
H
(MX )-
n
Scheme 4.
H3C
NHCOCH3
H3C
C
CO2CH3
C
CO2CH3
Indole
MX
n
14
N
H
N
¨
N
N
(MX )
n
H
Scheme 5.
Scheme 2.

5424
A. de la Hoz et al. / Tetrahedron 57 62001) 5421±5428
Given that aromatic amino acids of the phenyl glycine type
have found applications in the synthesis of semisynthetic
penicillins and cephalosporins,3 we attempted the reaction
with carbocycles.
alkylation reaction and elimination of acetamide. We could
not avoid this elimination in any case because this reaction
must be favoured by the higher steric hindrance of methoxy
groups and the higher temperature needed. Under these
conditions the catalysts Si2Al) and Si2Ti) led to decomposi-
tion of the alanine ester derivative 2entries 24 and 25), while
use of the Si2Zn) catalyst led to 91% yield in 20 min 2entry
23). Once again, the use of similar conditions 2temperature
and time) under thermal heating did not lead to any reaction.
Phenol and anisole were the ®rst starting materials investi-
gated. However, the reaction did not occur in these cases
and so more activated systems were tried. When this
reaction was extended to more activated benzene
derivatives like 1,3,5-trihydroxybenzene 2Table 1, entries
20±22) and 1,3,5-trimethoxybenzene 2Table 1, entries 23±
26) the reaction did proceed.
An effective co-ordination between the Lewis acid and the
alanine derivative 2as is shown in Scheme 3) can be deduced
by the fact that only a-amidoalkylation products were
observed when a carbocycle such as a 1,3,5-trihydroxy- or
trimethoxybenzene derivative was used.
For 1,3,5-trihydroxybenzene, the product obtained came
from an a-amidoalkylation followed by a transesteri®cation
reaction, although the reversal reaction order is also
possible. A similar product has been described by Ben-
Ishai et al.,14 who used glyoxylic acid derivatives as
synthetic equivalents of glycine cations in reactions with
aromatic compounds. On using the trihydroxy derivative
as the starting material, the best results were obtained
with a temperature of 608C for Si2Al) or Si2Ti) 2entries 21
and 22, respectively) and 1008C for Si2Zn) 2entry 20). The
best catalyst was Si2Ti), although the aromatic amino acid
derivative was obtained only in moderate yields. An
increase in the reaction time did not lead to an increase in
the yields.
The reactions reported here show that Si2M) systems are not
suf®ciently strong to produce the reaction to any great extent
unless a very activated carbocyclic or heterocyclic
compound is used. In order to increase the yields we
employed, in some cases, other stronger acid catalysts
È
such as a Bronsted acid 2p-toluenesulfonic acid) or an ion
exchange resin 2Dowex) 2Tables 2 and 3).
Thus, in the reaction of N-benzylpyrrole the yield increases
to 68% when p-TsOH was used in catalytic amounts 2Table
2, entry 2), nearly doubling the yield in comparison with
that obtained with silica-supported catalysts 2Table 1, entry
10). The best result was obtained using a temperature of
808C and a reaction time of 15 min. Under thermal heating
conditions the yield decreases to 30%.
Finally, in the reactions between the trimethoxybenzene
derivative and 1 using silica-supported Lewis acids as
catalysts, the product obtained arises due to the a-amido-
Table 2.
CO2CH3
NHCOCH3
p-TsOH
C
NHCOCH3
N
CH2Ph
+
CH3
N
CO2CH3
MW
CH2Ph
1
4
12
Entrya
Molar ratio 4:1
T 28C)
Power 2W)
Time 2min)
Yield 2%) 12
1
1:1
1:2
1:2
80
80
80
60
30
±
15
15
15
25
68
30
2
3b
a
In these reactions a catalytic amount of p-toluensulfonic acid 210 mg) was used.
Thermal heating.
b
Table 3.
HO
OH
HO
O
O
NHCOCH3
CO2CH3
Dowex
MW
+
CH3
OH
NHCOCH3
OH
1
7
17
Entrya
Molar ratio 7:1
T 28C)
Power 2W)
Time 2min)
Yield 2%) 17
1
1:3
1:3
1:3
60
100
100
30
30
±
10
10
10
,3
64
,3
2
3b
a
In these reactions 0.2 g of Dowex was used as catalyst.
Thermal heating.
b

A. de la Hoz et al. / Tetrahedron 57 62001) 5421±5428
5425
Table 4.
NHCOCH3
CO2CH3
N
base
MW
N
+
CO2CH3
N
N
H
CH2 CH
NHCOCH3
6
1
16
Entry
Basea
Molar ratio 6:1
T 28C)
Power 2W)
Time 2min)
Yield 2%) 16
1
2
NaHCO3
NaHCO3
Na2CO3
Na2CO3
1:1
1:1
1:2
1:2
120
120
120
120
150
150
150
±
10
10
15
15
42
50
80
,3
3
4b
a
For these reactions 0.5 g of base was used.
Thermal heating.
b
However, the use of p-TsOH with heterocycles such as
furan or pyrrole, which are more sensitive to acidic condi-
tions, led to decomposition of the reagents.
has been achieved using heterogeneous catalysts under
microwave irradiation. The products are easily prepared
by reaction of methyl a-acetamidoacrylate with hetero-
cycles such as furan, pyrrole, N-benzylpyrrole, indole,
pyrazole and benzene derivatives using silica-supported
Lewis acids as catalysts. For N-benzylpyrrole 24) or tri-
hydroxybenzene 27) the use of stronger acid catalysts,
such as p-TsOH and Dowex resin, improves the yields
over those obtained with silica gel catalysts. Similarly,
for pyrazole 26) the best results were obtained by
using bases such as sodium hydrogen carbonate or
sodium carbonate. We therefore conclude that the type
of catalyst used plays a crucial role in the conjugate
addition.
The reaction of 1,3,5-trihydroxybenzene produced a benzo-
furan derivative. This synthesis resembles the synthesis of
coumarin derivatives described by us.15 In consequence, we
tested the use of a Dowex resin as catalyst.
With this resin the benzofuran derivative was obtained in
64% yield after 10 min. It can be seen that this yield is
signi®cantly higher than those obtained with silica-
supported catalysts 2Table 1, entries 20±22). Again thermal
heating did not lead to any reaction 2Table 3, entry 3).
Finally, a base-catalyzed 2potassium hydrogen carbonate)
conjugate addition of a purine derivative to methyl tri¯uoro-
acetylaminoacrylate in dimethyl sulfoxide has been
described.2d This reaction opens the way for the use of
bases, such as NaHCO3 and Na2CO3, in the reaction
with pyrazole in order to improve the synthesis of the
b-substituted alanine derivative 16.
Thus, the formation of the a- or b-substituted alanine
derivative depends on the co-ordination of the Lewis acid
with methyl a-acetamidoacrylate and the presence in the
aromatic system of acidic NH groups. When the aromatic
compound is reactive enough, the best catalyst is Si2Zn)
because this does not produce decomposition of the
reagents. With compounds of lower reactivity a stronger
catalyst like Si2Ti) or Si2Al) is required. When competition
between a-amidoalkylation and Michael addition
reactions occurs, Si2Ti) and Si2Al) favour the ®rst reaction
whereas Si2Zn) favours the latter. With heterocycles like
furan and N-benzylpyrrole and carbocyclic systems, only
a-amidoalkylation occurs. Less reactive heterocycles did
not react and three activating groups are required for
carbocycles.
As shown in Table 4, the best results were obtained at 1208C
with Na2CO3 as the base. The pyrazole did not decompose
under these conditions and so we increased the ratio of
methyl a-acetamidoacrylate 21), a change that favoured
the reaction and afforded a yield of 80% in 15 min. The
use of sodium carbonate nearly doubled the yield over the
best one obtained using Si2Al) as the catalyst 2Table 4, entry
3 versus Table 1, entry 19). An increase in the reaction time
did not give better results and these were similar when half
the amount of catalyst was used 2data not shown). It is
important to bear in mind that the use of comparable condi-
tions involving classical heating does not give any reaction.
In all cases, the microwave irradiation produces
some sort of activation in the reaction. The reaction
times are very short in comparison to those
described in the literature for these types of reaction.
The effect of microwave irradiation is not exclusively
an acceleration of the reaction, as some compounds
did not react by classical heating in an oil bath
under comparable reaction conditions 2time and
temperature).
Moreover, it is interesting to note that the synthesis of this
product was reported by Pleixats et al.7c to require 144 h and
gave 54% yield. The reaction time is reduced considerably
with the method described here and also avoids the use of
contaminating catalysts.
Given that chiral N-acetyl-a,b-dehydroalanine esters can be
easily prepared16 and have proved to be successful in asym-
metric reactions,17 this method opens up a new route for
acyclic stereoselection in a-amidoalkylation and Michael
addition reactions.18
3. Conclusions
In conclusion, the synthesis of a range of alanine derivatives

5426
A. de la Hoz et al. / Tetrahedron 57 62001) 5421±5428
4. Experimental
methyl ester group 2dˆ3.76 ppm) using CH2Br2 as an
1
internal standard. H NMR 2CDCl3, d): 1.97 2s, 3H, CH3),
4.1. General
2.02 2s, 3H, COCH3), 3.76 2s, 3H, OCH3), 6.36±6.37 2m,
2H, 3-H and 4-H), 6.60 2bs, 1H, NH), 7.36±7.37 2m, 1H,
5-H). 13C NMR 2CDCl3, d): 21.7 2COCH3), 23.5 2CH3), 53.1
2OCH3), 58.9 2a-C), 107.4 23-C), 110.7 24-C), 142.2 25-C),
152.6 22-C), 168.9 and 171.5 22£CO).
All melting points were determined on a Gallenkamp
apparatus and are uncorrected. H- and 13C-NMR spectra
1
were recorded at 299.94 and 75.429 MHz, respectively, on
a Varian Unity 300 spectrometer. Chemical shifts are
reported in ppm 2d) using Me4Si as standard, and coupling
constants J are given in Hz. Total assignment was obtained
by the acquisition of NOE-difference spectra and 2D NMR
correlation experiments such as COSY and HETCOR.
Column chromatography was carried out with SiO2 2silica
gel, Merck type 60, 230±400 mesh). Microwave irradiations
were conducted in a focused microwave reactor 2Prolabo
MX350) with measurement and control of power and
temperature by infrared detection. Catalysts modi®ed with
Lewis acids were obtained by treating silica gel with 1 M
solutions of ZnCl2, AlEt2Cl or TiCl4 following the
previously described method.9±11 The silica contained
1.5 mmol of Zn g21, 1.4 mmol of Al g21 and 1.2 mmol of
Ti g21, respectively. For the Si2Zn) catalyst, activation for
2 h at 1508C under vacuum was necessary before use. Mass
spectra were obtained on a VG Autospec instrument
4.2.2. N-Acetyl-a-.2-pyrrolyl)alanine methyl ester .10)
and N-acetyl-b-.2-pyrrolyl)alanine methyl ester .11).
The pyrrole derivatives were puri®ed by column chromato-
graphy on silica gel using hexane±ethyl acetateˆ1:6 as
eluent, the elution order was: product 11 2yellow oil)
followed by compound 10 2mp 100±1038C, puri®ed by
washing the solid with hexane). Yields were determined
1
by integration of the H NMR signal of the NH acetamide
proton 2dˆ2.00 ppm) for compound 10 and the signal due to
the CH2 group 2dˆ3.17 ppm) for compound 13, both using
CH3NO2 as an internal standard.
N-Acetyl-a-.2-pyrrolyl)alanine methyl ester .10). MS
1
2EI) m/z 210.1 2M1). H NMR 2CDCl3, d): 1.91 2s, 3H,
CH3), 2.00 2s, 3H, COCH3), 3.77 2s, 3H, OCH3),
6.11±6.12 2m, 2H, 3-H and 4-H), 6.26 2bs, 1H, NHCO),
6.74±6.75 2m, 1H, 5-H), 9.41 2bs, 1H, NH). 13C NMR
2CDCl3, d): 22.6 2CH3), 23.3 2COCH3), 53.1 2OCH3), 57.6
2a-C), 106.2 and 107.4 23-C, 4-C), 118.7 25-C), 131.0 22-C),
170.5 and 172.7 22£CO). Anal. calcd for C10H14N2O3: C,
57.13; H, 6.71; N, 13.33. Found C, 57.35; H, 6.85; N, 13.1.
270 eV). Elemental analyses were determined on
a
Perkin±Elmer PE 2400 CHN apparatus. Reagents were
purchased from commercial suppliers or prepared by
literature methods.
4.2. General procedure
N-Acetyl-b-.2-pyrrolyl)alanine methyl ester .11). MS
1
2EI) m/z 210.1 2M1). H NMR 2CDCl3, d): 2.08 2s, 3H,
A mixture of methyl a-acetamidoacrylate 21) 21.0 mmol),
the appropriate heterocyclic 22±6) or benzene 27±8)
derivative 20.33±10 mmol) and 0.5 g of silica-supported
Lewis acid 2by dissolving the mixture in 10 mL of CH2Cl2
followed by evaporation of the solvent) was exposed to
microwave irradiation in a focused microwave reactor for
the time and power indicated in Table 1. For reactions with
other solid catalysts, such as p-toluenesulfonic acid, Dowex
50WX2-200 or a base 2NaHCO3, Na2CO3), amounts of 0.01,
0.2 and 0.5 g, respectively, were used 2Tables 2±4). In all
reactions, the products were isolated by addition of 75 mL
of CH2Cl2 2except for reactions of compound 7 where
CH3CN was used) and the catalyst was then separated by
®ltration. The solvent was removed under reduced pressure
and the crude reaction mixtures were analysed by 1H NMR
spectroscopy on samples in CDCl3 or DMSO-d6. Yields
COCH3), 3.17 2d, Jˆ5.4 Hz, 2H, CH2), 3.77 2s, 3H,
OCH3), 4.80 2dt, Jˆ5.4, 7.4 Hz, 1H, CH), 5.89±5.90 2m,
1H, 3-H), 6.10±6.12 2m, 1H, 4-H), 6.40 2d, Jˆ7.4 Hz, 1H,
NHCO), 6.69±6.71 2m, 1H, 5-H), 8.58 2bs, 1H, NH). 13C
NMR 2CDCl3, d): 23.2 2COCH3), 30.1 2CH2), 52.6 2CH),
52.7 2OCH3), 107.4 23-C), 108.4 24-C), 117.8 25-C), 125.5
22-C), 171.4 and 172.0 22£CO). Anal. calcd for
C10H14N2O3: C, 57.13; H, 6.71; N, 13.33. Found C, 57.25;
H, 6.8; N, 13.25.
4.2.3. N-Acetyl-a-.N-benzylpyrrol-2-yl)alanine methyl
ester .12). The pyrrole derivative was puri®ed by column
chromatography on silica gel using hexane±ethyl
acetateˆ3:1 as eluent 2isolated product 12, mp 116±1188C
from chloroform±hexane). Yields were determined by
integration of the 1H NMR signal of the methyl ester
group 2dˆ3.55 ppm) using CH3NO2 as an internal
standard.
1
were determined by H NMR spectroscopy using CH2Br2
2dˆ4.93 ppm) or CH3NO2 2dˆ4.32 ppm) as an internal
standard. The products were puri®ed by column chromato-
graphy of the crude reaction mixture on silica gel. All
compounds were characterised by analytical methods and
1H- and 13C NMR spectroscopy, using mono- and two-
dimensional techniques. The new compounds exhibit
NMR spectroscopic properties consistent with their struc-
tures and gave satisfactory molecular weight determinations
2mass spectrometry).
MS 2EI) m/z 300.1 2M1). 1H NMR 2CDCl3, d): 1.48 2s, 3H,
COCH3), 2.02 2s, 3H, CH3), 3.55 2s, 3H, OCH3), 5.11 2d,
Jˆ16.9 Hz, 1H, CH2), 5.35 2d, Jˆ16.9 Hz, 1H, CH2), 6.31
2dd, Jˆ2.8, 3.7 Hz, 1H, 4-H), 6.26 2bs, 1H, NH), 6.39 2dd,
Jˆ1.8, 3.7 Hz, 1H, 3-H), 6.67 2dd, Jˆ1.8, 2.8 Hz, 1H, 5-H),
6.88 2d, Jˆ7.1 Hz, 2H, o-Ph), 7.24±7.34 2m, 3H, Ph). 13C
NMR 2CDCl3, d): 23.1 2CH3), 23.3 2COCH3), 50.9 2CH2),
53.1 2OCH3), 58.1 2a-C), 107.6 24-C), 110.3 23-C), 125.1
25-C), 125.4 2o-Ph), 127.2 2p-Ph), 128.9 2m-Ph), 129.6
22-C), 139.1 2ipso-Ph), 168.5 and 173.1 22£CO). Anal.
calcd for C17H20N2O3: C, 67.98; H, 6.71; N, 9.33. Found
C, 68.10; H, 6.75; N, 9.45.
4.2.1. N-Acetyl-a-.2-furanyl)alanine methyl ester .9).
The furan derivative was puri®ed by column chromato-
graphy on silica gel using hexane±ethyl acetateˆ3:1 as
eluent 2isolated product 9, mp 92±938C7b). Yields were
1
determined by integration of the H NMR signal of the

A. de la Hoz et al. / Tetrahedron 57 62001) 5421±5428
5427
4.2.4. N-Acetyl-a-.3-indolyl)alanine methyl ester .13)
and methyl 2,2-.bisindol-3-yl)propanoate .14). The
indole derivatives were puri®ed by column chromatography
on silica gel using hexane±ethyl acetateˆ3:1 as eluent. The
elution order was: product 14 2mp 88±918C, puri®ed by
washing the solid with hexane) followed by compound 13
2mp 199±2028C, puri®ed by washing the solid with hexane).
CH), 6.24 2t, Jˆ2.2 Hz, 1H, 4-H), 6.67 2d, Jˆ7.3 Hz, 1H,
NH), 7.32 2d, Jˆ2.2 Hz, 1H, 5-H), 7.51 2d, Jˆ2.2 Hz, 1H,
3-H). 13C NMR 2CDCl3, d): 23.1 2COCH3), 52.1 2CH2), 52.8
2OCH3), 52.9 2CH), 105.8 24-C), 130.5 25-C), 140.4 23-C),
169.9 and 170.0 22£CO).
4.2.6.
3-Acetamido-4,6-dihydroxy-3-methyl-2-benzo-
1
furanone .17). The benzofuranone 17 was puri®ed by
column chromatography on silica gel using hexane±ethyl
acetateˆ1:6 as eluent. Yields were determined by integra-
tion of the 1H NMR signal of the methyl group
2dˆ1.49 ppm) using CH2Br2 as an internal standard. MS
Yields were determined by integration of the H NMR
signal of the NH proton 2dˆ6.73 ppm) for compound 14
and signal of the 4-H proton 2dˆ7.50 ppm) for compound
13 using CH3NO2 2dˆ4.32 ppm) as an internal standard.
1
2EI) m/z 237.1 2M1). H NMR 2DMSO, d): 1.49 2s, 3H,
N-Acetyl-a-.3-indolyl)alanine methyl ester .13). MS 2EI)
m/z 260.1 2M1). 1H NMR 2CDCl3, d): 2.00 2s, 3H, COCH3),
2.11 2s, 3H, CH3), 3.68 2s, 3H, OCH3), 6.73 2s, 1H, NHCO),
7.11 2d, Jˆ2.7 Hz, 1H, 2-H), 7.13 2dt, Jˆ1.2, 7.8 Hz, 1H,
5-H), 7.20 2dt, Jˆ1.2, 7.8 Hz, 1H, 6-H), 7.35 2dd, Jˆ1.2,
7.8 Hz, 1H, 7-H), 7.76 2dd, Jˆ1.2, 7.8 Hz, 1H, 4-H), 8.60
2bs, 1H, NH). 13C NMR 2CDCl3, d): 22.3 2CH3), 23.7
2COCH3), 52.9 2OCH3), 58.6 2a-C), 111.7 27-C), 119.8
23-C and 5-C), 119.9 24-C), 122.2 26-C), 123.2 22-C),
124.5 29-C), 136.7 28-C), 169.3 and 173.4 22£CO). Anal.
calcd for C14H16N2O3: C, 64.60; H, 6.20; N, 10.76. Found C,
64.73; H, 6.30; N, 10.60.
CH3), 1.77 2s, 3H, COCH3), 5.98 and 6.51 22£d,
Jˆ1.9 Hz, 2H, 5-H and 7-H), 8.88 2s, 1H, NH), 9.67 2bs,
2H, OH). 13C NMR 2DMSO, d): 21.4 2COCH3), 21.7 2CH3),
55.5 23-C), 89.9 and 98.3 25-C and 7-C), 105.7 29-C), 154.1
and 154.2 24-C and 6-C), 158.8 28-C), 168.3 and 176.3
22£CO). Anal. calcd for C11H11NO5: C, 55.70; H, 4.67; N,
5.90. Found C, 55.85; H, 4.72; N, 5.8.
4.2.7. Methyl 2-.20,40,60-trimethoxyphenyl)acrylate .18).
The styrene derivative was puri®ed by column chromato-
graphy on silica gel using hexane±ethyl acetateˆ3:1 as
eluent 2isolated product 18, mp 78±808C, hexane). Yields
were determined by integration of the 1H NMR signal of the
30-H and 50-H protons 2dˆ6.16 ppm) using CH2Br2 as an
internal standard. MS 2EI) m/z 252.2 2M1). 1H NMR
2CDCl3, d): 3.72 2s, 3H, COOCH3), 3.76 2s, 6H, 20-OCH3
and 60-OCH3), 3.82 2s, 3H, 40-OCH3), 5.74 2d, Jˆ2.0 Hz,
1H, Htrans), 6.16 2s, 2H, 30-H and 50-H), 6.50 2d, Jˆ2.0 Hz,
1H, Hcis). 13C NMR 2CDCl3, d): 51.9 2COOCH3), 55.3 and
55.8 240-C, 20-C and 60-C), 90.8 230-C and 50-C), 107.9
210-C), 128.9 23-C), 133.4 22-C), 158.5 220-C and 60-C),
161.1 240-C), 168.3 2CO). Anal. calcd for C13H16O5: C,
61.90; H, 6.39. Found C, 62.05; H, 6.37.
Methyl 2,2-.bisindol-3-yl)propanoate .14). MS 2EI) m/z
1
318.2 2M1). H NMR 2CDCl3, d): 2.11 2s, 3H, CH3), 3.66
2s, 3H, OCH3), 6.88 2d, Jˆ2.4 Hz, 2H, 2-H), 7.00 2dd,
Jˆ7.6, 8.0 Hz, 2H, 5-H), 7.15 2t, Jˆ7.6 Hz, 2H, 6-H),
7.32 2d, Jˆ7.6 Hz, 2H, 7-H), 7.50 2d, Jˆ8.0 Hz, 2H, 4-H),
7.96 2bs, 2H, NH). 13C NMR 2CDCl3, d): 25.9 2CH3), 46.2
2a-C), 52.2 2OCH3), 111.2 27-C), 119.0 23-C), 119.2 25-C),
121.2 24-C), 121.7 26-C), 122.9 22-C), 126.0 29-C), 136.7
28-C), 175.9 2CO). Anal. calcd for C20H18N2O2: C, 75.45; H,
5.70; N, 8.80. Found C, 75.61; H, 5.85; N, 8.68.
4.2.5. N-Acetyl-a-.1-pyrazolyl)alanine methyl ester .15)
and N-acetyl-b-.1-pyrazolyl)alanine methyl ester .16).
The pyrazole derivatives were puri®ed by column chroma-
tography on silica gel using hexane±ethyl acetateˆ1:1 as
eluent. The elution order was: product 15 2mp 121±1238C,
chloroform±hexane) followed by compound 16 2mp. 92±
948C,7c chloroform±diethyl ether). Yields were determined
Acknowledgements
Â
Financial Support from the Comision Interministerial de
Ciencia y Tecnologõa 2DGICyT, PB97-0429 and CICYT
Â
MAT 1999-1176) is gratefully acknowledged. We are also
Â
indebted to the Ministerio de Educacion y Cultura for a
1
by integration of the H NMR signal of the methyl group
Â
predoctoral grant to E. Vazquez.
2dˆ2.28 ppm) for compound 15 and the signal due to the
4-H proton 2dˆ6.24 ppm) for compound 16 using CH3NO2
as an internal standard.
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2EI) m/z 211.1 2M1). H NMR 2CDCl3, d): 2.00 2s, 3H,
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