Clean and efficient microwave-solvent-free synthesis of 1-(2′,4′-dichlorophenacyl) azoles

Article abstract of DOI:10.1016/S0040-4020(02)01622-8

Microwave induced N-alkylation of several azoles with 2,2′,4′-trichloroacetophenone (TCA) under solvent-free conditions allowed to obtain the corresponding 1-(2′,4′-dichlorophenacyl) azoles with satisfactory to good selectivities and yields. TGA and DSC measurements were achieved for the synthesized compounds and showed a close relationship between the thermal behavior and the reaction temperature under microwave heating. Non-purely thermal microwave effects were evidenced during the alkylation of pyrazole and 1H-indazole under the selected conditions.

Full text of DOI:10.1016/S0040-4020(02)01622-8

Tetrahedron 59 (2003) 865–870
Clean and efficient microwave-solvent-free synthesis
of 1-(20,40-dichlorophenacyl) azoles
a
Eduardo R. Perez, Andre Loupy, Marion Liagre, Ana M. de Guzzi Plepis
b
b
a
,
*
´
´
and Paulo J. Cordeiroa
a
´
Instituto de Quımica de Sa˜o Carlos, Cx. P. 780 CEP 13560-970, Universidade de Sa˜o Paulo, Sa˜o Paulo, Brazil
´
b
´ ´
Laboratoire des Reactions Selectives sur Supports, ICMMO, UMR 8615, Universite Paris-Sud, Batiment 410, 91405 Orsay Cedex, France
Received 1 July 2002; revised 28 October 2002; accepted 3 December 2002
Abstract—Microwave induced N-alkylation of several azoles with 2,20,40-trichloroacetophenone (TCA) under solvent-free conditions
allowed to obtain the corresponding 1-(20,40-dichlorophenacyl) azoles with satisfactory to good selectivities and yields. TGA and DSC
measurements were achieved for the synthesized compounds and showed a close relationship between the thermal behavior and the
reaction temperature under microwave heating. Non-purely thermal microwave effects were evidenced during the alkylation of pyrazole and
1H-indazole under the selected conditions. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
alkyl halides using aqueous or powdered potassium
hydroxide as a base in the presence of polyethylene glycols
(PEG) or their dialkyl ethers (PEG-ether) as phase transfer
catalysts.8
Selective N-alkylation of azoles is a useful reaction
commonly employed in the preparation of value inter-
mediates of fungicides and other pharmacologically inter-
esting compounds.1 Classical procedures have been
reported for the synthesis of N-alkylated azoles, most of
which suffer long reaction times and yielding complex
mixtures of products, which need further delicate separa-
tions. Moreover, they have shown low selectivity.2–4
Recently, several reports on microwave-assisted N-alkyl-
ation of azaheterocycles in dry media have appeared.9 Thus,
we want to report here the successful microwave-assisted
N-alkylation of several azoles with 2,20,40-trichloroaceto-
phenone (TCA) under solvent-free conditions and in
the absence of any base. The choice of TCA as electro-
phile is based on the fungicidal activity exhibited by
some pharmaceuticals containing the 2,4-dichlorobenzyl
moiety in their structures.10 The present clean protocol
shows excellent selectivity, leading to the corresponding
N1-monoalkylated azoles in satisfactory to good yields
(Table 1).
N-alkylations of aromatic compounds involving nitrogen
heterocycles with alkyl halides under phase transfer
catalytic conditions (PTC) have been reported.5,6 Thus,
KOH and t-BuOK were employed as a base and crown
ethers as phase transfer catalysts.7 On an other hand, was
reported the N-alkylation of nitrogen heterocycles with
Table 1. Microwave-assisted N-alkylation of azoles (1a–e) with TCA (Molar ratio 1a–e/TCA¼2:1)
Compound
Output powera (W)
Reaction time (min)
Temperature (8C)
% Conversionb
% Regioselectivityc
% N1 Yieldd
2a
2b
2c
2d
2e
100–15
150–15
150–15
240–15
240–15
30
15
30
30
10
90
82
N1
75
73
93
82
91
100
140
140
170
.98
.98
.98
.98
N1/N1,3¼77/23
N1/N1,3¼95/5
N1/N2¼87/13
N1/N1,3¼93/7
a
Range of modulation of MW power between optimal and minimal values to maintain constancy of temperature.
b
c
d
Based on% of consumed TCA.
Determined by HRGC and 1H NMR.
Isolated product.
Keywords: azoles; N-alkylation; microwave irradiation; solvent-free; fungicides.
*
Corresponding author. Tel.: þ33-1-69-15-76-50; fax: þ33-1-69-15-46-79; e-mail: aloupy@icmo.u-psud.fr
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01622-8

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E. R. Perez et al. / Tetrahedron 59 (2003) 865–870
866
Scheme 1.
2. Results and discussion
loss of weight in compounds were evaluated according to
the heating temperature range.
The general reaction representing N-alkylation of azoles
with TCA under microwave irradiation is illustrated in
Scheme 1.
The results given in Table 2 are in agreement with the
observed behavior during the synthesis of compounds 2a, c
and d according to reaction temperature. Thus, main
thermal decomposition of compound 2a occurred at
temperatures higher than 1158C, whereas bulky decompo-
sition of compounds 2c, d has been observed beyond 1408C.
The most relevant results obtained for the solvent-free
microwave-assisted protocol are given in Table 1.
In some cases, several regioisomers can be formed as
resulting from alkylation either in different positions
involving the sites 1 (N1) or 2 (N2) for 2d and 1 or 3 (N3)
or both successive sites (N1,3) for 2b, 2c and 2e (Scheme 2).
As a consequence, reactions were carried out at temperature
in the range of 75–908C for compound 2a and 130–1408C
for 2c and 2d, by modulation of the output microwave
power and reaction times. Quantitative conversions as well
as satisfactory to good yields and regioselectivities were
achieved for compounds 2c and 2d at 1408C under
experimental conditions indicated in Table 1.
TGA analyses for compound 2a revealed that no significant
loss of weight occurred neither at 75 (0.47%) nor at 908C
(2.22%) within 30 min and the small differences observed
from the sample weight could be only associated with loss
of the crystallization solvent.
Scheme 2.
In preliminary experiments, we have observed a delicate
compromise between the reaction temperatures and the
yields in N1-alkylazoles. Yields can be dramatically affected
by rather small variations of temperature. For instance,
unsatisfactory conversions and negligible yields of com-
pounds 2c and 2d were obtained at temperatures lower than
1208C, whereas, on the other hand, significant decompo-
sition occurred when the temperatures were higher than
1408C. In the same way, compound 2a decomposes close to
1208C whereas nil conversion was detected below 908C.
On isothermal TGA at 1408C for 30 min, compound 2c
shows a loss of weight corresponding to only 10% of the
starting value. Compound 2d, under the same TGA
conditions, showed even smaller loss of weight (2%).
Compound 2c has displayed the higher thermal stability
from TGA (Table 2) among analyzed products. Thus, higher
yield of 2c under microwave irradiation could be correlated
with its increased thermal stability.
Consequently, we have performed some thermogravimetric
analysis (TGA) for compounds 2a, 2c and 2d to obtain
information about their thermal stabilities (Table 2). The
Compound 2d showed a small peak for the loss of weight
starting from 808C but, on examining differential scanning
calorimetry (DSC) curves, any variation of heat was
Table 2. TGA for compounds 2a, 2c and 2d
Compound
Sample weight (mg)
1st Loss of weight (mg; %)
2nd Loss of weight (mg; %)
2a
2c
2d
5.3050
5.3980
5.0810
70–1158C (0.0589; 1.1)
138–4008C (3.7230; 68.9)
50–1538C (0.5327; 10.4)
115–2348C (5.2290; 98.7)
400–7058C (0.6923; 12.8)
153–3508C (4.2620; 83.8)

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E. R. Perez et al. / Tetrahedron 59 (2003) 865–870
867
Figure 1. DSC curves for compounds 2a, 2c and 2d.
detected at this temperature value. Hence, this could be due
to loss of crystallization solvent (small peak at about 808C
on DSC curve in Fig. 1), since NMR and GC–MS analyses
of the sample, previously heated up to 1008C, were in
agreement with the 2d proposed structure.
Preparation of 2c under microwave or reflux conditions in a
non-polar solvent (therefore transparent to microwaves) was
unsuccessful when temperature was kept below 1408C
(entries 1 and 2). The best situation was achieved in the
absence of any solvent where yields up to 90% (entries 5
and 6) were obtained irrespective of the mode of activation.
Results from thermal analysis are thus supporting the
satisfactory to good yields obtained for the synthesis of
compounds 2a, 2c and 2d operating at reported tempera-
tures (Table 1), and without significant thermal decompo-
sition of products (Table 3).
The use of p-xylene allows to reveal a noticeable MW effect
(entries 3 and 4). This effect is masked under solvent-free
conditions due to an increase in reactivity by higher
concentration effect11 as here yields are yet nearly
quantitative under classical heating.
Table 3. DSC results for compound 2a, 2c and 2d
The influence of the activation mode was next studied for
all compounds under experimental conditions described in
Table 1. Results are summarized in Table 5.
Compound
T
m (8C)
DHm (J g21
)
Decomposition peak (8C)
2a
2c
2d
112.0
147.3
186.1
134.9
121.7
270.0
234.6
269.0
265.3
Specific (purely thermal) MW effects were evidenced in the
case of pyrazole 1a and indazole 1d. Under the conditions
employed here, they disappeared with the other azoles 1b,
1c and 1e. As yields are yet quantitative under conventional
heating, in connection with a high temperature level, these
possible effects can be necessarily masked. They can of
course only appear in the case of less reactive systems when
initial yields are limited (i.e. 65 and 60%, respectively,
for 1a and 1d). It is now well known in a lot of cases that
MW specific effects could only appear when lowering
temperature and reaction time.12
For sake of comparison with more classical reaction
conditions, and to underline the interest of solvent-free
microwave-assisted method, reactions were performed
either in the presence or in the absence of solvent, under
similar set of conditions (time, temperature, and profiles of
raise in temperature), either under MW activation or
conventional heating inside a thermostated oil bath. Results
of this study are shown in Table 4 for the alkylation of
benzotriazole 1c with TCA as a model reaction.
Table 4. Influence of solvent and activation mode on the conversion and the yield in the synthesis of 1-(20,40-dichlorophenacyl) benzotriazole (2c)
(1c/TCA¼2:1, output power¼150–15 W, reaction time¼30 min)
Entry
Solvent
Activation
T (8C)
% Conversion
% Yield N1
% Yield N1,3
1
2
3
4
5
6
Toluene
Toluene
p-Xylene
p-Xylene
None
MW
Oil bath
MW
Oil bath
MW
Oil bath
110
110
140
140
140
140
9
5
79
50
98
91
9
5
71
46
94
83
0
0
4
2
2
4
None
Conversion and yield determined by 1H NMR and GC–MS (based on% consumed TCA).

´
E. R. Perez et al. / Tetrahedron 59 (2003) 865–870
868
Table 5. Solvent-free synthesis of compounds 2a–e under microwave irradiation or classical heating (thermostated oil bath) (conditions of Table 1)
Compound
Activation
Conditions
% Conversion
% Yielda N1
N1/N2
N1/N1,3
2a
2b
2c
2d
2e
MW
Oil bath
MW
Oil bath
MW
Oil bath
MW
Oil bath
MW
Oil bath
30 min, 908C
15 min, 1008C
30 min, 1408C
30 min, 1408C
10 min, 1708C
82
65b
98
98
98
91
98
60
78 (75)
60
77 (73)
70
95 (93)
83
85 (82)
54
–
–
–
–
–
–
–
–
77/23
70/30
95/5
83/4
–
87/13
90/10
–
–
100
100
93 (91)
88
93/7
88/12
–
a
Determined by 1H NMR and GC–MS and yield of isolated product in parenthesis.
Yield was improved to 66% (conversion¼70%) when extending reaction time up to 2 h.
b
Table 6. Some relevant parameters for predicting relative azole reactivites
This case of reaction is propitious to the observation of
specific MW effects when considering the mechanism.13
The polarity of the system is increased during the reaction
progress from the neutral ground state (GS) to the dipolar
transition state (TS) for both N1 and N2 alkylation of 1a
(Scheme 3). Consequently, as MW stabilizing effects by
dipole–dipole interactions with the electric field are
increased with the polarity of materials14, they are improved
from GS to TS, leading therefore to a decrease in the energy
of activation (Scheme 4). Such an explanation of MW
effects13 is supported by calculations suggesting a relation
between MW irradiation and the polarity (or polarizability)
of the transition state.15
b
Compound
pKa (azolium ions) EHOMOa (eV) En (eV)
qN
Pyrazole 1a
2.64
7.11
29.71
29.16
29.43
28.86
29.00
211.80 20.147
211.25 20.218
211.78 20.350
211.28 20.324
211.16 20.478
Imidazole 1b
Benzotriazole 1c
Indazole 1d
1.25
Benzimidazole 1e 5.68
a
Higher occupied molecular orbitals delocalized on aromatic ring (p-type)
Energy level of n-type (non liant) orbital located on reactive N atom.
b
1d.1e). Charge control can be eliminated when consider-
ing the total reverse in the sequence in qN when compared to
relative reactivities one. Considering HOMO levels, 1d and
1e would appear as the most reactive azoles whereas pKa
values would indicate an enhanced reactivity for 1b and 1e.
Certainly, to be more accurate in establishing the reactivity
sequence would need strict comparisons under similar sets
of conditions and determining half-time reaction.
The reactivity of the different azoles towards alkylation
could be tentatively justified by considering some relevant
parameters able to describe their nucleophilicities. They
involved:—the pKa of azolium ions16 which can reflect an
increased basicity (and possibly nucleoplilicity) when pKa
(NHþ) is increased,—the HOMO and n lone pairs energy
levels17 to take into account orbital control of the
reaction,—the net atomic charge on the reactive nitrogen
atoms (qN)17 under charge-controlled reactions. The main
values are given in Table 6.
3. Experimental
The microwave reactor was a monomode system (Synthe-
18
´ ´
wave 402 from Societe Prolabo) with focused waves
When considering the data indicated in the table, it appears
that there is not one unique parameter able to justify the
experimental sequence and that certainly a combination of
factors is responsible for relative reactivities (1a.1b.1c,
operating at 2.45 GHz. The temperature was controlled and
evaluated by an infrared detector, previously calibrated with
the use of an optical fiber. It was monitored by a computer
and maintained constant at a constant value by a discrete
Scheme 3.
Scheme 4.

´
E. R. Perez et al. / Tetrahedron 59 (2003) 865–870
869
modulation of delivered MW power. Mechanical stirring
was used to provide homogeneity of temperature inside the
reaction medium.
(CH2, C-6), 121.3 (C-4þC-5), 128.0 (C-12), 130.3 (C-2),
130.6 (C-10), 132.7 (C-13), 134.3 (C-8), 137.7 (C-9), 138.6
(C-11), 195.1 (C-7); MS (EI, 70 eV): m/z 254 (Mþ), 256
(Mþ2), 173 (100), 175, 177, 145, 147, 149, 109, 81; IR
(KBr): cm21 1690 (CvO), 1590–1530 (C aromatics).
Thermal analyses were performed using a TA Instruments
TGA 2950 DSC 2910 apparatus (dynamic flow of N2: 90
and 80 mL min21 for TGA and DSC respectively, heating
rate for the TGA and DSC¼108C min21, temperature range:
25–7108C for TGA and 25–3508C for DSC, weight of
sample: 5 mg for TGA and DSC, internal calibration with In
for DSC, sample support was Platinum for TGA and
Aluminum for DSC).
3.3. 1-(20,40-Dichlorophenacyl) benzotriazole 2c
White crystals; mp (DSC) 147.18C (ethyl ether), lit.20
1
1458C; H NMR (250 MHz, DMSO-d6): d 6.45 (s, CH2,
2H), 7.45 (dd, J¼8.5, 18 Hz, 1H), 7.59 (dd, J¼8.5, 18 Hz,
1H), 7.72 (dd, J¼1.6, 8.5 Hz, 1H), 7.83 (d, J¼8.5 Hz, 1H),
7.88 (d, J¼1.6 Hz, 1H), 8.11 (d, J¼18 Hz, 1H), 8.18 (d,
J¼18 Hz, 1H); 13C NMR (62.50 MHz, DMSO-d6): d 55.9
(CH2, C-10), 110.7 (C-6), 119.1 (C-7), 123.9 (C-16), 127.4
(C-17), 127.6 (C-14), 130.5 (C-5), 131.5 (C-8), 132.1
(C-12), 133.4 (C-4), 133.5 (C-9), 137.4 (13), 145.0 (C-15),
193.1 (C-11); MS (EI, 70 eV): m/z 305 (Mþ, 4), 307 (Mþ2),
214 (13), 216 (5), 173 (42), 175 (27), 177 (5), 145 (17), 147
(11), 149 (2), 132, 104, 77 (100); IR (KBr): cm21 1690
(CvO), 1570–1520 (C aromatics).
1H and 13C NMR spectra were recorded using a Bruker AC
250 apparatus. GC–MS analyses were carried out using the
HP 5890 gas chromatograph coupled to a HP 5970 Series
Mass Selective Detector. A HP-1 column (50 mm£0.20
mm£0.33 mm) was used. The temperature, of both the
injector and the interface, was set at 3008C. Infrared spectra
were recorded with a Perkin–Elmer 1310 apparatus. The
elementary analyses were performed on an EA 1110 CE
Instruments apparatus.
3.4. 1-(20,40-Dichlorophenacyl) indazole 2d
Syntheses of the compounds 2a–e were carried out either
under microwave irradiation or conventional heating. In a
Pyrex open vessel adapted to the Synthewave reactor,
6 mmol of the0 azolic compound (1a–e) were mixed with
3 mmol of 2,2 ,40-trichloroacetophenone (TCA). The mix-
ture was irradiated under conditions described in Table 1.
Reactions in classical heating (thermostated oil bath) were
carried out under similar experimental conditions (weight of
reactants, time and temperature) as determined in micro-
wave-assisted experiments. To ensure independence from
the thermal effects, in experiments under conventional
heating, the temperature was measured by insertion of a
Quick digital thermometer into the reaction mixture and the
profile of temperature rise was adjusted to be similar to that
registered under microwave irradiation. Physical properties
and structural characterization of the products are as follows:
White crystals; mp (DSC) 186.38C (after chromatography
1
on silica G 60 and elution with 8:2 EtOAc/n-pentane); H
NMR (250 MHz, DMSO-d6): d 6.06 (s, CH2, 2H), 7.04 (dd,
J¼ 8.0, 8.3 Hz, 1H), 7.24 (d, J¼8.3 Hz, 1H), 7.58 (d,
J¼8.3 Hz, 1H), 7.62 (dd, J¼1.6, 8.4 Hz, 1H), 7.74 (d,
J¼8.3 Hz, 1H), 7.80 (d, J¼1.6 Hz, 1H), 8.01 (d, J¼8.4 Hz,
1H), 8.42 (s, 1H); 13C NMR (62.50 MHz, DMSO-d6): d 61.1
(CH2, C-10), 116.3 (C-6), 121.0 (C-7), 121.4 (C-4þC-9),
121.6 (C-5), 126.6 (C-16), 127.6 (C-8), 130.4 (C-14), 131.5
(C-17), 132.1 (C-12), 133.7 (C-13), 137.4 (C-15), 147.3
(C-3), 193.3 (C-11); MS (EI, 70 eV): m/z 304 (Mþ, 18), 306
(Mþ2, 11), 308 (Mþ4, 2), 275, 277, 279, 173 (100), 175
(61), 177 (11), 145, 147, 149, 131, 103, 77; IR (KBr): cm21
1675 (CvO), 1570–1510 (C aromatics). Anal. calcd for
C15H10Cl2N2O: C, 59.21; H, 3.28; N, 9.21. Found: C, 58.59;
H, 3.07; N, 8.97.
3.1. 1-(20,40-Dichlorophenacyl) pyrazole 2a
3.5. 1-(20,40-Dichlorophenacyl) benzimidazole 2e
1
White crystals; mp (DSC) 112.08C (ethyl ether); H NMR
1
(250 MHz, DMSO-d6): d 5.66 (s, CH2, 2H), 6.28 (dd, J¼
1.6, 2.2 Hz, 1H), 7.45 (d, J¼1.6 Hz, 1H), 7.58 (dd, J¼2.0,
8.4 Hz, 1H), 7.73 (d, J¼2.2 Hz, 1H), 7.76 (d, J¼2.2 Hz,
1H), 7.86 (d, J¼8.4 Hz, 1H); 13C NMR (62.50 MHz,
DMSO-d6): d 59.6 (CH2, C-6), 105.7 (C-4), 127.5 (C-3),
130.3 (C-12), 131.0 (C-5), 131.5 (C-10), 131.6 (C-8), 134.3
(C-9), 136.9 (C-11), 139.3 (C-13), 195.0 (C-7); MS (EI,
70 eV): m/z 254 (Mþ, 1), 256 (Mþ2), 173 (100), 175 (64),
177 (11), 145 (20), 147 (13), 149 (2), 109, 81; IR (KBr):
cm21 1690 (CvO), 1580–1540 (C aromatics). Anal. calcd
for C11H8Cl2N2O: C, 51.76; H, 3.13; N, 10.90. Found: C,
51.42; H, 3.01; N, 10.67.
White crystals; mp dec. (ethyl ether); H NMR (250 MHz,
DMSO-d6): d 5.93 (s, CH2, 2H), 7.23–7.29 (m, 1H), 7.36–
7.41 (m, 1H), 7.55–7.59 (m, 1H), 7.68 (dd, J¼2.0, 8.4 Hz,
1H), 7.67–7.75 (m, 1H), 7.84 (d, J¼2.0 Hz, 1H), 8.08 (d,
J¼ 8.4 Hz, 1H), 8.32 (s, 1H); MS (EI, 70 eV): m/z 304
(Mþ), 306 (Mþ2), 308 (Mþ4), 275, 277, 279, 173 (100),
175 (60), 177 (10%), 145, 147, 149, 131, 103, 77; IR (KBr):
cm21 1660 (CvO), 1610–1540 (C aromatics). Anal. calcd
for C15H10Cl2N2O: C, 59.10; H, 3.20; N, 9.11. Found: C,
58.62; H, 3.02; N, 8.83.
3.2. 1-(20,40-Dichlorophenacyl) imidazole 2b
Acknowledgements
White crystals; mp 76–788C (ethyl ether), lit.19 76–788C;
1H NMR (250 MHz, DMSO-d6): d 5.60 (s, CH2, 2H), 6.96
(d, J¼2.2 Hz, 1H), 7.15 (d, J¼2.2 Hz, 1H), 7.63 (dd, J¼2.0,
8.4 Hz, 1H), 7.67 (s, 1H), 7.80 (d, J¼2.0 Hz, 1H), 7.95 (d,
J¼8.4 Hz, 1H); 13C NMR (62.50 MHz, DMSO-d6): d 55.2
We are grateful to FAPESP (Brazil) for financial support.
´
One of us, Eduardo R. Perez is thankful for a CIES
(France) fellowship. Professor Rene Couffignal (Versailles
´
University, France) is sincerely acknowledged from
stimulating discussions.

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E. R. Perez et al. / Tetrahedron 59 (2003) 865–870
870
10. (a) Staub, T.; Schwinn, F.; Urech, P. Phytopathology 1979, 69,
References
1046. (b) Arnoldi, A.; Carzaniga, R.; Morini, G.; Merlini, L.;
Farina, G. J. Agric. Food. Chem. 2000, 48, 2547–2555.
11. Loupy, A. Modern solvents in organic synthesis; Top. Curr.
Chem. 1999, 206, 153–207.
¨
1. (a) Bohnen, K.; Pfiffner, A.; Siegle, H.; Locher, F. Pest. Dis.
1980, 27. (b) Grima, J.; Silvestrini, B.; Cheng, C. Y. Biol.
Reprod. 2001, 64, 1500–1508.
¨
2. Kramer, W. Chemistry of Plant Protection; Haug, G.,
12. (a) Radoiu, M. T.; Kurfustova, J.; Hajek, M. J. Mol. Catal.
2000, 160, 383–393. (b) Chatti, S.; Bortolussi, M.; Loupy, A.
Tetrahedron 2000, 56, 5877–5883. (c) Gotov, B.; Cvengros,
J.; Toma, S.; Loupy, A. International Conference on
Microwave Chemistry, Antibes, France, September 4–7,
2000; pp 87–90. (d) Loupy, A.; Chatti, S.; Delamare, S.;
Lee, D. Y.; Chung, J. H.; Jun, C. H. J. Chem. Soc., Perkin
Trans. 1 2002, 10, 1280–1285.
Hoffmann, H., Eds.; Springer: Berlin, 1986; Vol. 1, p 36.
3. Smith, K.; Small, A.; Hutchings, M. G. Chem. Lett. 1990,
347–350.
4. Godefroi, E. F.; Heeres, J.; Van Cutsem, J.; Janssen, P. A.
J. Med. Chem. 1969, 12, 784–791.
5. Mathias, L. J.; Burkett, D. Tetrahedron Lett. 1979, 49,
4709–4712.
6. (a) Diez-Barra, E.; de La Hoz, A.; Sanchez-Migallon, A.;
Tejeda, J. Synth. Commun. 1990, 20, 2849–2853. (b) Hamaide,
T. Synth. Commun. 1990, 20, 2913–2920. (c) Diez-Barra, E.;
de La Hoz, A.; Sanchez-Migallon, A.; Tejeda, J. Synth.
Commun. 1993, 23, 1783–1786. (d) Diez-Barra, E.; de La
Hoz, A.; Sanchez-Migallon, A. J. Heterocycl. Chem. 1994, 31,
1715–1717.
13. (a) Loupy, A.; Perreux, L.; Liagre, M.; Burle, K.; Moneuse, M.
Pure Appl. Chem. 2001, 73, 161–166. (b) Perreux, L.; Loupy,
A. Tetrahedron 2001, 57, 9199–9223.
14. Gedye, R. N.; Wei, J. B. Can. J. Chem. 1998, 76,
525–532.
15. (a) Arrieta, A.; Lecea, B.; Cossio, F. P. J. Org. Chem. 1998, 63,
5869–5876. (b) Langa, F.; de la Cruz, P.; de la Hoz, A.;
Espildora, E.; Cossio, F. P.; Lecea, B. J. Org. Chem. 2000, 65,
2499–2507.
7. (a) Santaniello, E.; Farachi, C.; Ponti, F. Synthesis 1979,
617–618. (b) Guida, W. C.; Mathre, D. J. J. Org. Chem. 1980,
45, 3172–3176.
´
16. Catalan, J.; Claramunt, R. M.; Elguero, J.; Laynez, J.;
´
Menendez, M.; Anvia, F.; Quian, J. K.; Taagepera, M.; Taft,
8. Sukata, K. Bull. Chem. Soc. Jpn 1983, 56, 280–284.
9. (a) Abenhaim, D.; Diez-Barra, E.; de La Hoz, A.; Loupy, A.;
Sanchez-Migallon, A. Heterocycles 1994, 38, 793–802.
(b) Huang, Z. Z. Org. Prep. Proc. Int. 1996, 28, 121–123.
(c) Bogdal, D.; Pielichowski, J.; Jaskot, K. Synth. Commun.
1997, 27, 1553–1560. (d) Bogdal, D.; Pielichowski, J.; Jaskot,
K. Heterocycles 1997, 45, 715–722. (e) De la Cruz, P.; de la
R. W. J. Am. Chem. Soc. 1988, 110, 4105–4111.
17. Semi-empirical calculations were carried out using the MP3
program in the Hyperchem version 5.1 avalaible from
Hypercube.
18. Loupy, A.; Petit, A.; Hamelin, J.; Texier-Boullet, F.;
´
Jacquault, P.; Mathe, D. Synthesis 1998, 1213–1234.
´
Hoz, A.; Font, L. M.; Langa, F.; Perez-Rodriguez, M. C.
Tetrahedron Lett. 1998, 39, 6053–6056. (f) Bogdal, D.
´
Molecules 1999, 3, 333. (g) Rodriguez, H.; Perez, R.; Suarez,
19. Katritzky, A. R.; Kuzmierkiewicz, W.; Greenhill, J. V. Recl.
Trav. Chim. Pays-Bas 1991, 110, 369–373.
20. Mostefa-Kara, B. PhD Thesis, University of Paris VI, 1995.
M.; Lam, A.; Cabrales, N.; Loupy, A. Heterocycles 2001, 55,
291–301.