Multistep Microwave-Assisted Solvent-Free Organic Reactions: Synthesis of 4-Oxo-tetrahydro-pyridine

Article abstract of DOI:10.1081/SCC-120027272

Preparation and ring-closure of 2-dimethylaminomethylene-5-substituted-3-oxo-pent-4-enoic acid benzyl esters to dihydropyridine rings are efficiently and quickly carried out under solvent-free conditions in an open-vessel microwave system. The syntheses o

Full text of DOI:10.1081/SCC-120027272

This article was downloaded by: [University of Southern Queensland]
On: 09 October 2014, At: 03:59
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer
House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
Multistep Microwave-Assisted Solvent-Free Organic
Reactions: Synthesis of 4-Oxo-tetrahydro-pyridine
Mauro Panunzio a , Maria Antonietta Lentini a , Eileen Campana b , Giorgio Martelli b ,
Emiliano Tamanini a & Paola Vicennati b
a I. S. O. F.-C.N.R, Dipartimento di Chimica “G. Ciamician” , Via Selmi 2, I-40126,
Bologna, Italy
b I. S. O. F.-C.N.R. , Bologna, Italy
Published online: 18 Oct 2011.
To cite this article: Mauro Panunzio , Maria Antonietta Lentini , Eileen Campana , Giorgio Martelli , Emiliano Tamanini
& Paola Vicennati (2004) Multistep Microwave-Assisted Solvent-Free Organic Reactions: Synthesis of 4-Oxo-tetrahydro-
pyridine, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
34:2, 345-359, DOI: 10.1081/SCC-120027272
To link to this article: http://dx.doi.org/10.1081/SCC-120027272
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained
in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of
the Content. Any opinions and views expressed in this publication are the opinions and views of the authors,
and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied
upon and should be independently verified with primary sources of information. Taylor and Francis shall
not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other
liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or
arising out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any
form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://
www.tandfonline.com/page/terms-and-conditions

SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 2, pp. 345–359, 2004
Multistep Microwave-Assisted Solvent-Free
Organic Reactions: Synthesis of
4-Oxo-tetrahydro-pyridine
1
Mauro Panunzio,1, Maria Antonietta Lentini,
*
Eileen Campana,2 Giorgio Martelli,2 Emiliano Tamanini,1
and Paola Vicennati2
1I. S. O. F.-C.N.R, Dipartimento di Chimica “G. Ciamician,”
Bologna, Italy
2I. S. O. F.-C.N.R., Bologna, Italy
ABSTRACT
Preparation and ring-closure of 2-dimethylaminomethylene-5-substituted-
3-oxo-pent-4-enoic acid benzyl esters to dihydropyridine rings are
efficiently and quickly carried out under solvent-free conditions in an
open-vessel microwave system. The syntheses of 1,6-disubstituted-4-oxo-
1,4,5,6-tetrahydro-pyridine-3-carboxylic acid benzyl esters are reported.
Key Words: Microwave irradiation; 4-Oxo-tetrahydro-pyridine;
Solvent-free; Chirality; Stereoselective synthesis.
*
Correspondence: Mauro Panunzio, I. S. O. F.-C.N.R, Dipartimento di Chimica
“G. Ciamician,” Via Selmi 2, I-40126 Bologna, Italy; Fax: þ39 051 209 9456; E-mail:
panunzio@ciam.unibo.it.
345
DOI: 10.1081/SCC-120027272
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

ORDER
REPRINTS
346
Panunzio et al.
Figure 1. 2,3-dihydro-1H-pyridin-4-one.
The 2,3-dihydro-1H-pyridin-4-one ring with the appropriate substitution
pattern (Fig. 1) is an interesting intermediate in the synthesis of several
pharmaceuticals. In fact, chiral dihydropyridones are versatile building blocks
in the enantioselective synthesis of piperidine,[1,2] quinolizidine,[3] indolizi-
dine,[4] perhydroquinoline[5] and other alkaloid ring systems,[6,7] azasugars,[8]
pipecolic acid derivatives,[9,10] azasteroids,[11,12] pyridin-4-ones.[13] Recent
years have witnessed the importance of microwaves in mediating organic
reactions[14–27] because of their advantages respect to classical organic
chemistry in terms of shorter reaction times, minimum waste, generally higher
yields, possibility of carrying out reactions in the absence of solvents and in
safe conditions. We wish to report our results on the use of microwave
technique in a multi-step synthesis of a small library of 1,6-disubstituted-4-
oxo-1,4,5,6-tetrahydropyridine-3-carboxylic acid benzyl ester 8.
Our approach to the target compounds 8, summarized in Sch. 1, utilizes as
key compound the intermediate 4 obtained via the recent developed
methodology for the synthesis of acetoacetate esters by means of microwave
technique.[28] To this purpose, phosphonate 1, which is the milestone pre-
cursor, has been prepared by known route.[29] Wittig reaction of 1 with
aldehydes 2 (LiHMDSA, THF, 2788C) gave rise to the adducts 3.
Scheme 1. Reagents and conditions: a: LiHMDSA, RCHO (2),THF, 27808C to
room temperature. b: Benzyl alcohol, MW, 300 W. c: Dimethylformamide dimethyl-
acetal, MW, 300 W. d: R1NH2 (6), MW, 300 W. e: MW, 300 W.

ORDER
REPRINTS
Solvent-Free Organic Reactions
347
Table 1. Substituents and yields of the product compounds 3, 4 and 5.
a
d
g
h
i
R
3
4
5
90
73
76
87
82
80
65
80
40
23
65
35
80
70
a
aThis product, because its instability, was used as such, without any
purification and identification, in the next step of the synthetic process.
Dioxin-4-one ring opening by benzyl alcohol, upon solvent-free microwave
irradiation,[28,30] in a Synthewave system, gave the expected benzyl esters 4 in
quantitative yields. Treatment of 4-en-3-keto-benzyl esters 4 with dimethyl-
formamide dimethylacetal, under microwave solvent-free conditions, resulted
in the formation of the 2-dimethylaminomethylene derivatives 5.
Yields of the compounds 3, 4 and 5 are reported in Table 1. Treatment of
5 with amines 6, once again under microwave irradiation, gave rise to the
compounds 7, which, upon microwave irradiation, cyclized to the target
compounds 8 (Sch. 1, Table 2).
It has to be underlined that microwave procedures are compatible with a
high functionalization degree of the substrata and with the presence of chiral
centers on the reactive species. In fact, the microwave mediated four-step
pathway from the substrate 3d to the target products 8d, e, f (Sch. 1, Tables 1
and 2) preserves the chirality of the lactic residue of the starting reagent 3d.
Whereas 8f is a mixture 50 : 50 of the two isomers, (6R, 60R, anti) and (6S, 60R,
syn), the products 8d and 8e are obtained as single stereoisomers presenting
the (6R, 60R, anti) configuration (see Experimental for details). These
configurations have been tentatively assigned on the basis of the coupling
constant value (Janti ¼ 6 Hz, Jsyn ¼ 3.3 Hz).[31],a
The sequence from the adduct 3d to the final product 8d was moreover
performed with classical heating method (for reaction conditions see the
experimental part, Method B), results are reported in Table 3: it comes out
that respect to the microwave method, reaction times are longer, yields are
lower and solvents are necessary.
In conclusion, we have encountered all the above mentioned typical
benefits of the microwave protocol, with the advantage of the possibility of
aWork is in progress to delucidate this surprising high stereoinduction. The results will
be reported in due course.

ORDER
REPRINTS
348
Panunzio et al.

ORDER
REPRINTS
Solvent-Free Organic Reactions
349
Table 3. Conventional and dielectric heating, a comparison.
Reaction
Time
Yields %
3d ! 4d
4d ! 5d
5d ! 7d
7d ! 8d
3d ! 8d
6 hrs [5 min]
2 hrs [5 min]
3 hrs [5 min]
8 hrs [5 min]
l9 hrs [20 min]
65 [82]
a [80]
49 [a]
46 [86]
15 [56]
Note: In square brackets times and yields for microwave
heating are reported.
aThis product was not isolated.
applying this procedure to the stereoselective synthesis of chiral compounds.
Extension of this work to more challenging cases is currently in progress in
our laboratories. The possibility of finding out an efficient combination
between microwave and solid phase synthesis[32] have been preliminary
explored and the results, which will be reported in due course, are encouraging
showing that this combination is particularly useful.
EXPERIMENTAL
All starting compounds, unless otherwise stated, were purchased. Micro-
wave reactions were carried out in a Prolabo Synthewave 402 oven under the
experimental conditions below reported. Specific rotation measurements were
carried out on a Perkin–Elmer 343 polarimeter, FT-IR Spectra were recorded
on a Perkin–Elmer infrared spectrometer, mass spectra on Finnigan MAT
instrument, NMR spectra on a Varian VXR 200, on a Varian Gemini
300 MHz, or on a Varian Mercury 400 MHz spectrometer using the residual
signal of the solvent as internal standard.
General Procedure for the Wittig Reaction Between the
Dioxin-Derivative 1 and the Aldehyde 2. Synthesis of 3
To a solution of LiHMDSA (1.8 mL of a 1 N solution in THF, 1.8 mmol)
in THF (12 mL) was added 1 (0.5 g, 1.8 mmol) in THF (4 mL) at 08C. The
solution was stirred for 45 min at the same temperature and cooled at 2788C.
A solution of aldehyde 2 (1.9 mmol) in THF (3 mL) was added dropwise. The
solution was stirred for 10 hrs while the temperature was allowed to rise to
258C, then the mixture was filtered on Celite. The solvent was removed to give
crude 3 of sufficient purity (NMR testing) to be used as such in the next step.

ORDER
REPRINTS
350
Panunzio et al.
2,2-Dimethy1–6-(3-methylpent-1-enyl)-[1,3]dioxin-4-one (3a). From
2-methyl-propionaldehyde 2a. IR: 2963, 1724, 1651 cm21. H NMR: 6.44
(dd, J1 ¼ 7.9, J1 ¼ 15.6 Hz, 1H); 5.85 (dd, J1 ¼ 1.0, J2 ¼ 15.6 Hz, 1H); 5.24
(s, 1H); 2.24 (m, 1H); 1.71 (s, 6H); 1.46 (m, 2H); 1.05 (d, J ¼ 6.7 Hz, 3H);
0.88 (t, J ¼ 7.7 Hz, 3H). 13C NMR: 163.45, 161.83, 147.58, 120.82, 106.05,
93.14, 77.00, 38.38, 28.89, 24.84, 18.96, 11.47.Ms m/z: 211(Mþ1 þ 1), 152,
137, 124, 109, 95, 81.
1
2,2-Dimethyl-6-[4-methyl-3-(triisopropyl-silanyoxy)-pent-1-enyl]-
[1,3]dioxin-4-one (3d). From (S)-triisopropylsilyloxy-propanaldehyde 2d.
1
Oil, [a]2D0 ¼ þ 7.9 (c 1.70, CHCl3). IR: 2945, 2867, 1713, 1654 cm21. H
NMR: 6.45 J2 ¼ 15. 6 Hz, 1H); 6.01 (dd, J1 ¼ 0.92, J2 ¼ 15.6 Hz, 1H); 5.2
(s, 1H); 4.17 (t, J ¼ 5.6Hz, 1H); 1.83 (m, 1H); 1.66 (s, 3H); 1.63 (s, 3H); 1.00
(s, 21H); 0.85 (d, J ¼ 6.8Hz, 3H); 0.80 (d, J ¼ 6.8Hz, 3H). 13C NMR: 162.77,
161.67, 141.97, 122.28, 106.19, 94.26, 76.98, 34.94, 25.12, 24.47, 17.90, 17.57,
16.70, 12.30. Ms m/z: 383 (Mþ þ 1), 339, 281, 253, 239, 225, 211, 121, 75.
6-(2-Cyclohexylvinyl)-2,2-dimethyl-[1,3]dioxin-4-one (3g). From
1
cyclohexylcarboxaldehyde 2g. IR: 2930, 1711, 1651 cm21. H NMR: 6.49
(dd, J1 ¼ 7.1, J2 ¼ 15.8 Hz, 1H); 5.83 (dd, J1 ¼ 1.4, J2 ¼ 15.8 Hz, 1H); 5.23
(s, 1H); 2.16 (m, 1H); 1.85–1.55 (m, 4H); 1.70 (s, 6H); 1.45–1.00 (m, 6H).
13C NMR: 163.84, 162.09, 147.56, 120.21, 106.24, 93.35, 40.88, 32.02, 25.94,
25.76, 25.05. Ms m/z: 237 (Mþ þ 1), 178, 163, 149, 136, 123, 98.
6-(2-Phenylvinyl)-2,2-dimethyl-[1,3]dioxin-4-one (3h). From benzal-
dehyde 2h. IR: 3008, 1714, 1636, 1591 cm21. 1H NMR: 7.60–7.30 (m, 5H);
7.31 (d, J ¼ 15.9 Hz, 1H); 6.54 (d, J ¼ 15.9 Hz, 1H); 5.43 (s, 1H); 1.76 (s, 6H).
13C NMR: 163.24, 161.56, 137.70, 134.67, 129.87, 128.87, 127.66, 119.63,
106.39, 94.89, 24.99. Ms m/z: 230 (Meþ), 171, 144, 131, 116, 103, 77.
6-[2-(3-Methylthiophen-2-yl)-vinyl]-2,2-dimethyl-[1,3]dioxin-4-
one (3i). From 3-methyl-2-thiophene-carboxaldehyde 2i. IR: 2987, 1711,
1
1624 cm21. H NMR: 7.40 (d, J ¼ 15.9 Hz, 1H); 7.24 (d, J ¼ 4.9 Hz, 1H);
6.85 (d, J ¼ 5.1 Hz, 1H); 6.23 (d, J ¼ 15.4 Hz, 1H); 5.35 (s, 1H); 2.32 (s, 3H);
1.75 (s, 6H). 13C NMR: 163.27, 161.85, 140.43, 134.28, 131.25, 128.76,
126.72, 117.78, 106.34, 94.11, 25.05, 14.15. Ms m/z: 250 (Mþ), 192, 177,
164, 150, 135, 123.
General Procedure for Microwave Mediated Synthesis of
Benzyl Esters 4 from 3 and Benzylic Alcohol
Method A. 2,2,6-Trimethyl-1,3-dioxin-4-one derivative 3 (1 mmol) and
benzyl alcohol (2 mmol) were irradiated at 300 W for 5 minutes. The reaction
mixture was subjected as such to a short flash chromatography to give 4.
6-Methyl-3-oxo-oct-4-enoic acid benzyl ester (4a). From 3a. IR: 2963,
1
1743, 1664, 1632, 1596 cm21. H NMR (ketonic form): 7.45–7.25 (m, 5H);

ORDER
REPRINTS
Solvent-Free Organic Reactions
351
6.76 (dd, J1 ¼ 7.5, J2 ¼ 16.0 Hz, 1H); 6.10 (dd, J1 ¼ 1.1, J2 ¼ 16.0 Hz, 1H);
5.20 (s, 2H); 3.65 (s, 2H); 2.21 (m, 1H); 1.36 (m, 2H); 1.04 (dd, J1 ¼ 2.0,
J2 ¼ 6.8 Hz, 3H); 0.86 (t, 3H); (enolic form): 11.86 (s,1H); 7.45–7.25 (m, 5H),
6.58 (dd, J1 ¼ 7.9, J2 ¼ 15.6Hz, 1H); 5.76 (dt, J1 ¼ 1.2, J2 ¼ 15.5, 1H); 5.22 (s,
2H); 5.16 (s, 1H); 2.21 (m, 1H); 1.36 (m, 2H); 1.04 (dd, J1 ¼ 2.0, J2 ¼ 6.9 Hz,
3H); 0.88 (t, 3H). 13C NMR (ketonic form): 191.99, 167.18, 154.99, 146.59,
135.40, 128.47–127.88, 66.93, 46.86, 38.35, 28.64, 18.68, 11.46; (enolic form):
172.65, 170.07, 136.00, 128.47–127.88, 122.68, 89.75, 65.66, 38.30, 29.08,
19.21, 11.56. Ms m/z: 260 (Mþ), 203, 169, 152, 126, 111, 91.
7-Methyl-3-oxo-6-(triisopropyl-silanyloxy)-oct-4-enoic acid benzyl
ester (4d). From 3d. (Oil, [a]D20 ¼ þ 5.3 (c 2.36, CHCl3). IR: 2962, 2867,
1
1739, 1665 cm–1. H NMR (ketonic form): 7.45–7.25 (m, 5H); 6.85 (dd,
J1 ¼ 5.5, J2 ¼ 15.9 Hz, 1H); 6.33 (dd, J1 ¼ 1.4, J2 ¼ 15.9 Hz, 1H); 5.19
(s, 2H); 4.83 (s, 2H); 4.25 (m, 1H); 1.92 (m, 1H); 1.20–1.00 (s, 21H); 1.00–
0.80 (m, 6H); (enolic form): 11.82 (s, 1H); 7.45–7.25 (m, 5H); 6.67 (dd,
J1 ¼ 5.8, J2 ¼ 15.6 Hz, 1H); 6.00 (dd, J1 ¼ 1.4, J2 ¼ 15.6 Hz, 1H); 5.20
(s, 2H); 5.16 (s, 1H); 4.25 (m, 1H); 1.92 (m, 1H); 1.20–1.00 (s, 21H); 1.00–
0.80 (m, 6H). 13C NMR (ketonic form): 191.58, 167.00, 149.40, 135.80,
128.83, 128.52–128.13, 76.62, 67.04, 47.13, 35.09, 18.21, 16.52, 12.38;
(enolic form): 172.56, 169.36, 140.79, 135.84, 128.52–128.13, 124.23, 90.72,
76.97, 65.78, 34.98, 18.21, 16.52, 12.38. Ms m/z: 432 (Mþ), 389, 281, 149, 91.
5-Cyc1ohexyl-3-oxo-pent-4-noic acid benzyl ester (4g). From 3g. IR:
1
2930, 1738, 1666, 1623 cm21. H NMR (ketonic form): 7.40–7.25 (m, 5H);
6.79 (dd, J1 ¼ 6. 8, J2 ¼ 16.1 Hz, 1H); 6.07 (dd, J1 ¼ 1.3, J2 ¼ 16.0 Hz, 1H);
5.17 (s, 2H); 3.63 (s, 2H); 2.16 (m, 1H); 1.75 (m, 4H); 1.26 (m, 6H); (enolic
form): 11.88 (s, 1H); 7.40–7.25 (m, 5H); 6.64 (dd, J1 ¼ 6.8, J2 ¼ 16.1 Hz,
1H); 5.77 (dd, J1 ¼ 1.3, J2 ¼ 16.0 Hz, 1H); 5.18 (s, 2H); 5.08 (s, 1H); 2.16
(m, 1H); 1.75 (m, 4H); 1.26 (m, 6H). 13C NMR: 192.33, 170.32, 167.29,
154.89, 146.52, 135.43, 128.51, 128.48, 128.27, 127.05, 121.86, 89.81, 66.98,
46.86, 40.62, 31.51, 25.80, 25.57. Ms m/z: 286 (Mþ), 195, 179, 152, 91.
5-Phenyl-3-oxo-pent-4-enoic acid benzyl ester (4h). From 3h. IR:
3014, 1737, 1650, 1595 cm21. 1H NMR (ketonic form): 7.58 (d, J1 ¼ 16.5 Hz,
1H); 7.52–7.35 (m, 10H); 6.79 (d, J1 ¼ 6.2 Hz, 1H); 5.23 (s, 2H); 3.76 (s, 2H);
(enolic form): 11.91 (s, 1H); 7.55–7.15 (m, 11H); 6.45 (d, J1 ¼ 15.6 Hz, 1H);
5.21(s, 2H); 5.17 (s, 1H). 13C NMR: 172.29, 169.56, 137.03, 135.64, 135.12,
129.37, 128.78, 128.55, 128.24, 128.14, 127.57, 121.74, 91.64, 65.91. Ms
m/z: 280 (Mþ), 189, 145, 131, 103, 91.
5-(3-Methy1-thiophen-2-y1)-3-oxo-pent-4-enoic acid benzyl ester
1
(4i). From 3i. IR: 3022, 1737, 1622, 1589 cm21. H NMR (ketonic form):
7.82 (dd, J1 ¼ 1.6, J2 ¼ 14.0 Hz, 1H); 7.39–7.31 (m, SH); 7.21 (dd, J1 ¼ 1.6,
J2 ¼ 3.6 Hz, 1H); 6.87 (ddd, J1 ¼ 2.0, J2 ¼ 3.6, J3 ¼ 14.8 Hz, 1H); 6.54 (dd,
J1 ¼ 1.6, J2 ¼ 15.6 Hz, 1H); 5.20 (s, 2H); 3.35 (s, 2H); 2.27 (s, 3H); (enolic

ORDER
REPRINTS
352
Panunzio et al.
form): 11.95 (s, 1H); 7.60 (dd, J1 ¼ 1.2, J2 ¼ 16.0 Hz, 1H); 7.39–7.31
(m, 5H); 7.21 (dd, J1 ¼ 1.6, J2 ¼ 3.60 Hz, 1H); 6.87 (ddd, J1 ¼ 2.0, J2 ¼ 3.6,
J3 ¼ 14.8 Hz, 1H); 6.18 (d, J ¼ 15.6 Hz, 1H); 5.20 (s, 2H); 5.16 (s, 1H); 2.27
(s, 3H). 13C NMR (ketonic form): 191.34, 167.56, 143.60, 137.49, 136.15,
135.63, 133.85, 131.70, 131.43, 128.83–128.40, 122.81, 67.38, 14.51; (enolic
form): 172.86, 169.81, 140.04, 134.93, 134.78, 132.00, 130.30, 128.83–
128.40, 120.21, 91.26, 66.13, 47.94, 14.36. Ms m/z: 300 (Mþ), 285, 209, 165,
151, 91.
General Procedure for the Synthesis of 5 from 4
Method A. Compound 4 (1 mmol) and dimethylformamidedimethyla-
cetal (1 mmol) were irradiated at 300 W for 5 minutes. The reaction mixture
was subjected as such to a short flash chromatography (hexane 30/ethyl
acetate 70) to give 5.
2-Dimethylaminomethylene-6-methyl-3-oxo-oct-4-enoic acid benzyl
1
ester (5a). From 4a. IR: 2962, 1686, 1648 cm21. H NMR: 7.68 (s, 1H);
7.42–7.22 (m, 5H); 6.64 (dd, J1 ¼ 7.5, J2 ¼ 15.5 Hz, 1H); 6.44 (d,
J ¼ 16.1 Hz, 1H); 5.19 (s, 2H); 2.98 (bs, 6H); 2.12 (m, 1H); 1.34 (m, 2H);
0.96 (d, J ¼ 6.8 Hz, 3H); 0.82 (t, J ¼ 7.3 Hz, 3H). Ms m/z: 315 (Mþ), 271,
258, 224, 192, 178, 150, 91.
2-Dimethylaminomethylene-7-methyl-3-oxo-6-(triisopropyl-silany-
loxy)-oct-4-enoic acid benzyl ester (5d). From 4d. Oil, [a]2D0 ¼ þ 6.9
1
(c 1.70, CHCl3) IR: 2961, 2867, 1683, 1648 cm21. H NMR: 7.67 (s, 1H);
7.40–7.20 (m, 5H); 6.71 (dd, J1 ¼ 5.3, J2 ¼ 15.5 Hz, 1H); 6.60
(d, J ¼ 15.5 Hz, 1H); 5.20 (d, J ¼ 1.2 Hz, 1H); 5.12 (d, J ¼ 1.2 Hz, 1H);
4.14 (dd, J1 ¼ 0.50, J2 ¼ 5.1 Hz, 1H); 2.90 (bs, 6H); 1.80 (m, 1H); 1.00
(s, 21H); 0.82 (pt, J ¼ 6.5 Hz, 6H). Ms m/z: 487 (Mþ), 444, 318, 282, 188, 91.
5-Cyclohexyl-2-dimethylaminomethylene-3-oxo-pent-4-enoic
acid
benzyl ester (5g). From 4g. IR: 3685, 3016, 1682, 1643 cm21. H NMR:
7.67 (s, 1H); 7.34 (m, 5H); 6.68 (dd, J1 ¼ 6.6, J2 ¼ 15.6 Hz, 1H); 6.42
(dd, J1 ¼ 1.0, J2 ¼ 15.5 Hz, 1H); 5.18 (s, 2H); 2.98 (bs, 6H); 2.16 (m, 1H);
1.68 (m, 4H); 1.25 (m, 6H). 13C NMR: 190, 168.10, 156.66, 149.77, 136.45,
128.49, 128.40, 128.22, 127.91, 126.92, 65.82, 40.43, 31.85, 29.66, 25.98;
25.82. Ms m/z: 341 (Mþ), 297, 250, 233, 206, 161, 150, 91.
1
5-Phenyl-2-dimethylaminomethylene-3-oxo-pent-4-enoic acid benzyl
ester (5h). From 4h. This compound, because of its instability, was used as
such, without any purification and identification, in the next step of the
synthetic process.
5-(3-Methyl-thiophen-2-yl)-2-dimethylaminomethylene-3-oxo-
pent-4-enoic acid benzyl ester (5i). From 4i. IR: 3020, 1680, 1597 cm21. 1H

ORDER
REPRINTS
Solvent-Free Organic Reactions
353
NMR: 7.76 (s, 1H); 7.71 (d, J ¼ 15.3 Hz, 1H); 7.45–7.24 (m, 5H); 7.19
(d, J ¼ 5.1 Hz, 1H); 7.00 (d, J ¼ 15.3 Hz, 1H); 6.83 (d, J ¼ 5.1 Hz, 1H); 5.22
(s, 2H); 3.00 (bs, 6H); 2.30 (s, 3H). 13C NMR: 190.00, 167.91, 157.24, 140.69,
139.45, 136.42, 134.86, 132.72, 132.15, 130.93, 128.37, 128.10, 127.79,
125.96, 65.84, 15.48, 14.10. Ms m/z: 355 (Mþ), 264, 236, 221, 193, 155.
General Procedure for the Synthesis of 1,4,5,6-Tetrahydro-
pyridine-3-carboxylic Acid Benzyl Ester 8 from 5
Method A–a. One-pot two step preparation of 8 from 5: intermediate 5
(1 mmol) and amine 6 (1.1 mmol) were irradiated at 300 W for 5 minutes. The
reaction mixture was subjected as such to a short flash chromatography to
give 8.
Method A–b. Preparation and isolation of open-chain intermediate 7
from 5 and subsequent cyclization of 7 to give 8: intermediate 5 (1 mmol) and
amine 6 (1.1 mmol) were irradiated at 300 W for 5 minutes. The reaction
mixture was subjected, to a short flash chromatography (ethyl acetate/hexane,
from 70/30 to 100/0) to give 7.
Compound 7, dissolved in DMF, is irradiated at 300 W for 5 minutes to
obtain compound 8.
6-sec-Butyl-1-(2-hydroxyethyl)-4-oxo-1,4,5,6-tetrahydro-pyridine-3-
carboxylic acid benzyl ester (8a). Method A–a. From 5a and 2-amino-
1
ethanol 6a. IR: 3427, 3012, 1714, 1652 cm21. H NMR: 8.16 (s, 1H); 7.47–
7.19 (m, 5H); 5.21 (d, J ¼ 12.5 Hz, 1H); 5.05 (d, J ¼ 12.5 Hz,1H); 3.79 (m,
2H); 4.80 (bs, 1H); 3.43 (m, 3H); 2.65 (dd, J1 ¼ 7.7, J2 ¼ 16.4 Hz, 1H); 2.30
(dd, J1 ¼ 2.9, J2 ¼ 16.6 Hz, 1H); 1.82 (m, 1H); 1.27 (m, 2H); 0.85 (m, 6H).
13C NMR: 187.83, 164.67, 159.90, 136.94, 128.38, 128.06, 128.01, 99.13,
65.14, 61.19, 60.51, 58.30, 37.17, 36.13, 25.94, 14.30, 11.62. Ms m/z: 331
(Mþ), 300, 274, 242, 225, 197, 184, 166, 140, 91.
6-sec-Butyl-1-(4-methoxyphenyl)-4-oxo-1,4,5,6-tetrahydro-pyridine-
3-carboxylic acid benzyl ester (8b). Method A–a. From 5a and 4-methoxy-
1
phenylamine 6b. IR: 3019, 1718, 1660, 1581, 1511 cm21. H NMR: 8.33
(s, 1H); 7.48–7.21 (m, 5H); 7.17 (d, J ¼ 8.9 Hz, 2H); 6.91 (d, J ¼ 9.0 Hz, 2H);
5.22 (s, 2H); 4.14 (m, 1H); 3.79 (s, 3H); 2.89 (m, 1H); 2.61 (dd J1 ¼ 3.0,
J2 ¼ 16.3 Hz, 1H); 1.72 (m, 1H); 1.20 (m, 2H); 0.90–0.55 (m, 6H). 13C NMR:
186.61, 164.58, 158.59, 157.73, 137.09, 136.75, 128.20, 127.66, 127.49,
124.64, 114.83, 100.83, 65.19, 64.27, 55.41, 37.69, 36.63, 25.67, 13.82, 11.36.
Ms m/z: 393 (Mþ), 336, 286, 259, 246, 202, 91.
6-sec-Butyl-l-methoxycarbonylmethyl-4-oxo-l,4,5,6-tetrahydro-pyri-
dine-3-carboxylic acid benzyl ester (8c). Method A–a. From 5a and

ORDER
REPRINTS
354
Panunzio et al.
1
amino-acetic acid methyl ester 6c. IR: 3013, 1752, 1720, 1671 cm21. H
NMR: 8.06 (s, 1H); 7.51–7.29 (m, 5H); 5.22 (d, J ¼ 1.2 Hz, 1H); 5.15 (d,
J ¼ 1.2 Hz, 2H); 4.12 (d, J ¼ 2.0 Hz, 2H), 3.78 (s, 3H); 3.44 (m, 1H); 2.90 (m,
1H); 2.47 (m, 1H); 1.79 (m, 1H); 1.26 (m, 2H); 0.87 (m, 6H). 13C NMR:
186.68, 168.46, 164.41, 159.81, 136.75, 128.29, 127.78, 127.60, 100.96,
65.28, 61.96, 55.95, 52.81, 37.09, 36.27, 25.80, 15.52, 11.56. Ms m/z: 359
(Mþ), 302, 270, 253, 225, 212, 168, 91.
1-Methoxycarbonylmethyl-6-[2-methyl-l-(triisopropyl-silanyloxy)-
propyl]-4-oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid benzyl ester
(8d). Method A–a. From 5d and amino-acetic acid methyl ester 6c. Oil,
[a]2D0 ¼ 245.1 (c 1.42, CHCl3). IR: 2948, 1751, 1721, 1664 cm21. 1H NMR:
7.98 (s, 1H); 7.50–7.25 (m, 5H); 5.22 (m, 2H); 4.40 (d, J ¼ 17.6 Hz, 1H); 4.07
(d, J ¼ 17.6 Hz, 1H); 3.88–3.81 (m, 1H); 3.78–3.70 (m, 1H); 3.58 (s, 3H);
2.98 (dd, J1 ¼ 9.0, J2 ¼ 16.6 Hz, 1H); 2.59 (dd, J1, ¼ 2.7, J2 ¼ 16.4 Hz, 1H);
1.85 (m, 1H); 1.03 (s, 21H); 0.95 (d, J ¼ 7.1 Hz, 3H); 0.91 (d, J ¼ 7.1 Hz, 3H).
13C NMR: 185.71, 168.50, 164.51, 160.30, 136.86, 128.27, 127.79, 127.75,
100.82, 79.54, 65.21, 60.71, 50.07. 52.77, 37.99, 31.69, 18.09, 17.87, 13.18.
Ms m/z: 488 (Mþ), 444,401, 382, 368, 324, 303, 212, 149, 91.
2-[(Methoxycarbonylmethyl-amino)-methylene]-7-methyl-3-oxo-6-
(triisopropyl-silanyloxy)-oct-4-enoic acid benzyl ester (7d). Oil, [a]D20
¼
224.7 (c 2.00, CHCl3). IR: 2959, 2867, 1754, 1693 cm21. H NMR: 11.45
(m, 1H); 8.01 (d, J ¼ 13.3 Hz, 1H); 7.50–7.27 (m, 6H); 6.80 (dd, J, 7.0,
J2 ¼ 15.5 Hz, 1H); 5.20 (s, 2H); 4.20 (m, 1H); 4.08 (d, J ¼ 6.2 Hz, 2H); 3.68
(s, 3H); 1.80 (m, 1H); 1.05 (m, 21H); 0.90 (d, J ¼ 3.0 Hz, 3H); 0.87
(d, J ¼ 3.0 Hz, 3H). 13C NMR: 189.55, 168.36, 166.40, 161.20, 144.92,
136.58, 128.94, 128.43, 128.13, 128.04, 101.34, 77.58, 65.61, 52.63, 50.23,
35.30, 18.05, 17.09, 12.38. Ms m/z: 488 (Mþ), 362, 326, 284, 91.
1
1-(2-Hydroxy-ethyl)-6-[2-methyl-1-(triisopropyl-silanyloxy)-propyl]-
4-oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid benzyl ester (8e).
Method A–b. From 5d and 2-amino-ethanol 6a through 7e.
2-[(2-Hydroxy-ethylamino)-methylene]-7-methyl-3-oxo-6-(triisopro-
pyl-silanyloxy)-oct-4-enoic acid benzyl ester (7e). 7e. Oil, [a]2D0 ¼ 221.2
(c 1.46, CHCl3). IR: 3624, 2975, 2876, 1690 cm21. 1H NMR: 11.37 (m, 1H);
8.11 (d, J ¼ 13.7 Hz, 1H); 7.50–7.32 (m, 6H); 6.74 (dd, J1 ¼ 7.1,
J2 ¼ 15.5 Hz, 1H); 5.19 (s, 2H); 4.20 (dd, J1 ¼ 0.50, J2 ¼ 6.5 Hz, 1H); 3.72
(dd, J1 ¼ 0.50 Hz, J2 ¼ 6.5 Hz, 2H); 3.42 (dd, J1 ¼ 0.50, J2 ¼ 6.5 Hz, 2H);
3.15 (bs, 1H); 1.82 (m, 1H); 1.15 (s, 21H); 0.89 (d, J ¼ 2.4 Hz, 3H); 0.85
(d, J ¼ 2.2 Hz, 3H). 13C NMR: 189.44, 166.87, 161.79, 144.46, 136.69,
129.18, 128.47, 128.10, 127.97, 100.24, 77.61, 65.59, 61.38, 52.10, 35.32,
18.18, 17.10, 12.40. Ms m/z: 503 (Mþ þ 1), 460, 334, 298, 134, 91. 8e. Oil,
[a]2D0 ¼ 264.2 (c 1.60, CHCl3). IR: 3280, 2948, 1672, 1601 cm21. 1H NMR:
8.20 (s, 1H); 7.40–7.20 (m, 5H); 5.18 (d, J ¼ 12.6 Hz, 1H); 4.97 (d,

ORDER
REPRINTS
Solvent-Free Organic Reactions
355
J ¼ 12.7 Hz, 1H); 4.55 (bs, 1H); 3.90 (m, 1H); 3.75 (m, 2H); 3.40 (m, 2H);
2.88 (dd, J1 ¼ 0.50, J2 ¼ 18.0 Hz, 1H); 2.58 (dd, J1 ¼ 0.50, J2 ¼ 17.5 Hz, 1H);
1.80 (m, 1H); 0.95 (m, 27H). 13C NMR: 187.27, 164.68, 160.56, 136.83,
128.18, 127.86, 127.76, 98.37, 78.52, 64.93, 59.66, 58.61, 57.77, 36.81, 32.81,
18.64, 18.09, 18.01,13.25.
1-Cyclopropyl-6-[2-methyl-1-(triisopropyl-silanyloxy)-propyl]-4-oxo-
1,4,5,6-tetrahydro-pyridine-3-carboxylic acid benzyl ester (8f). Method
A–b. From 5a and cyclopropylamine 6f through 7f.
2-Cyclopropylaminomethylene-7-methyl-3-oxo-6-(triisopropyl-silanyl-
oxy)-oct-4-enoic acid benzyl ester (7f). Oil, [a]2D0 ¼ 236.2 (c 1.77, CHCl3).
IR: 2961, 1685, 1649, 1617 cm21. 1H NMR: 11.38 (d, J ¼ 13.6 Hz, 1H); 8.19
(d, J ¼ 13.4 Hz, 1H); 7.45–7.27 (m, 6H); 6.74 (dd, J1 ¼ 7.12, J2 ¼ 15.5 Hz,
1H); 5.25 (s, 2H); 4.18 (ddd, J1 ¼ 1.1, J2 ¼ 4.8, J3 ¼ 7.1 Hz, 1H); 2.95
(m, 1H); 1.82 (m, 1H); 1.05 (s, 21H); 0.95–0.70 (m, 10H). 13C NMR: 189.18,
166.59, 161.18, 144.32, 136.76, 129.11, 128.41, 128.00, 127.87, 100.39,
77.60, 65.44, 35.29, 30.19, 18.04, 17.10, 12.36, 6.38. Ms m/z: 500 (Mþ þ 1),
456, 330, 294, 91.
8f anti. Oil, [a]2D0 ¼ 267.8 (c 0.80, CHCl3). IR: 2497, 1719, 1658,
1593 cm21. 1H NMR: 8.21 (s, 1H); 7.50–7.20 (m, 5H); 5.28 (d, J ¼ 15.5 Hz,
1H); 5.19 (d, J ¼ 15.5 Hz, 1H); 4.13 (dd, J1 ¼ 2.8, J2 ¼ 6.3 Hz, 1H); 3.76
(m, 1H); 3.15 (m, 1H); 2.67 (dd, J1 ¼ 7.6, J2 ¼ 16.7 Hz, 1H); 2.55 (dd,
J1 ¼ 2.5, J2 ¼ 16.8 Hz, 1H); 1.95 (m, 1H); 1.20–0.55 (m, 31H). 13C NMR:
186.10, 165.05, 159.57, 153.62, 137.22, 128.31, 127.66, 127.50, 99.88, 77.92,
65.18, 60.59, 37.94, 36.31, 33.29, 18.84, 18.20, 13.38, 8.45, 6.65. Ms m/z:
499, 456, 412, 369, 336, 271, 180, 149, 91.
8f syn. Oil, [a]2D0 ¼ 2.0 (c 0.80, CHCl3). IR: 2947, 1719, 1662,
1593 cm21. 1H NMR: 8.21 (s, 1H); 7.50–7.25 (m, 5H); 5.24 (s, 2H); 4.20 (dd,
J1 ¼ 1.6, J2 ¼ 3.5 Hz, 1H); 3.75 (m, 1H); 3.05 (m, 1H); 2.75 (dd, J1 ¼ 3.7,
J2 ¼ 16.8 Hz, 1H); 2.63 (dd, J1 ¼ 7.8, J2 ¼ 16.5 Hz, 1H); 1.93 (m, 1H); 1.20–
0.55 (m, 31H). 13C NMR: 186.02, 164.67, 159.17, 137.11, 128.33, 127.79,
127.75, 100.03, 74.88, 65.23, 60.89, 38.64, 37.77, 31.73, 19.00, 18.20, 13.11,
7.92, 6.53. Ms m/z: 499, 456, 412, 369, 336, 271, 180, 149, 91.
6-Cyclohexyl-1-(4-methoxyphenyl)-4-oxo-1,4,5,6-tetrahydro-pyri-
dine-3-carboxylic acid benzyl ester (8g). Method A–a. From 5g and 4-
inethoxy-phenylainine 6b. IR: 3019, 2933, 1719, 1660, 1580 cm21. 1H NMR:
8.40 (s, 2H); 7.50–7.28 (m, SH); 7.28–7.15 (m, 2H); 7.00–6.88 (m, 2H); 5.26
(s, 2H); 4.06 (m, 1H); 3.85 (s, 3H); 2.93 (dd, J1 ¼ 7.8, J2 ¼ 16.3 Hz, 1H); 2.69
(dd, J1 ¼ 2.3, J2 ¼ 16.3 Hz, 1H); 1.88 (m, 6H); 1.46 (m, 1H); 1.06 (m, 4H).
13C NMR: 186.77, 164.88, 158.59, 157.41, 137.55, 136.94, 128.39, 127.86,
127.67, 124.39, 115.02, 101.17, 65.45, 64.55, 55.60, 40.25, 38.30, 29.76,
27.93, 25.91. Ms m/z: 419 (Mþ), 336, 313, 285, 246, 228, 202, 91.

ORDER
REPRINTS
356
Panunzio et al.
6-Phenyl-1-(4-methoxyphenyl)-4-oxo-1,4,5,6-tetrahydro-pyri-
dine-3-carboxylic acid benzyl ester (8h). Method A–a. From 5h and 4-
methoxy-phenylainine 6b. IR: 3021, 1720, 1666, 1576 cm21. H NMR: 8.61
1
(s, 1H), 7.50–7.15 (m, 10H); 7.14–6.98 (m, 2H); 6.90–6.85 (m, 2H); 5.27
(s, 2H); 5.22 (dd, J1 ¼ 2.9, J2 ¼ 7.3 Hz, 1H); 3.75 (s, 3H); 3.29 (dd, J1 ¼ 7.3,
J2 ¼ 15.9 Hz, 1H); 2.78 (dd, J1 ¼ 3.2, J2 ¼ 15.9 Hz, 1H). 13C NMR: 185.22,
164.73, 158.34, 156.46, 137.50, 137.25, 136.74, 129.16, 128.39, 127.84,
127.70, 126.08, 122.80, 114.73, 102.91, 65.60, 63.47, 55.49, 44.04. Ms m/z:
413 (Mþ), 324, 307, 279, 91.
6-(3-Methylthien-2-yl)-1-cyclopropyl-4-oxo-1,4,5,6-tetrahydro-pyri-
dine-3-carboxylic acid benzyl ester (8i). Method A–a. From 5i and
cyclopropylainine 6f. IR: 3016, 1720, 1662 cm21. 1H NMR: 8.3 (s, 1H); 7.50–
7.20 (m, 5H); 7.11 (d, J ¼ 5.1 Hz, 1H); 6.77 (d, J ¼ 5.1 Hz, 1H); 5.27 (s, 2H);
5.11 (dd, J1 ¼ 4.2, J2 ¼ 7.3 Hz, 1H); 2.99 (dd, J1 ¼ 7.3, J2 ¼ 16.1 Hz, 1H);
2.83 (m, 1H); 2.65 (dd, J1 ¼ 4.0, J2 ¼ 15.9 Hz, 1H); 2.26 (s, 3H); 1.10–0.68
(m, 4H). 13C NMR: 185.14, 164.74, 158.61, 136.96, 135.41, 133.93, 129.60,
127.71, 127.60, 124.19, 120.81, 101.19, 65.42, 56.32, 43.82, 35.96, 13.92,
7.18, 6.56. Ms m/z: 367 (Mþ), 276, 261, 260, 233, 194, 124, 91.
Method B. Classical heating method from 3d to 8d.
4d. 3d (1 mmol) was dissolved in toluene, benzylic alcohol (1.1 mmol)
was added and the mixture was refluxed until TLC spot-test revealed the
disappearance of the starting compounds (about 6 hours needed). The solvent
was removed in vacuo and the mixture was subjected to a short flash
chromatography to give 4d.
5d. 4d (1 mmol) was dissolved in toluene, dimethylformamidedimethyl-
acetal (1.1 mmol) was added and the mixture was refluxed 2 hours. 1H-NMR
testing showed the formation of 5d. The crude reaction mixture was processed
as such in the next step of synthetic process.
7d. To the crude mixture of the reaction of formation of 5d was added
DIPEA (1.1 mmol) and amino-acetic acid methyl ester 6c (1.1 mmol). The
mixture was refluxed 3 hrs. The solvent was removed in vacuo and the mixture
was subjected to a short flash chromatography to give 7d.
8d. 7d was dissolved in toluene and the reaction mixture was refluxed 8
hours. The solvent was removed in vacuo and the mixture was subjected to a
short flash chromatography to give 8d.
ACKNOWLEDGMENTS
This work was partially supported by “Progetto Strategico sulle appli-
cazioni delle Microonde, CNR, Rome.”

ORDER
REPRINTS
Solvent-Free Organic Reactions
357
REFERENCES
1. Comins, D.L.; Sandelier, M.J.; Abad Grillo, T. Asymmetric synthesis of
(þ)- deoxoprosopinine. J. Org. Chem. 2001, 66, 6829–6832.
2. Ofner, S.; Hauser, K.; Schilling, W.; Vassout, A.; Veenstra, S.J. SAR of
2-benzyl-4-aminopiperidines: CGP 49823, an orally and centrally active
non-peptide NK1 antagonist. Bioorg. Med. Chem. Lett. 1996, 6,
1623–1628.
3. Waldmann, H.; Kirschbaum, S. Construction of the tricyclic benzo-
quinolizine ring system by combination of a tandem Mannich–Michael
reaction with a Heck reaction. Tetrahedron Lett. 1997, 38, 2829–2832.
4. Ma, D.; Sun, H. A simple and stereospecfic route to 2,6-disubstituted
4-hydroxypiperidines. Synthesis of dendrobate alkaloid (þ)-241D and
formal synthesis of (2)-indolizidine 167B. Org. Lett. 2000, 2,
2503–2505.
5. Comins, D.L.; Libby, M.J. Asymmetric synthesis of the lycopodium
alkaloid, Na-acetyl-Nb-methylphlegmarine. J. Org. Chem. 1999, 64,
2184–2185.
6. Kuethe, J.T.; Comins, D.L. Addition of metallo enolates to chiral
1-acylpyridinium salts: total synthesis of (þ)-cannabisativine. Org. Lett.
2000, 2, 855–857.
7. Huang, S.; Comins, D.L. Total synthesis of (þ)-streptazolin. Chem.
Commun. 2000, 7, 569–570.
8. Comins, D.L.; Fulp, A.B. Enantiopure 2,3-dihydro-4-pyridones as
synthetic intermediates: asymmetric synthesis of 1-deoxynojirimycin.
Tetrahedron Lett. 2001, 42, 6839–6841.
9. Bousquet, Y.; Anderson, P.C.; Bogri, T.; Duceppe, J.-S.; Grenier, L.;
Guse, I. Preparation of enantiopure 4-oxygenated pipecolic acid deriva-
tives. Tetrahedron 1997, 53, 15671–15680.
10. Comins, D.L.; Brooks, C.A. Asymmetric synthesis of (2S,4R)-4-
hydroxypipecolic acid. Tetrahedron Lett. 2000, 41, 3551–3553.
11. Guarna, A.; Occhiato, E.G.; Scarpi, D.; Zorn, C.; Danza, G.; Comerci, A.;
Mancina, R.; Serio, M. Synthesis of 8-chloro-benzo[c]quinolizin-3-ones
as potent and selective inhibitors of human steroid 5a-reductase 1. Bioorg.
Med. Chem. Lett. 2000, 10, 353–356.
12. Guarna, A.; Occhiato, E.G.; Machetti, F.; Trabocchi, A.; Scarpi, D.;
Danza, G.; Mancina, R.; Comerci, A.; Serio, M. Effect of C-ring
modifications in benzo[c]quinolizin-3-ones, new selective inhibitors of
human 5a-reductase 1. Bioorg. Med. Chem. 2001, 9, 1385–1393.
13. Bassini, C.; Bismara, C.; Carlesso, R.; Feriani, A.; Gaviraghi, G.;
Marchioro, C.; Perboni, A.; Shaw, R.E.; Tamburini, B.; Tarzia, G.;
Xerri, L. Synthesis and antimicrobial activity of DNA-gyrase inhibiting

ORDER
REPRINTS
358
Panunzio et al.
derivatives of 4-oxo-1,4-dihydro-3-pyridinecarboxylic acid. Il Farmaco
1993, 48, 159–189.
14. Loupy, A. Microwaves in Organic Synthesis; Wiley-VCH: Weinheim,
2002.
15. Hayes, B.L. Microwave Synthesis: Chemistry at the Speed of Light; CEM
Publishing: Matthews, NC, 2002.
16. Lidstrom, P.; Tierney, J.; Wathey, B.; Westman, J. Microwave assisted
organic synthesis—a review. Tetrahedron 2001, 57, 9225–9283.
17. de la Hoz, A.; Diaz-Ortis, A.; Moreno, A.; Langa, F. Cycloadditions under
microwave irradiation conditions: methods and applications. Er J. Org.
Chem. 2000, 3659–3673.
18. Langa, F.; De La Cruz, P.; De La Hoz, A.; Diaz-Ortiz, A.; Diez-Barra, B.
Microwave irradiation: more than just a method for accelerating
reactions. Contemp. Org. Synth 1997, 373–386.
19. Dittmer, D. “No-solvent” organic synthesis. Chem. Ind.-London 1997,
780–784.
20. Galema, S.A. Microwave chemistry. Chem. Soc. Rev. 1997, 26,
233–238.
21. Strauss, C.R.; Trainor, R.W. Invited review—developments in micro-
wave-assisted organic-chemistry. Aust. J. Chem. 1995, 48, 1665–1692.
22. Caddick, S. Microwave assisted organic reactions. Tetrahedron 1995, 51,
10403–10432.
23. Loupy, A.; Petit, A.; Mathe, D.; Hamelin, J.; Texier-Boullet, F.;
Jacquault, P. New solvent free organic synthesis using focused micro-
waves. Synthesis 1998, 1213.
24. Larhed, M.; Moberg, C.; Hallberg, A. Microwave-accelerated homo-
geneous catalysis in organic chemistry. Acc. Chem. Res. 2002, 35,
717–727.
25. Lew, A.; Krutzik, P.O.; Hart, M.E.; Chamberlin, A.R. Increasing rates of
reaction: microwave-assisted organic synthesis for combinatorial chem-
istry. J. Comb. Chem. 2002, 4 (2), 95–105.
26. Perreux, L.; Loupy, A. A tentative rationalization of microwave effects in
organic synthesis according to the reaction medium, and mechanistic
considerations. Tetrahedron 2001, 57 (45), 9199–9223.
27. khajavi, M.S.; Mohammadi, A.A.; Sadat Hosseini, S.S. Microwave
irradiation promoted reactions of anthraniliic acid with ketones. Prepara-
tion of substituted acridinones and quinolines. Synthetic Commun. 2001,
31 (23), 3647–3652.
28. Gianotti, M.; Martelli, G.; Mendozza, M.; Panunzio, M.; Campana, E.
Solvent-free microwave-assisted organic reactions preparation of beta-
keto esters. Synthetic Commun. 2000, 30, 1725.

ORDER
REPRINTS
Solvent-Free Organic Reactions
359
29. Boeckmann, R.K.J.; Thomas, A.J. Methodology for the synthesis of
phosphorus-activated tetramic acids: applications to the synthesis of
unsaturated 3-acyltetramic acids. J. Org. Chem. 1982, 47, 2823–2824.
30. Panunzio, M.; Castiglioni, E.; Campana, E.; Favi, G.; Vicennati, P.
Application of Microwaves Technique to Organic Synthesis; Acierno, D.,
Leonelli, C., Pellacani, G.C., Eds.; Mucchi Editore: Modena, 2000;
83–92.
31. Bongini, A.; Panunzio, M.; Bandini, E.; Campana, E.; Martelli, G.;
Spunta, G. Synthesis of perhydroxazin-4-ones. Competitive Mukaiyarna
versus hetero Diels–Alder in the cycloaddition of 2-aza-3-trimethylsi-
lyloxy-1,3-butadiene and aldehydes. Tetrahedron: Asymm. 2001, 12,
439–454.
32. Bradley, D. The nuke’s the thing for synthesis. Modern Drug Discovery,
2001, 32–36.
Received in the UK May 7, 2003

Request Permission or Order Reprints Instantly!
Interested in copying and sharing this article? In most cases, U.S. Copyright
Law requires that you get permission from the article’s rightsholder before
using copyrighted content.
All information and materials found in this article, including but not limited
to text, trademarks, patents, logos, graphics and images (the "Materials"), are
the copyrighted works and other forms of intellectual property of Marcel
Dekker, Inc., or its licensors. All rights not expressly granted are reserved.
Get permission to lawfully reproduce and distribute the Materials or order
reprints quickly and painlessly. Simply click on the "Request Permission/
Order Reprints" link below and follow the instructions. Visit the
U.S. Copyright Office for information on Fair Use limitations of U.S.
copyright law. Please refer to The Association of American Publishers’
Fair Use in the Classroom.
(AAP) website for guidelines on
The Materials are for your personal use only and cannot be reformatted,
reposted, resold or distributed by electronic means or otherwise without
permission from Marcel Dekker, Inc. Marcel Dekker, Inc. grants you the
limited right to display the Materials only on your personal computer or
personal wireless device, and to copy and download single copies of such
Materials provided that any copyright, trademark or other notice appearing
on such Materials is also retained by, displayed, copied or downloaded as
part of the Materials and is not removed or obscured, and provided you do
not edit, modify, alter or enhance the Materials. Please refer to our
Website
User Agreement for more details.
Request Permission/Order Reprints
Reprints of this article can also be ordered at
http://www.dekker.com/servlet/product/DOI/101081SCC120027272