Microwave-assisted rapid and simplified hydrogenation

Article abstract of DOI:10.1021/jo981516s

Catalytic transfer hydrogenation has been conducted under microwave irradiation in open vessels using high-boiling solvents such as ethylene glycol (bp 198 °C) as the microwave energy transfer agent. Reduction of double bonds and hydrogenolysis of several functional groups were carried out safely and rapidly (3-5 min) at about 110-130 °C with 10% Pd/C as an efficient catalyst and ammonium formate as the hydrogen donor. Diverse types of β-lactam synthons were prepared by the reduction of ring substituents containing alkene and alkylidene groups or conjugated unsaturated esters. Cleavage of the β-lactam ring by hydrogenolysis of the N-C₄ bond of 4- aryl-2-azetidinones was a facile reaction with 10% Pd/C as the catalyst; but no ring scission occurred when Raney nickel catalyst was employed. Dehalogenation of aromatic compounds was also successful with ammonium formate and Pd/C catalyst. Hydrogenolysis of phenylhydrazone of methyl benzoylformate gave the methyl ester of phenylglycine in excellent yield. The techniques described here for microwave assisted hydrogenation are safe, rapid, and efficient and are suitable for research investigation as well as for undergraduate and high school laboratory exercises.

Full text of DOI:10.1021/jo981516s

5746
J . Org. Chem. 1999, 64, 5746-5753
Micr ow a ve-Assisted Ra p id a n d Sim p lified Hyd r ogen a tion 1,†
Bimal K. Banik,‡ Khaled J . Barakat,§ Dilip R. Wagle, Maghar S. Manhas, and Ajay K. Bose*
George Barasch Bioorganic Research Laboratory, Department of Chemistry and Chemical Biology,
Stevens Institute of Technology, Hoboken, New J ersey, 07030
Received J uly 30, 1998
Catalytic transfer hydrogenation has been conducted under microwave irradiation in open vessels
using high-boiling solvents such as ethylene glycol (bp 198 °C) as the microwave energy transfer
agent. Reduction of double bonds and hydrogenolysis of several functional groups were carried out
safely and rapidly (3-5 min) at about 110-130 °C with 10% Pd/C as an efficient catalyst and
ammonium formate as the hydrogen donor. Diverse types of â-lactam synthons were prepared by
the reduction of ring substituents containing alkene and alkylidene groups or conjugated
unsaturated esters. Cleavage of the â-lactam ring by hydrogenolysis of the N-C4 bond of 4-aryl-
2-azetidinones was a facile reaction with 10% Pd/C as the catalyst; but no ring scission occurred
when Raney nickel catalyst was employed. Dehalogenation of aromatic compounds was also
successful with ammonium formate and Pd/C catalyst. Hydrogenolysis of phenylhydrazone of methyl
benzoylformate gave the methyl ester of phenylglycine in excellent yield. The techniques described
here for microwave assisted hydrogenation are safe, rapid, and efficient and are suitable for research
investigation as well as for undergraduate and high school laboratory exercises.
In tr od u ction
remote locations may not have all of these facilities
available at short notice. Many teaching laboratories are
often not equipped with multiple units for frequent use
by groups of students.
Some hydrogenation processes are more effective under
higher pressure (1000 psi or more) and thus require more
elaborate equipment. Considerable amounts of hydrogen
are wasted during the flushing of such equipment.
Hydrogen and air mixtures are potentially hazardous if
flames or sparks are produced in the neighborhood of
hydrogenators.
Laboratory-scale catalytic hydrogenation2 plays a key
role in chemical research and the synthesis of organic
intermediates. Any simplification of this operation is,
therefore, potentially useful provided the total process
is safe and ecologically friendly. Industrial-scale hydro-
genation, which has special requirements, will not be
considered here.
In most organic laboratories it is a common practice
to conduct catalytic reduction or hydrogenolysis under
40 psi pressure in a commercially available apparatus.
Pure hydrogen gas from a cylinder fitted with an ap-
propriate valve system is required. The air in the
hydrogenator has to be completely removed either by
flushing the system for several minutes with hydrogen,
or, by repeatedly pumping the system down to a low
pressure and refilling with hydrogen. Laboratories in
Resu lts a n d Discu ssion
Ca ta lytic Tr a n sfer Hyd r ogen a tion . In recent years
a few laboratories have started to employ catalytic
transfer hydrogenation (CTH).3 This is a safe and simple
operation in which a catalyst and hydrogen gas are
replaced with a catalyst and a hydrogen donor such as
cyclohexane,4 hydrazine,5 formic acid,6 ammonium for-
mate,7 cyclohexadiene,8 and phosphinic acid,9 sodium
hypophosphite.10 This type of hydrogenation is usually
conducted in flasks fitted with a magnetic stirrer and a
reflux condenser. Ethyl alcohol is a widely used solvent
for CTH.
† Dedicated to Prof. Sasanka C. Bhattacharyya on the occasion of
his 80th birthday.
‡ Present address: University of Texas, M. D. Anderson Cancer
Center, Houston, TX 77030.
§ Present address: Merck Company, Rahway, NJ 07065.
Present address: Alteon Inc., Ramsey, NJ 07446.
(1) Microwave-induced organic reaction enhancement (MORE) chem-
istry. Part 13. For Part 12, see: Banik, B. K.; J ayaraman, M.; Srirajan,
V.; Manhas, M. S.; Bose, A. K. J . Ind. Chem. Soc. 1997, 74, 951. For
Part 11, see: Bose, A. K.; Banik, B. K.; Lavlinskaia, N.; J ayaraman,
M.; Manhas, M. S. Chemtech 1997, 27 (9), 18.
(3) (a) Rajagopal, S.; Anwer, M. K.; Spatola, A. F. In Peptides:
Design, Synthesis and Biological Activity; Basava, C., Anantharamaiah,
G. M., Eds.; Birkhauser: Boston, 1994; Chapter 2, p 11. (b) Rao, H. S.
P.; Reedy, K. S. Tetrahedron Lett. 1994, 35, 171. (c) Ram, S.;
Ehrenkaufer, R. E. Synthesis 1988, 91.
(4) (a) Viswanatha, V.; Hruby, V. J . Org. Chem. 1980, 45, 2010. (b)
J ackson, A. E.; J ohnstone, R. A. W. Synthesis 1977, 685. (c) Brieger,
G.; Nestrick, T. J . Chem. Rev. 1974, 74, 567. (d) Braude, E. A.; Listead,
R. P. J . Chem. Soc. 1954, 3544.
(5) (a) Anwer, M. K.; Khan, S. A.; Sivanandaiah, K. M. Synthesis
1978, 751. (b) Furst, A.; Berlo, R. C.; Hooton, S. Chem. Rev. 1965, 65,
51.
(6) (a) Gray, B. D.; J effs, P. W. J . Chem. Soc. Chem. Commun. 1987,
1329. (b) Elamin, B.; Anantharamaiah, G. M.; Royer, G. P.; Means, G.
E. J . Org. Chem. 1979, 44, 3442.
(2) For some heterogeneous hydrogenation methods, see: (a) Ry-
lander, P. N.; Hydrogenation Methods; Academic Press: Orlando, FL,
1985. (b) J ohnstone, R. A. W.; Wilby, A. H.; Entwistle, I. D. Chem.
Rev. 1985, 85, 129. (c) Weir, I. R.; Patel, B. A.; Heck, R. F. J . Org.
Chem. 1980, 45, 4926. (c) Brown, C. A. J . Org. Chem. 1970, 35, 1900.
For some homogeneous hydrogenation methods, see: (d) Greenspoon,
N.; Keinan, E. J . J . Org. Chem. 1988, 53, 3723. (e) Tsuji, J .; Suguira,
T.; Mainami, I. Synthesis 1987, 603. (f) Grigg, R.; Mitchell, T. R. B.;
Sutthivaiyakit, S. Tetrahedron Lett. 1979, 1067. (g) J ames, B. R.
Homogeneous Hydrogenation; Wiley: New York, 1973 and references
therein. Use of finely dispersed metal particles or colloids in a polymer
matrix has attracted attention recently for hydrogenation. See: Tour,
J . M.; Cooper, J . P.; Pendalwar, S. L. J . Org. Chem. 1990, 55, 3452
and references therein.
10.1021/jo981516s CCC: $18.00 © 1999 American Chemical Society
Published on Web 07/20/1999

Microwave-Assisted Hydrogenation
J . Org. Chem., Vol. 64, No. 16, 1999 5747
Recently we11 have demonstrated that catalytic trans-
fer hydrogenation can be conducted very rapidly and in
essentially quantitative yield inside an unmodified do-
mestic microwave oven. We present here details of our
technique and indicate the scope of reduction and hy-
drogenolysis achieved under microwave irradiation.
Micr ow a ve-Assisted Rea ction s. Two pioneering pa-
pers12 appeared in 1986 on remarkable acceleration of
many organic reactions upon irradiation with microwaves
(2450 MHz). Since then, a number of laboratories, includ-
ing our own, have been studying microwave-assisted
chemical synthesis.13 Some research groups conduct their
reactions in sealed tubes, which can withstand several
atmospheres of pressures, but occasional explosions have
been reported due to the high pressure from a rapid rise
in temperature.
A few laboratories14a avoid the risk of explosions by
conducting microwave-assisted reactions at ambient
pressure by irradiating reactants adsorbed on solid
supports such as clay, alumina, or silica gel.
Special microwave ovens have been designed by some
groups to prevent explosions caused by run away
reactions.14b We prefer to conduct experiments in open
vessels in inexpensive, unmodified, domestic microwave
ovens. A wide variety of compounds have been synthe-
sized using our microwave-induced organic reaction
enhancement (MORE) chemistry techniques.15
Sch em e 1
ent to microwaves. The solvent (microwave energy trans-
fer agent) should be polar and with a suitably high boiling
point at least 20 or 30° higher than the projected reaction
temperature.
Domestic microwave ovens produce 2450 MHz radia-
tion at a rate that is controlled to a moderate degree by
an “on-off” cycle. For finer control of the microwave
energy input into small-scale reaction mixtures, it is
convenient to use a “heat sink”sa beaker of water placed
next to the reaction vessels inside the oven. This heat
sink with appropriate amounts of water captures a
significant amount of the microwave energy thereby
reducing the energy supplied to the reaction mixture.
Since microwave energy is absorbed by all of the polar
molecules and ions at the same time, no stirrer is
required for reaction mixtures in shallow layers. Flasks
with ground glass joints, heating mantles, and the other
standard equipment of a conventional organic laboratory
are not needed. Reflux condensers are unnecessary since
liquids are maintained well below their boiling points
when MORE chemistry techniques are used.
Micr ow a ve-Assisted CTH. Ethylene glycol (bp 198
°C) or more eco-friendly 1,3-propanediol, bp 210-212 °C,
as the solvent and ammonium formate as the hydrogen
donor form an excellent combination for catalytic transfer
hydrogenation under microwave irradiation. Hydrazine
hydrate was used as the hydrogen donor in a few cases
but ammonium formate proved to be more convenient.
Most of our studies on CTH reactions have been con-
ducted with Pd/C (10%) catalyst. A few experiments were
catalyzed with Ra/Ni catalyst. Since Pd/C catalyst is
sometimes a pyrophoric powder, a specific protocol for
CTH experiments was developed for ensuring safety (see
the Experimental Section). Representative examples of
CTH experiments are described below.
Red u ction a n d Hyd r ogen olysis of â-La cta m s. At
the beginning of these studies, test runs with ammonium
formate reduction in the presence of 10% Pd/C showed
that oleic and linoleic acids (on a 1-2 g scale), were
completely reduced to stearic acid in only 1-2 min at
about 110-130 °C. We were, therefore, encouraged to
undertake a detailed examination of CTH experiments
of various types.
In the course of studies on substituted â-lactams as
synthons for natural products, various â-lactams with
unsaturated substituents were prepared. Some of these
had been reduced in the past by conventional low-
pressure hydrogenation in the presence of Raney nickel
or Pd/C catalysts. Now the microwave-assisted CTH
technique was applied to several of these compounds
using commercially available Raney nickel catalyst when
reduction products were obtained in about 80% yield or
better in a few minutes. Thus, 1 with an N-allyl group
was reduced to 2 with an N-propyl group (Scheme 1). The
vinyl group at C-3 was converted to the ethyl group
during the reduction of 3 to 4 (Scheme 2).
These techniques are also very convenient for rapid
and safe catalytic transfer hydrogenation experiments.
MORE Ch em istr y Tech n iqu es. We have developed
an unconventional experimental set up for conducting
organic reactions to take advantage of the special nature
of microwave energy.
Erlenmeyer flasks or beakers with loose covers are
preferred reaction vessels for ambient pressure reactions
in unmodified domestic microwave ovens. The upper
parts of these vessels remain cool since glass is transpar-
(7) (a) Anwer M. K.; Spatola, A. F. Synthesis 1980, 929, and later
publications. (b) Adger, B. M.; O’Farrell, C.; Lewis, N. J .; Mitchell, M.
B. Synthesis 1987, 53. (c) Carpino, L.; Tunga, A. J . Org. Chem. 1986,
11, 1930. (d) Ram, S.; Ehrenkaufer, R. E. Synthesis 1986, 133. (e)
Overman, L. E.; Sugai, S. Helv. Chim. Acta 1985, 68, 745. (f) For a
recent review see: Ranu, B. C.; Sarkar, A.; Guchhait, S. K.; Ghosh, K.
J . Ind. Chem. Soc. 1998, 75, 690.
(8) (a) Bajwa, J . S. Tetrahedron Lett. 1992, 33, 2299. (b) Felix, A.
M.; Heimer, E. P.; Lambros, T. J .; Tzougraki, C.; Meienhofer, J . J . Org.
Chem. 1978, 43, 4194.
(9) (a) Entwistle, I. D.; Gilkerson, T.; J ohnstone, R. A. W.; Telford,
R. P. Tetrahedron 1978, 34, 313. (b) Entwistle, I. D.; J ohnstone, R. A.
W.; Telford, R. P. J . Chem. Res. (S) 1977, 117.
(10) Marques, C. A.; Selva, M.; Tundo, P. J . Chem. Soc., Perkin
Trans. I 1993, 529.
(11) (a) Bose, A. K.; Banik, B. K.; Barakat, K. J .; Manhas, M. S.
Synlett 1993, 575. (b) Bose, A. K.; Manhas, M. S.; Ghosh, M.; Shah,
M.; Raju, V. S.; Bari, S. S.; Newaz, S. N.; Banik, B. K.; Chaudhary, A.
G.; Barakat, K. J . J . Org. Chem. 1991, 56, 6968.
(12) (a) Gedye, R. N.; Smith, F.; Westaway, K.; Ali, H.; Baldisera,
L.; Laberge, L.; Roussell, J . Tetrahedron Lett. 1986, 27, 279. (b)
Giguere, R. J .; Bray, T. L.; Duncan, S. M.; Majetich, G. Tetrahedron
Lett. 1986, 27, 4945.
(13) For a recent review, see: Caddick, S. Tetrahedron 1995, 51,
10403.
(14) (a) Villemin, D.; Labiad, B. Synth. Commun. 1990, 20, 3213.
(b) Csiba, M.; Cleophax, J .; Loupy, A.; Malthete, J .; Gero, S. D.
Tetrahedron Lett. 1993, 34, 1787. (c) Pilard, J . F.; Klein, B.; Texier-
boullet, F.; Hamelin, J . Synlett. 1992, 3, 219. (d) Varma, R. S.; Dahiya,
R.; Kumar, S. Tetrahedron Lett. 1997, 38, 203. (e) Cablewski, T.; Faux,
A. F.; Strauss, C. R. J . Org. Chem. 1944, 59, 3408.
(15) (a) Bose, A. K.; Banik, B. K.; Lavlinskaia, N.; J ayaraman, M.;
Manhas, M. S. Chemtech 1997, 27, 18. (b) Banik, B. K.; Manhas, M.
S.; Robb, E. W.; Bose, A. K. Heterocycles 1997, 44, 405. (c) Bose, A. K.;
Manhas, M. S.; Banik, B. K.; Robb, E. W. Res. Chem. Intermed. 1994,
20, 1. (d) Banik, B. K.; Manhas, M. S.; Barakat, K. J .; Bose, A. K.
Tetrahedron Lett. 1992, 33, 3603.
When 10% Pd/C was used as the catalyst the â-lactam
5 underwent selective hydrogenolysis of the O-benzyl

5748 J . Org. Chem., Vol. 64, No. 16, 1999
Banik et al.
Sch em e 2
Sch em e 5
Sch em e 6
Sch em e 3
yield and in a few minutes. It is useful to note that under
these conditions Ra-Ni did not cause cleavage of the
â-lactam ring in 3 (See Scheme 2).
The hydrogenation of 4-styryl-2-azetidinones (17 and
19) showed an interesting pattern (Scheme 8): the alkene
groups were reduced but there was only partial â-lactam
ring scission under the conditions used with Pd/C cata-
lyst. Thus, the two products (18a ,b), namely, the satu-
rated â-lactam and the open chain amide, were formed
in approximately 6:4 ratio. It would appear that the
vinylogous aryl group led to the scission of the C4-N
bond, but if the styryl group were reduced first, ring
cleavage was of course no longer possible. The relative
rates of reduction of the styryl group and hydrogenolysis
of the â-lactam ring can therefore be expected to be
influenced by the level of microwave irradiation.
Sch em e 4
Ster eoselective P r ep a r a tion of â-La cta m Syn -
th on s. A convenient procedure has been developed in our
laboratory19 for resolving hydroxy-â-lactams (e.g., 23) by
the formation of two diastereomeric glycosides via the
Ferrier reaction involving a glucal (e.g., 22) (Scheme 9).
The determination of the stereochemistry of the glycosidic
linkages in these compounds was necessary. The problem
appeared to have a reliable solution if the unsaturation
group and reduction of the unsaturated ester to a
saturated ester side chain to give the â-lactam 6 which
retained the N-benzyl group intact (Scheme 3).
1
could be easily removed, and the H NMR spectra of the
Using conventional catalytic hydrogenation (ambient
pressure of hydrogen at 50 °C in methanol with Pd/C as
the catalyst), Ojima et al.16 have cleaved N-C4 bonds in
4-phenyl-2-azetidinones to produce phenylalanine deriva-
tives (for example, see Scheme 4) in a convenient fashion
and in high yield. We17 had observed earlier that, in the
presence of a large excess of Raney nickel catalyst and
hydrogen, 3-methoxy-1,4-diphenyl-2-azetidinone under-
went â-lactam scission to provide a small amount of the
anilide of R-methoxy-â-phenylpropionic acid (Scheme 5).
However, under milder conditions, cleavage of the â-lac-
tams ring does not occur. For several years now mild
catalytic hydrogenation (5-10% Pd/C catalyst, room
temperature) under conventional conditions have been
the standard method in our laboratory for the reduction
of R-azido-â-lactams to R-amino-â-lactams (for example,
see Scheme 6).
Recently we11 have studied microwave assisted cata-
lytic transfer hydrogenolysis at 120-130 °C using 10%
Pd/C as the catalyst. Rapid scission of 4-phenyl-2-
azetidinones was observed in every case. The N-benzyl
group of the â-lactam 9 was not hydrogenolyzed, but the
O-Bn group at C-3 was converted to an OH group;
alkenes (11, 13, and 15) were reduced to alkyl groups
(Scheme 7). The reduction product was obtained in high
chair-shaped pyranosides could be studied. CTH reaction
using 10% Pd/C was tested on 24a and found to be
successful: the unsaturation in the sugar moiety was
removed without ring fission of the â-lactam to give 25a .
Allylic deacetoxylation also occurred to a limited extent
and gave 25b.
Microwave-assisted CTH reaction of 26 resulted in the
formation of a reduced and deacetylated product 27. The
proton NMR spectrum of this compound was useful for
assigning the stereochemistry of the glycosidic bond.
In the course of studies on carbapenem synthons, a
series of monocyclic â-lactams were generated with an
exo-alkene group at C-3.15b,20 These conjugated double
bonds could be reduced easily under microwave-assisted
CTH reaction (Scheme 10). Furthermore, because of the
essentially planar shape of the â-lactam ring and the bulk
of the substituent at C4, the hydrogenation was stereo-
specific: only cis â-lactams were obtained because the
catalyst surface was always placed trans to the large
substituent at C4. Such stereospecificity is of course
highly desirable from the point of view of atom economy.
(18) Bose, A. K.; Anjaneyulu, B.; Bhattacharya, S. K.; Manhas, M.
S. Tetrahedron 1967, 23, 4769.
(19) (a) Banik, B, K.; Manhas, M. S.; Bose, A. K. J . Org. Chem. 1994,
59, 4714. (b) Banik, B. K.; Manhas, M. S.; Bose, A. K. Tetrahedron
Lett. 1997, 38, 5077. (c) Banik, B. K.; Zegrocka, O.; Manhas, M. S.;
Bose A. K. Heterocycles 1987, 46, 173.
(16) (a) Ojima, I.; Suga, S.; Abe, R. Chem. Lett. 1980, 853. (b) Ojima,
I. Acc. Chem. Res. 1995, 28, 383, and references therein.
(17) Bose A. K.; Manhas, M, S.; Chib, J . S.; Chawla, H. P. S.; Dayal,
B. J . Org. Chem. 1974, 39, 2877.
(20) Banik, B. K.; Manhas, M. S.; Newaz, S. N.; Bose, A. K. Biomed.
Chem. Lett. 1993, 3, 2363.

Microwave-Assisted Hydrogenation
J . Org. Chem., Vol. 64, No. 16, 1999 5749
Sch em e 7
Deh a logen a tion Rea ction . Rajagopal and Spatola21
have studied CTH methods for the dehalogenation of
aromatic compounds. They have observed that the order
of addition of reagents plays an important role in the
dehalogenation process. According to them, the catalytic
activity of the Pd/C catalyst is improved significantly
when it is activated before the addition of the hydrogen
acceptor. Thus, the dechlorination of 4-chlorotoluene is
completed in 90 min at room temperature when am-
monium formate is added to the catalyst after the
introduction of the substrate. In contrast it required only
15 min for complete reduction if the sequence of the
addition of the formate and the halo-compound were
reversed.
We22 have observed, however, that when microwave-
assisted CTH reactions are used for dehalogenation, the
end products and the time for complete reduction are
independent of the order of addition of the reactants.
Several â-lactams (such as, 28 and 33) and isoquinoline
derivatives (e.g., 31 were smoothly dehalogenated (Scheme
11) in a few minutes.
isotope effect. On the basis of these findings they sug-
gested that transfer of the formyl hydrogen of the donor
to the catalyst surface is the rate-determining step.
Wiener et al,23 have observed a significant kinetic isotope
effect in the decomposition of sodium formate (HCO2Na-
H2O vs DCO2Na-D2O) catalyzed by 5% Pd/C at 35 °C.
But, they24 concluded from their study on the reduction
of nitro-toluene with formate that there was no kinetic
isotope effect.
Syn th esis of Am in es. Hydrazones are formed in
excellent yield in minutes under microwave irradiation
of ketones such as 35 and with hydrazine or phenyl-
hydrazine in ethylene glycol solution. Such hydrazones
can be converted to amines by microwave-assisted CTH
reaction. Thus, methyl benzoylformate (35) gave the
phenylhydrazone (36) in 90% yield in 6 min. Reduction
of (36) during 4 min of microwave irradiation in the
presence of ammonium formate and 10% Pd/C led to the
amine (37) which was acetylated to give methyl N-acetyl
phenylglycinate (38) in excellent yield (Scheme 13).22
During microwave-assisted dehalogenation of chloro-
benzene and p-bromoanisole, the formation of biphenyls
(Scheme 12) in about 10% yield was detected. No coupling
to dimeric products was observed during the dehalogen-
ation of 1-bromonaphthalene and 9-bromoanthracene.
Rajagopal and Spatola23 studied the kinetics of the
dehalogenation of o-chlorotoluene by HCO2Na-EtOH-
H2O and DCO2Na-EtOD-D2O and noted a kinetic
Su m m a r y a n d Ou tlook
In summary, we have devised safe, rapid, and efficient
techniques for conducting catalytic hydrogenation and
hydrogenolysis using just beakers and flasks and un-
modified domestic microwave ovens. Runaway reac-
tions under microwave irradiation leading to possible
explosion are prevented by operating under ambient
pressure in open systems. The source of hydrogen for this
catalytic transfer hydrogenation method was ammonium
(21) Rajagopal, S.; Spatola, A. F. J . Org. Chem. 1995, 60, 1347.
(22) Barakat, K. J . Ph.D. Dissertation, Stevens Institute of Technol-
ogy, Hoboken, New J ersey, 1992.
(23) Wiener, H.; Sasson, Y.; Blum, J . J . Mol. Catal. 1986, 35, 277.
(24) Wiener, H.; Blum, J .; Sasson, Y. J . Org. Chem. 1991, 56, 4481.

5750 J . Org. Chem., Vol. 64, No. 16, 1999
Banik et al.
Sch em e 8
Sch em e 9
formate, which is inexpensive and easy to store and
transportsunlike pure hydrogen gas under pressure in
cylinders.
Field tests at Stevens Institute of Technology and
neighboring inner city high schools have shown that the
microwave-assisted techniques described here for reduc-
tion and hydrogenolysis are safe and suitable for research
investigations as well as laboratory exercises for college
and pre-college students. With minor modifications these
techniques could also be used for many industrial proc-
esses.
Recent publications show increasing use of catalytic
transfer hydrogenation methods. Thus, Albanese et al.25
have found these methods to be the best for the hydro-
genolysis of 4-nitrobenzyl esters of cephalosporin anti-
biotics without isomerizing or reducing the conjugated
double bond. Knochel and co-workers26 have reported new
efficient catalysts for enantioselective transfer hydro-
genations. There is every reason to believe that these and
other new developments27 can be enhanced by the ap-
plication of microwave-assisted techniques described by
us here.
Exp er im en ta l Section
Melting points were determined with a Mel-temp apparatus
and are uncorrected. IR spectra were recorded on a Perkin-
Elmer Model 1310 instrument. NMR spectra were recorded
on a Bruker AC-20 spectrometer using TMS as an internal
standard. Chemical ionization mass spectra were recorded on
a Biospect. instrument using CH4 as the reagent gas. Thin-
layer chromatography was performed with Whatman plates,
and the spots were detected by UV. Microanalyses were
performed by Schwartzkopf Microanalytical Laboratory, NY.
Compounds described here are racemates.
Gen er a l P r oced u r e for â-La cta m s. The reaction of
substituted acetyl chlorides with Schiff bases and tertiary
amines (triethylamine for conventional experiments; N-meth-
ylmorpholine for reactions under microwave irradiation) was
used for the synthesis of acetoxy-, benzyloxy-, methoxy-, and
(25) Albanes, D.; Leone, M.; Penso, M.; Seminati, M.; Zenoni, M.;
Tetrahedron Lett. 1998, 39, 2405.
(26) Pu¨ntener, K.; Schwink, L.; Knochel, P. Tetrahedron Lett. 1996,
37, 8165.
(27) Stinson, S. C. Chem. Eng. News 1998, J une 1, 21-22.

Microwave-Assisted Hydrogenation
J . Org. Chem., Vol. 64, No. 16, 1999 5751
Sch em e 10
Sch em e 12
Sch em e 11
Sch em e 13
Gen er a l P r oced u r e for CTH Rea ction . On the basis of
several years of experience, we have found the following
protocol to be safe for conducting catalytic transfer hydrogena-
tion. Caution must be exercised, however, since some of the
catalysts are pyrophoric; also mixtures of hydrogen and air
can cause an explosion if ignited by a spark or a flame. An
unmodified domestic microwave oven (600-1000 W) placed in
a hood should be used. The reaction vessel should be a beaker
or an Erlenmeyer flask of fairly large size. A beaker of water
should be placed near this reaction vessel to serve as a “heat
sink” to provide a finer control on the amount of microwave
energy input into the hydrogenation mixture. Water absorbs
microwave energy very efficiently and thereby reduces the
amount of energy absorbed by the reaction mixture. The
approximate amount of water to be used can be determined
with a trial run involving only the solvent and without the
catalyst.
31
32
The desired temperature of the solvent should rise to 110-
120 °C in about 3 min. The catalyst should be quickly
introduced into the reaction vessel and covered with the
solvent (such as ethylene glycol, bp 198 °C) and made into a
slurry by gentle swirling motion of the beaker or the conical
flask. The compound to be reduced is dissolved in the solvent
(ethylene glycol or 1,3-propanediol) and then added to the
reaction vessel. The hydrogen donor (such as ammonium
formate) is added now. Microwave irradiation for the pre-
determined period of time to reach a temperature of 110-130
°C should be applied. The microwave oven door should be
opened, and the temperature of the reaction mixture should
be checked to be in the desired range.
phenoxy-substituted â-lactams (for example, 1, 5, 17, and 28).
For the preparation of R-vinyl-â-lactams (for example, 3 and
19), R, â-unsaturated acid chlorides were substituted for acetyl
chlorides and the reaction was conducted under microwave
irradiation.28
Schiff bases were prepared by the reaction of an aldehyde
with an amine in methylene chloride solution in the presence
of molecular sieves.29
Almost all of the â-lactams used as starting material for
this study are known compounds described in the literature.
Many of these â-lactams have been reported in our earlier
publications.30
The oven door should be closed and irradiation with
microwave should be resumed for another 3-4 min. The
microwave oven should be switched off, and the reaction vessel
(28) Manhas, M. S.; Ghosh, M.; Bose, A. K. J . Org. Chem. 1990, 55,
575.
(29) Bose, A. K.; Anjaneyulu, B.; Bhattacharya, S. K.; Manhas, M.
S.; Tetrahedron 1967, 23, 4769.
(30) Banik, B. K.; J ayaraman, M.; Srirajan, V.; Manhas, M. S.; Bose,
A. K. J . Ind. Chem. Soc. 1997, 74, 943-947, and references therein.

5752 J . Org. Chem., Vol. 64, No. 16, 1999
Banik et al.
removed from the oven. Careful decantation of the reaction
mixture after cooling followed by the addition of glycol to the
reaction vessel would preserve the catalyst for the next
experiment.
12b: yield 80%; mp 107 °C; IR (CH2Cl2) 1640 cm-1; 1H NMR
7.58 (s, 1H), 7.34-7.15 (m, 3H), 6.81 (d, J ) 6.61 Hz, 2H),
6.25-6.22 (m, 1H), 6.02-6.01 (m, 1H), 3.73 (s, 3H), 3.05-2.68
(m, 2H), 2.58-2.44 (m, 1H), 1.87-1.43 (m, 2H), 0.97 (t, J )
7.35 Hz, 3H); CIMS (CH4 gas) m/z 258 (M + H)+. Anal. Calcd
for C16H19NO2: C, 74.68; H, 7.44; N, 5.44. Found C, 74.01; H,
7.38; N, 5.19.
It is customary in our laboratory to place a beaker cover or
a filter funnel on top of the reaction vessel to prevent any
accidental spillage. Since glass is nearly transparent to
microwaves, the upper parts of the beaker of flask serves as a
condenser for any small amounts of vapors formed. After the
hydrogenation the reaction mixture was cooled and then
filtered. The filtrate was diluted with water and extracted with
ethyl acetate, and the organic layer was washed with water.
Evaporation of the solvent from the organic layer (dried over
anhydrous Na2SO4) followed by crystallization gave the pure
product in 80-90% yield. We have observed that the optimal
ratio of the catalyst (10% Pd/C) to substrate is 0.3:1 by weight
for each reducible group. Five equivalents of ammonium
formate for each reducible group gave good results.
14: yield 80%; IR (Nujol) 1650 cm-1; 1H NMR 7.18-7.02 (m,
H), 6.71-6.64 (m, 2H), 3.67 (s, 3H), 2.85 (d, J ) 6.81 Hz, 1H),
2.06-1.93 (m 2H), 1.03 (d, J ) 6.26 Hz, 3H), 0.97 (d, J ) 6.18
Hz, 3H); CIMS (CH4 gas) m/z 258 (M + H)+.
16: yield 87%; mp 69 °C; IR (Nujol) 3350, 1730 cm-1 1H
;
NMR 8.30 (brs, 1H), 7.51-6.81 (m, 9H), 4.02 (dd, J 1 ) 3.5 Hz,
J 2 ) 7.59 Hz, 1H), 3.85 (s, 3H), 3.42 (m, 2H), 3.03 (dd, J 1
)
7.7 Hz, J 2 ) 3.9 Hz, 2H), 1.59 (m, 2H), 0.90 (t, 3H); CIMS (NH3
reagent gas) m/z 314 (M + H)+.
1
18a : yield 60%; mp 70 °C; IR (Nujol) 1740 cm-1; H NMR
7.09 (m, 14H), 5.90 (d, J ) 4.9 Hz, 1H), 4.72 (m, 1H), 3.84 (s,
3H), 2.63 (m, 2H), 1.81 (m, 2H); CIMS (NH3 reagent gas) m/z
399 (M + 18)+. Anal. Calcd for C24H23NO3: C, 77.21; H, 6.16;
N, 3.75. Found: C, 76.39; H, 6.61; N, 3.81.
1
2: yield 75%; mp 108 °C; IR (CH2Cl2) 1740 cm-1; H NMR
7.30-6.69 (m, 10H), 5.43 (d, J ) 4.30 Hz, 1H), 4.93 (d, J )
4.32 Hz, 1H), 3.53-3.39 (m, 1H), 3.00-2.86 (m, 1H), 2.03-
1.82 (m, 2H), 1.11 (t, J ) 7.37 Hz, 3H); CIMS (CH4 gas) m/z
282 (M + H)+; Anal. Calcd for C18H19NO2: C, 76.84; H, 6.80;
N, 4.97. Found: C, 76.67; H, 6.67; N, 4.89.
4a : yield 80%; mp 118 °C; IR (CH2Cl2) 1740 cm-1; 1H NMR
7.35-6.99 (m, 10H), 4.67 (d, J ) 2.34 Hz), 3.10-3.01 (m, 1H),
2.03-1.82 (m, 1H), 1.11 (t, J ) 7.37 Hz, 3H); CIMS (CH4 gas)
m/z 252 (M + H)+. Anal. Calcd for C17Hl7NO: C, 81.24; H, 6.81;
N, 5.57. Found: C, 80.99; H, 6.67; N, 4.89.
1
18b: yield 30% oil; IR (CH2Cl2) 3300, 1640 cm-1; H NMR
7.42-7.16 (m, 13H), 6.84 (d, J ) 8.95 Hz, 2H), 3.77 (s, 3H),
2.64 (t, J ) 7.19 Hz, 1H), 2.33 (t, J ) 6.97 Hz, 2H), 1.72 (m,
4H); CIMS (CH4 reagent gas) m/z 376 (M + H)+. Anal. Calcd
for C24H25NO3: C, 76.76; H, 6.71; N, 3.73. Found: C, 76.51;
H, 6.53; N, 3.81.
20a : yield 40%; mp 72 °C; IR (CH2Cl2); 1740 cm-1; 1H NMR
7.36-7.17 (m, 7H), 6.86 (d, J ) 8.81 Hz, 2H), 4.15-4.08 (m,
1H), 3.78 (s, 3H), 3.42-3.20 (m, 1H), 2.83-2.57 (m, 2H), 2.32-
1.67 (m, 4H), 1.17 (t, J ) 7.43 Hz, 3H); CIMS (CH4 gas) m/z
326 (M + H)+. Anal. Calcd for C20H23NO2: C, 77.64; H, 7.49;
N, 4.52. Found: C, 77.76; H, 7.40; N, 4.57.
4b: yield 85%; mp 109 °C; IR (CH2Cl2) 1740 cm-1; 1H NMR
7.32 (s, 5H), 7.15 (d, 2H), 6.69 (d, 2H), 4.54 (d, J ) 2.27 Hz,
1H), 3.74 (s, 3H), 2.94-2.90 (m, 2H), 2.07-1.69 (m, 2H), 1.04
(t, 3H). Anal. Calcd for C18H19NO2: C, 76.84; H, 6.80; N, 4.97.
Found: C, 76.62; H, 6.92; N, 5.0.
20b: yield 35%; mp 50 °C; IR (CH2Cl2) 1740 cm-1; 1H NMR
7.36 (m, 7H), 6.85 (d, J ) 6.7 Hz, 2H), 4.16 (dd, J 1 ) 5.54 Hz,
1
4c: yield 85%, oil; IR (neat) 1740 cm-1; H NMR 7.37 (brs,
J 2 ) 11.23 Hz, 1H), 3.84 (s, 3H), 3.08 (dd, J 1 ) 5.63 Hz, J 2
)
1H), 7.25 (d, J ) 8.9 Hz, 2H), 6.7 (d, J ) 8.9 Hz, 2H), 6.38-
6.29 (m, 2H), 4,66 (d, J ) 2.38 Hz, 1H), 3.71 (s, 3H), 3.30-
3.31 (m, 1H), 2.01-1.72 (m, 2H), 1.05 (t, J ) 7.4l Hz, 3H);
10.00 Hz, lH), 2.82-2.65 (m, 2H), 2.27-1.88 (m, 3H), 1.28 (d,
J ) 6.54 Hz, 3H), 1.06 (d, 6.39 Hz); CIMS (CH4 gas) m/z 324
(M + H)+. Anal. Calcd for C2lH25NO2: C, 77.98; H, 7.79; N,
4.33. Found: C, 77.71; H, 7.64; N, 4.39.
CIMS (CH4 gas) m/z 272 (M + H)+. Anal. Calcd for C16H17
-
NO3: C, 70.83; H, 6.31 N, 5.16. Found: C, 70.59, H, 6.11; N,
5.02.
21a : yield 40%; mp 87 °C; IR (CH2Cl2) 3320, 1640 cm-1; 1H
NMR 7.79 (s, 1H), 7.43 (d, J ) 8.9 Hz, 2H), 7.32-7.15 (m, 5H),
6.85 (d, J ) 8.9 Hz, 2H), 3.79 (s, 3H), 2.63 (t, J ) 6.78 Hz,
2H), 2.08-2.06 (m, 1H), 1.79-1.50 (m, 6H), 0.94 (t, J ) 7.34
Hz, 3H); CIMS (CH4 gas) m/z 312 (M + H)+. Anal. Calcd for
6a : yield 90%; mp 109-110 °C; IR (Nujol) 3300, 1730 cm-1
;
1H NMR 7.41 (d, 2H), 6.92 (d, 2H), 5.04 (d, J ) 4.9 Hz, 1H),
4.37 (m, 1H), 3.82 (s, 3H), 3.72 (s, 3H), 2.61 (m, 2H), 2.12 (m,
2H); CIMS (NH3 reagent gas) m/z 297 (M + 18)+. Anal. Calcd
for C14Hl7NO5; C, 60.20; H, 6.10; N, 5.01. Found: C, 59.61, H,
6.26, N, 5.00.
C
20H25NO2: C, 77.13; H, 8.09; N, 4.49. Found: C, 77.00; H,
8.37; N, 4.34.
21b: yield 35%; mp 12l°C; IR (CH2Cl2) 3350, 1650 cm-1; 1H
NMR 7.41 (d, J ) 8.77 Hz, 2H), 7.35-7.14 (m, 6H), 6.83 (d, J
) 9 Hz, 2H), 3.78 (s, 3H), 2.63 (t, J ) 7.07 Hz, 2H), 1.91-1.51
(m, 6H), 0.98 (d, J ) 5.76 Hz, 3H); CIMS (CH4 gas) m/z 326
(M + H)+. Anal. Calcd for C21H27NO2: C, 77.49; H, 8.36; N,
4.30. Found: C, 77.77; H, 8.35; N, 4.44.
6b: yield 85%; oil, IR (Nujol) 3350, 1730 cm-1; 1H NMR 7.40
(s, 5H), 5.23 (m, 1H), 4.94 (t, 1H), 4.67 (d, J ) 15.4 Hz, 1H),
4.20 (d, J ) 15.4 Hz, 1H), 3.75 (s, 3H), 3.24 (m, 1H), 2.41 (m,
2H), 2.0 (m, 2H); CIMS (NH3 reagent gas) m/z 281 (M + 18)+.
8: yield 84%; mp 123-125 °C; IR (Nujol) 3300, 1640 cm-1
;
1H NMR 7.80 (brs, 1H) 7.00 (m, 14H), 4.93 (dd, J 1 ) J 2 ) 3.91
Hz, 1H), 3.8 (s, 3H), 3.33 (d, J 1 ) J 2 ) 14.16 Hz, 2H); 13C NMR
168.80, 157.25, 136.40, 129.84, 128.32, 126.28, 122.42, 122.14,
115.82, 114.23, 80.16, 55.49, 38.97. Anal. Calcd for C22H2lNO3;
C, 76.00; H, 6.05; N, 4.03. Found: C, 75.55; H,6.12; N, 3.99.
1
29: mp 108 °C; IR (CH2Cl2) 1740 cm-1; H NMR 7.30-6.60
(m, 10H), 5.43 (d, J ) 4.31 Hz, 1H), 4.93 (d, J ) 4.32 Hz, 1H),
3.53-3.39 (m, 1H), 3.00-2.86 (m, 1H), 1.57-1.46 (m, 2H), 0.89
(t, J ) 7.32 Hz, 3H); CIMS (CH4 gas) m/z 282 (M + H)+. Anal.
Calcd for C18H19NO2: C, 76.84; H, 6.80; N, 4.97. Found C,
76.67; H, 6.67; N, 4.89.
1
10a : yield 83%; mp 89 °C; IR (Nujol) 3300, 1630 cm-1; H
30: IR (CH2Cl2) 1650 cm-1 1H NMR 7.40-6.51 (m, 11H),
;
NMR 7.25 (m, 10H), 4.23 (m, 2H), 3.40 (brs, 1H), 3.12 (dd, 2H),
2.64 (dd, 1H); CIMS (NH3 reagent gas) m/z 273 (M + 18)+.
Anal. Calcd for C26H17NO2: C 75.29; H, 6,66; N, 5.49. Found:
C, 75.13, H, 6.69; N, 5.58.
4.83 (dd, J 1 ) 6.80 Hz, J 2 ) 10.70 Hz, 1H), 2.99-2.48 (m, 3H),
2.52-2.48 (m, 1H), 1.43-1.28 (m, 2H), 0.75 (t, J ) 7.42 Hz,
3H).
1
10b: yield 80%; mp 128 °C; IR (Nujol) 3300, 1640 cm-1; H
32: IR (Nujol) 1660 cm-1; 1H NMR 8.37-8.32 (m, 1H), 7.59-
7.22 (m, 8H), 5.49 (brs, 1H), 4.36-4.19 (m, 1H), 4.12 (brs, 1H),
3.69 (s, 3H), 3.01-2.87 (m, 1H), 1.93-1.74 (m, 2H), 1.08 (t, J
) 7.33 Hz, 3H). Anal. Calcd for C20H21NO3: C, 74,28; H 6.54;
N, 4,33. Found C, 74.39; H, 6.41; N, 4.38.
1
NMR 8.20 (brs, H), 7.51-6.80 (m, 9H), 4.4 (m, 1H), 3.85 (s,
3H), 3.42 (dd, J 1 ) 7.80 Hz, J 2 ) 7.80 Hz, 1H), 3.09 (dd, J 1
)
8.30 Hz, J 2 ) 14.10 Hz, 1H), 2.63 (d, J ) 8.30 Hz, 1H); CIMS
(NH3 reagent gas) m/z 289 (M + H)+. Anal. Calcd for C16H17
-
1
34: oil; IR (Nujol) 1750 cm-1; H NMR 7.2 (s, 5H), 4.75 (d,
NO3: C, 66.43; H, 6.51; N, 4.48. Found C, 66.65; H, 5.84; N,
4.76.
J ) 16.0 Hz, 1H), 4.20 (d, J ) 16.0 Hz, 1H), 4.0 (m, 1H), 3.65-
3.40 (m, 2H), 3.01 (dd, J 1 ) 5 Hz, J 2 ) 16 Hz, 1H), 2.55 (dd, J l
) 5 Hz, J 2 ) 16 Hz, 1H), 1.30 (s, 3H), 1.20 (s, 3H); CIMS (NH3
reagent gas) m/z 279 (M + 18)+.
Meth yl P h en ylglycin a te (37). Methyl benzoyl formate
(35) (6.1 mmol), phenyl hydrazine (7 mmol) and ethylene glycol
1
12a : yield 83%; mp 113-115 °C; IR (Nujol) 1640 cm-1; H
NMR 7.10-6.65 (m, 9H), 3.73 (s, 3H), 2.82 (m, 2H), 2.21 (m,
1H), 1.75 (m, 2H), 0.90 (t, 3H); CIMS (NH3 reagent gas) m/z
301 (M + 18)+. Anal. Calcd for C18H21NO2: C, 76.32; H, 7.42;
N, 4.84. Found: C, 75.80; H, 7.79; N, 4.84.

Microwave-Assisted Hydrogenation
J . Org. Chem., Vol. 64, No. 16, 1999 5753
(5 mL) were placed in an Erlenmeyer flask (125 mL). The
mixture was heated for 6 min at low power setting. The desired
phenyl hydrazone (36) precipitated out on scratching under
ice cold condition. It was filtered, washed with hexane, and
dried (yield 90%, mp 86-88 °C).
Ammonium formate (200 mg) and 10% Pd/C (100 mg) were
added to phenylhydrazone (36) (2 mmol) in ethylene glycol (5
mL). The mixture was irradiated for 4 min. After the usual
workup, the amine (37) was isolated (92%): IR 1710 cm-1; 1H
NMR (CDCl3) 7.40 (s, 5H), 4.6 (s, 1H), 3.61 (s, 3H), 2.0 (brs,
2H): 13C NMR 174.19, 140.11, 128.56, 127.77, 126.69, 59.15,
52.11; CIMS (NH3 reagent gas) m/z 183 (M + 18)+. A portion
of (37) was acetylated with acetic anhydride and pyridine to
afford (38): mp 85-86 °C; IR (Nujol) 1700 cm-1; 1H NMR 8.9
(brs, 1H), 7.31 (s, 5H), 5.60 (d, J ) 8.24 Hz, 1H), 3.70 (s, 3H),
2.0 (s, 3H); 13C NMR 168.79, 138.02, 128.83, 127.15, 119.98,
61.90, 56.56, 24.33; CIMS (NH3 reagent gas) m/z 225 (M +
18)+.
Ack n ow led gm en t. This research was supported by
Stevens Institute of Technology (in part) and by the
Howard Hughes Medical Institute [through a grant to
our Chemical Biology Education Enhancement (CBEE)
Program]. For technical help we thank Keiko Tabei and
Raza Naqvi, undergraduate research participants Gre-
gory Morriello, Kavita Mistry, and Madhumeeta Patel,
and pre-college research trainees Ingrid Callejas and
Varsha Valecha (supported by Project SEED of the
American Chemical Society).
J O981516S