Microwave-enhanced Goldberg reaction: A novel route to N-arylpiperazinones and N-arylpiperazinediones

Article abstract of DOI:10.1016/S0040-4039(01)02334-6

An unprecedented microwave-enhanced Goldberg reaction constitutes the key strategic step in the synthesis of N-arylpiperazinones, N-arylpiperazinediones and N-aryl-3,4-dihydroquinolinones. Microwave irradiation greatly accelerates the Goldberg reaction using NMP as solvent. Alkylation at the 3-position of the formed N-aryl-2-piperazinones furnishes new N-aryl-3-alkyl-2-piperazinones.

Full text of DOI:10.1016/S0040-4039(01)02334-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1101–1104
Microwave-enhanced Goldberg reaction: a novel route to
N-arylpiperazinones and N-arylpiperazinediones
Jos H. M. Lange,* Lovina J. F. Hofmeyer, Floris A. S. Hout, Stefan J. M. Osnabrug,
Peter C. Verveer, Chris G. Kruse and Rolf W. Feenstra
Solvay Pharmaceuticals, Research Laboratories, PO Box 900, 1380 DA Weesp, The Netherlands
Received 10 October 2001; revised 20 November 2001; accepted 6 December 2001
Abstract—An unprecedented microwave-enhanced Goldberg reaction constitutes the key strategic step in the synthesis of
N-arylpiperazinones, N-arylpiperazinediones and N-aryl-3,4-dihydroquinolinones. Microwave irradiation greatly accelerates the
Goldberg reaction using NMP as solvent. Alkylation at the 3-position of the formed N-aryl-2-piperazinones furnishes new
N-aryl-3-alkyl-2-piperazinones. © 2002 Elsevier Science Ltd. All rights reserved.
powerful synthetic methodology in organic synthesis,5
Microwave irradiation of organic reactions has rapidly
albeit the nucleophilic replacement of a leaving group
on an aryl ring by nitrogen is now being studied
intensively.6 Although a number of newer Goldberg
variations7–9 has been reported there is still a need for a
simple and fast procedure.
gained in popularity as it accelerates a variety of syn-
thetic transformations1,2 via time- and energy-saving
protocols. Herein, we report the microwave-enhanced
formation of N-aryl-2-piperazinones and N-aryl-2,5-
piperazinediones from aryl bromides and protected 2-
piperazinones or 2,5-piperazinediones, respectively.
Although the use of ultrasound in the Goldberg reac-
tion has been reported for the synthesis of N-arylan-
thranilic acids,10 the application of microwave
irradiation is still unprecedented. In general, Goldberg
reactions are carried out either under solvent-free con-
ditions by refluxing the mixed reactants for a prolonged
period or in polar solvents such as DMF,11 DMSO12 or
nitrobenzene.13 Our preliminary studies wherein bro-
mobenzene 1a and acetanilide 2 (Scheme 1) were
reacted under solvent-free conditions using microwave
irradiation gave unsatisfactory conversion rates. It is
obvious that in the absence of solvent both the reflux
temperature and the polarity of the reaction mixture
N-Aryl-2-piperazinones are of great interest as farnesyl-
transferase inhibitors.3 In addition, both N-aryl-2-
piperazinones and N-aryl-2,5-piperazinediones are
synthetic precursors for N-arylpiperazines which consti-
tute key elements in current medicinal chemistry, espe-
cially in the area of monoamine receptor active drugs.
The Goldberg reaction,4 the copper-catalysed amida-
tion of aryl halides, usually requires drastic reaction
conditions. Due to this drawback which limits its scope,
the Goldberg reaction has not been recognised as a
Scheme 1.
* Corresponding author. Tel.: +31 (0)294 479731; fax: +31 (0)294 477138; e-mail: jos.lange@solvay.com
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02334-6

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J. H. M. Lange et al. / Tetrahedron Letters 43 (2002) 1101–1104
will strongly depend on the particular Goldberg reac-
tion that is being carried out. As the absorption rate of
microwave energy is very dependent2 on the polarity
and dielectric properties of the reaction mixture our
investigations continued with seeking the optimal
organic solvent for performing microwave-enhanced
Goldberg reactions in order to improve their reproduci-
bility and scope.
round-bottomed flask equipped with a reflux condenser
was irradiated in a microwave oven (type: Milestone
Ethos 900) for 40 min at 250 W power under a gentle
stream of nitrogen. The mixture was allowed to attain
rt and diluted with diethyl ether (200 mL). After filtra-
tion over hyflo, the diethyl ether layer was successively
washed with three portions (10 mL each) of NH4OH
aq. solution and three portions of NaHCO3 (5% aq.
solution). The aqueous layers were extracted with
diethyl ether and the combined diethyl ether fractions
were dried over MgSO4, filtered and concentrated in
vacuo to produce a brown oil (6.2 g). This oil was
purified by flash chromatography (silica gel, petroleum
ether/EtOAc=3/1 (v/v)) to furnish 3a (4.0 g, 76% yield
as a white solid, mp 101–103°C (lit.14 mp 99°C; lit.15 mp
102–103°C)). CAUTION These microwave-enhanced
Goldberg reactions should be performed in an open
reaction system in order to enable gaseous products to
escape, thus avoiding the risk of explosion.
Starting from the Goldberg reaction conditions that
Freeman5 used (10 mol% CuI, solvent-free, reflux tem-
perature, 72 h) we added different polar solvents
(DMF, DMSO, NMP, HMPA, nitrobenzene) and
determined the respective reaction rates and chemical
yields of the reaction of bromobenzene 1a and acetani-
lide 2 (Scheme 1) with and without applying microwave
irradiation, respectively. The optimal solvent for both
reaction types turned out to be N-methyl-2-pyrrolidi-
none (NMP). The addition of a relatively small amount
(2 molar equivalents) of NMP without the use of
microwave irradiation induced a complete conversion,
according to HPLC analysis in 17 h, to the N-
acetyldiphenylamide 3a, which was isolated in 71%
yield. Furthermore, we established that the optimal
amount of CuI catalyst (2.5 mol%) for both the reac-
tion in NMP and the solvent-free process is consider-
ably lower than the amount that Freeman5 used. In
general, the reaction rates of the Goldberg reactions in
NMP are approximately three to four times higher in
comparison with the solvent-free procedure.
The scope of our microwave-enhanced Goldberg reac-
tion was further explored by reacting the bicyclic amide
3,4-dihydro-1H-quinolin-2-one 4 (which can be viewed
as a cyclised derivative of 2) with bromobenzene 1a
(Scheme 2). It is interesting to note that reaction of the
cyclic amide 4 proceeded relatively fast (4 h) under
thermal conditions to produce 1-phenyl-3,4-dihydro-
1H-quinolin-2-one16 5 (isolated yield: 77%). Microwave
irradiation induced an even faster reaction (30 min at
200°C, followed by 1 h at 190°C) but the time-saving
was less pronounced in comparison with the reaction in
Scheme 1. In this case, microwave irradiation offers no
substantial benefit.
Microwave irradiation conditions (40 min, 250 W) were
applied and gave a complete conversion according to
HPLC analysis from 1a and 2 in NMP into the N-aryl-
ated product 3a, which was isolated in 76% yield. The
corresponding reaction of 2-bromoanisole 1b with 2
proceeded even more quickly (20 min, 250 W) and gave
N-acetyl-2-methoxyphenyl-phenylamide13 3b in 56%
isolated yield. A somewhat higher yield of 3a (80%)
could be obtained by keeping a constant temperature
(190°C, 40 min) during the microwave irradiation pro-
cess. These findings clearly demonstrate the time- and
energy-saving effect of microwave irradiation in both
Goldberg reactions.
The Goldberg reaction of 4-benzylpiperazin-2,5-dione17
6 with bromobenzene 1a requires 20 h heating at reflux
temperature under thermal conditions in NMP. This
conversion was tremendously accelerated by microwave
irradiation to furnish 4-benzyl-1-phenylpiperazin-2,5-
dione18 7 within 20 min in an isolated yield of 51%
(Scheme 3). To our knowledge this is the fastest Gold-
berg reaction that has been reported.
The Goldberg reaction of 4-benzylpiperazin-2-one19
8
with bromobenzene 1a (Scheme 4) also proceeded
slowly in NMP (20 h) at 200°C under thermal condi-
tions. This particular reaction without microwave irra-
diation was optimised earlier under solvent-free
conditions (2.5 mol% CuI, 140°C) and was shown to be
completed in 72 h. To our satisfaction this reaction was
completed within 1 h using microwave irradiation by
maintaining the reaction temperature between 190 and
It was established that 10 mol% of CuI catalyst is the
optimal amount for microwave enhanced Goldberg
reactions. The synthesis of 3a is representative. A
stirred mixture of bromobenzene 1a (3.95 mL, 37.5
mmol) and acetanilide 2 (3.38 g, 25.0 mmol), NMP (5
mL, 52 mmol), CuI (0.5 g, 2.5 mmol) and dried pow-
dered K2CO3 (3.45 g, 25 mmol) in a three necked
Scheme 2.

J. H. M. Lange et al. / Tetrahedron Letters 43 (2002) 1101–1104
1103
Scheme 3.
Scheme 4.
200°C, to produce 4-benzyl-1-phenylpiperazin-2-one20
9a in an isolated yield of 57%. The reaction of the
corresponding methoxy derivative 1b with 8 furnished
4-benzyl-1-(2-methoxyphenyl)piperazin-2-one21,22 9b in
an isolated yield of 66% within 1 h.
References
1. Bose, A. K.; Banik, B. K.; Lavlinskaia, N.; Jayaraman,
M.; Manhas, M. S. Chemtech 1997, 27, 18–24.
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5. Freeman, H. S.; Butler, J. R.; Freedman, L. D. J. Org.
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39, 4492–4494 and references cited therein.
N-Arylpiperazinones are key synthetic precursors for
the pharmaceutically important class of N-arylpiperazi-
nes. Further functionalisation of 9a would enable a
straightforward synthetic entry into a variety of novel
3-substituted 1-arylpiperazines. This consideration
prompted us to perform alkylation reactions at the
3-position of 9a. Deprotonation of 9a at its C3-position
with LDA in THF/DMPU (1,3-dimethyl-3,4,5,6-tetra-
hydro-2(1H)-pyrimidinone), followed by reaction with
an alkyl halide gave the 3-alkylated phenylpiperazi-
nones 10a,23 10b24 and 10c,25 respectively. It should be
noted that the presence of DMPU is essential in these
C-alkylation reactions.
7. Renger, B. Synthesis 1985, 856–860.
8. Greiner, A. Synthesis 1989, 312–313.
9. Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. J.
Am. Chem. Soc. 2001, 123, 7727–7729.
In conclusion, rapid and practical procedures for the
N-arylation of piperazinediones, piperazinones and 3,4-
dihydroquinolinones were developed which demon-
strate the time- and energy-saving effect of microwave
irradiation in the applied Goldberg reactions.
10. Carrasco, R.; Pello´n, R. F.; Elguero, J.; Goya, P.; Pa´ez,
J. A. Synth. Commun. 1989, 19, 2077–2080.
11. Pello´n, R. F.; Carrasco, R.; Marquez, T.; Mamposo, T.
Tetrahedron Lett. 1997, 38, 5107–5110.
12. Joergensen, T. K.; Andersen, K. E.; Lau, J.; Madsen, P.;
Huusfeld, P. O. J. Heterocyclic Chem. 1999, 36, 57–64.
13. Ishii, H.; Sugiura, T.; Kogusuri, K.; Watanabe, T.;
Murakami, Y. Chem. Pharm. Bull. 1991, 39, 572–578.
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Acknowledgements
We wish to thank Mrs. Alice Borst, Mrs. Danielle
Henning and Mr. Karel Stegman for analytical
support.
15. Herz, E.; Wagner, J. Monatsh. Chem. 1947, 76, 32–37.
16. Mortelmans, C.; Van Binst, G. Tetrahedron 1978, 34,
363–369.

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J. H. M. Lange et al. / Tetrahedron Letters 43 (2002) 1101–1104
(29), 91 (100); HRMS (EI): calcd for C18H20N2O (M+ free
base) 280.1576; found 280.1579.
17. Groves, J. T.; Chambers, R. R. J. Am. Chem. Soc. 1984,
106, 630–638.
24. Analytical data for 3-allyl-4-benzyl-1-phenylpiperazin-2-
18. Analytical data for 4-benzyl-1-phenylpiperazin-2,5-dione
7: mp 157–158°C; 1H NMR (200 MHz, CDCl3): l 4.04 (s,
2H), 4.42 (s, 2H), 4.66 (s, 2H), 7.23–7.48 (m, 10H); 13C
NMR (100 MHz, DMSO-d6): l 48.8, 50.5, 53.0, 126.1,
127.4, 128.2, 128.7, 129.3, 129.5, 136.8, 141.0, 164.6,
164.7; MS (ESI+): (MH)+ m/z 281; MS (EI): m/z (rel.
intensity) 280 (72), (189 (5), 161 (29), 105 (35), 104 (39),
91 (100); HRMS (EI): calcd for C17H16N2O2 (M+)
280.1212; found 280.1213.
1
one 10b: mp 118–119°C; H NMR (200 MHz, CDCl3): l
2.50–2.81 (m, 2H), 2.85–3.08 (m, 2H), 3.32–3.53 (m, 3H),
3.65–3.81 (m, 1H), 4.10 (d, J=13 Hz, 1H), 5.08–5.26 (m,
2H), 5.91–6.14 (m, 1H), 7.18–7.43 (m, 10H); 13C NMR
(100 MHz, DMSO-d6): 35.0, 46.7, 49.1, 58.1, 65.2, 117.3,
126.5, 126.9, 127.8, 128.9, 129.4, 129.5, 135.9, 138.8,
143.4, 169.0; MS (ESI+): (MH)+ m/z 307; MS (EI): m/z
(rel. intensity) 265 (30), 91 (100); HRMS (EI): calcd for
C17H17N2O
265.1355.
(M+−CH2CHꢀCH2)
265.1341;
found
19. Uchida, H.; Ohta, M. Bull. Chem. Soc. Jpn. 1973, 46,
3612–3613.
25. Analytical data for 3,4-dibenzyl-1-phenylpiperazin-2-one
10c: mp 109–111°C; 1H NMR (200 MHz, CDCl3): l
2.50–2.63 (m, 1H), 2.93–3.05 (m, 1H), 3.15–3.42 (m, 4H),
3.49 (d, J=13 Hz, 1H), 3.59–3.65 (m, 1H), 4.15 (d, J=13
Hz, 1H), 6.98–7.07 (m, 2H), 7.17–7.40 (m, 13H); 13C
NMR (100 MHz, DMSO-d6): 36.7, 46.2, 48.7, 58.3, 66.5,
126.5, 126.7, 127.0, 127.7, 128.4, 128.9, 129.4, 129.5,
130.5, 138.6, 139.4, 143.3, 169.1; MS (ESI+): (MH)+ m/z
357; MS (EI): m/z (rel. intensity) 265 (34), 91 (100);
HRMS (EI): calcd for C17H17N2O (M+−CH2C6H5)
265.1341; found 265.1352. Synthesis of 3,4-dibenzyl-1-
phenylpiperazin-2-one 10c: 4-Benzyl-1-phenylpiperazin-2-
one (3.50 g, 13.2 mmol) was dissolved in a mixture of dry
THF (35 mL) and DMPU (17.5 mL) under a nitrogen
atmosphere. The resulting solution was cooled to −78°C
and LDA (6.59 mL, 2 M solution in THF, 13.2 mmol)
was added. After stirring for 35 min benzyl bromide (1.8
mL, 15.2 mmol) was added and the resulting solution was
allowed to attain room temperature and stirred
overnight. A solution of NaHCO3 (5% aq., 175 mL) and
diethyl ether were added. The organic layer was twice
washed with water, dried over MgSO4, filtered and con-
centrated in vacuo. The resulting oil was crystallised from
diethyl ether to furnish 3,4-dibenzyl-1-phenylpiperazin-2-
one (3.53 g, 75% yield) as a white solid.
20. Analytical data for 4-benzyl-1-phenylpiperazin-2-one 9a:
mp 104–105°C; 1H NMR (200 MHz, CDCl3): l 2.76–2.85
(m, 2H), 3.34 (s, 2H), 3.62 (s, 2H), 3.63–3.72 (m, 2H),
7.20–7.45 (m, 10H); MS (ESI+): (MH)+ m/z 267.
21. Bruderer, H.; Kierstead, R. W.; Mullin, J. G.; Naka-
mura, K.; O’Brien, J. P.; Tateishi, M.; Teitel, S. Eur.
Patent 0126480, 1984; Chem. Abstr. 1984, 102, 132070.
22. Analytical data for 4-benzyl-1-(2-methoxyphenyl)-
piperazin-2-one 9b: mp 113–114°C (lit.20 mp 109–111°C);
1H NMR (200 MHz, CDCl3): l 2.80 (t, J=6 Hz, 2H),
3.34 (s, 2H), 3.52–3.62 (m, 2H), 3.64 (s, 2H), 3.83 (s, 3H),
6.93–7.02 (m, 2H), 7.16–7.40 (m, 7H); 13C NMR (100
MHz, DMSO-d6): l 49.6, 56.3, 57.8, 61.3, 113.1, 121.3,
127.9, 129.0, 129.5, 129.7, 129.8, 131.1, 137.9, 155.4,
166.5; MS (ESI+): (MH)+ m/z 297; MS (EI): m/z (rel.
intensity) 296 (28), 267 (80), 205 (91), 91 (100); HRMS
(EI): calcd for C18H20N2O2 (M+) 296.1525; found
296.1533.
23. Analytical data for 4-benzyl-3-methyl-1-phenylpiperazin-
1
2-one hydrochloride 10a: mp 206–207°C; H NMR (200
MHz, CDCl3): l 1.56 (d, J=7 Hz, 3H), 2.55–2.68 (m,
1H), 2.96–3.10 (m, 1H), 3.33–3.75 (m, 4H), 4.00 (d, J=13
Hz, 1H), 7.20–7.53 (m, 10H); MS (ESI+): (MH)+ m/z
281; MS (EI): m/z (rel. intensity) 280 (4), 237 (65), 189