Synthesis of piperazinones and benzopiperazinones from 1,2-diamines and organoboronic acids

Article abstract of DOI:10.1016/S0040-4039(00)01717-2

Alkenyl, aryl and heteroaryl boronic acids react with 1,2-diamines and glyoxylic acid to give directly in one step the corresponding piperazinones (2-oxopiperazines). Similarly, the use of monoprotected 1,2-phenylenediamine leads to benzopiperazinones (1,2,3,4-tetrahydroquinoxalin-2-ones). (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01717-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 9607–9611
Synthesis of piperazinones and benzopiperazinones from
1,2-diamines and organoboronic acids†
Nicos A. Petasis* and Zubin D. Patel
Department of Chemistry and Loker Hydrocarbon Research Institute, University of Southern California,
Los Angeles, CA 90089-1661, USA
Received 31 August 2000; revised 2 October 2000; accepted 3 October 2000
Abstract
Alkenyl, aryl and heteroaryl boronic acids react with 1,2-diamines and glyoxylic acid to give directly in
one step the corresponding piperazinones (2-oxopiperazines). Similarly, the use of monoprotected
1,2-phenylenediamine leads to benzopiperazinones (1,2,3,4-tetrahydroquinoxalin-2-ones). © 2000 Elsevier
Science Ltd. All rights reserved.
The design and synthesis of peptidomimetics continues to be an area of intense interest in
medicinal and combinatorial chemistry.1 Among the most common approaches is the develop-
ment of conformationally restricted molecules which mimic a given peptide conformation. Two
interesting examples that mimic conformation (1) in peptides are the piperazinones2 (2-oxopiper-
azines) (2) and the benzopiperazinones3 (1,2,3,4-tetrahydro-quinoxalin-2-ones) (3). Herein we
report a new synthesis of these types of molecules.
Following our earlier report on the use of organoboronic acids in a Mannich type reaction,4a
we have recently introduced a new multi-component process4b–d involving the one-step conden-
sation of alkenyl, aryl or heteroaryl boronic acids with amines and certain carbonyl compounds
to form new functionalized amine derivatives. We have used this concept to devise a new,
general and practical one-step approach to the synthesis of a-amino acids4b,c as well as b-amino
* Corresponding author. Fax: 213 740-6684; e-mail: petasis@usc.edu
†
Dedicated to Professor Harry H. Wasserman, on the occasion of his 80th birthday.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01717-2

9608
alcohols.4d Herein, we report the use of this chemistry for the direct synthesis of piperazinones
(8) and benzopiperazinones (11) (Scheme 1).
Scheme 1.
For the synthesis of piperazinones (8), we explored the one-step reaction among 1,2-diamines
(5), organoboronic acids (4), and glyoxylic acid (6). Based on a recent report by Yamamoto,5 we
expected that the resulting amino acid adduct (7) might undergo in situ cyclization catalyzed by
the boronic acid 4. Indeed, we have found that the desired heterocyclic products 8 could be
formed in one step by reacting 4, 5, and 6. Noteworthy in this process is the dual role of
organoboronic acids (4) serving both as reactants and as catalysts for the subsequent cyclization
step.
Table 1 shows several examples of this chemistry. By examining a variety of reaction
conditions, we have found that this process is usually most efficient in refluxing acetonitrile.
Several types of alkenyl (12), aryl (13 and 14) and heteroaryl (15–18) boronic acids afforded the
expected piperazinones in variable yields (not optimized).6
Typical experimental procedure (entry 4): To a mixture of diamine 19 (240 mg, 1 mmol) and
glyoxylic acid monohydrate (92 mg, 1.0 mmol) in acetonitrile (20 mL), was added (E)-2-
phenylethenyl boronic acid (12, 144 mg, 1.0 mmol) and the solution was heated at reflux while
monitored by TLC (2:3 EtOAc–hexanes). After 2 hours, the solvent was evaporated and the
product was isolated by flash chromatography using 3:7 EtOAc–hexanes affording piperazinone
22 (291 mg, 76%).7
The present process was most efficient with secondary 1,2-diamines, while primary 1,2-
diamines (e.g. 33) did not work in this manner. However, conversion of 33 to a secondary
1,2-diamine (35) via reductive amination with an aldehyde (34), followed by the three-compo-
nent process, gave the piperazinone (36) with modest diastereoselectivity (40% de) (Scheme 2).
Removal of the benzyl groups from 36 can give the piperazinone that would have been produced
from 33. Alternatively, use of the monoprotected derivative 37 gave the amino acid product 38
with somewhat improved diastereoselectivity (73% de) (configuration unknown). Treatment of
38 with acid gave the corresponding N-unsubstituted piperazinone (39). It should be noted that

9609
Table 1
One step synthesis of piperazinones from organoboronic acids, diamines and glyoxylic acid monohydrate

9610
Scheme 2.
the diastereoselectivity in this case was comparable to other chiral amines, but it was not as high
as that observed previously with phenylglycinol.4b
A similar stepwise approach was found to be quite useful for the synthesis of benzopiperazi-
nones (Scheme 3). Thus, while the parent 1,2-phenylenediamine (40) was not effective in our
process, the reaction of the monoprotected derivative (9) with boronic acids and glyoxylic acid,
followed by acidic treatment, gave the expected products (e.g. 42, 44 and 46) in good overall
yields. Interestingly, since the resulting heterocycles have the N-atoms differentiated, they can be
used again in our three-component process to react selectively at the available amine site to give
even more functionalized peptidomimetic heterocycles (e.g. 47).
Scheme 3.

9611
In summary, we have shown that organoboronic acids and 1,2-diamines can serve as versatile
precursors for the synthesis of peptidomimetics, such as 8 and 11. This direct approach to such
complex heterocycles from readily available components is very useful for the synthesis of
combinatorial libraries of these potentially bioactive molecules. Further use of this chemistry for
the synthesis of other heterocyclic systems is currently under way.
Acknowledgements
We gratefully acknowledge the National Institutes of Health (grant GM 45970) for support of
this research. We also thank the Loker Hydrocarbon Research Institute for a Harold Moulton
Graduate Fellowship to Z.D.P.
References
1. (a) Hanessian, S.; McNaughton-Smith, G.; Lombart, H.-G.; Lubell, W. D. Tetrahedron 1997, 53, 12789. (b) Nefzi,
A.; Ostresh, J. M.; Houghten, R. A. Chem. Rev. 1997, 97, 449. (c) Babine, R. E.; Bender, S. L. Chem. Rev. 1997,
97, 1359. (d) Advances in Amino Acid Mimetics and Peptidomimetics; Abell, A., Ed.; Jai Press: Greenwich, CT,
1999; Vol. 2, pp. 1–301. (e) Franzen, R. G. J. Comb. Chem. 2000, 2, 195.
2. (a) Pohlmann, A.; Schanen, V.; Guillaume, D.; Quirion, J.-C.; Husson, H.-P. J. Org. Chem. 1997, 62, 1016. (b)
Shreder, K.; Zhang, L.; Goodman, M. Tetrahedron Lett. 1998, 39, 221. (c) Goff, D. A. Tetrahedron Lett. 1998, 39,
1473. (d) Weissman, S. A.; Lewis, S.; Askin, D.; Volante, R. P.; Reider, P. J. Tetrahedron Lett. 1998, 39, 7459. (e)
Hulme, C.; Peng, J.; Louridas, B.; Menard, P.; Krolikowski, P.; Kumar, N. V. Tetrahedron Lett. 1998, 39, 8047.
(f) Mohamed, N.; Bhatt, U.; Just, G. Tetrahedron Lett. 1998, 39, 8213. (g) Hansen, T. K.; Schlienger, N.; Hansen,
B. S.; Andersen, P. H.; Bryce, M. R. Tetrahedron Lett. 1999, 40, 3651. (h) Tong, Y.; Fobian, Y. M.; Wu, M.;
Boyd, N. D.; Moeller, K. D. J. Org. Chem. 2000, 65, 2484. (i) Dinsmore, C. J.; Zartman, C. B. Tetrahedron Lett.
2000, 41, 6309 and references cited therein.
3. (a) Lee, J.; Murray, W. V.; Rivero, R. A. J. Org. Chem. 1997, 62, 3874. (b) Morales, G. A.; Corbett, J. W.;
DeGrado, W. F. J. Org. Chem. 1998, 63, 1172. (c) Zaragoza, F.; Stephensen, H. J. Org. Chem. 1999, 64, 2555. (d)
Mazurov, A. Tetrahedron Lett. 2000, 41, 7.
4. (a) Petasis, N. A.; Akritopoulou, I. Tetrahedron Lett. 1993, 34, 583. (b) Petasis, N. A.; Zavialov, I. A. J. Am.
Chem. Soc. 1997, 119, 445. (c) Petasis, N. A.; Goodman, A.; Zavialov, I. A. Tetrahedron 1997, 53, 16463. (d)
Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1998, 120, 11798.
5. (a) Ishihara, K.; Ohara, S.; Yamamoto, H. J. Org. Chem. 1996, 61, 4196. (b) Ishihara, K.; Yamamoto, H. Eur. J.
Org. Chem. 1999, 527.
6. The indicated yields are of purified products, after flash column chromatography. All products gave satisfactory
spectroscopic and analytical data.
1
7. Data for 22: H NMR (250 MHz, CD3OD) l 7.48–7.20 (m, 15H), 6.76 (d, J=15.9 Hz, 1H), 6.33 (dd, J=15.9 Hz,
7.9 Hz, 1H), 4.64 (dd, J=17.5 Hz, 4.7 Hz, 1H), 3.92 (d, J=13.3 Hz, 1H), 3.86 (d, J=7.9 Hz, 1H), 3.43 (d, J=13.3
Hz, 1H), 3.23 (t, J=5.2 Hz, 2H), 3.02 (m, 1H), 2.54 (m, 1H). 13C NMR (62.5 MHz, CD3OD) l 170.52, 139.02,
137.91, 137.87, 137.06, 130.10, 129.78, 129.67, 129.47, 129.10, 128.97, 128.71, 128.42, 127.63, 126.32, 69.15, 59.43,
51.15, 46.82, 46.50. HRMS calcd for C26H27N2O+: 383.2045, found 383.2127.
.