Efficient synthesis of substituted piperazinones via tandem reductive amination-cyclization

Article abstract of DOI:10.1016/S0040-4039(00)01063-7

A new strategy for the preparation of substituted piperazinones features a tandem reductive coupling and S(N)2-cyclization of a 2-chloro-N-(2-oxoalkyl)acetamide (1) and a primary amine (2). The method is convenient for diversity-oriented synthesis, since a wide variety of amines may be used in the ring-forming reaction to produce N-substituted piperazinones (3). (C) 2000 Published by Elsevier science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01063-7

Tetrahedron Letters 41 (2000) 6309±6312
Ecient synthesis of substituted piperazinones via tandem
reductive amination±cyclization
Christopher J. Dinsmore* and C. Blair Zartman
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA
Received 26 May 2000; accepted 20 June 2000
Abstract
A new strategy for the preparation of substituted piperazinones features a tandem reductive coupling
and SN2-cyclization of a 2-chloro-N-(2-oxoalkyl)acetamide (1) and a primary amine (2). The method is
convenient for diversity-oriented synthesis, since a wide variety of amines may be used in the ring-forming
reaction to produce N-substituted piperazinones (3). # 2000 Published by Elsevier Science Ltd.
The piperazinone ring is a widely used structure in medicinal chemistry. Because of its similarity
to a conformationally constrained peptide, it serves as an e€ective and versatile template for the
construction of biologically active molecules.1,2 Consequently, many methods have been
developed for the synthesis of piperazinones with substitution at various ring positions.1 4 Several
of these methods are based on a ring-forming coupling reaction of a primary amine with a doubly
activated substrate.4 In almost all of these processes, the substituent on the amine reactant is
destined to be the amide substituent in the derived piperazinone;4a c only one report describes an
addition reaction of amines (via tandem SN2-Michael reaction) to install diversity at the 4-position
of 2-piperazinones.4d We have found that cyclization of 2-chloro-N-(2-oxoalkyl)acetamides 1 and
primary amines 2 under reductive amination conditions produces piperazinones 3 through the
intermediacy of 4 in a single-pot transformation (Eq. (1)). Because a wide variety of amines
may be used in the ring-forming reaction, the method is convenient for the rapid syntheses of
4-substituted-2-piperazinone analogs with structural diversity at the amino position.
ꢀ1†
To explore the scope of the reaction, the substrate 1a5a was subjected to reductive amination in
the presence of several amines using sodium triacetoxyborohydride (Table 1). Most aliphatic
primary amines were successful in directly producing piperazinones 3 in good yield (entries 1±7).
* Corresponding author. E-mail: christopher_dinsmore@merck.com
0040-4039/00/$ - see front matter # 2000 Published by Elsevier Science Ltd.
PII: S0040-4039(00)01063-7

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The reactions of relatively unhindered amines (entries 1±3, 57±70% yields) were accompanied by
a minor by-product (5±10%) from a second reductive alkylation of intermediate 4 with 1a.
However, branched amines (entries 4±6) were less prone to this pathway, a€ording improved
yields (75±85%) of the corresponding piperazinone products. This enhancement in reaction
eciency may be derived in part from an increased rate of the intramolecular SN2 cyclization due
to inductive donation from the additional alkyl substituents of the amine.
Table 1
Reductive alkylations of aldehyde 1a and ketone 1b with amines 2 to provide piperazinones 3
Phenylglycinol behaved well in the reductive amination±cyclization (entry 7), but the reaction
of the corresponding a-amino ester 2h (entry 8) resulted in rapid accumulation of intermediate 4h,
followed by slow conversion to two piperazinone products 3h and 6 in equal proportions (Scheme 1).
The isolation of 6 from this reaction implicates a transacylation equilibrium (e.g. 4h$5) which is
likely operative because the intramolecular SN2 displacement of chloride from 4 is slow.6 Inter-
estingly, the cyclization of putative intermediate 5 occurred via acylation to provide 6 rather than
alkylation to give 7. Since the use of anilines (entries 10±12) also resulted in accumulation of
intermediates 4 under the standard reaction conditions, a modi®ed protocol was used to induce
piperazinone formation in the cases of amines with diminished nucleophilicity. Thus, following
reductive amination of 1a with 2h-k, the intermediate products 4 were isolated after 1±2 h, and
then treated with base to provide 3.7 Notably, in the case of amine 2h, the use of these modi®ed
conditions completely suppressed formation of 6 (entry 9).
The ketone substrate 1b5b was investigated as a means to incorporate substitution at C5 of the
piperazinone products. Both an aliphatic amine (entry 13) and aromatic amine (entry 14)
were successfully coupled and cyclized under the standard reaction conditions. An asym-
metric 5-methyl-2-piperazinone synthesis was accomplished using a chiral amine as an aux-
iliary (Scheme 2). Thus, reductive alkylation with (R)-a-methylbenzylamine provided a separable

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Scheme 1. Reaction of 1a and 2h (Table 1, entry 8)
Scheme 2. Reagents: (a) Na(AcO)3BH, (R)-a-methylbenzylamine, 4 A MS, DCE, 0ꢁC±rt, 48 h; (b) H2, 10% Pd(OH)2/
C, MeOH, 4 h
6:1 mixture of isomers (85% yield), with 8 as the major product in accordance with the predicted
sense of diastereoselection.8 Hydrogenolysis of 8 provided 9 in good yield, the stereochemical
assignment of which was supported by analysis of Mosher's amide derivatives.9,10
In summary, we have developed a convenient method for the incorporation of amines into
2-piperazinones via tandem reductive amination±cyclization reactions of 2-chloro-N-(2-
oxoalkyl)acetamides 1. The transformation is most amenable to the use of aliphatic amines, but
aromatic and other non-nucleophilic amines are also viable substrates under modi®ed conditions.
Representative procedure: 1-Benzyl-4-cyclohexyl-2-piperazinone (3e): To a solution of aldehyde
1a (315 mg, 1.40 mmol) in 3.0 mL of 1,2-dichloroethane at 0ꢁC were added 4 A powdered
molecular sieves (300 mg). Cyclohexylamine (192 mL, 1.68 mmol, 1.2 equiv.) was added, followed
within 1 min by sodium triacetoxyborohydride (354 mg, 1.67 mmol, 1.2 equiv.). After 5 min, the
solution was warmed to room temperature, and the reaction was stirred for 12 h. Aqueous 3N
HCl (1 mL) was added to hydrolyze boron±amine complexes, and after 30 min the mixture was
partitioned between EtOAc and saturated NaHCO3 solution. The aqueous phase was re-extracted
with EtOAc, and the combined organic phases were washed with brine, dried with Na2SO4,
®ltered, and concentrated in vacuo. Puri®cation by ¯ash chromatography (4Â6 cm silica gel, 70%
EtOAc/hexanes) provided piperazinone 3e as a pale yellow oil (317 mg, 83% yield). Rf 0.28 (70%
EtOAc/hexane); 1H NMR (400 MHz, CDCl3) ꢀ 7.24±7.35 (m, 5H), 4.59 (s, 2H), 3.36 (s, 2H), 3.21 (t,
J=5.5 Hz, 2H), 2.72 (t, J=5.5 Hz, 2H), 2.28 (m, 1H), 1.74±1.88 (m, 4H), 1.63 (bd, J=12.4 Hz, 1H),
1.08±1.30 (m, 5H); HRMS (ES) exact mass calcd for C17H24N2O (M+H+): 273.1961; found: 273.1977.
Acknowledgements
We are grateful to Dr. M. J. Bogusky for NMR investigations, Dr. C. W. Ross III for mass
spectra, Mr. D. C. Beshore and Dr. B. W. Trotter for helpful discussions, and Ms. M. A.
Guttman for manuscript assistance.

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References
1. (a) DiMaio, J.; Belleau, B. J. Chem. Soc., Perkin Trans. 1 1989, 1687±1689. (b) Kolter, T.; Dahl, C.; Giannis, A.
Liebigs Ann. 1995, 625±629.
2. (a) Farnesyltransferase inhibitors: Williams, T. M.; Bergman, J. M.; Brashear, K.; Breslin, M. J.; Dinsmore, C. J.;
Hutchinson, J. H.; MacTough, S. C.; Stump, C. A.; Wei, D. D.; Zartman, C. B.; Bogusky, M. J.; Culberson, J. C.;
Buser-Doepner, C.; Davide, J.; Greenberg, I. B.; Hamilton, K. A.; Koblan, K. S.; Kohl, N. E.; Liu, D.; Lobell,
R. B.; Mosser, S. C.; O'Neill, T. J.; Rands, E.; Schaber, M. D.; Wilson, F.; Senderak, E.; Motzel, S. L.; Gibbs,
J. B.; Graham, S. L.; Heimbrook, D. C.; Hartman, G. D.; Oli€, A. I.; Hu€, J. R. J. Med. Chem. 1999, 42, 3779±
3784. (b) Growth hormone secretagogues: Hansen, T. K.; Schlienger, N.; Hansen, B. S.; Andersen, P. H.; Bryce,
M. R. Tetrahedron Lett. 1999, 40, 3651±3654. (c) Enkephalin analogs: Sreder, K.; Zhang, L.; Goodman, M.
Tetrahedron Lett. 1998, 39, 221±224. (d) GP IIb/IIIa antagonists: Takada, S.; Kurokawa, T.; Miyazaki, K.; Iwasa,
S.; Ogawa, Y. Int. J. Pharm. 1997, 146, 147±157. (e) Substance-P receptor antagonists: Lewis, R. T.; McLeod,
A. M.; Merhant, K. J.; Kelleher, F.; Sanderson, I.; Herbert, R. H.; Cascieri, M. A.; Sadowski, S.; Ball, R. G.;
Hoogsteen, K. J. Med. Chem. 1995, 38, 923±933. (f) CCK receptor ligands: Batt, A. R.; Kendrick, D. A.;
Matthew, E.; Rooker, D. P.; Ryder, H.; Semple, G.; Szelke, M. Bioorg. Med. Chem. Lett. 1994, 4, 867±872.
3. (a) Struve, G. E.; Gazzola, C.; Kenyon, G. L. J. Org. Chem. 1977, 42, 4035±4040. (b) Jain, S.; Sujatha, K.;
Krishna, K. V. R.; Roy, R.; Singh, J.; Anand, N. Tetrahedron 1992, 48, 4985±4998. (c) Cossec, B.; Marsura, A.;
Luu-Duc, C. Pharmazie 1989, 44, 643. (d) Schanen, V.; Cherrier, M.-P.; deMelo, S. J.; Quirion, J.-C.; Husson, H.-
P. Synthesis 1996, 833±837. (e) Pohlmann, A.; Schanen, V.; Guillaume, D.; Quirion, J.-C.; Husson, H.-P. J. Org.
Chem. 1997, 62, 1016±1022. (f) Weissman, S. A.; Lewis, S.; Askin, D.; Volante, R. P.; Reider, P. J. Tetrahedron
Lett. 1998, 39, 7459±7462. (g) Mohamed, N.; Bhatt, U.; Just, G. Tetrahedron Lett. 1998, 39, 8213±8216. (h)
Patino-Molina, R.; Herranz, R.; Garcia-Lopez, M. T.; Gonzalez-Muniz, R. Tetrahedron 1999, 55, 15001±15010.
4. (a) Yahiro, N.; Ito, S. Bull. Chem. Soc. Jpn. 1986, 59, 321±322. (b) Valls, N.; Segarra, V. M.; Bosch, J. Heteocycles
1986, 24, 943±946. (c) Askew, B. C.; McIntyre, C. J.; Hunt, C. A.; Claremon, D. A.; Gould, R. J.; Lynch, R. J.;
Armstrong, D. J. Bioorg. Med. Chem. Lett. 1995, 5, 475±480. (d) Go€, D. A. Tetrahedron Lett. 1998, 39, 1473±1476.
5. (a) Synthesis of 1a: (i) N-Benzylethanolamine, ClCH2COCl, EtOAc, sat. NaHCO3, 0ꢁC, 20 min, 83%; (ii) DMSO,
(COCl)2, Et3N, CH2Cl2, ^78ꢁC±rt, 45 min, 80%; (b) synthesis of 1b: (i) BnBr (1 equiv.), 2-hydroxypropylamine (2
equiv.), CH3CN, 30 min; (ii) ClCH2COCl, EtOAc, sat. NaHCO3, 0ꢁC, 20 min, 53% (two steps); (iii) DMSO,
ꢁ
(COCl)2, Et3N, CH2Cl2, ^78 C±rt, 45 min, 98%.
6. The intermediate 4 is typically not observed in reactions of aliphatic amines.
7. Treating the reaction of 1a and 2i with base (Et3N or aq. NaHCO3) after formation of 4, but prior to aqueous
work-up, gave a 64:36 mixture of 3 and the compound derived from displacement of chloride in 4 by acetate.
8. (a) Nichols, D. E.; Lloyd, D. H.; Johnson, M. P.; Ho€man, A. J. J. Med. Chem. 1988, 31, 1406±1412. (b) David,
D. M.; Pyne, S. G.; Kanemaguire, L. A. P. J. Chem. Soc., Chem. Commun. 1990, 888±889. (c) Fuller, J. C.; Belisle,
C. M.; Goralski, C. T.; Singaram, B. Tetrahedron Lett. 1994, 35, 5389±5392.
9. For 9: ‰ꢁŠ2D4=^92.9 (c 0.010, CHCl3). The absolute con®guration was determined using the NMR-based method of
Hoye and Renner for cyclic secondary amines (Ref. 10c). Thus, compound 9 was converted to the corresponding
(S)- and (R)-MTPA amides i and ii (1.2 equiv MTPA±Cl, 1.5 equiv iPr2EtN, CH2Cl2). Dominant conformations
1
are illustrated below for i (amide rotamer ratio 61:39) and ii (64:36). Selected H NMR spectral data (CDCl3)
indicate chemical shift di€erences consistent with (R)-stereochemistry at C5 of 9.
10. (a) Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969, 34, 2543±2549. (b) Ohtani, I.; Kusumi, T.;
Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc. 1991, 113, 4092±4096. (c) Hoye, T. R.; Renner, M. K. J. Org.
Chem. 1996, 61, 2056±2064.