Preparation of Substituted Piperazinones via Tandem Reductive Amination-(N,N′-Acyl Transfer)-Cyclization

Article abstract of DOI:10.1021/ol025644l

matrix presented A one-pot, tandem reductive amination-transamidation-cyclization reaction was employed to produce substituted piperazin-2-ones in good yields. Various amino acid methyl esters and transferable acyl groups were examined to establish the re

Full text of DOI:10.1021/ol025644l

ORGANIC
LETTERS
2002
Vol. 4, No. 7
1201-1204
Preparation of Substituted
Piperazinones via Tandem Reductive
Amination−(N,N′-Acyl
Transfer)−Cyclization
Douglas C. Beshore* and Christopher J. Dinsmore
Department of Medicinal Chemistry, Merck Research Laboratories,
West Point, PennsylVania 19486
douglas_beshore@merck.com
Received January 30, 2002
ABSTRACT
A one-pot, tandem reductive amination−transamidation−cyclization reaction was employed to produce substituted piperazin-2-ones in good
yields. Various amino acid methyl esters and transferable acyl groups were examined to establish the reaction’s scope.
Piperazinone rings have been used often in medicinal
chemistry because of their structural similarity to constrained
Scheme 2
peptides, and numerous methods of ring assembly have been
developed with the introduction of substitution at varying
positions.1a There are many examples of multiple bond-
forming reactions between primary amines and doubly
activated substrates to produce piperazinone products.1,2 In
a previous report (Scheme 1),2 reductive amination of
Scheme 1
The reaction pathway outlined in Scheme 2 accounts for
the conversion of 1 to 3 and describes the basis for a novel
approach to the synthesis of piperazinones. An N-(2-
2-chloro-N-(2-oxoethyl)acetamide 1 with L-phenylanaline
methyl ester resulted in the expected product 2, as well as
the unanticipated piperazinone 3.
oxoethyl)amide 4, when treated with an R-amino ester 5
under reductive amination conditions, produces N-acylpip-
erazinone 6 through the intermediacy of 7 and 8, which
presumably interconvert via an intramolecular N,N′-acyl
transfer. An attractive feature of this synthetic scheme is that
the incorporation of piperazinone C3-substitution is facilitated
(1) (a) Review: Dinsmore, C. J.; Beshore, D. C. Org. Prep. Proced.
Int. 2002, 34, in press. (b) Goff, D. A. Tetrahedron Lett. 1998, 39, 1473.
(c) Yahiro, N.; Ito, S. Bull. Chem. Soc. Jpn. 1986, 59, 321. (d) Valls, N.;
Segarra, V. M.; Bosch, J. Heterocycles 1986, 24, 943. (e) Askew, B. C.;
McIntyre, C. J.; Hunt, C. A.; Claremon, D. A.; Gould, R. J.; Lynch, R. J.;
Armstrong, D. J. J. Bioorg. Med. Chem. Lett. 1995, 5, 475.
(2) Dinsmore, C. J.; Zartman, C. B. Tetrahedron Lett. 2000, 41, 6309.
10.1021/ol025644l CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/14/2002

by the wide availability of natural and unnatural R-amino
acids.
Table 2. Reductive Amination of Aldehydes 4a-g with
D-Phe-OMe to Provide Piperazinones 6a-g
In an effort to explore this new method of piperazinone
synthesis, we replaced the R-chloroacetyl group of 1 with
various acyl groups to determine substrate compatibility.
Initial attempts to effect the transformation were focused on
the reductive amination3 of N-(2-oxoethyl)acetamide (4a,
X ) Me, Scheme 2) with L-phenylalanine methyl ester in
the presence of sodium triacetoxyborohydride and 4 Å
molecular sieves in 1,2-dichloroethane (DCE). After initial
formation of intermediate 7a (X ) Me, R1 ) H, R2 ) Bn),
refluxing the reaction for two weeks afforded only 80%
conversion to the desired piperazinone product 6a.
It was immediately apparent that N,N′-acyl transfer (7f8)
was the rate-determining step.4 Transamidation has been well
studied in the context of peptide segment coupling5 and has
been applied to medium- and large-ring syntheses via a ring-
expanding “Zip” reaction.6 To optimize the conversion of 7
to 8, the reductive amination product 7a was synthesized
and subjected to various solvents and additives to examine
their effect on the transamidation-cyclization reaction rate
(Table 1). This study revealed that the only additive to
efficiently promote piperazinone formation over 24 h was
acetic acid with maximal conversion in acetonitrile.
entry aldehyde
X
reflux time (h) product % yielda % eeb
1
2
3
4
5
6
7
4a
4b
4c
4d
4e
4f
Me
Et
7
190
96c
48c
4
0d
72c
6a
6b
6c
6d
6e
6f
69
76
78
92
86
87
81
95
65
15
i-Pr
t-Bu
Ph
CF3
OBn
27
>99
>99
44
4g
6g
a Yields of isolated 6a-g. b Determined by chiral HPLC analysis, using
authentic opposite enantiomer as a standard. c Reaction was performed in
a sealed tube. Upon completion of the reductive amination, the vessel was
heated at 120 °C for the specified time. d Reaction was complete after 18
h at room temperature.
group increased (4a-d, entries 1-4). Presumably, this was
due to increased steric demand imposed upon the transition
state for the rate-limiting transacylation step (vide infra).
With the more reactive amides 4e and 4f (entries 5 and 6,
respectively), the reaction time decreased and no racemiza-
tion was detected. When benzyl carbamate 4g was employed
(entry 7), the reaction proceeded smoothly, albeit slowly and
in low enantiomeric excess. However, treatment of N-(2-
oxoethyl)sulfonamides to the reaction conditions provided
only the corresponding reductive amination products with
no detectable piperazinones after prolonged heating (data not
shown).8
Table 1. Optimization of Transamidation-Cyclization
Sequence: Conversion of 7a to Piperazinone 6aa
additive (% conversion)
To explore the effect of the amino acid side chain on the
reaction rate, various amino acid methyl esters were treated
with aldehyde 4a to produce piperazinones 6h-n in moder-
ate to good yields (Table 3). Substitution of the amino acid
extended the reaction time considerably (entry 1 vs 2-8).
Furthermore, the degree of substitution at the â-carbon of
the amino ester influenced the reaction rate. Monosubstitution
to the â-carbon slowed the reaction slightly (entry 2 vs 3-6),
while disubstitution slowed the reaction even further (entry
2 vs 7-8).
solvent
none
aq HCl
TFA
AcOH
MsOH
Et3N
DCE
THF
DMSO
ACN
0
0
0
0
0b
0b
0
0
1-5
0
0
50
40
10
55
0
0
0
0
0
0
0
0
0b
a Reactions were run in 1 mL of the desired solvent at 1.0 M substrate
and 1.0 M additive concentrations for 24 h at 40 °C in a thermocontrolled
LC sample tray. Aliquots were analyzed by HPLC every 2 h. Values denote
the percent conversion of 7a to product 6a after 24 h. b Hydrolysis of the
acetamide 7a was observed.
(7) Representative Procedure: (3R)-4-Benzoyl-1,3-dibenzylpiperazin-
2-one (6e). To a 0 °C stirring suspension of D-Phe-OMe hydrochloride (100
mg, 0.464 mmol, 1.0 equiv), 4 Å molecular sieves (200 mg), AcOH (79
µL, 1.4 mmol, 3 equiv), and Na(AcO)3BH (147 mg, 0.693 mmol, 1.5 equiv)
in 5 mL of ACN was added dropwise over 5 min a 2.5 mL ACN solution
of aldehyde 4e (129 mg, 0.675 mmol, 1.1 equiv). After the reaction mixture
was stirred for 90 min, the ice bath was removed and the reaction mixture
was warmed to ambient temperature and stirred for 18 h. The reaction
mixture was heated to reflux for 4 h, cooled, and poured into aqueous
saturated NaHCO3 solution, which was then extracted three times with
DCM. The combined organic extracts were dried (Na2SO4), filtered, and
concentrated in vacuo. Purification by flash chromatography (0 to 50%
EtOAc in DCM) provided piperazinone 6e as a colorless oil (153 mg, 86%
yield). For full characterization of compounds described herein, see
Supporting Information.
To explore the transferability of various acyl groups
(X in 4), we subjected several aldehydes (4a-g) to the
optimized reaction conditions (Table 2).7 When alkyl sub-
stituents were employed, both the reaction time and extent
of racemization increased dramatically as the size of the alkyl
(3) Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C. A.;
Shah, R. D. J. Org. Chem. 1996, 61, 3849.
(4) In each example studied, rapid accumulation of 7 was followed by
gradual formation of piperazinone 6, as assessed by LC/MS analysis. None
of 8 was observed.
(5) For a review, see: Coltart, D. M. Tetrahedron 2000, 56, 3449.
(6) (a) Kramer, U.; Guggisberg, A.; Hesse, M.; Schmid, H. Angew. Chem.
1977, 89, 899. (b) Doll, M. K.-H.; Guggisberg, A.; Hesse, M. HelV. Chim.
Acta 1996, 79, 541.
(8) Both the methanesulfonamide and toluenesulfonamide versions of
amide 4 were prepared and subjected to the reaction conditions. After 120
h at 80 °C, the only detectable product (LC/MS analysis) was the
corresponding reductive amination product.
1202
Org. Lett., Vol. 4, No. 7, 2002

room temperature. In comparison to the same reactions with
acetamide 4a (see Table 3), racemization was reduced
significantly in the case of 6f and 6o (Table 4, entries 1 and
2, respectively) and dramatically in the case of phenylglycine-
derived 6p (entry 3). Furthermore, the yields were uniformly
good. Unfortunately, the use of an R,R-disubstituted amino
ester (entry 4) remained problematic; the reaction to give
6q proceeded with low conversion even at higher tempera-
tures and prolonged reaction times.
Examination of molecular models for the tetrahedral
intermediate10 mediating the rate-limiting interconversion of
7 and 8 reveals the nature of the interactions responsible for
slowing the reaction time. The calculated lowest energy
structure11 of the intermediate leading to piperazinone 6b
(Figure 1) shows one of several orientations that may be
Table 3. Reductive Amination of Aldehyde 4a with R-Amino
Esters to Provide Piperazinones 6a,h-n
reflux
%
%
eeb
entry R1
R2
time (h) product yielda
1
2
3
4
5
6
7
8
9
H
H
H
H
H
H
H
H
H
H
Me
1
3
7
10
10
10
24
16
0
6h
6i
6a
6j
6k
6l
6m
6n
9c
53
80
69
76
30
54
58
84
40
75
99
95
92
>99
82
86
CH2Ph
i-Bu
CH2OH
CH2CO2Me
i-Pr
Ph
17
nd
(CH2)2CO2Me
10
Me Me
72d
10e
a,b See corresponding footnotes in Table 2. c Product 9 is the methyl
pyroglutamate, derived from direct cyclization of intermediate 7. d See
footnote c in Table 2. e Product 10 is the 2,3-dihydro-1-pyrrolo[1,2-
a]imidazol-6-one illustrated in ref 9c.
Some R-amino esters failed to produce piperazinone
products. Not surprisingly, reductive amination with glutamic
acid dimethyl ester (Table 3, entry 9) was followed by
premature lactamization of the amino group in intermediate
7 onto the R2 side chain ester to afford pyroglutamate 9 (not
shown) as the sole product. The use of an R,R-disubstituted
amino ester (entry 10) resulted in the exclusive formation
of fused bicyle 109a,b by a novel process involving dehydra-
tion and intramolecular Claisen-type reaction.9c
The trifluoroacetamide 4f is the most versatile synthon
for the synthesis of piperazinones, not only because the
products are easily deprotected for further functionalization
but also because reaction times are short and optical purities
are high (Table 4). Unlike the other amide derivatives
studied, reactions of 4f with R-amino esters proceeded at
Figure 1. Calculated lowest energy conformation of tetrahedral
intermediate leading to acyl-group transfer for piperazinone 6b.
relevant. Clearly, branching at the R-carbon of the transfer-
ring acyl group and at the R- or â-carbon of the amino ester
moiety results in an increased number of gauche and syn-
pentane-like interactions, presumably raising the overall
energy required for N,N′-acyl transfer to occur.
The methodology described herein was used to synthesize
a conformationally restricted inhibitor of the posttranslational
protein processing enzyme farnesyltransferase (FTase). In-
hibitors of FTase (FTIs) are promising antitumor agents, and
several are currently being evaluated in human clinical
trials.12 During our investigations of piperazinone FTIs, we
discovered that they adopt a folded conformation when bound
Table 4. Reductive Amination of Aldehyde 4f with R-Amino
Esters to Provide Piperazinones 6f,o-q
(9) (a) Wang, L.-B.; Yu, C.-Y.; Huang, Z.-T. Synthesis 1994, 12, 1441.
(b) Armati, A.; De Ruggieri, P.; Rossi, E.; Stradi, R. Synthesis 1986, 7,
573. (c) Formation of 10 was thought to arise from facile dehydration of
11 (from 7, X ) R1 ) R2 ) Me) to give 12, followed by cyclization.
Dehydration of 11 presumably relieves severe syn-pentane-like interactions
(cf. Figure 1).
time at
%
%
eeb
entry
R1
R2 room temp (h) product yielda
1
2
3
4
CH2Ph
i-Pr
Ph
H
H
H
Me
18
40
40
6f
87
79
81
10d
>99
100
95
(10) (a) Kemp, D. S.; Choong, S.-L. H.; Pekaar, J. J. Org. Chem. 1974,
39, 3841.
6o
6p
6q
(11) (a) Molecular modelling: conformations were generated using metric
matrix distance geometry algorithm JG (S. Kearsley, Merck & Co., Inc.,
unpublished). Structures were subjected to energy minimization within the
Macromodel program (ref 11b) using MMFF force field. (b) Mohamadi,
F.; Richards, N. G. J.; Guida, W. C.; Liskamp, R.; Caufield, C.; Chang,
G.; Hendrickson, T.; Still, W. C. J. Comput. Chem. 1990, 11, 440.
Me
168c
a,b See corresponding footnotes in Table 2. c Heated at reflux. d Percent
conversion by LC-MS detection. Product 6q was not isolated.
Org. Lett., Vol. 4, No. 7, 2002
1203

to the enzyme and that a macrocyclic constraint (e.g., 13,
Figure 2) enhances their potency by preorganizing the bound
Scheme 3. Synthesis of Farnesyltransferase Inhibitor 14a
Figure 2. Piperazinone farnesyltransferase inhibitors 13 and 14.
conformation.13 In the interest of altering the metabolic fate
of 13 by blocking key positions, the (R)-3-methyl-2-
piperazinone analogue 14 was prepared.
Protection of 4-chloro-3-methylphenol (Scheme 3) as the
corresponding tert-butyldiphenylsilyl ether followed by benz-
ylic bromination provided compound 15. Displacement of
the bromide with ethanolamine provided the amino alcohol
16, which underwent EDC-mediated acylation with acid 18,
derived from oxidation of the previously reported aldehyde
17.13a The resulting alcohol was subjected to Swern oxidation
conditions to provide the key aldehyde 19.
a Reagents and conditions: (a) TBDPSCl, imidazole, DMF,
100%; (b) NBS, AIBN, CCl4, 80 °C, 53%; (c) HOCH2CH2NH2,
NaHCO3, EtOAc/H2O, 100%; (d) NaClO2, NaH2PO4, t-BuOH/2-
methyl-2-butene/H2O, 46%; (e) 18, EDC, HOBt, 16, DIEA, DMF,
74%; (f) (ClCO)2, DMSO, Et3N, DCM, from -78 °C to rt, 100%;
(g) D-Ala-OMe, Na(AcO)3BH, 4 Å molecular sieves, AcOH, ACN,
from 0 °C to rt to 80 °C, 72%; (h) KF‚AlO3, ACN, 80 °C, 82%.
Compound 19 was subjected to reductive amination
conditions in the presence of D-Ala-OMe, and after 3 h of
reflux, the piperazinone 20 was isolated in 72% yield.
Tandem deprotection-macrocyclization was accomplished
in the presence of KF on alumina in refluxing acetonitrile
to provide the FTI 14 in good yield. The FTase inhibitory
activity of 14 (IC50 ) 4 nM) was 6-fold less potent than
that of 13 (IC50 0.7 nM), which may be attributed to the
presence of the carbonyl group between the imidazole and
piperazinone rings.14
We have developed a one-pot synthesis of substituted
N-acylpiperazinones from N-(2-oxoethyl)amides and R-ami-
no esters by a novel tandem reductive amination-transami-
dation-cyclization process. The rate of the reaction is
governed largely by the character of the transferring acyl
group and by steric congestion at the R- and â-carbons of
the amino ester. N-(2-Oxoethyl)trifluoroacetamides (e.g., 4f)
undergo the most efficient transformation to piperazinones,
with minimal racemization. The new method was applied
effectively to a convergent synthesis of the conformationally
constrained FTase inhibitor 14.
(12) (a) Karp, J. E.; Kaufmann, S. H.; Adjei, A. A.; Lancet, J. E.; Wright,
J. J.; End, D. W. Curr. Opin. Oncol. 2001, 13, 470. (b) Gibbs, J. B. J. Clin.
InVest. 2000, 105, 9. (c) Bell, I. M. Exp. Opin. Ther. Patents 2000, 10,
1813.
(13) (a) Dinsmore, C. J.; Bogusky, M. J.; Culberson, J. C.; Bergman, J.
M.; Homnick, C. F.; Zartman, C. B.; Mosser, S. D.; Schaber, M. D.;
Robinson, R. G.; Koblan, K. S.; Huber, H. E.; Graham, S. L.; Hartman, G.
D.; Huff, J. R.; Williams, T. M. J. Am. Chem. Soc. 2001, 123, 2107. (b)
Dinsmore, C. J.; Bergman, J. M.; Bogusky, M. J.; Culberson, J. C.;
Hamilton, K. A. Graham, S. L. Org. Lett. 2001, 3, 865.
(14) Dinsmore, C. J.; Bergman, J. M.; Wei, D. D.; Zartman, C. B.;
Davide, J. P.; Greenberg, I. B.; Liu, D.; O’Neill, T. J.; Gibbs, J. B.; Koblan,
K. S.; Kohl, N. E.; Lobell, R. B.; Chen, I.-W.; McLoughlin, D. A.; Olah,
T. V.; Graham, S. L.; Hartman, G. D.; Williams, T. M. Bioorg. Med. Chem.
Lett. 2001, 11, 537.
Acknowledgment. We thank J. Christopher Culberson
for providing Figure 1 and Carl F. Homnick for generously
providing chiral HPLC analyses.
Supporting Information Available: Experimental pro-
cedures and characterization data for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL025644L
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Org. Lett., Vol. 4, No. 7, 2002