Convenient synthesis of 1,3-substituted-6-phenylpiperazin-2-ones

Article abstract of DOI:10.1016/j.tetlet.2009.04.036

The convenient preparation of novel 6-phenylpiperazin-2-ones from simple starting materials via a practical two-step procedure is presented. This methodology involves an initial alkylation of 2-bromoacetophenone with an amino ester followed by a one-pot r

Full text of DOI:10.1016/j.tetlet.2009.04.036

Tetrahedron Letters 50 (2009) 3817–3819
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Tetrahedron Letters
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Convenient synthesis of 1,3-substituted-6-phenylpiperazin-2-ones
*
Steven N. Gallicchio , Ian M. Bell
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 20 November 2008
Revised 3 April 2009
Accepted 6 April 2009
Available online 14 April 2009
The convenient preparation of novel 6-phenylpiperazin-2-ones from simple starting materials via a prac-
tical two-step procedure is presented. This methodology involves an initial alkylation of 2-bromoaceto-
phenone with an amino ester followed by a one-pot reductive amination and cyclization step to furnish
the desired substituted piperazinones.
Ó 2009 Elsevier Ltd. All rights reserved.
The synthesis of pharmacologically interesting molecules con-
taining a piperazinone ring has been stimulated by reports that they
can be ligands for a variety of receptor sites.1–5 The core structure of
the piperazinone ring has been commonly assembled using one of
two general strategies. These strategies defined by the C–N bond(s)
formed during reaction (see Scheme 1).6 The first method involves
the construction of a suitable precursor that is cyclized to furnish
the piperazinone nucleus (see, for example, Scheme 1A). The second
strategy for ring formation is accomplished by a two-step sequence
involving an initial intermolecular reaction followed by an intramo-
lecular ring closure step (see, for example, Scheme 1B).
As part of our effort to identify novel calcitonin gene-related
peptide (CGRP) receptor antagonists, we became specifically inter-
ested in the synthesis of 1,3-substituted-6-phenylpiperazin-2-
ones. None of the known piperazinone syntheses allowed facile ac-
cess to the compounds of interest, therefore a new and efficient
route was required. We envisioned a strategy for incorporating
the necessary functionality by disconnection of the piperazinone
ring at the N1–C2 bond (Scheme 2), generating an amino-ester
intermediate. Continuing the retrosynthetic analysis to the end of
amine intermediate may be stored as a salt, for example, the
hydrochloride salt, under argon at À20 °C for several weeks with
minimal decomposition. Reductive amination of 3a with benzyl-
amine (6a) and subsequent cyclization were carried out using ex-
cess AcOH (4 equiv) and NaBH3CN (1.5 equiv) in MeOH at 50 °C,
and the reaction was complete after 18 h. The major byproduct ob-
served was reduction of the starting b-ketoamine 3a to the corre-
sponding alcohol. Standard workup of the reaction mixture and
isolation of the product on silica gel afforded the desired piperaz-
inone 5a in good yield (see Table 1).
In order to investigate the importance of
glycine 2b was allowed to react with 1 to give intermediate 3b
in poor yield (Table 1). Apparently, the lack of -substitution leads
a-substitution in 2a,
a
to increased instability of intermediate 3b. This intermediate was
isolated by aqueous workup and, without purification, was sub-
jected to the aforementioned reductive amination–cyclization con-
ditions. However, only a small amount of 5b was observed by LC/
MS, and no pure product was isolated.
The potential for epimerization during the two-step synthetic
method was evaluated using 3-methyl piperazinones 5c and 5d
as a model. (S)-Alanine methyl ester hydrochloride (2c) and (R)-
alanine methyl ester hydrochloride (2d) were reacted with 1 to
give b-ketoamines 3c and 3d, respectively. Reductive amination
of the b-ketoamines with 6a and tandem cyclization produced a
1:1 mixture of diastereomeric piperazinones 5c (S,S and S,R) and
the sequence would then lead to
a-halo ketone and amino ester
starting materials. This approach should allow flexibility for instal-
lation of substituents at the N1 and C3 positions of the piperazinone
ring and should permit rapid access to the desired compounds.
In this Letter, we report a successful and efficient synthesis of a
series of novel substituted 6-phenylpiperazinones utilizing this
approach.
We first investigated the alkylation of commercially available 2-
bromoacetophenone (1) with amine hydrochloride 2a in DMF at
ambient temperature (Scheme 3).
The resulting b-ketoamine was quickly purified either by nor-
mal or by reverse phase chromatography. It should be noted that
intermediate 3a is somewhat unstable at ambient temperature
and undergoes oxidative dimerization on standing. The b-keto-
O
O
2
2
2
2
Intramolecular cyclization
at N1-C2
A)
B)
N
N
N1
N
N
N1
O
N1
6
O
Tandem inter/intramolecular
formation at N1-C2 and N1-C6
N1
6
* Corresponding author. Tel.: +1 215 652 0280; fax: +1 215 652 7310.
E-mail address: steve_gallicchio@merck.com (S. N. Gallicchio).
Scheme 1. Representative examples of the C–N bond forming reactions for the
generation of piperazinone rings.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.04.036

3818
S. N. Gallicchio, I. M. Bell / Tetrahedron Letters 50 (2009) 3817–3819
Compounds 7b–l presented in Table 2 were generated by reduc-
tive amination of 3a with amines 6b–l to show an extension of this
method (Scheme 4). The isolated yields after silica gel purification
were modest to good. Although reductive alkylation of 6j with
intermediate 3a was observed, subsequent cyclization to the de-
sired compound 7j did not occur.
In conclusion, we have developed a novel synthesis for the
preparation of 1,3-substituted-6-phenylpiperazin-2-ones in which
diverse functionality can be readily incorporated into the 1 and 3
positions of the ring system. Beginning with simple starting mate-
rials, this straightforward synthesis avoids protecting groups and
allows for the generation of elaborate ring systems without the
loss of stereochemical integrity.
X
Y
X
Y
X
HN
Y
N
O
R
HN CO2Me
NHR
HN CO2Me
O
Br
X
Y
O
H2N CO2Me
Scheme 2. Retrosynthetic analysis of 6-phenyl-piperazin-2-ones.
Representative procedure: 1-benzyl-3,3-dimethyl-6-phenylpipera-
O
O
H
zin-2-one (5a). Methyl
a-aminoisobutyrate hydrochloride (2a)
X
Br
NaHCO3
DMF, r.t.
Y
N
CO2Me
(400 mg, 2.60 mmol), 2-bromoacetophenone
1
(570 mg, 2.86
+
H2N CO2Me
X Y
mmol), and NaHCO3 (547 mg, 6.51 mmol) were combined in anhy-
drous DMF (15 mL) and stirred for 18 h at ambient temperature. The
reaction mixture was quenched with HCl (1 N, 10 mL) and extracted
with EtOAc (25 mL). The aqueous layer was made alkaline with sat-
urated aqueous NaHCO3 and extracted with EtOAc (3 Â 25 mL). The
combined organic layers were dried (Na2SO4), filtered, and concen-
trated. Purification by flash chromatography on silica gel, eluting
with a gradient of hexane:EtOAc/100:0 to 20:80, provided 3a as a
white solid (328 mg, 54% yield); 1H NMR (500 MHz, CDCl3) d 7.93
(dd, J = 8.4, 1.1 Hz, 2H), 7.57 (t, J = 7.5 Hz, 1H), 7.46 (t, J = 6.9 Hz,
2H), 4.10 (s, 2H), 3.68 (s, 3H), 1.42 (s, 6H); MS: m/z = 236 (M+1). b-
3a-k
2a-k
1
X Y
O
HN
6a, AcOH,
NaBH3CN
N
MeOH, 50 °C
5a-k
Scheme 3. Synthesis of 1-benzyl-6-phenylpiperazin-2-ones.
Ketoamine 3a (100 mg, 0.286 mmol, TFA salt), amine 6a (47.0
ll,
5d (R,R and R,S) in excellent yield. Chiral purity determination of
the diastereomeric mixtures of 5c and 5d by chiral HPLC revealed
that there was no observable epimerization of the 3-position
stereocenter.7
In order to investigate the scope of this method, a variety of
amino ester hydrochlorides (2e–k) were allowed to react with 1
to give the corresponding intermediates 3e–k as shown in Table
1. Treatment of these intermediates with 6a as described above
gave piperazinones 5e–k in good to excellent yields. The yield for
piperazinone 5e was low compared to other entries in Table 1
due to incomplete cyclization to the desired product.
0.429 mmol), and AcOH (82.0 L, 1.43 mmol) were dissolved in
l
MeOH (1.0 mL) and stirred for 5 min. NaBH3CN (27 mg. 0.429 mmol)
was added and the resulting solution heated to 50 °C for 18 h. The
reaction mixture was quenched with saturated aqueous NaHCO3
(2 mL), H2O (3 mL) was added, and the product was extracted into
EtOAc (3 Â 10 mL). The combined organic extracts were dried
(Na2SO4), filtered, and concentrated. Purification by flash chroma-
tography on silica gel, eluting with a gradient of hexane:EtOAc/
100:0 to 0:100, provided 5a as a white solid (53 mg, 63% yield); 1H
NMR (500 MHz, CDCl3) d 7.42 (m, 2H), 7.26–7.37 (m, 4H), 7.17 (d,
J = 7.1 Hz, 2H), 7.15 (d, J = 7.0 Hz, 2H), 5.61 (d, J = 14.6 Hz, 1H) 4.39
Table 1
Synthesis of b-ketoamine intermediates 3a–ka and piperazinones 5a–kb
X Y
O
HN
O
O
H
N
X
N
X
Br
Y
CO2Me
Y
+
H2N CO2Me
3a-k
2a-k
1
5a-k
X
Y
Amino-ester
Intermediate
Yield of intermediate 3c (%)
Product
Yield of product 5c (%)
Me
H
Me
H
Me
H
H
Me
H
2a
2b
2c
2d
2e
2f
2g
2h
2i
3a
3b
3c
3d
3e
3f
3g
3h
3i
54
7d
5a
5b
5c
5d
5e
5f
5g
5h
5i
63
0e
46
47
74
83
59
74
49
30
74
73
74
39f
67
59
60
94
60
67
Cyclohexyl
–(CH2)2–
–(CH2)5–
Benzyl
CH2NHCO2t-Bu
CH2CO2t-Bu
4-Nitrobenzyl
H
H
H
H
2j
2k
3j
3k
5j
5k
a
Reaction conditions: 1–3 mmol amino ester 2a–k; 1.1 equiv 2-bromoacetophenone (1); 2.5 equiv NaHCO3; DMF, ambient temperature.
Reaction conditions: 0.25–0.40 mmol ketone 3a–k; 1.5 equiv amine; 4.0 equiv AcOH; 1.5 equiv NaBH3CN; MeOH, 50 °C.
Yields of isolated intermediates and products.
Intermediate was not purified. Yield estimated by LC/MS.
Small amount of desired 5b observed by LC/MS, but no pure product was obtained.
Only 39% conversion to piperazinone 5e, but recovered 25% of uncyclized intermediate.
b
c
d
e
f

S. N. Gallicchio, I. M. Bell / Tetrahedron Letters 50 (2009) 3817–3819
3819
Table 2
Synthesis of piperazinones 5a and 7b–la
O
R
6a-l, HOAc
NaCNBH3
HN
O
H
N
N
CO2Me
O
R
HN
O
H
N
N
MeOH, 50 °C
CO2Me
3a
5a, 7b-l
3a
Scheme 4. Synthesis of 3,3-dimethyl-6-phenylpiperazin-2-ones.
5a, 7b-l
Amine
R
Product
Yieldb (%)
Benzylamine (6a)
Aniline (6b)
Phenethylamine (6c)
CH2Ph
Ph
CH2CH2Ph
5a
7b
7c
63
32
65
(t, J = 3.5 Hz, 1H), 3.41 (dd, J = 14.0, 4.2 Hz,1H) 3.35 (d, J = 14.9 Hz,
1H) 2.87 (dd, J = 13.9, 2.9 Hz,1H) 1.62 (bs, 1H), 1.51 (s, 3H) 1.50 (s,
3H); HRMS: m/z = 295.1811; calcd m/z = 295.1805 for C19H22N2O.
4-Methoxybenzylamine (6d)
4-Cyanobenzylamine (6e)
4-Pyridylmethylamine (6f)
7d
7e
7f
71
31
88
OMe
N
Acknowledgments
The authors wish to thank Jim Perkins for assistance in chiral
HPLC analysis of diastereomers; the MRL West Point mass spec-
troscopy and NMR spectroscopy groups for spectroscopic data;
and Dan Paone, Donnette Staas, Mike Wood, and Blair Zartman
for helpful suggestions.
N
(1H-indol-2-ylmethyl)amine (6g)
3-Thienylmethylamine (6h)
7g
7h
43
41
References and notes
N
H
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2. Chambers, M. S.; Street, L. J. J. Med. Chem. 1999, 42, 691.
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S
4. Logan, M. E.; Goswami, R.; Tomczuk, B. E.; Venepalli, B. R. Annu. Rep. Med. Chem.
1989, 26, 43.
5. Kendrick, D. A.; Ryder, H.; Semple, G.; Szelke, M. Bioorg. Med. Chem. Lett. 1992, 2,
9.
6. (a) Dinsmore, C. J.; Beshore, D. C. Org. Prep. Proced. Int. 2002, 34, 367; (b) Hulme,
C.; Peng, J.; Louridas, B.; Menard, P.; Krolikowski, P.; Kumar, N. V. Tetrahedron
Lett. 1998, 39, 8047; (c) Kennedy, A. L.; Fryer, A. M.; Josey, J. A. Organic Lett. 2002,
4, 1167; (d) Hulme, C.; Gore, V. Curr. Med. Chem. 2003, 10, 51; (e) Nixey, T.; Kelly,
M.; Hulme, C. Tetrahedron Lett. 2000, 41, 8729.
Methylamine (6i)
Me
Cyclopentyl
CH2CH2CO2t-Bu
H
7i
7j
7k
7l
53
0c
31
48
Cyclopentylamine (6j)
b-Alanine tert-butyl ester (6k)
Ammonia (6l)
a
Reaction conditions: 0.25–0.40 mmol amines 6a–l; 1.5 equiv ketone 3a;
4.0 equiv AcOH; 1.5 equiv NaBH3CN; MeOH, 50 °C.
b
Yields of isolated products.
Only intermediate formed and no cyclization to desired 7j.
7. Chiral HPLC conditions—column: Chiracel OJ; eluent: EtOH; <1% of other
diastereomer detected.
c