Synthesis of new polysubstituted piperazines and dihydro-2H-pyrazines by selective reduction of 2-oxo-piperazines

Article abstract of DOI:10.1016/j.tetasy.2009.12.025

New enantiomerically enriched 1,4,5-piperazines and 1,4,5-dihydro-2H-pyrazines have been prepared by reduction of the corresponding 2-oxo-piperazines. Selective reduction can be achieved by careful control of the reaction conditions using LiAlH₄

Full text of DOI:10.1016/j.tetasy.2009.12.025

Tetrahedron: Asymmetry 21 (2010) 191–194
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis of new polysubstituted piperazines and dihydro-2H-pyrazines
by selective reduction of 2-oxo-piperazines
a
b
b
b
Gianna Reginato a, , Barbara Di Credico , Daniele Andreotti , Anna Mingardi , Alfredo Paio ,
*
Daniele Donati c, Bernardo Pezzati a, Alessandro Mordini a
a ICCOM, CNR, Dipartimento di Chimica Organica ‘U. Schiff’, Via della Lastruccia 13, 50019 Sesto Fiorentino, Italy
b GlaxoSmithKline, Medicine Research Centre, Via A. Fleming 4, 37135 Verona, Italy
c Nerviano Medical Science S.r.l, Viale Pasteur, 10, 20014 Nerviano, Milano, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
New enantiomerically enriched 1,4,5-piperazines and 1,4,5-dihydro-2H-pyrazines have been prepared by
reduction of the corresponding 2-oxo-piperazines. Selective reduction can be achieved by careful control
of the reaction conditions using LiAlH4. Notably the two nitrogen atoms of the final compounds are
orthogonally protected.
Received 24 November 2009
Accepted 21 December 2009
Available online 9 February 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
The method we designed, which takes advantage of naturally
occurring amino acids as starting materials, allows us to prepare
Many pharmaceutical agents contain piperazines as part of
their core structure.1 Examples can be found in quinolone antibiot-
ics,2 HIV-protease inhibitors,3 5HT-anxiolytics,4 anti-hyperten-
some new piperazinones in which the substitution and the stereo-
chemistry at C-5 could be pivoted by the choice of the starting ami-
no acid and the anti substitution at C-3 could be accomplished
diastereoselectively via enolate formation and reaction with elec-
trophiles (Scheme 1). In addition, the two nitrogens of the ring
were orthogonally protected as this would be a crucial strategy
to facilitate the stepwise positioning of substituents when it is re-
quired to use the oxopiperazine core as a molecular scaffold.
sives5 and d- and
j
-opioid receptor agonists.6–8 In order to find
novel receptor ligands, various substituents have been introduced
onto the piperazine ring; for instance, derivatives bearing substit-
uents at the 3-position have been shown to strongly interact with
various receptors within the central nervous system.9 In addition
to being used as base templates and substituents to impart the de-
sired pharmacological and pharmacokinetic properties to a com-
pound, piperazines can also behave as bifunctional linking agents
to couple two components of an analogue through a six-membered
heterocycle.10 In recent years, they have also been used as efficient
chiral ligands in enantioselective catalysis.11,12
Bn
N
Bn
N 1
NHBoc
OH
O
O
E
Base
E
3
5
4
N
Boc
R
R
N
Boc
R
For these reasons, the synthesis of piperazines bearing substitu-
tion at different ring positions is of particular significance, and
many methods have been developed to achieve this goal. The syn-
thesis of piperazines and 2-substituted piperazines is usually per-
formed by ring construction and reduction of diketopiperazines or
2-ketopiperazines,13,14 by various cyclization reactions,15–17 via
O
Scheme 1.
alkylation and reduction of 2-methylpyrazines,18,19 or by
a-lithia-
These oxopiperazines can be considered as starting materials to
obtain the corresponding piperazines after reduction. Herein we
report our results on the reduction of oxopiperazines 1a–d and
show that they can be selectively converted into the corresponding
piperazines 2a–d or dihydro-2H-pyrazines 3a–d just depending on
the reaction conditions (Scheme 2). These latter compounds have
not been previously reported and might be useful building blocks
for obtaining more decorated piperazine cores.
tion and alkylation of N-Boc piperazines.20
Stemming from our interest in the asymmetric synthesis of
biologically interesting compounds, we have recently reported a
general and highly stereoselective approach to 1,4,5-tri-substi-
tuted- and 1,3,4,5-tetra-substituted 2-oxo-piperazines.21
* Corresponding author. Tel.: +39 0554573558; fax: +39 0554573580.
E-mail address: gianna.reginato@unifi.it (G. Reginato).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.12.025

192
G. Reginato et al. / Tetrahedron: Asymmetry 21 (2010) 191–194
Bn
N
Bn
N
Bn
N
Bn
N
O
LiAlH4 (5 eq)
rt, 12 h
LiAlH4 (1.2 eq)
-30 ºC, 2 h
R
R
N
N
Boc
2a-d
R
N
Boc
1a-d
N
Boc
R
R
Bn
N
a = CH3
Boc
2a-d
Bn
b = CH(CH3)2
c = CH2CH(CH3)2
O
3a-d
3a : 97% 3b : 48%
2a : 61% 2b : 57%
R
N
Boc
1a-d
d
=
3c : 77% 3d : 82%
H2C
2c : 91% 2d : 53%
N
OBn
Scheme 3.
N
Boc
3a-d
Boc
N
Boc
N
LiAlH4 1.5 eq.
THF, r.t., 2 h
Scheme 2.
N
Bn
O
N
Bn
5
4
2. Results and discussion
71%
Scheme 4.
Lithium aluminum hydride (LiAlH4) is the most commonly used
reagent for the reduction of lactams, however milder and more
chemoselective methods have also been developed using diisobu-
tylaluminum hydride (DIBAL-H), borane or sodium borohydride.22
In order to find suitable and mild reaction conditions to reduce
oxopiperazines 1, compound 1c was reacted in the presence of ex-
cess of LiAlH4 at 0 °C. After one hour, the reaction mixture was
worked up and 1H NMR analysis of the crude revealed that two
compounds in a roughly 1/1 ratio were present: the expected
piperazine 2c and the partially reduced dihydro-2H-pyrazines 3c.
Intrigued by this interesting result, we decided to screen different
reaction conditions in order to verify the possibility of selectively
obtaining the two different compounds. The results are reported
in Table 1.
reported.21 Thus we could understand that our optimized condi-
tions were not suitable for such substrate which proved to be less
reactive (Scheme 4). However, reduction to the corresponding
dihydropiperazine 5 was achieved using 1.5 equiv of LiAlH4 and
by carrying out the reaction at room temperature. Although com-
pound 5 was obtained in good yield after purification, it decom-
posed rapidly in solution, thus hampering a full characterization.
Attempts to obtain the corresponding fully reduced 3,5-disub-
stituted piperazine were not successful as the required reaction
conditions were too harsh (50–60 °C for 12 h) for our substrate
and only decomposition products were observed.
The use of a milder reducing agent such as DIBAL-H always gave
reaction mixtures containing the partially reduced dihydro-2H-
pyrazines as the major product, together with piperazine and unre-
acted starting material. On the other hand, BH3 reacted sluggishly
at room temperature, leading to a low conversion of the starting
material. When a large amount of reagent was used at reflux tem-
perature, piperazine 2c was obtained in good yield with no trace
amounts of the partially reduced compound 3c. Finally LiAlH4
proved to be the reagent of choice providing the total conversion
into piperazine 2c when used in large excess (5 equiv) at room
temperature and a high yield of dihydro-2H-pyrazines 3c when
used in a stoichiometric amount at low temperature.
To prove the generality of the method, these reaction conditions
were extended to three other substrates, compounds 1a,b,d, and
the corresponding reduced products were obtained in all cases, iso-
lated in reasonable yields after flash chromatography and were
fully characterized (Scheme 3).
3. Conclusions
In conclusion, the reduction of orthogonally protected oxopip-
erazines has been studied and the conditions for the selective con-
version into the corresponding enantiomerically enriched
piperazines or dihydro-2H-pyrazines have been optimized using
LiAlH4 as a reagent. These latter compounds were previously unre-
ported and their application for obtaining more decorated pipera-
zine cores is currently under investigation.
4. Experimental part
4.1. General methods
The reactions were monitored by TLC on SiO2, detection was
made using a basic KMnO4 solution. Flash column chromatography
was performed using glass columns (10–50 mm wide) and SiO2
(230–400 mesh). 1H NMR were recorded at 200 or 400 MHz. 13C
Finally, we also tried to extend these procedures to the 3,5-
disubstituted oxopiperazine 4 which was prepared as previously
Table 1
Products of the reduction of oxopiperazine 1c
Reducing agent
Number of equivalents (equiv)
T (°C)
Solvent and time
2ca
3ca
LiAlH4
3
2
2
2
4
5
1.2
0
0
THF/1 h
60%
15%
10%
15%
82%
40%
55%
70%
70%
DIBAL-Hb
DIBAL-Hb
DIBAL-H
THF/1.30 h
THF/12 h
Et2O/12 h
THF/2 h
THF/12 h
THF/2 h
ꢀ25
ꢀ25
Reflux
rt
b
BH3
—
—
LiAlH4
LiAlH4
100% (91%)c
5%
ꢀ30
95% (77%)c
Determined by 1H NMR analysis of the crude mixture.
1 M in THF solution.
Yield of isolated compound.
a
b
c

G. Reginato et al. / Tetrahedron: Asymmetry 21 (2010) 191–194
193
NMR spectra were recorded at 50.3 MHz. Chemical shifts were
determined relative to the residual solvent peak (CHCl3, d 7.26
ppm for 1H NMR; CHCl3, d 77.00 ppm for 13C NMR). For those com-
pounds which are present as slowly interconverting rotamers, the
signals of the most abundant rotamer are reported and those of the
less abundant are in parenthesis. When possible, 1H NMR experi-
ments were performed at 50 °C and signals of the averaged spec-
trum are given. Polarimetric measurements were performed at k
= 589 nm, and the temperature is specified case by case. All com-
mercial reagents were used without further purification. Oxopiper-
azines 1a–d were prepared according to the literature.21 THF was
dried by distillation over sodium benzophenone ketyl. CH2Cl2
was dried over CaCl2 and was stored over 4 Å molecular sieves.
DMF was distilled over CaCl2 and was stored over 4 Å molecular
sieves. Petroleum ether, unless specified, is the 40–70 °C boiling
fraction.
J = 13.5 Hz] ; 3.53 [d, 1H, JAB = 12.5 Hz]; 3.36 [d, 1H, JAB = 12.5 Hz];
2.98 [m, 1H]; 2.65 [d, 1H, J = 9.5 Hz]; 2.55 [d, 1H, J = 11.0 Hz]; 1.98
[dd, 1H, J = 3.7 Hz, J = 10.0 Hz]; 1.92 [dd, 1H, J = 3.7 Hz, J = 10.0 Hz];
1.63–1.56 [m, 1H]; 1.45 [s, 9H]; 1.39–1.33 [m, 2H]; 0.91 [d, 3H,
J = 11.8 Hz]; 0.89 [d, 3H, J = 11.8 Hz]. 13C NMR (50.3 MHz) d:
154.6; 138.1; 128.4 (ꢁ2); 127.9 (ꢁ2); 126.7 79.0; 62.6; 55.3;
53.2; 49.5; 49.3; 38.7; 28.2; 24.5; 22.7; 22.5.
½
a 2D5
ꢂ
¼ þ27:1
(c 1.19, CHCl3). Anal. Calcd for C20H32N2O2: C, 72.25; H, 9.70; N,
8.43. Found: C, 72.28; H, 9.65; N, 8.38.
4.2.4. (S)-tert-Butyl-2-[4-(benzyloxy)benzyl]-4-benzyl-piperazine-
1-carboxylate 2d
Oxopiperazine 1d (100 mg, 0.2 mmol) was dissolved in THF
(5 mL) and was reacted with LiAlH4 (43 mg, 1.0 mmol). Workup
and purification [hexane/ethyl acetate = 3/1] gave 2d as a low
melting white solid (47 mg, 53%). Rf: 0.1. 2d: 1H NMR (200 MHz)
d: 7.33–7.28 [m, 5H]; 7.23–7.19 [m, 5H]; 6.88 [d, 2H, J = 8.6 Hz];
6.71 [d, 2H, J = 8.6 Hz]; 4.93 [s, 2H]; 4.04–3.78 [m, 1H+1H]; 3.46
[d, 1H, JAB = 12.8 Hz]; 3.27 [d, 1H, JAB = 12.5 Hz]; 3.11 [m, 1H];
3.00–2.87 [m, 1H]; 2.81–2.64 [m, 2H]; 2.56 [d, 1H, J = 11.4 Hz];
1.99 [dd, 1H, J = 3.0 Hz, J = 11.4 Hz]; 1.93 [dd, 1H, J = 3.8 Hz,
J = 11.4 Hz]; 1.32 [s, 9H]. 13C NMR (50.3 MHz) d: 156.9; 151.2;
138.2; 137.1;131.6; 130.2 (ꢁ2); 129.1 (ꢁ2); 128.4 (ꢁ2); 128.1
(ꢁ2); 127.7; 127.3 (ꢁ2); 127.1; 114.6 (ꢁ2); 79.4; 70.0; 63.0;
4.2. Synthesis of piperazines 2a–d: general procedure
Oxopiperazines 1a–d (1 equiv) were dissolved in dry THF and
the solution was cooled to 0 °C. Next, LiAlH4 (5 equiv) was added
and, after heating to room temperature, the mixture was stirred
overnight. After the addition of water and extraction with ethyl
acetate, the organic phase was washed with brine, dried over
Na2SO4 and then concentrated to afford piperazines 2a–d, which
were purified by flash chromatography.
53.6; 53.4 (ꢁ2); 39.4; 35.2; 28.5. ½a D27
¼ þ1:0 (c 0.5, CHCl3). Anal.
ꢂ
Calcd for C30H36N2O3: C, 76.24; H, 7.68; N, 5.93. Found: C, 76.35;
H, 7.72; N, 5.91.
4.2.1. (S)-tert-Butyl-2-methyl-4-benzylpiperazine-1-carboxylate
2a
4.3. Synthesis of 3,4-dihydropyrazine-1(2H)-carboxy-lates 3a–
Oxopiperazine 1a (60 mg, 0.2 mmol) was dissolved in THF
(5 mL) and was reacted with LiAlH4 (40 mg, 1.0 mmol). Workup
and purification [petroleum ether/ethyl acetate = 25/1] gave 2a
as a colourless oil (35 mg, 61%). Rf: 0.2 2a: 1H NMR (200 MHz) d:
7.33–7.25 [m, 5H]; 4.23–4.10 [m, 1H]; 3.76 [d, 1H, J = 13.2 Hz];
3.55 [d, 1H, JAB = 13.2 Hz]; 3.41 [d, 1H, JAB = 13.2 Hz]; 3.10 [m,
1H]; 2.75 [d, 1H, J = 10.0 Hz]; 2.59 [d, 1H, J = 11.3 Hz]; 2.16–1.95
[m, 2H]; 1.45 [s, 9H]; 1.24 [d, 3 H, J = 7.0 Hz]. 13C NMR
(50.3 MHz) d: 154.3; 137.1; 128.4 (ꢁ2); 127.9 (ꢁ2); 126.6; 79.1;
d: general procedure
Oxopiperazines 1a–d (1 equiv) were dissolved in dry THF and
the solution was cooled to ꢀ30 °C. LiAlH4 (1.2 equiv) was added
and stirred at ꢀ30 °C for 2 h. After the addition of water, the reac-
tion mixture was warmed up to room temperature and was ex-
tracted with ethyl acetate. The organic phase was washed with
brine, dried over Na2SO4 and then concentrated to afford pirazines
3a–d, which were purified by flash chromatography.
62.5; 57.1; 53.0; 48.6; 38.8; 28.2; 15.7. ½a D28
¼ þ21:3 (c 0.5, CHCl3)
ꢂ
{lit.23
½
a 2D5
ꢂ
¼ þ56 (c 0.44, EtOH)}. Anal. Calcd for C17H26N2O2: C,
4.3.1. (S)-tert-Butyl-2-methyl-4-benzyl-3,4-dihydro-pyrazine-
1(2H)-carboxylate 3a
70.31; H, 9.02; N, 9.65. Found: C, 70.27; H, 9.05; N, 9.57.
Oxopiperazine 1a (75 mg, 0.2 mmol) was dissolved in THF
(8 mL) and was reacted with LiAlH4 (11 mg, 0.3 mmol). Workup
and purification [petroleum ether/ethyl acetate = 25/1] gave 3a as
a colourless oil (72 mg, 97%). Rf: 0.3. 3a: 1H NMR (400 MHz) d:
7.34–7.25 [m, 5H]; 5.79 (5.95) [d, 1H, J = 6.0 Hz]; 5.37 (5.48) [d,
1H, J = 6.0 Hz]; 4.36 [br m, 2H]; 4.23 [br m, 1H]; 4.07–3.99 [d,
1H, JAB = 14.3.0 Hz]; 4.07–3.99 [d, 1H, JAB = 14.3 Hz]; 3.97–3.90 [d,
1H, JAB = 14.3 Hz]; 2.80 [br s, 2H]; 1.47 [s, 9H]; 1.20 [d, 3H,
J = 6.6 Hz]. 13C NMR (50.3 MHz) d: 152.2; 137.9; 128.42 (ꢁ2);
128.23 (ꢁ2); 127.33; 118.92; 101.13; 79.73; 59.0; 50.7; 45.9;
4.2.2. (S)-tert-Butyl-2-isopropyl-4-benzylpiperazine-1-
carboxylate 2b
Oxopiperazine 1b (92 mg, 0.3 mmol) was dissolved in THF
(5 mL) and was reacted with LiAlH4 (49 mg, 1.2 mmol). Workup
and purification [petroleum ether/ethyl acetate = 3/1] gave 2b as
a low melting white solid (51 mg, 57%). Rf: 0.2 2b: 1H NMR
(200 MHz) d: 7.32–7.27 (m, 5H); 3.93 (3.58) [br s, 1H]; 3.54 [d,
1H, JAB = 12.8 Hz]; 3.34 [d, 1H, JAB = 12.8 Hz]; 2.99 [m, 1H]; 2.84
[d, 1H, J = 12.0 Hz]; 2.75 [d, 1H, J = 12.0 Hz]; 2.48–2.29 [m, 1H];
2.06 [dd, 1H, J = 3.6 Hz, J = 11.0 Hz]; 1.97 [dd, 1H, J = 3.6 Hz,
J = 11.0 Hz]; 1.74 [m, 1H]; 1.45 [s, 9H]; 0.84 [d, 3H, J = 8.0 Hz];
0.79 [d, 3H, J = 8.0 Hz]. 13C NMR (50.3 MHz) d: 154.8; 138.3;
128.7 (ꢁ2); 128.0 (ꢁ2); 126.9; 79.2; 63.0; 60.9; 53.7; 53.5; 39.1;
28.4; 17.1.
½
a 2D8
ꢂ
¼ ꢀ78:0 (c 0.85, CHCl3). Anal. Calcd for
C17H24N2O2: C, 70.80; H, 8.39; N, 9.71. Found: C, 70.76; H, 8.35;
N, 9.76.
29.7; 28.5; 26.4; 20.2. ½a D28
ꢂ
¼ þ31:0 (c 1.25, CHCl3). Anal. Calcd
4.3.2. (S)-tert-Butyl-2-isopropyl-4-benzyl-3,4-dihydro-pyrazine-
1(2H)-carboxylate 3b
for C19H30N2O2: C, 71.66; H, 9.50; N, 8.80. Found: C, 71.63; H,
9.54; N, 8.78.
Oxopiperazine 1b (50 mg, 0.2 mmol) was dissolved in THF
(5 mL) and was reacted with LiAlH4 (8 mg, 0.3 mmol). Workup
and purification [hexane/ethyl acetate = 9/1] gave 3b as a colour-
less oil (25 mg, 48%). Rf: 0.3. 3b: 1H NMR (200 MHz) d: 7.35–7.27
[m, 5H]; 5.79 (5.87) [d, 1H, J = 6.2 Hz]; 5.39 (5.45) [d, 1H,
J = 6.2 Hz]; 4.06–3.88 [m, 2H]; 3.89 (3.76) [d, 1H, J = 6.2 Hz];
3.16–2.98 [m, 1H]; 2.69 [dd, 1H, J = 11.7, J = 3.5 Hz]; 2.07–1.88
[m, 1H]; 1.46 [s, 9H]; 0.87 [d, 3H, J = 8.8 Hz]; 0.78 [d, 3H,
J = 8.8 Hz].13C NMR (50.3 MHz) d: 151.1; 137.9; 128.3 (ꢁ2); 127.4
4.2.3. (S)-tert-Butyl-2-isobutyl-4-benzylpiperazine-1-
carboxylate 2c
Oxopiperazine 1c (102 mg, 0.3 mmol) was dissolved in THF
(5 mL) and was reacted with LiAlH4 (50 mg, 1.2 mmol). Workup
and purification [petroleum ether/ethyl acetate = 3/1] gave 2c as
a colourless oil (88 mg, 91%). Rf: 0.1. 2c: 1H NMR (200 MHz) d: d
(CDCl3, 200 MHz): 7.34–7.23 [m, 5H]; 4.03 [br s, 1H]; 3.79 [d, 1H,

194
G. Reginato et al. / Tetrahedron: Asymmetry 21 (2010) 191–194
(ꢁ2); 127.0; 119.9; 101.1; 79.8; 59.0; 57.1; 55.4; 47.1; 28.4; 19.7;
ature and stirred for 2 h. After the addition of water and extraction
with ethyl acetate, the organic phase was washed with brine, dried
over Na2SO4 and then concentrated. Purification [petroleum ether/
ethyl acetate = 20/1] gave 27 mg (71%) of 5 as a yellow oil which
rapidly decomposed in solution 1H NMR (200 MHz, CDCl3) d:
7.40–7.24 [m, 10H]; 5.60 [s, 1H]; 4.37 [br s, 1H]; 4.08–4.01 [m,
2H]; 3.28 [d, 2 H, J = 15 Hz]; 2.88 [dd, 1H, J = 3.7 Hz, J = 11.5 Hz];
2.71 [d, 1H, J = 11.5 Hz]; 1.47 [s, 9H]; 0.78 [s, 3H].
19.3. ½a 2D6
¼ ꢀ39:6 (c 1.05, CHCl3). Anal. Calcd for C19H28N2O2: C,
ꢂ
72.12; H, 8.92; N, 8.85. Found: C, 72.18; H, 8.88; N, 8.76.
4.3.3. (S)-tert-Butyl-2-isobutyl-4-benzyl-3,4-dihydro-pyrazine-
1(2H)-carboxylate 3c
Oxopiperazine 1c (310 mg, 0.9 mmol) was dissolved in THF
(20 mL) and was reacted with LiAlH4 (38 mg, 1.0 mmol). Workup
and purification [hexane/ethyl acetate = 30/1] gave 3c as white
crystals (230 mg, 77%). Rf: 0.4. 3c: 1H NMR (200 MHz) d: 7.33–
7.28 [m, 5H]; 5.78 (5.94) [d, 1H, J = 5.9 Hz]; 5.38 (5.50) [d, 1H, J =
5.9 Hz]; 4.38–4.21 (4.08–4.19) [m, 1H]; 4.04 [d, 1H, JAB = 14.3 Hz];
3.93 [d, 1H, JAB = 14.3 Hz]; 2.95–2.72 [m, 2H]; 1.54–1.51 [m, 1H];
1.48 [s, 9H]; 146–1.40 [m, 2H]; 0.95–0.91 [m, 6H].13C NMR
(50.3 MHz) d: 151.1; 137.6; 128.1 (ꢁ2); 127.8 (ꢁ2); 127.1; 118.9;
References
1. Vieth, M.; Siegel, M. G.; Higgs, R. E.; Watson, I. A.; Robertson, D. H.; Savin, K. A.;
Durst, G. L.; Hipskind, P. A. J. Med. Chem. 2004, 47, 224.
2. Miyamota, T.; Matsumoto, J.; Chiba, K.; Egawa, H.; Shibamori, K.; Minamida, A.;
Nishimura, Y.; Okada, H.; Kataoka, M.; Fujita, M.; Hirose, T.; Nakano, J. J. Med.
Chem. 1990, 33, 1645.
3. Serradji, N.; Bensaid, O.; Martin, M.; Kan, E.; Bosquet, N. D.; Redeuilh, C.; Huet,
J.; Heymans, F.; Lamouri, A.; Clayette, P.; Dong, C. Z.; Dormont, D.; Godfroid, J. J.
J. Med. Chem. 2000, 43, 2149.
4. Parihar, H. S.; Suryanarayanan, A.; Ma, C.; Joshi, P.; Venkataraman, P.; Schulte,
M. K.; Kirschbaum, K. S. Bioorg. Med. Chem. Lett. 2001, 11, 2133.
5. Giardinh, D.; Gulini, U.; Massi, M.; Piloni, M. G.; Pompei, P.; Rafaiani, G.;
Melchiorre, C. J. Med. Chem. 1993, 36, 690.
6. Lopez, J. A.; Okayama, T.; Hosohata, K.; Davis, P.; Porreca, F.; Yamamura, H. I.;
Hruby, V. J. J. Med. Chem. 1999, 42, 5359.
7. Naylor, A.; Judd, D. E.; Lloyd, J. E.; Scopes, D. I.; Hayes, A. G.; Birch, P. J. J. Med.
Chem. 1993, 36, 2075.
8. Soukara, S.; Maier, C. A.; Predoiu, U.; Ehret, A.; Jackisch, R.; Wünsch, B. J. Med.
Chem. 2001, 44, 2814.
9. Bedürftig, S.; Wünsch, B. Eur. J. Med. Chem. 2006, 41, 387.
10. Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003, 103, 893.
11. Eriksson, J.; Arvidsson, P. I.; Davidsson, O. Chem. Eur. J. 1999, 5, 2356.
12. Itsuno, S.; Matsumoto, T.; Sato, D.; Inoue, T. J. Org. Chem. 2000, 65, 2540.
13. Dinsmore, C. J.; Beshore, D. C. Tetrahedron 2002, 58, 3297.
14. Dinsmore, C. J.; Beshore, D. C. Org. Prep. Proced. Int. 2002, 34, 367.
15. See for instance: Macleod, C.; Martinez-Teipel, B. I.; Barker, W. M.; Dolle, R. E. J.
Comb. Chem. 2006, 8, 132.
16. Liu, K. G.; Robichaud, A.-J. Tetrahedron Lett. 2005, 46, 7921.
17. Nordstrom, L. U.; Madsen, R. Chem. Commun. 2007, 5034.
18. See for instance: Binisti, C.; Assogba, L.; Touboul, E.; Mounier, C.; Huet, J.;
Ombetta, J.-E.; Dong, C. Z.; Redeuilh, C.; Heymans, F.; Godfroid, J.-J. Eur. J. Med.
Chem. 2001, 36, 809.
100.7; 79.6; 58.7; 49.3; 48.2; 39.5 28.2; 24.5; 23.1; 22.0. ½a D26
¼
ꢂ
ꢀ17:7 (c 1.42, CHCl3). Anal. Calcd for C20H30N2O2: C, 72.69; H,
9.15; N, 8.48. Found: C, 72.57; H, 9.19; N, 8.52.
4.3.4. (S)-tert-Butyl-2-[4-(benzyloxy)benzyl]-4-benzyl-3,4-
dihydropyrazine-1(2H)-carboxylate 3d
Oxopiperazine 1d (100 mg, 0.2 mmol) was dissolved in THF
(5 mL) and was reacted with LiAlH4 (10 mg, 0.3 mmol). Workup
and purification [hexane/ethyl acetate = 8/1] gave 3d as a pale yel-
low oil (80 mg, 82%). Rf: 0.3. 3d: 1H NMR (400 MHz) d: 7.43–7.39
[m, 5H]; 7.34–7.28 [m, 5H]; 7.02 (6.94) [d, 2H, J = 8.2 Hz]; 6.81
(6.79) [d, 2H, J = 8.2 Hz]; 5.86 (6.01) [d, 1H, J = 6.2 (6.6) Hz]; 5.43
(5.56) [d, 1H, J = 6.2 (6.6) Hz]; 5.05–4.9) [dapp, 2H]; 4.37–4.28
(4.23–4.14) [m, 1H]; 3.98 [dd, 1H, JAB = 14.0 JAC = 4.3 Hz]; 3.92
[dd, 1H, JAB = 14.0 JAC = 4.3 Hz]; 2.85–2.62 [m, 2H+2H]; 1.45
(1.37) [s, 9H]. 13C NMR (50.3 MHz) d: 157.3 (156.9); 154.5;
137.6; 134.6 (134.3); 131.0; 130.9; 130.4 (ꢁ2); 129.2; 128.5
(ꢁ2); 128.4 (ꢁ2); 127.3 (ꢁ2); 127.8 (ꢁ2); 127.3 (ꢁ2); 120.2
(119.1); 114.8 (114.5); 101.3 (101.1); 80.1 (79.6); 70.0; 59.2;
46.8 (47.2); 36.7 (36.1); 28.4. ½a D26
¼ ꢀ86:0 (c 0.6, CHCl3). Anal.
ꢂ
Calcd for C30H34N2O3: C, 76.57; H, 7.28; N, 5.95. Found: C, 76.51;
H, 7.34; N, 5.89.
19. Scapecchi, S.; Martini, E.; Manetti, D.; Ghelardini, C.; Martelli, C.; Dei, S.;
Galeotti, N.; Guandalini, L.; Romanelli, M. N.; Teodori, E. Bioorg. Med. Chem.
2004, 12, 71.
20. Berkheij, M.; Sluis, L. v. d.; Sewing, C.; Boer, D. J. d.; Terpstra, J. W.; Hiemstra, H.;
Bakker, W. I. I.; Hoogenband, A. v. d.; Maarseveen, J. H. v. Tetrahedron Lett. 2005,
46, 2369.
21. Reginato, G.; Di Credico, B.; Andreotti, D.; Mingardi, A.; Paio, A.; Donati, D.
Tetrahedron: Asymmetry 2007, 18, 2680.
4.4. Synthesis of (S)-tert-butyl-4,6-dibenzyl-2-methyl-3,4-
dihydropyrazine-1(2H)-carboxylate 5
Oxopiperazine 4 (40 mg, 0.1 mmol) was dissolved in THF (5 mL)
and the solution was cooled to 0 °C. Next, LiAlH4 (6 mg, 0.15 mmol)
was added, and the reaction mixture was warmed at room temper-
22. Hudlicky, M. Reductions in Organic Chemistry, 2nd ed.; Washington DC, 1998.
23. Mickelson, J. W.; Belonga, K. L.; Jacobsen, E. J. J. Org. Chem. 1995, 60, 4177.