Regioselective thionation of bicyclic piperazinediones

Article abstract of DOI:10.1016/S0040-4020(01)00324-6

In order to modify and improve the reduction of bicyclic piperazinediones to yield enantiomerically pure piperazine derivatives the preparation and reduction of the corresponding thiolactams were investigated. With a reduced amount of Lawesson reagent the

Full text of DOI:10.1016/S0040-4020(01)00324-6

TETRAHEDRON
Pergamon
Tetrahedron 57 /2001) 4359±4363
Regioselective thionation of bicyclic piperazinediones
Stella Soukara and Bernhard WuÈnschp
È
Pharmazeutisches Institut der Universitat Freiburg, Hermann-Herder-Str. 9, D-79104Freiburg i. Br., Germany
Received 16 January 2001; revised 14 March 2001; accepted 16 March 2001
AbstractÐIn order to modify and improve the reduction of bicyclic piperazinediones to yield enantiomerically pure piperazine derivatives
the preparation and reduction of the corresponding thiolactams were investigated. With a reduced amount of Lawesson reagent the bicyclic
piperazinediones reacted predominantly at the C-5 carbonyl moiety to provide C-5 monothiolactams. q 2001 Elsevier Science Ltd. All
rights reserved.
1. Introduction
only 16 mass units. Obviously, only one carbonyl group
has been transformed into a thiocarbonyl group. /Scheme 2)
Recently we described the synthesis and the stereoselective
k-receptor binding of all four stereoisomeric piperazines 4.
The synthesis of the stereoisomeric piperazines 4 started
from the proteinogenic amino acid threonine /1) or its
enantiomer.1 A crucial step in the synthesis of the piperazine
derivatives 4 was the reaction of the bicyclic piperazine-
diones 2 with LiAlH4, which led to reduction of both
lactam carbonyl groups and reductive ring opening of the
N/O-acetal establishing the N-benzyl protective group
/!3). The reduction of the bicyclic piperazinediones 2
required, however, heating with a large excess of LiAlH4
for a long period /48±72 h) and in some cases side reactions
took place.2 /Scheme 1)
A larger excess of Lawesson reagent or elongation of the
reaction time did not improve the yield of the dithiolactam
6a. However, reaction of the piperazinedione 5a with only
0.5 molar equivalents of Lawesson reagent raised the yield
of the monothiolactam 7a to 86%. The dithiolactam 6a was
not detected. We assume, that steric effects are responsible
for the preferred thionation in position 5. Whereas two
branched substituents are adjacent to the C-8 carbonyl
moiety the C-5 carbonyl moiety is shielded by only one
large substituent /oxazolidine ring).
In this communication we report on our attempts to improve
this reaction step by transformation of the lactam carbonyl
groups of 2 into thiolactam moieties. The reduction of thio-
lactam groups should be possible by more careful reaction
conditions.3
2. Results and discussion
For this purpose the bicyclic piperazinedione 5a was heated
with 1.2 molar equivalents of Lawesson reagent /LR).4±6
Surprisingly two products were formed which could be
separated by ¯ash chromatography. The mass spectrum of
the less polar, minor compound /27%) indicated the incor-
poration of two sulfur atoms which is in accordance with the
expected dithiolactam 6a. In comparison with the molar
mass of the piperazinedione 5a the molar mass of the
more polar, major product 7a /54%) was increased by
Keywords: medicinal chemistry; piperazines; regioselective thionation;
thiolactams; reduction.
p
Corresponding author. Fax: 149-7-61-203-6321;
e-mail: wuensch@ruf.uni-freiburg.de
Scheme 1.
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020/01)00324-6

È
S. Soukara, B. Wunsch / Tetrahedron 57 -2001) 4359±4363
4360
Scheme 2.
The same observations were made during thionation of the
diastereomeric bicyclic piperazinedione 5b with /S)-con-
®guration in position 3. As described for 5a 1.2 molar
equivalents of Lawesson reagent led to the monothiolactam
7b as main product /60%) and the dithiolactam 6b as minor
component /37%). Variation of the reaction conditions did
not improve the yield of the dithiolactam 6b. However, the
yield of the monothiolactam 7b could be increased by
lowering the amount of Lawesson reagent to 0.5 molar
equivalents. These results led to the conclusion, that the
preferred thionation of the C-5 carbonyl moiety is not
dependent on the stereochemistry in position 3 near at the
reacting C-5 carbonyl moiety.
The number of sulfur atoms incorporated into the piperazine
ring system is deduced from the mass spectra of the products
6 and 7. In comparison with the piperazinediones 5 the
molecular ion peak of the more polar monothio compounds
7 is increased by 16 mass units, whereas the molecular mass
of the less polar dithiolactams 6 differ by 32 mass units. The
IR spectra of the dithiolactams 6 reveal one absorption at
1490±1494 cm21 for both thiolactam groups /amide II).7 On
the other hand two absorptions are seen in the IR spectra of
the monothiolactams 7, which are caused by the lactam
carbonyl group /1669±1686 cm21, amide I) and the thio-
lactam moiety /1491±1494 cm21, amide II), respectively.7
The position of the sulfur atom /thiocarbonyl moiety) in the
monothiolactams 7 is derived from the 1H NMR spectra. In
Table 1 the signals caused by the aliphatic protons of the
lactams 5, the dithiolactams 6 and the monothiolactams 7
are summarized. Little differences in the chemical shifts of
the protons in position 8a /8a-H) and the protons of the
OCHCH3 moiety are found. Introduction of a sulfur atom
in position 5 /compounds 6 and 7) leads to a down®eld shift
of about 0.4±0.6 ppm of the adjacent 6-CH2-proton signals.
A characteristic change is observed for the signals of the
N±CH2±Ph group. In the spectra of the monothiolactams 7
with the C-8-carbonyl moiety the signals for the N±CH2±Ph
protons appear at almost unchanged positions compared
with the lactams 5. In contrast, the corresponding spectra
of the dithiolactams 6 /C-8-thiocarbonyl) reveal the
Next, we investigated the in¯uence of the substituent in
position 7 on the regioselective thionation with Lawesson
reagent. Heating of the bicyclic piperazinedione 5c, which
differed from 5a by a phenyl instead of a benzyl residue in
position 7, with 1.2 molar equivalents of Lawesson reagent
provided two products. In this case, however, the less polar
dithiolactam 6c predominated with an isolated yield of 58%,
whereas the more polar monothiolactam 7c was isolated in
only 38% yield. Obviously, the difference in reactivity of
the two carbonyl moieties in the phenyl substituted pipera-
zinedione 5c is smaller than in the benzyl substituted
piperazinediones 5a and 5b. This may be due to the acet-
anilide substructure of 5c, which enhances the C-8 carbonyl
activity.
Table 1. Comparison of the 1H NMR data /CDCl3) of 5±7: chemical shifts of the aliphatic protons
Compound
1-H
CH±CH3
3-H
6-H
6-H
N±CH2Ph
N±CH2Ph
8a-H
5a[2]
5b[2]
5c[2]
6a
6b
6c
7a
7b
7c
4.49
4.24
4.54
4.64
4.49
4.66
4.53
4.21±4.32
4.52
1.60
1.74
1.59
1.61
1.80
1.61
1.57
1.64
1.51
6.28
6.32
6.36
6.50
6.21
6.59
6.52
6.35
6.53
3.80
3.77
4.21
4.29
4.19±4.22
4.66
4.34
4.21±4.32
4.69
4.07
4.02
4.65
4.58
4.42
4.66
4.34
4.21±4.32
4.84
4.61
4.45
±
5.17
4.80
±
4.60
4.71
4.77
±
5.33
5.63
±
4.77
4.84
±
3.98
4.04
4.11
3.96
4.19±4.22
4.14
3.95
4.04
4.07
4.21±4.32
±

È
S. Soukara, B. Wunsch / Tetrahedron 57 -2001) 4359±4363
4361
3. Conclusion
The regioselective thionation of the bicyclic piperazine-
diones 5 combined with the reduction of the products
under various conditions provides access to differently
substituted mono- and bicyclic piperazines /e.g. 8±10),
which are valuable building blocks for the synthesis of
pharmacologically active piperazine derivatives1,9±11 as
well as peptidomimetics.12,13
4. Experimental
4.1. General
Unless otherwise noted, moisture sensitive reactions were
conducted under dry nitrogen. Thin layer chromatography
/tlc): Silica gel 60 F254 plates /Merck). Flash chroma-
tography /fc)14: Silica gel 60, 0.040±0.063 mm /Merck);
parentheses include: Diameter of the column [cm], eluent,
fraction size [ml], Rf. Melting points: Melting point appa-
ratus Dr Tottoli /BuÈchi), uncorrected. Optical rotation:
Polarimeter 241 /Perkin±Elmer); lˆ589 nm; 1.0 dm tube;
concentration c [g/100 ml]. Elemental analyses: CHN
elemental analyzer Rapid /Heraeus) and Elemental Ana-
lyzer 240 /Perkin Elmer). MS: Mass spectrometer 5989A
/Hewlett±Packard), MAT 312, MAT 8200, MAT 4456, and
TSQ 7000 /Finnigan); EIˆelectron impact, CIˆchemical
ionization. IR: IR spectrophotometer 1600 FT-IR, 2000
1
FT-IR, and 841-IR /Perkin±Elmer). H NMR /400 MHz):
1
GSX FT NMR spectrometer /Jeol); H NMR /300 MHz),
13C NMR /75 MHz): Unity 300 FT NMR spectrometer
/Varian), tetramethylsilane as internal standard, d in ppm;
coupling constants are given with 0.5 Hz resolution; the
assignments of 13C and of 1H NMR signals were supported
by two-dimensional NMR techniques /COSY, DEPT).
Scheme 3.
N±CH2±Ph signals down®eld shifted by about 0.5 ppm.
Interestingly, the changes of the 3-H signals are depending
on the con®guration of the N/O-acetalic stereogenic center.
In the /R)-series /a and c compounds) changing of the
C-5-carbonyl into a C-5-thiocarbonyl moiety leads to a
down®eld shift of about 0.2 ppm, whereas the /3S)-con®gu-
rated derivatives /b series) reveal almost unchanged
chemical shifts for the 3-H proton signals.
4.1.1. *1R,3R,8aS)-7-Benzyl-1-methyl-3-phenyl-1,6,7,8a-
tetrahydro[1,3]oxazolo[3,4-a]-pyrazine-5,8-dithione *6a)
and *1R,3R,8aS)-7-Benzyl-1-methyl-3-phenyl-5-thioxo-
1,6,7,8a-tetrahydro[1,3]oxazolo-[3,4-a]pyrazin-8*5H)-one
*7a). /a) Reaction of 5a with 1.2 molar equivalents of
Lawesson reagent. A mixture of 5a2 /1.62 g, 4.81 mmol),
Lawesson reagent /2.66 g, 5.77 mmol) and THF abs.
/50 mL) was heated to re¯ux for 24 h. The suspension
was concentrated in vacuo and the residue puri®ed by fc
/4 cm, petroleum ether/ethyl acetate 3:1, 15 mL).
Reduction of the dithiolactam 6b with an excess of LiAlH4
afforded the hydroxyethyl substituted 1,4-dibenzylpipera-
zine 8 in 76% yield. In comparison with the analogous
reduction of the corresponding bicyclic piperazinedione
5b2 the yield of 8 was slightly increased whereas the
reaction time was reduced from 48 h to 16 h. Hence, the
LiAlH4 reduction of bicyclic piperazinedithiones represents
an attractive alternative for the preparation of 8 /Scheme 3).
6a /Rfˆ0.60): Pale yellow solid, colorless needles /metha-
nol), m.p. 2088C, yield 480 mg /27%). [a]25ˆ134.8
/cˆ1.52, CH2Cl2). C20H20N2OS2 /368.5) calcd. C 65.2 H
5.47 N 7.60 found C 65.0 H 5.62 N 7.55. MS /EI): m/z
Hydrogenation of the dithiolactam 6a in the presence of the
catalyst Raney±Nickel only led to reduction of the thio-
carbonyl moieties.8 In contrast to the reduction with
LiAlH4 the acetalic 1,3-oxazolidine substructure remains
unaffected yielding the bicyclic piperazine derivative 9.
Treatment of the monothiolactam 7a with hydrogen and
Raney±Nickel provided the bicyclic piperazin-8-one 10
with intact C-8-lactam carbonyl and oxazolidine moieties.
The reductive elimination of the C-5-thiocarbonyl moiety of
7a additionally proves the position of the sulfur atom /thio-
carbonyl group).
/%)ˆ368 /M, 52), 335 /M-HS, 31), 91 /Bn, 100). IR
1
/®lm): nˆ1490 /s, amide IINCˆS), 694 cm21 /m). H NMR
Ä
/300 MHz, CDCl3): d /ppm)ˆ1.61 /d, Jˆ5.9 Hz, 3 H,
CHCH3), 3.96 /d, Jˆ8.8 Hz, 1 H, CSCH), 4.29 /d,
Jˆ17.1 Hz, 1 H, CSCH2), 4.58 /d, Jˆ17.1 Hz, 1 H,
CSCH2), 4.64 /dq, Jˆ8.8/5.9 Hz, 1 H, CHCH3), 5.17 /d,
Jˆ14.4 Hz, 1 H, CH2Ph), 5.33 /d, Jˆ14.6 Hz, 1 H,
CH2Ph), 6.50 /s, 1 H, NCHO), 7.07±7.11 /m, 2 H, arom.),
7.22±7.35 /m, 8 H, arom.).
7a /Rfˆ0.49): Pale yellow solid, m.p. 161±1648C, yield

È
S. Soukara, B. Wunsch / Tetrahedron 57 -2001) 4359±4363
4362
918 mg /54%). [a]25ˆ236.4 /cˆ1.38, CH2Cl2).
C20H20N2O2S /352.5) calcd. C 68.2 H 5.72 N 7.95 found
C 67.9 H 5.80 N 7.96. MS /EI): m/z /%)ˆ352 /M, 48), 319
100). IR /®lm): nˆ1494 /s, amide IINCˆS), 696 cm21 /m).
Ä
1H NMR /300 MHz, CDCl3): d /ppm)ˆ1.61 /d, Jˆ5.8 Hz, 3
H, CHCH3), 4.14 /d, Jˆ8.7 Hz, 1 H, CSCH), 4.66 /dq,
Jˆ8.5/5.9 Hz, 1 H, CHCH3), 4.66 /s, 2 H, CSCH2), 6.59
/s, 1 H, NCHO), 7.16±7.26 /m, 4 H, arom.), 7.30±7.39
/m, 4 H, arom.), 7.41±7.49 /m, 2 H, arom.).
/M-HS, 30), 105 /PhCO, 80), 91 /Bn, 100). IR /®lm):
1
nˆ1676 /s, CˆO), 1491 /s, amide IINCˆS), 700 /m). H
Ä
NMR /300 MHz, CDCl3): d /ppm)ˆ1.57 /d, Jˆ6.0 Hz, 3
H, CHCH3), 3.95 /d, Jˆ9.3 Hz, 1 H, COCH), 4.34 /s, 2 H,
CSCH2), 4.53 /dq, Jˆ9.3/5.9 Hz, 1 H, CHCH3), 4.60 /d,
Jˆ14.7 Hz, 1 H, CH2Ph), 4.77 /d, Jˆ14.7 Hz, 1 H,
CH2Ph), 6.52 /s, 1 H, NCHO), 7.14±7.21 /m, 2 H, arom.),
7.25±7.43 /m, 8 H, arom.).
7c /Rfˆ0.55): Pale yellow oil, yield 158 mg /38%).
[a]20ˆ28.0 /cˆ0.18, CH2Cl2). C19H18N2O2S /338.4). MS
/EI): m/z /%)ˆ338 /M, 72), 105 /PhCO, 100). IR /®lm):
nˆ1686 /s, CˆO), 1494 /s, amide IINCˆS), 734 /m),
Ä
1
695 cm21 /m). H NMR /300 MHz, CDCl3): d /ppm)ˆ
/b) Reaction of 5a with 0.5 molar equivalents of Lawesson
reagent. A mixture of 5a /475 mg, 1.41 mmol), Lawesson
reagent /283 mg, 0.70 mmol) and THF abs. /20 mL) was
heated to re¯ux for 16 h. Work-up and puri®cation were
performed as described under a) 7a /Rfˆ0.49) pale yellow
solid, m.p. 161±1648C, yield 426 mg /86%).
1.51 /d, Jˆ6.0 Hz, 3 H, CHCH3), 4.07 /d, Jˆ9.2 Hz, 1 H,
COCH), 4.52 /dq, Jˆ9.2/5.9 Hz, 1 H, CHCH3), 4.69 /d,
Jˆ17.1 Hz, 1 H, CSCH2), 4.84 /d, Jˆ17.1 Hz, 1 H,
CSCH2), 6.53 /s, 1 H, NCHO), 7.15±7.43 /m, 10 H, arom.).
4.1.4. *1R)-1-[*2R)-1,4-Dibenzylpiperazin-2-yl]ethan-1-
ol *8).2 A solution of LiAlH4 /1 M in Et2O, 1.7 mL,
1.7 mmol) was added to a solution of 6b /63 mg,
0.17 mmol) in THF /25 mL) and the reaction mixture was
heated to re¯ux for 16 h. H2O /0.5 mL) and 3 N NaOH
/0.3 mL) were cautiously added and the mixture was heated
to re¯ux for 30 min. The precipitate was separated by ®l-
tration, the ®ltrate was concentrated in vacuo, the residue
was dissolved in ethyl acetate and the organic layer was
washed with 2N NaOH /2 x) and a saturated solution of
NaCl. The organic layer was dried /MgSO4), evaporated
in vacuo and the residue was puri®ed by fc /3 cm, petroleum
ether/ethyl acetate 1: 2, 20 mL, Rfˆ0.26). Pale yellow oil,
yield 40 mg /76%). Analytical and spectroscopic data see
ref. 2.
4.1.2. *1R,3S,8aS)-7-Benzyl-1-methyl-3-phenyl-1,6,7,8a-
tetrahydro[1,3]oxazolo[3,4-a]pyrazine-5,8-dithione *6b)
and *1R,3S,8aS)-7-Benzyl-1-methyl-3-phenyl-5-thioxo-
1,6,7,8a-tetrahydro[1,3]oxazolo[3,4-a]-pyrazin-8*5H)-one
*7b). As described for the synthesis of 6a/7a under /a) a
mixture of 5b2 /400 mg, 1.19 mmol), Lawesson reagent
/577 mg, 1.43 mmol) and THF abs. /50 mL) was heated to
re¯ux for 24 h. The residue was puri®ed by fc /2 cm, petro-
leum ether/ethyl acetate 3: 1, 15 mL).
6b: /Rfˆ0.75): Colorless oil, yield 164 mg /37%). [a]20ˆ
21.11 /cˆ0.21, CH2Cl2). C20H20N2OS2 /368.5) calcd. C
65.2 H 5.47 N 7.60 found C 65.3 H 5.49 N 7.52. MS /EI):
m/z /%)ˆ368 /M, 70), 335 /M-HS, 100). IR /®lm): nˆ1492
Ä
/s, amide IINCˆS), 696 cm21 /m). 1H NMR /400 MHz,
CDCl3): d /ppm)ˆ1.80 /d, Jˆ6.0 Hz, 3 H, CHCH3), 4.19±
4.22 /m, 2 H, CSCH and CSCH2), 4.42 /d, Jˆ16.7 Hz, 1 H,
CSCH2), 4.49 /dq, Jˆ8.2, 5.9 Hz, 1 H, CHCH3), 4.80 /d,
Jˆ14.1 Hz, 1 H, CH2Ph), 5.63 /d, Jˆ14.5 Hz, 1 H, CH2Ph),
6.21 /s, 1 H, NCHO), 7.26±7.33 /m, 10 H, arom.).
4.1.5. *1R,3R,8aR)-7-Benzyl-1-methyl-3-phenyl-1,5,6,7,
8,8a-hexahydro[1,3]oxazolo[3,4-a]-pyrazine *9). Ethanol
/10 mL) was added to a suspension of Raney Nickel
/1.5 g in water). The solvent was decanted and ethanol
/10 mL) was added. Then, a solution of 6a /175 mg,
0.48 mmol) in ethanol /15 mL) was added and the suspen-
sion was stirred at room temperature under an atmosphere of
hydrogen /1.3 bar) for 16 h. The suspension was ®ltered, the
®ltrate was concentrated in vacuo and the residue was
puri®ed by fc /2 cm, petroleum ether/ethyl acetate 2: 1,
10 mL, Rfˆ0.38). Pale yellow oil, yield 40 mg /27%).
[a]20ˆ135.2 /cˆ0.78, CH2Cl2). C20H24N2O /308.4). MS
/EI): m/z /%)ˆ308 /M, 10), 91 /PhCH2, 100). IR /®lm):
7b /Rfˆ0.55): Colorless oil, yield 250 mg /60%). [a]20ˆ
237.1 /cˆ0.81, CH2Cl2). C20H20N2O2S /352.5). MS /EI):
m/z /%)ˆ352 /M, 60), 335 /M-HS, 100). IR /®lm): nˆ1669
Ä
/s, CˆO), 1494 /s, amide IINCˆS), 736 /s), 699 cm21 /s). 1H
NMR /300 MHz, CDCl3): d /ppm)ˆ1.64 /d, Jˆ5.9 Hz, 3 H,
CHCH3), 4.04 /d, Jˆ9.0 Hz, 1 H, COCH), 4.21±4.32 /m, 4
H, CHCH3, CSCH2 and CH2Ph), 4.84 /d, Jˆ14.5 Hz, 1 H,
CH2Ph), 6.35 /s, 1 H, NCHO), 7.14±7.21 /m, 2 H, arom.),
7.25±7.43 /m, 8 H, arom.).
nˆ3030 /w, CHarom.), 2931 /m, CHalkyl), 2811 /m, CHalkyl),
Ä
741 /m), 699 cm21 /s). H NMR /300 MHz, CDCl3): d
1
/ppm)ˆ1.20 /d, Jˆ5.9 Hz, 3 H, CHCH3), 2.10 /ªtº, Jˆ
9.5 Hz, 1 H, 8-H), 2.18 /dd, Jˆ10.3/2.6 Hz, 1 H, 6-H),
2.26 /td, Jˆ10.3/2.7 Hz, 1 H, 5-H), 2.39 /td, Jˆ9.0/
2.6 Hz, 1 H, 8a-H), 2.53 /dt, Jˆ9.8/2.7 Hz, 1 H, 5-H),
2.67 /d broad, Jˆ10.7 Hz, 1 H, 6-H), 2.88 /d broad,
Jˆ10.1 Hz, 1 H, 8-H), 3.55 /s, 2 H, CH2Ph), 3.94 /dq,
Jˆ8.8/6.0 Hz, 1 H, CHCH3), 4.76 /s, 1 H, NCHO),
7.18±7.32 /m, 8 H, arom.), 7.36±7.43 /m, 2 H, arom.).
13C NMR /75.4 MHz, CDCl3): d /ppm)ˆ18.2 /1 C,
CHCH3), 46.1 /1 C, C-5), 51.9 /1 C, C-6), 53.7 /1 C,
C-8), 62.8 /1 C, CH2Ph), 68.1 /1 C, C-8a), 75.8 /1 C,
CHCH3), 95.4 /1 C, NCHO), 127.2 /1 C, arom. CH),
127.9 /2 C, arom. CH), 128.3 /4 C, arom. C), 128.9 /1 C,
arom. CH), 129.1 /2 C, arom. CH), 13.9 /1 C, arom. C), /1
C, arom. C).
4.1.3. *1R,3R,8aS)-1-Methyl-3,7-diphenyl-1,6,7,8a-tetra-
hydro[1,3]oxazolo[3,4-a]pyrazine-5,8-dithione *6c) and
*1R,3R,8aS)-1-Methyl-3,7-diphenyl-5-thioxo-1,6,7,8a-
tetrahydro[1,3]oxazolo[3,4-a]-pyrazin-8*5H)-one *7c).
As described for the synthesis of 6a/7a under a) a mixture
of 5c2 /394 mg, 1.22 mmol), Lawesson reagent /560 mg,
1.39 mmol) and THF abs. /20 mL) was heated to re¯ux
for 24 h. The residue was puri®ed by fc /4 cm, petroleum
ether/ethyl acetate 4: 1, 10 mL).
6c /Rfˆ0.75): Pale yellow solid, m.p. 1808C, yield 250 mg
/58%). [a]20ˆ2128.6 /cˆ0.86, H2Cl2). C19H18N2OS2
/354.5). MS /EI): m/z /%)ˆ354 /M, 81), 321 /M-HS,

È
S. Soukara, B. Wunsch / Tetrahedron 57 -2001) 4359±4363
4363
2. Soukara, S.; WuÈnsch, B. Synthesis 1999, 1739±1746.
4.1.6. *1R,3R,8aS)-7-Benzyl-1-methyl-3-phenyl-1,6,7,8a-
tetrahydro[1,3]oxazolo[3,4-a]pyrazin-8*5H)-one *10).
3. Jones, D. N. Comprehensive Organic Chemistry: The
Synthesis and Reactions of Organic Compounds; Pergamon
Press: Oxford, 1979; 1 ed., Vol. 3, pp 448±452.
4. Scheibye, S.; Pedersen, B. S.; Lawesson, S. O. Bull. Soc.
Chim. Belg. 1978, 87, 229±241.
As described for 9 a solution of the monothiolactam 7a
/200 mg, 0.57 mmol) in ethanol /40 mL) was hydrogenated
/1.3 bar) with the catalyst Raney Nickel /1.5 g). The product
was isolated by fc /2 cm, petroleum ether/ethyl acetate 1: 1,
10 mL, Rfˆ0.49). Pale yellow oil, yield 48 mg /26%).
[a]20ˆ252.7 /cˆ0.84, CH2Cl2). C20H22N2O2 /322.4). MS
5. Cherkasov, R. A.; Kutyrev, G. A.; Pudovlk, A. N. Tetrahedron
1985, 41, 2567±2624.
6. Cava, M. P.; Levinson, M. I. Tetrahedron 1985, 41, 5061±
5087.
/CI): m/z /%)ˆ.323 /M1H, 100). IR /®lm): nˆ1646 /s,
Ä
CˆO), 1449 /m), 736 /m), 702 cm21 /m). 1H NMR
/300 MHz, CDCl3): d /ppm)ˆ1.51 /d, Jˆ6.1 Hz, 3 H,
CHCH3), 2.22 /dt, Jˆ11.5/3.5 Hz, 1 H, 5-H), 2.46 /td, Jˆ
11.2/3.7 Hz, 1 H, 5-H), 2.95 /dt, Jˆ12.2/3.3 Hz, 1 H, 6-H),
3.27 /td, Jˆ12.0/3.6 Hz, 1 H, 6-H), 3.59 /d, Jˆ8.1 Hz, 1 H,
8a-H), 4.31 /dq, Jˆ8.3/6.1 Hz, 1 H, CHCH3), 4.47 /d, Jˆ
14.7 Hz, 1 H, CH2Ph), 4.58 /d, Jˆ14.7 Hz, 1 H, CH2Ph),
5.47 /s, 1 H, NCHO), 7.12±7.32 /m, 8 H, arom.), 7.39 /dd,
Jˆ7.6/1.5 Hz, 2 H, arom.).
7. Hesse, M.; Meier, H.; Zeeh, B. Spektroskopische Methoden in
der organischen Chemie; Georg Thieme Verlag: Stuttgart,
1995; 5 ed., pp 29±70.
8. Hurd, R. N.; De LaMater, G. Chem Rev. 1961, 61, 45±86.
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Acknowledgements
This work was ®nancially supported by the Deutsche
Forschungsgemeinschaft and the Fonds der Chemischen
Industrie. Thanks are also due to the Degussa AG for
donation of chemicals.
13. Falorni, M.; Porcheddu, A.; Giacomelli, G. Tetrahedron:
Asymmetry 1996, 7, 1999±2005.
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