Synthesis of 1,4-diazines by ring expansion of 1,3-diazines

Article abstract of DOI:10.1021/jo026756t

Fully saturated piperazin-3-one and quinoxalin-3-one derivatives were prepared by reactions of 2-anilino-2-ethoxy-3-oxothiobutanoic acid anilide with aliphatic 1,2-diamines. An unusual ring expansion of the intermediate 1,3-diazines leads to 1,4-diazines.

Full text of DOI:10.1021/jo026756t

Syn th esis of 1,4-Dia zin es by Rin g Exp a n sion of 1,3-Dia zin es
Barbara Zaleska,*,† Robert Socha,† Marcin Karelus,† Edward Szneler,†
J acek Grochowski,‡ and Paweł Serda‡
Department of Organic Chemistry, J agiellonian University, Regional Laboratory of Physicochemical
Analyses and Structural Research, ul. Ingardena 3, PL 30-060 Krako´w, Poland
zaleska@chemia.uj.edu.pl
Received November 23, 2002
Fully saturated piperazin-3-one and quinoxalin-3-one derivatives were prepared by reactions of
2-anilino-2-ethoxy-3-oxothiobutanoic acid anilide with aliphatic 1,2-diamines. An unusual ring
expansion of the intermediate 1,3-diazines leads to 1,4-diazines. Moreover, quinoxalin-3-one
derivatives from chiral trans-1,2-diaminocyclohexane were obtained with diastereoselectivity >95%.
In tr od u ction
Resu lts a n d Discu sion
We now wish to report the efficient synthesis of
piperazin-3-one and quinoxalin-3-one derivatives by novel
ring expansion of the heterocyclic five-membered rings
of 1,3-diazine (imidazolidine) to six-membered rings of
1,4-diazine (piperazine).
The piperazinone derivatives are a well-known class
of farnesyl transferase inhibitors1-3 that show antitumor
activity. They exemplify the new kind of biologically
active compounds such as tachykinin inhibitors4-6 that
are useful in the treatment of a variety of human
diseases, including asthma and bronchitis. Piperazinone
derivatives exhibit activity on the central nervous
system,7-9 and have been used as potassium channels
openers.10 Some derivatives of this type have significant
industrial applications, such as antioxidants for plas-
tics11-13 and saturated quinoxaline derivatives used in
the photographic process.14
Studies15,16 on the synthesis of heterocyclic systems
obtained in the reactions of 3-oxothiobutanoic acid de-
rivatives with various diamines have been our subject
of interest. The method based on the binucleophilic attack
of an appropriate diamine on C-2 of 2-anilino-2-ethoxy-
3-oxothiobutanoic acid anilide 1 with ring closure of
heterocyclic systems is particularly interesting. Recently,
we have found that good leaving groups at C-2 of
compounds 1 offer entry17 to formation of six- and seven-
membered rings, by the treatment with aliphatic 1,3- and
1,4-diamines, respectively. We have reported17 a novel
and convenient route to synthesize zwitterionic deriva-
tives 3 of saturated pyrimidinylium and 1,3-diazepin-
ylium derivatives (Scheme 1).
† Department of Organic Chemistry.
‡ J agiellonian University.
(1) Dinsmore, C. J .; Hutchinson, J . H.; Williams, T. M. PCT Int.
Appl. WO 99 09,985 (Cl. A61K31/495), Mar 4, 1999; GB Appl. 98/975,
J an 16, 1998.
(2) Baudoin, B.; Dereu, N.; El-Ahmad, Y.; J imonet, P.; Le Brun, A.
PCT Int. Appl. WO 99 41,242 (Cl. C07D241/08), Aug 19, 1999; U.S.
Appl. PV 81,602, Apr 14, 1998.
This heterocyclization process, by binucleophilic attack
of appropriate aliphatic 1,3- or 1,4-diamines on C-2 of
2-anilino-2-ethoxy-3-oxothiobutanoic acid anilides, fol-
lowed by novel sigmatropic rearrangement of the inter-
mediate 2 leads to zwitterionic compounds 3 (Scheme 1).
X-ray analysis17 of compound 3 indicated that stereo-
electronic stabilization of diaminocarbenium ions at
position 2 of saturated pyrimidine 3 is most favorable in
six-membered systems (sofa conformation) as well as in
the seven-membered 1,3-diazepine ring. Analogous zwit-
terionic derivatives of the five-membered imidazolidine
system 4 with aliphatic 1,2-diamine were not obtained.
Probably anything smaller than a six-membered ring
implies a different pathway of reaction.
(3) Anthony, N. J .; Ciccarone, T. M.; Dinsmore, C. J .; Gomez, R. P.;
Williams, T. M.; Hartman, G. D. U.S. 5,856,326 (Cl. 514-252; A61 K31/
495), J an 5, 1999; U.S. Appl. 470,690, J un 6, 1995.
(4) Burkholder, T. P.; Kudlacz, M. E.; Le Tieu-Binh PCT Int. Appl.
WO 96 28,441 (Cl. C07D403/06), Sep 19, 1996; U.S. Appl. 404,788, Mar
15, 1995.
(5) Matsuo, M.; Hagiwara, D.; Miyake, H. PCT Int. Appl. WO 96
37,488 (Cl. C07D403/06), Nov 28, 1996; GB Appl 95/10,600, May 25,
1995.
(6) Burkholder, T. P.; Le Tieu-Binh; Kudlacz, E. M. PCT Int. Appl.
WO 96 32,385 (Cl. C07D241/04), Oct 17, 1996; U.S. Appl. 421,719, Apr
13, 1995.
(7) Farmitalia, C. E. J pn. Kokai Tokkyo Koho J P 61,167,686
[86,167,686] (Cl. C07D457/02), J ul 29, 1986; GB Appl. 85/1,078, J an
16, 1985.
(8) Schoenafinger, K.; Beyerle, R.; Schindler, W. Eur. Pat. Appl.
3,817,198, May 20, 1988.
(9) Lumma, W. C.; Saari, W. S. U.S. 4,163,849 (Cl. 544-357; A61
K31/495), Aug 07, 1979; Appl. 887,693, Mar 17, 1978.
(10) Shiozawa, A.; Inubushi, A.; Narita, K.; Shimada, K.; Hosono,
M. J pn. Kokai Tokkyo Koho J P 08 27,154 [9627,154] (Cl. C07D491/
052), J an 30, 1996; Appl. 94/198,080, J ul 20, 1994.
(11) Kosinski, L.; Raymond E. Eur. Pat. Appl. EP 448,037 (Cl.
C08K5/3492), Sep 25, 1991; U.S. Appl. 495,665, Mar 19, 1990.
(12) J ennings, E. Can. Pat. Appl. CA 2,019,285 (Cl. C08L47/00), Dec
21, 1990; U.S. Appl. 369,573, J un 21, 1989.
(14) Hayakawa, H.; Morimoto, K.; Fujimoto, H. J pn. Kokai Tokkyo,
Koho J P 06,148,840 [94,148,840] (Cl. G03C7/407), May 27, 1994; Appl.
92/293,515, Oct 30, 1992.
(15) Zaleska, B.; Socha, R.; Ciechanowicz-Rutkowska, M.; Pilati, T.
Monatsh. Chem. 2000, 131, 1151-1160.
(16) Zaleska, B.; Socha, R. Monatsh. Chem. 2000, 131, 1061-1066.
(17) Zaleska, B.; Bazanek, T.; Socha, R.; Karelus, M.; Grochowski,
J .; Serda, P. J . Org. Chem. 2002, 67, 4526-4529.
(13) Kletecka, G.; Lai, J . T.; Son, P. N. U.S. 5,098,944 (Cl. 524-100;
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10.1021/jo026756t CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/21/2003
2334
J . Org. Chem. 2003, 68, 2334-2337

Synthesis of 1,4-Diazines
SCHEME 1
SCHEME 2
Surprisingly, the reactions of 2-anilino-2-ethoxy-3-
oxothiobutanoic acid anilide 1 with aliphatic 1,2-diamines
led to unexpected 1,4-diazine derivatives 5 (Scheme 1).
The X-ray analysis of product 5b confirmed the general
structure of the molecules. Their isolation indicated a
different mechanism of formation than with aliphatic 1,3-
and 1,4-diamines or with aromatic 1,2-diamines17 (namely
attack on C-2 and C-3 of 1).
confirms the presence of the substituent at position N-1
of piperazine 5b. Moreover the signal at δH 11.22-12.10
ppm confirms the presence of a thioanilide -NHCS-
fragment at C-2 of piperazines 5a -c. A signal at δH 8.50-
9.00 ppm, typical of the two equivalent polar NH groups
of heterocyclic systems of zwitterionic derivatives 3, was
not observed. The 13C NMR spectra also confirm that the
heterocyclization reaction of 1 with aliphatic 1,2-diamines
gave piperazine derivatives 5. A significant change in the
electron density of the thiocarbonyl carbon atom is
reflected in its chemical shift, δC 200.10-201.62 ppm in
5, whereas the value of δCS for zwitterionic compounds 3
is in the range of 187.42-189.19 ppm.
The results presented above indicate the possibility
that reaction of 2-anilino-2-ethoxy-3-oxothiobutanoic acid
anilide 1a -d with trans-1,2-diaminocyclohexane could
have given quinoxaline derivatives rather than previ-
ously reported16 perhydrobenzimidazolidine derivatives
6 (Scheme 2). We have reinvestigated the products of
these reactions. The NMR data of compounds 7a -d
indicated the presence of the quinoxaline system. In
support of this hypothesis, we have obtained S-alkylated
product 9a . Quinoxaline derivative 7a treated with trans-
1,2-dibromocyclohexane in DMF allows one to obtain,
through intermediate 8, the crystalline form of one of two
diastereoisomeric forms of compound 9a (R-cyclohexenyl)
(Scheme 2).
Crystals of 9a have been subjected to X-ray diffraction
study. Compound 9a , with empirical formula C22H29N3-
OS and molecular weight 383.54, crystallized in a triclinic
crystal system with space group P1h. The diffraction
experiment was carried out on a sample 0.25 × 0.15 ×
0.1 mm3 in size, at room temperature, using a Kappa
CCD diffractometer with Mo KR radiation. The unit cell
parameters were determined as a ) 9.4700(2) Å, b )
9.7190(2) Å, c ) 12.9690(3) Å, R ) 71.2330(10)°, â )
75.7190(10)°, γ ) 68.7990(10)°, cell volume 1042.15(4) Å3,
and Z ) 2. A total of 10828 reflections were collected in
the θ range 3.07 to 31.98° and merged to give 7165
independent reflections with R(int) ) 0.0214. The struc-
ture was solved with SHELXS97 and refined with the
full-matrix least-squares method against F2 with the
SHELXL97 program system. Final discrepancy indices
Compound 5b, with empirical formula C14H19N3OS and
molecular weight 277.384, crystallizes in the monoclinic
crystal system, space group P21/a. The diffraction experi-
ment was carried out on a sample 0.25 × 0.2 × 0.15 mm3
in size, at room temperature, using a Kappa CCD
diffractometer and Mo KR radiation. The unit cell
parameters were determined as a ) 13.8549(2) Å, b )
6.3197(1) Å, c ) 16.6171(4) Å, â ) 96.12(1)°, cell volume
1446.69(4) Å3, and Z ) 4. A total of 12 407 reflections
were collected up to 2θ equal 60.09° and merged to give
4205 independent reflections with R(int) ) 0.0237. The
structure was solved with SHELXS97 and refined with
the full-matrix least-squares method against F2 with the
SHELXL97 program system. Final discrepancy indices
were R1 ) 0.0441, wR2 ) 0.1275 for I > 2σ(I) and R1 )
0.0589 for all 4205 data and 249 refined parameters, with
a goodness-of-fit of 1.063. The final electron density
difference Fourier map was featureless with the largest
peak and hole equal to 0.33 and -0.28 e‚Å-3, respectively.
The six-membered heteroring has a sofa conformation
with slight distortion caused by unequal C-N bond
lengths within the ring: the bond length at the carbonyl
group is 1.34 Å, whereas the remaining bonds are longer
(about 1.46 Å). The vicinity of the carbonyl group is
planar (the sum of valence angles equal to 360.0(3)°),
while the ethyl-substituted nitrogen atom is nonplanar
with the sum of valence angles equal to 338.8(3)°. The
ethyl group orientation is periplanar with respect to the
sofa cusp (C8). The double bond CdS is rather short (1.64
Å). The intramolecular hydrogen bond N13-N9 (2.582
Å) stabilizes the value of the torsion angle N13-C2-C3-
N9 to 35.1°. The medium-strength intermolecular hydro-
gen bond N6‚‚‚O5 (2.903 Å) joins molecules into dimeric
forms.
1
The H and 13C NMR and mass spectra of compounds
5a -c were consistent with the structure determined by
1
X-ray diffraction of compound 5b. The H NMR spectra
of derivatives 5 show signals different from those of
zwitterionic compounds 3. Compounds 5a ,c exhibit two
separate NH signals from the heterocyclic system (δH
3.44-3.92 and 6.21-6.56 ppm), whereas 5b shows only
one signal, at 7.05 ppm, from the CONH group, which
J . Org. Chem, Vol. 68, No. 6, 2003 2335

Zaleska et al.
SCHEME 3
F IGURE 1.
were R1 ) 0.0455, wR2 ) 0.1026 for I > σ(I) and R1 )
0.0733, wR2 ) 0.1152 for all 7165 data and 360 refined
parameters, with a goodness-of-fit of 1.037. The final
electron density difference Fourier map was featureless
with the largest peak and hole equal to 0.304 and -0.301
e‚Å-3, respectively.
Similar to 5b, the six-membered heteroring of 9a has
a sofa conformation: the root-mean-square distance of
both rings superimposed has a value of 0.06 Å. The
hydrogen atom attached to C12 (H3) is in the trans
position with respect to the hydrogen atom attached to
C7, and in the cis position with respect to the methyl
group (C14). The relevant torsion angle, C14-C3-C12-
H3, is equal to 27.5(1)° and the cis configuration of C14
and H3 is preserved in the other molecule within the unit
cell (by symmetry operation).
The agreement between the X-ray results of 5b and
9a proves that heterocyclization with chain as well as
cyclic aliphatic 1,2-diamines, contrary to previously
published results,16 proceeds with ring expansion of the
1,3-diazine ring to a 1,4-diazine ring.
Furthermore, when chiral (R,R)- or (S,S)-trans-1,2-
diaminocyclohexane was used in heterocyclization with
2-anilino-2-ethoxy-3-oxothiobutanoic acid anilide 1a , the
final products 7a ′ and 7a ′′ were isolated as single
diastereoisomers (Figure 1).
azolidine). This resulting intermediate 4 (Scheme 1) or
6 (Scheme 3) with sterically congested C-2 undergoes
sigmatropic rearrangement with enlargement of the five-
membered imidazolidine ring to the six-membered pip-
erazine ring. Moreover, when a chiral 1,2-diamine was
used, migration of the methylide group was stereo-
controlled.
Con clu sion s
We have developed a simple and efficient route to
piperazin-3-ones and fused 1,4-diazines, such as quinoxa-
lin-3-ones. Novel rearrangement following heterocycliza-
tions with chiral trans-1,2-diaminocyclohexane demon-
strates the concept of using 2-anilino-2-ethoxy-3-oxo-
thiobutanoic acid anilide 1 as an excellent synthon for
construction of optically active heterocyclic systems. The
chiral quinoxaline derivative 7 has potential application
as a chiral auxiliary.
Exp er im en ta l Section
The position C-2 of the (4aR,8aR)- or (4aS,8aS)-2-
phenylthiocarbamoyl-2-methyl-trans-perhydroquinoxalin-
3-one 7a ′ and 7a ′′ becomes a new stereogenic center
(Figure 1). The relative configuration at positions C-2 and
C-8a was determined by NOE experiment: when the
peak of the CH3 group was irradiated, a significant NOE
effect was observed for 8aH. These results prove the cis
orientation of 8aH and the CH3 group and are in
agreement with X-ray analysis, confirming the fact that
chiral diamine reagents such as 1,2-trans-diaminocyclo-
hexane control the diasteroselectivity of the rearrange-
ment of the imidazolidine ring to the piperazine system
(Scheme 3).
Melting points were determined on a digital melting point
apparatus and are uncorrected. Column chromatographic
separations were performed with silica gel 60 (35-70 mesh
ASTM). Centrifugal chromatography was performed with a 2
mm sorbent layer (silica gel 60 PF-254), with visualization by
UV light. The IR spectra were obtained at room temperature.
1H and 13C NMR spectra were recorded with TMS as internal
standard. Chemical shifts are reported in ppm downfield from
TMS.
Gen er a l P r oced u r e for th e P r ep a r a tion of 5a , 5b, a n d
5c. A solution of 4.58 mmol of appropriate aliphatic 1,2-
diamine and 3.06 mmol of 2-anilino-2-ethoxy-3-oxothiobutanoic
acid anilide 1 in 20 mL of anhydrous ethanol was refluxed for
5 min. Removal of the solvent gave a dark residue that was
purified by crystallization from ethanol.
Additional measurement of NMR spectra of optically
active compound 7a ′ with the shift reagent, tris[3-(tri-
fluoromethylhydroxymethylene)-d-camphorato]europi-
um(III), Eu(tfc)3, was carried out. For all signals of the
complex, split lines from the other enantiomer could not
be observed above the noise level. It was deduced that
enantiomeric purity is better than 95%. Remarkably, the
ring expansion can occur with high levels of diastereo-
selectivity, leading exclusively to one of the two possible
diastereoisomers of the quinoxaline derivatives.
We propose the following mechanism for ring expan-
sion of intermediate 1,3-diazine derivatives. Initially,
binucleophilic attack of the appropriate aliphatic 1,2-
diamine on the electrophilic C-2 center of compound 1
leads to the five-membered ring of a 1,3-diazine (imid-
2-P h en ylth ioca r ba m oyl-2-m eth yl-p ip er a zin -3-on e (5a ).
Yield 45%; colorless crystals; mp 135 °C; IR (KBr) 3293, 3174,
1
1661 cm-1; H NMR (CDCl3) δ 11.44 (s, 1H), 7.81 (d, J ) 8.7
Hz, 2H), 7.40 (t, J ) 7.5 Hz, 2H), 7.26 (t, J ) 6.0 Hz, 1H), 6.56
(s, 1H), 3.9 (s, 1H), AA′BB′ spin system: 3.56-3.62 (m, 1H),
3.19-3.23 (m, 1H), 2.89-2.96 (m, 2H), 1.65 (s, 3H); 13C NMR
(CDCl3) δ 201.6, 173.1, 139.1, 128.8, 126.7, 122.9, 68.3, 42.9,
39.4, 30.8. Anal. Calcd for C12H15N3OS (249.33): C, 57.80; H,
6.06; N, 16.85; S, 12.86. Found: C, 57.46; H, 6.01; N, 16.59; S,
12.76. EIMS: m/z (%) 136 (PhNHCS, 40), 113 (M+ - PhNHCS,
38), 85.1 (16), 77 (12).
1-N-Eth yl-2-p h en ylth ioca r ba m oyl-2-m eth yl-p ip er a zin -
3-on e (5b). Yield 60%; yellow crystals; mp 187 °C; IR (KBr)
3299, 3186, 1659 cm-1; 1H NMR (CDCl3) δ 11.22 (s, 1H), 7.79
(d, J ) 7.9 Hz, 2H), 7.38 (t, J ) 7.6 Hz, 2H), 7.22 (t, J ) 7.5
Hz, 1H), 7.05 (s, 1H), 3.57 (m, 1H), 3.36 (m, 1H), 3.12 (d, 1H),
2336 J . Org. Chem., Vol. 68, No. 6, 2003

Synthesis of 1,4-Diazines
2.80 (m, 1H), 2.54, 2.41 (qq, 2 H, J ) 6.4 Hz), 1.74 (s, 3H),
1.56 (t, 3 H, J ) 6.8 Hz); 13C NMR (CDCl3) δ 200.5, 169.8,
138.8, 128.9, 126.3, 122.6, 75.7, 44.5, 42.1, 41.5, 16.3, 13.9;
Anal. Calcd for C14H19N3OS (277.39): C, 60.62; H, 6.90; N,
15.14; S, 11.56. Found: C, 60.66; H, 7.04; N, 15.14; S, 11.49.
EIMS: m/z (%) 141 (M+ - PhNHCS, 100), 135 (PhNCS, 2.3),
113 (10.95), 42 (8).
(()-2-(4-Meth ylp h en ylth ioca r ba m oyl)-2-m eth yl-tr a n s-
per h ydr oqu in oxalin -3-on e (7b). Yield 77%; colorless needles;
1
mp 223 °C; IR (KBr) 3366, 3190, 1685, 1112 cm-1; H NMR
(CDCl3) δ 11.76 (s, 1H), 7.65 (d, J ) 8.3 Hz), 7.20 (d, 2H, J )
8.2 Hz), 6.28 (s, 1H), 3.01 (m, 1H), 2.96 (d, J ) 6.8 Hz, 1H),
2.74 (dt, 1H, J 1 ) 3.7 Hz, J 2 ) 9.8 Hz), 2.36 (s, 3H), 2.01 (m,
1H), 1.87 (m, 1H), 1.82 (m, 1H), 1.77 (s, 3H), 1.76 (m, 1H),
1.35 (t, 2H, J ) 10.8 Hz), 1.27 (t, 2H, J ) 8.8 Hz); 13C NMR
(CDCl3) δ 200.3, 172.5, 136.5, 136.3, 129.4, 122.7, 68.1, 56.7,
56.2, 31.6, 31.0, 24.6, 23.6, 29.1, 21.1. Anal. Calcd for C17H23N3-
OS (317.44): C, 64.35; H, 7.20; N, 13.24; S, 10.10. Found: C,
64.25; H, 6.90; N, 13.47; S, 9.90.
2-P h e n ylt h ioca r b a m oyl-2,6-d im e t h yl-p ip e r a zin -3-
on e (5c). Yield 51%; colorless crystals; mp 201 °C; IR (KBr)
3218, 3205, 1681, 1164 cm-1; 1H NMR (CDCl3) δ 12.1 (s, 1H),
7.78 (d, J ) 7.7 Hz, 2H), 7.40 (t, J ) 7.6 Hz, 2H), 7.26 (t, J )
7.5 Hz, 1H), 6.22 (s, 1H), 3.44 (s, 1H), 3.27 (m, 1H), 3.10 (m,
2H), 1.79 (s, 3H), 1.27 (d, J ) 6.3 Hz, 2H); 13C NMR (CDCl3)
δ 200.1, 173.1, 138.9, 128.8, 126.7, 126.3, 123.1, 66.3, 49.1, 45.1,
29.6, 19.3. Anal. Calcd for C13H17N3OS (263.36): C, 53.28; H,
6.50; N, 15.95; S, 12.17. Found: C, 53.07; H, 6.62; N, 15.88; S,
12.48. EIMS: m/z (%) 136 (PhNHCS, 41), 128 (M+ - PhNHCS,
100), 99.1 (11), 77 (14), 28 (3).
(()-2-(4-Meth oxyph en ylth iocar bam oyl)-2-m eth yl-tr a n s-
per h ydr oqu in oxalin -3-on e (7c). Yield 25%; colorless needles;
1
mp 222 °C; IR (KBr) 3362, 3193, 1674, 1110 cm-1; H NMR
(CDCl3) δ 11.71 (s, 1H), 7.67 (d, 2H, J 1 ) 8.9 Hz), 6.91 (d, 2H,
J 1 ) 8.9 Hz), 6.03 (s, 1H), 3.82 (s, 3H), 3.02 (m, 1H), 2.96 (d,
J ) 6.8 Hz, 1H), 2.75 (dt, 1H, J 1 ) 3.8 Hz, J 2 ) 9.8 Hz), 2.01
(m, 1H), 1.86 (m, 1H), 1.83 (m, 1H), 1.78 (s, 3H), 1.77 (m, 1H),
1.37 (t, 2H, J ) 10.7 Hz), 1.28 (t, 2H, J ) 11.6 Hz); 13C NMR
(CDCl3) δ 200.1, 172.5, 157.9, 131.9, 124.5, 114.0, 67.9, 56.9,
56.1, 32.1, 31.5, 24.6, 23.7, 55.5, 29.1. Anal. Calcd for
Gen er a l P r oced u r e for th e P r ep a r a tion of 7a -d .16
A
solution of 0.55 mL of trans-(()-1,2-diaminocyclohexane (4.58
mmol) and 3.06 mmol of the corresponding 2-anilino-2-ethoxy-
3-oxothiobutanoic acid anilide 1a -d in 20 mL of anhydrous
ethanol was refluxed for 5 min. Removal of the solvent gave a
dark residue that was purified by crystallization from benzene.
(()-2-P h en ylth ioca r ba m oyl-2-m eth yl-tr a n s-p er h yd r o-
qu in oxa lin -3-on e (7a ). Yield 54%; colorless needles; mp 220
°C; IR (KBr) 3366, 3177, 1684, 1120 cm-1; 1H NMR (CDCl3) δ
11.86 (s, 1H), 7.81 (d, 2H, J ) 7.7 Hz), 7.41 (t, 2H, J ) 7.8
Hz), 7.25 (t, 2H, J ) 7.5 Hz), 6.08 (s, 1H), 3.03 (m, 1H), 2.95
(d, J ) 6.78 Hz, 1H), 2.75 (dt, 1H, J 1 ) 3.8 Hz, J 2 ) 10.2 Hz),
2.01 (m, 1H), 1.87 (m, 1H), 1.86 (m, 1H), 1.78 (s, 3H); 1.77 (m,
1H), 1.38 (t, 2H, J ) 10.3 Hz), 1.28 (t, 2H, J ) 11.1 Hz); 13C
NMR (CDCl3) δ 200.5, 172.4, 138.8, 128.9, 126.6, 122.3, 68.2,
56.6, 56.3, 31.5, 31.0, 24.6, 23.6, 29.1. Anal. Calcd for C16H21N3-
OS (303.42): C, 63.36; H, 6.90; N, 13.86; S, 10.41. Found: C,
63.01; H, 7.41; N, 14.01; S, 10.29. EIMS: m/z (%) 304 (MH+,
1), 167 (M+ - PhNHCS, 100), 135 (PhNCS, 4), 98 (8), 41 (9).
(+)-(2R,4a R,8a R)-2-P h en ylt h ioca r b a m oyl-2-m et h yl-
tr a n s-p er h yd r oqu in oxa lin -3-on e (7a ′). Yield 74%; mp 186
°C; [R]546 +160 (c 1, ethanol).
C
17H23N3O2S (333.44): C, 61.26; H, 6.90; N, 12.60; S, 9.60.
Found: C, 61.41; H, 7.04; N, 12.60; S, 9.21.
(()-2-(4-Ch lor op h en ylth ioca r ba m oyl)-2-m eth yl-tr a n s-
per h ydr oqu in oxalin -3-on e (7d). Yield 55%; colorless needles;
1
mp 223 °C; IR (KBr) 3362, 3180, 1687, 1113 cm-1; H NMR
(CDCl3) δ 11.94 (s, 1H), 7.77 (d, 2H, J ) 8.8 Hz), 7.36 (d, 2H,
J ) 8.7 Hz), 6.29 (s, 1H), 3.02 (m, 1H), 2.92 (d, J ) 6.0 Hz,
1H), 2.75 (dt, 1H, J 1 ) 3.8 Hz, J 2 ) 10.4 Hz), 2.01 (m, 1H),
1.87 (m, 1H), 1.85 (m, 1H), 1.77 (s, 3H), 1.76 (m, 1H), 1.38 (t,
2H, J ) 8.3 Hz), 1.28 (t, 2H, J ) 9.3 Hz); 13C NMR (CDCl3) δ
200.9, 172.4, 137.3, 131.6, 128.9, 124.1, 68.1, 56.9, 56.1, 31.5,
30.9, 24.6, 23.6, 29.3. Anal. Calcd for C16H20N3OSCl (337.86):
C, 56.9; H, 5.90; N, 12.44; S, 9.48. Found: C, 57.4; H, 6.14; N,
12.45; S, 9.62.
P r oced u r e for th e P r ep a r a tion of 9a . To a solution of 1
g (3.3 mmol) of 2-phenythiocarbamoyl-2-methyl-trans-per-
hydroquinoxalin-3-one 7a in 25 mL of anhydrous DMF was
added 0.237 g (9.87 mmol) of sodium hydride at 0 °C with
stirring. The solution was stirred for an hour and then 0.44
mL (3.3 mmol) of trans-1,2-dibromocyclohexane was added.
The resulting mixture was stirred for 24 h at room tempera-
ture. Removal of the solvent gave a residue that was purified
by column chromatography eluting with a gradient solvent of
CHCl3 through 30% CH3COCH3/CHCl3. The last fraction gave
a residue that was purified by centrifugal chromatography
eluting with a gradient solvent of CHCl3 through 30% CH3-
COCH3/CHCl3. The last fraction was concentrated giving a
residue that was purified by crystallization from ethanol.
(-)-(2S ,4a S ,8a S )-2-P h e n ylt h ioca r b a m oyl-2-m e t h yl-
tr a n s-p er h yd r oqu in oxa lin -3-on e (7a ′′). Yield 78%; mp 186
°C; [R]546 -160 (c 1, ethanol).
The shift reagent tris[3-(trifluoromethylhydroxymethylene)-
d-camphorato]europium(III), Eu(tfc)3, was used. Eu(tfc)3 was
chosen for its solubility in CDCl3, good Lewis acid properties,
and nice effect in similar works.18 Spectra were recorded on a
500.13 MHz (1H) or 125.76 (13C) spectrometer equipped with
a 5-mm QNP probe. Typical conditions for recording one-
dimensional spectra were as follows: spectral width 13 (1H)
or 35 kHz (13C), data point 128K or 64K words, flip angle 45°
or 30°, and pulse repetition 6 or 2 s. Resolution enhancement
was performed by using exponential or Lorentzian to Gaussian
windows for carbon and proton, respectively.
All measurements were carried out at a probe temperature
of 24.0 ( 0.1 °C and the chemical shifts were initially
referenced to the TMS (proton) and the solvent values of 77
ppm (carbon).
For the gradient method, a solution containing 0.026 mmol
of compound (+)-7a ′ or (-)-7a ′′ in 0.8 mL of CDCl3 was
prepared and the corresponding spectra (1H, 13C) were re-
corded. Then a known amount (ca. 4 mg) of shift reagent was
added to the solution and the spectra were recorded again.
This procedure was repeated several times: The ∆δ (in ppm)
values (∆δ ) δobs - δ0) were determined for F e 1 (F )
[Eu(tfc)3]/[compound]).
S-(3-Cycloh exen yl)-2-p h en ylth ioca r ba m oyl-2-m eth yl-
tr a n s-p er h yd r oqu in oxa lin -3-on e (9a ). Yield 20%; colorless
needles; mp 213 °C; IR (KBr) 3331, 3180, 1669, 1632 cm-1; 1H
NMR (CDCl3) δ 7.29 (t, 1H, J ) 7.3 Hz), 7.05 (d, 2H, J ) 8.2
Hz), 7.03 (d, 2H, J ) 6.5 Hz), 5.76 (s, 1H), 5.66 (m, 1H, J 1
)
5.1 Hz, J 2 ) 10.1 Hz), 5.25 (d, 1H, J ) 7.6 Hz), 3.26 (m, 1H),
3.05 (m, 1H), 2.75 (m, 1H), 1.73-1.81 (m, 7H), 1.72 (s, 1H),
1.28-1.48 (m, 7H); 13C NMR (CDCl3) δ 170.9, 164.1, 130.9,
125.7, 148.7, 129.0, 123.8, 118.9, 70.1, 57.3, 55.2, 39.9, 31.0,
30.8, 24.8, 23.7, 18.7, 23.9. Anal. Calcd for
C22H29N3OS
(383.55): C, 68.89; H, 7.62; N, 10.95; S, 8.36. Found: C, 68.60;
H, 7.72; N, 10.75; S, 8.40. EIMS: m/z (%) 383.2 (M+, 1), 167
(100), 149 (5), 79 (11).
Su p p or tin g In for m a tion Ava ila ble: X-ray molecular
structures, crystal data tables, and Ortep figures for 5b and
9a . This material is available free of charge via the Internet
at http://pubs.acs.org.
For all signals of the complex, split lines from other
enantiomers or its intensity were less then noise. In this case
the enantiomeric purity of compound 7a is better then 95%.
(18) Belleney, J .; Bui, C.; Carriere, F. J . Magn. Reson Chem. 1990,
28, 606.
J O026756T
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