Synthesis of (5R)-4-methyl-5-phenyl-1,3,4-oxadiazinan-2-one and some N-acyl derivatives from (R)-phenylglycine

Article abstract of DOI:10.1055/s-2005-872101

(5R)-4-Methyl-5-phenyl-1,3,4-oxadiazinan-2-one was synthesized from (R)-phenylglycine in five steps and in 65% overall yield. In addition, a convenient and practical method for N-acylation of 1,3,4-oxadiazinan-2-one directly with acids in the presence of

Full text of DOI:10.1055/s-2005-872101

2578
PAPER
Synthesis of (5R)-4-Methyl-5-phenyl-1,3,4-oxadiazinan-2-one and Some
N-Acyl Derivatives from (R)-Phenylglycine
S
ynthesis of 1,3,4-
l
O
xadia
e
zinan-2-on
s
es sandro Rodrigues,*a Paulo Roberto Olivato,*a Roberto Rittnerb
a
Conformational Analysis and Electronic Interactions Laboratory, Instituto de Química, Universidade de São Paulo, C.P. 26077,
São Paulo, SP 05513-970, Brazil
Fax +55(11)38155579; E-mail: alessand@iq.usp.br; E-mail: prolivat@iq.usp.br
b
Physical Organic Chemistry Laboratory, Chemistry Institute, State University of Campinas, C.P. 6154, Campinas, SP 13084-971, Brazil
Received 30 March 2005; revised 4 May 2005
chiral starting materials. Therefore, we present in this pa-
per the synthesis of the heterocycle 1 (Scheme 1) and a
simple method to prepare the N3-acylated-1,3,4-oxadiazi-
nan-2-ones (Scheme 2). The synthesis of heterocycle 1
Abstract: (5R)-4-Methyl-5-phenyl-1,3,4-oxadiazinan-2-one was
synthesized from (R)-phenylglycine in five steps and in 65% overall
yield. In addition, a convenient and practical method for N-acyl-
ation of 1,3,4-oxadiazinan-2-one directly with acids in the presence
of DCC and catalytic quantities of DMAP is described. The acyl- was readily performed in five steps from (R)-phenylgly-
ated products were obtained in excellent yields.
cine (3) on a multigram scale without chromatographic
purification in 65% overall yield.
Key words: (R)-phenylglycine, 1,3,4-oxadiazinan-2-ones, hetero-
cycles, acylation, carboxylic acids
The starting point was the synthesis of N-formyl-(R)-phe-
nylglycine (4), which was obtained in quantitative yield
by the treatment of (R)-phenylglycine (3)4 with formic
acid and acetic anhydride (Scheme 1).
In 1968, Trepanier and co-workers1 reported the first syn-
thesis of the 3,4,5,6-tetrahydro-2H-1,3,4-oxadiazin-2-
ones 2 as candidates for central nervous system stimulant
activity. The synthesis of substituted 1,3,4-oxadiazinan-2-
ones has attracted attention because of their promising
general application as chiral auxiliaries in asymmetric al-
dol addition reactions.2
O
O
Ph
OH
Ph
HCOOH, Ac2O
NaBH4/I2
THF
OH
H
NH
NH2
O
3
4
Heterocycles 2 (Figure 1) were synthesized by Hitchcock
and co-workers3 from (1R,2S)-ephedrine and (1S,2S)-
pseudoephedrine, which have limited utility in creating
diverse 1,3,4-oxadiazinan-2-ones, because the N4-posi-
tion is substituted with a methyl group and both the C-5
and C-6 substituents are fixed (methyl and phenyl groups,
respectively).
Ph
Ph
OH
OH
NaNO2/HCl
H2O–THF
LiAlH4
THF
N
NH
H3C
NO
O
H3C
5
6
Ph
H
OH
O
N
N
CDI
THF
N
H3C
NH2
CH3
O
O
Ph
7
1
O
3
N
1
O
3
N
H
H
2
5
2
5
1
H
R2
N
4
N
4
6
6
R1
CH3
CH3
H
Scheme 1
CH3
Ph
2
1
Compound 4 was cleanly reduced5 to N-methyl-(R)-phe-
nylglycinol (5) with NaBH4/I2 in THF in 94% yield. Com-
pound 5 was treated6 with NaNO2 in the presence of
aqueous HCl and THF to conveniently give the desired N-
methyl-N-nitrosamine (6) in 96% yield. N-Nitrosamine 6
was reduced7 with LiAlH4 in THF leading to hydrazine 7.8
Subsequent treatment9 with carbonyldiimidazole (CDI)
furnished the cyclic diazacarbamate 1 in 75% yield.
2a: R1 = H, R2 = Ph
2b: R1 = Ph, R2 = H
Figure 1 1,3,4-Oxadiazinan-2-ones (1 and 2)
We have developed another 1,3,4-oxadiazinan-2-one
framework – the (5R)-4-methyl-5-phenyl-1,3,4-oxadiazi-
nan-2-one (1) – starting from (R)-phenylglycine (3),
which can be replaced by other amino acids; these are ex-
cellent templates for the creation of new 1,3,4-oxadiazi-
nan-2-ones due to the wide range and diversity of these
DCC and DMAP are known as synthetically useful and
mild reagents for the preparation of esters and amides.10,11
This chemistry was used to prepare (in one step) the N3-
acylated 1,3,4-oxadiazinan-2-ones 8a–j using carboxylic
acids, DCC, and DMAP (cat., 5 mol%) in CH2Cl2, at room
temperature (Scheme 2). The N3-acylated products 8a–j
were obtained in excellent yields (Table 1).
SYNTHESIS 2005, No. 15, pp 2578–2582
x
x.
x
x
.
2
0
0
5
Advanced online publication: 25.07.2005
DOI: 10.1055/s-2005-872101; Art ID: M01605SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of 1,3,4-Oxadiazinan-2-ones
2579
O
O
O
NMR spectra were recorded on a Varian Unity Inova 1 and on a
Bruker DRX 500 spectrometer operating at 299.948 MHz or
500.132 MHz (1H NMR), and 75.429 MHz or 125.773 MHz (13C
NMR). 1H and 13C chemical shifts (d) are reported in ppm relative
to TMS as internal standard. Coupling constants (J) are given in Hz.
IR spectra were measured on a MB-100 Michelson-Bomem FTIR
instrument. Elemental analyses were carried out on a Perkin Elmer
2400 CHN-standard analyzer. Low resolution mass spectra were re-
corded on a SHIMADZU QP5050A GC-MS spectrometer (DB5
column, EI). Mps were measured on a Büchi melting point appara-
tus. Optical rotations were determined at 25 °C with a JASCO DIP-
370 polarimeter (1 dm cell). Column chromatography was per-
formed on Merck silica gel 60 (230–400 mesh). All reactions were
conducted with magnetic stirring in oven-dried glassware under an-
hyd N2. Solvents were purified and dried according to standard pro-
cedures. Other reagents were commercially available.
O
O
NH
N
DCC, DMAP (cat.)
CH2Cl2
O
N
N
R
HO
R
CH3
CH3
Ph
Ph
1
8a–j
Scheme 2
Table 1 Synthesis of N3-Acyl-(5R)-4-methyl-5-phenyl-1,3,4-oxa-
diazinan-2-ones 8a–j from Carboxylic Acids and 1,3,4-Oxadiazinan-
2-one 1 Using DCC and DMAP
Entry Product
RCOOH
Time (h) Yield (%)a
O
1
2
3
8a
8b
8c
2.5
90
92
90
(2R)-2-(N-Formyl)amino-2-phenylacetic Acid (4)
OH
O
Ac2O (185 mL) was added dropwise to a mixture of (R)-phenylgly-
cine (3; 40.00 g, 264 mmol) in formic acid (550 mL, 99%) at such
a rate that the temperature of the reaction mixture was maintained
between 5–15 °C. After the addition was complete the mixture was
stirred at r.t. for 1 h; iced-water (400 mL) was introduced and the
mixture was concentrated at reduced pressure to give 4 as white
crystals in 100% yield (47.41 g); mp 178.1–178.8 °C (dec.) (Lit.12
3
OH
OH
5
O
25
20
178 °C); [a]D –247.0 (c 1.00, MeOH); {Lit.12 [a]D –252.0
4
5
6
7
8
9
8d
8e
8f
12
87
85
85
90
83
90
O
(c 1.00, MeOH)}.
1H NMR (300 MHz, DMSO-d6): d = 8.92 (d, 1 H, 3J = 7.7 Hz), 8.08
(s, 1 H), 7.39–7.28 (m, 5 H), 5.39 (d, 1 H, 3J = 7.7 Hz).
Ph
Ph
OH
16
2
O
(2R)-2-(N-Methyl)amino-2-phenylethanol (5)
OH
To a stirred solution of amino acid 4 (38.00 g, 180 mmol), NaBH4
(19.38 g, 510 mmol), and anhyd THF (500 mL) cooled to 0 °C in an
ice bath, was slowly added dropwise a solution of I2 (53.85 g, 212
mmol) in THF (200 mL). Upon addition of I2 gas evolution oc-
curred, once this had ceased the flask was heated at reflux for 18 h
and then cooled to r.t.; MeOH was added cautiously until the mix-
ture became clear. After stirring for 30 min, the solvent was re-
moved by rotary evaporator leaving a white paste, which was
dissolved by the addition of KOH (20% aq, 200 mL). The resulting
solution was stirred for 1 h and extracted with CH2Cl2 (3 × 150 mL).
The organic extracts were dried over Na2SO4 and concentrated un-
der vacuum, affording 5 as a colorless liquid in 94% yield (30.15 g,
200 mmol); [a]D25 –85.5 (c 1.08, CHCl3).
O
O
OH
8g
8h
8i
20
5
O
O
S
Ph
Et
OH
OH
O
24
O
O
OH
10
8j
8
80
IR (film): 3303, 3063, 2855, 2798, 1455, 1060, 1024, 761, 702 cm–1.
O
1H NMR (300 MHz, CDCl3): d = 7.36–7.22 (m, 5 H), 3.72–3.54 (m,
3 H), 3.07 (br s, 2 H), 2.29 (s, 3 H).
Ph
OH
a Isolated yields after chromatography.
13C NMR (75 MHz, CDCl3): d = 140.31, 128.57, 127.56, 127.39,
66.68, 66.55, 34.13.
The reaction does not require rigorously dried solvents or
reagents, and eliminates the need for strong bases, such as
BuLi or LiH. In addition, arylacetic acids and conjugated
enoic acids can be employed to provide the desired N3-
acyl-oxadiazinan-2-ones free of by-products.
(2R)-2-(N-Methylnitroso)amino-2-phenylethanol (6)
To a solution of 5 (26.50 g, 175 mmol) in THF (75 mL) was added
an aq solution of HCl (3 M, 75 mL, 225 mmol) followed by the ad-
dition of NaNO2 (13.95 g, 202 mmol); the resulting mixture was
stirred for 12 h. The mixture was then diluted with a sat. aq solution
of NaHCO3 until its pH was >7. The reaction mixture was extracted
with EtOAc (4 × 100 mL), washed with a sat. solution of brine (80
mL), dried (Na2SO4), and the solvent was removed by rotary evap-
oration to give 6 as an orange oil (30.50 g, 96%); [a]D25 –4.0 (c 1.17,
CHCl3)
In conclusion, we have prepared (5R)-4-methyl-5-phenyl-
1,3,4-oxadiazinan-2-one in a five-step reaction and 65%
overall yield. In addition, the method described provides
a mild and efficient process for N3-acylation mediated by
DCC/DMAP, resulting in a large variety of N3-acylated-
oxadiazinan-2-ones and this method should be easily ex-
tend to acylations with more complex substrates. The ini-
tial reaction can also be extended to other amino acids
besides (R)-phenylglycine described in this paper.
IR (film): 3390, 3063, 3034, 2941, 2885, 1439, 1342, 1195, 1069,
1045, 704 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.39–7.23 (m, 5 H), 5.43 (dd,
3J = 9.0 Hz, 3J = 4.6 Hz, 1 H), 4.44 (dd, 2J = 12.2 Hz, 3J = 9.0 Hz, 1
Synthesis 2005, No. 15, 2578–2582 © Thieme Stuttgart · New York

2580
A. Rodrigues et al.
PAPER
H), 4.17 (dd, 2J = 12.2 Hz, 3J = 4.6 Hz, 1 H), 3.58 (s, 1 H), 2.94 (s,
3 H).
Anal. Calcd for C12H14N2O3 (234.25): C, 61.53; H, 6.02; N, 11.96.
Found: C, 61.52; H, 5.83; 12.11.
13C NMR (75 MHz, CDCl3): d = 135.47, 129.10, 128.78, 127.28,
69.87, 62.95, 31.57.
(5R)-4-Methyl-5-phenyl-3-propionyl-1,3,4-oxadiazinan-2-one
(8b)
25
Yield: 92%; white crystals; mp 103–104 °C; [a]D +36.3 (c 1.02,
CHCl3).
(5R)-4-Methyl-5-phenyl-1,3,4-oxadiazinan-2-one (1)
To a stirred suspension of LiAlH4 (20.10 g, 529 mmol) in THF (500
mL) was added dropwise a solution of 6 (30.50 g, 170 mmol) in
THF (250 mL) at r.t. The mixture was then heated at reflux for 6 h.
The cooled and stirred mixture was quenched with H2O (20 mL),
15% aq NaOH (20 mL), H2O (60 mL), filtered, dried (Na2SO4), and
the solvent was removed by rotary evaporation. This process afford-
ed 7 as a viscous yellow oil (27.65 g, 98%), which was >95% pure,
as determined by 1H NMR spectroscopy. The hydrazine 7 was di-
rectly converted into the corresponding oxadiazinone derivative 1
due to its facile decomposition. CDI (35.02 g, 216 mmol) was added
to a solution of 7 (27.65 g, 166 mmol) in THF (180 mL). The mix-
ture was stirred for 24 h at r.t., concentrated, dissolved in H2O (70
mL), and extracted with CH2Cl2 (3 × 15 mL). The organic extracts
were washed with brine (50 mL), dried (Na2SO4), and evaporated.
This process yielded a yellow solid, which was purified by recrys-
tallization (EtOAc–hexane) to give heterocycle 1 as white crystals
(23.93 g, 75%); [a]D25 –100.6 (c 1.08, CHCl3); mp 103–104 °C.
IR (CCl4): 3067, 2984, 2943, 2801, 1769, 1730, 1458, 1257, 1218,
1189 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.42–7.30 (m, 5 H), 4.82 (dd,
2J = 11.5 Hz, 3J = 5.6 Hz, 1 H), 4.66 (dd, 2J = 11.5 Hz, 3J = 7.8 Hz,
1 H), 4.35 (dd, 3J = 7.8 Hz, 3J = 5.6 Hz, 1 H), 2.85–2.59 (m, 2 H),
2.78 (s, 3 H), 1.08 (t, 3J = 7.3 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 173.70, 150.13, 135.59, 128.97,
128.58, 127.05, 67.71, 61.98, 42.61, 29.88, 8.84.
MS (EI): m/z (%) = 192 (94), 118 (22), 105 (17), 104 (100), 103
(12), 101 (20), 91 (15), 78 (15), 77 (21).
Anal. Calcd for C13H16N2O3 (248.28): C, 62.89; H, 6.50; N, 11.28.
Found: C, 63.17; H, 6.53; 11.53.
(5R)-3-(Cyclopropylcarbonyl)-4-methyl-5-phenyl-1,3,4-oxadi-
azinan-2-one (8c)
25
Yield: 90%; white crystals; mp 89–91 °C; [a]D +37.6 (c 0.96,
CHCl3).
IR (KBr): 3353, 3208, 3090, 2957, 2790, 1725, 1477, 1363, 1306,
1152, 1082, 901, 882, 749, 725, 698 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.37 (s, 1 H), 7.39–7.33 (m, 5 H),
4.55–4.42 (m, 2 H), 3.84 (dd, J = 8.1 Hz, J = 3.6 Hz, 1 H), 2.52 (s,
3 H).
IR (CCl4): 3067, 3016, 2962, 2801, 1766, 1739, 1713, 1451, 1389,
1259, 1188 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.39–7.33 (m, 5 H), 4.77 (dd,
2J = 11.5 Hz, 3J = 5.8 Hz, 1 H), 4.57 (dd, 2J = 11.5 Hz, 3J = 8.6 Hz,
1 H), 4.35 (dd, 3J = 8.6 Hz, 3J = 5.8 Hz, 1 H), 2.82 (s, 3 H), 2.59–
2.53 (m, 1 H), 1.10–1.07 (m, 2 H), 0.94–0.88 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 152.93, 135.06, 128.98, 128.72,
127.78, 68.52, 62.70, 44.00.
MS (EI): m/z (%) = 192 (36), 118 (34), 105 (18), 104 (83), 103 (19),
91 (21), 78 (27), 77 (36), 40 (100).
13C NMR (75 MHz, CDCl3): d = 174.06, 150.48, 135.79, 128.98,
128.62, 127.07, 68.17, 63.07, 43.52, 13.21, 10.41 (2 C).
Anal. Calcd for C10H12N2O2 (192.21): C, 62.49; H, 6.29; N, 14.57.
Found: C, 62.53; H, 6.43; N, 14.77.
MS (EI): m/z (%) = 192 (9), 118 (11), 104 (29), 103 (17), 78 (18),
77 (18), 69 (48), 42 (22), 41 (100), 39 (76).
N3-Acylation; General Procedure
Anal. Calcd for C14H16N2O3 (260.29): C, 64.60; H, 6.20; N, 10.76.
Found: C, 64.60; H, 6.25; N, 10.95.
To a mixture of 1,3,4-oxadiazinan-2-one (1; 500 mg, 2.60 mmol),
DMAP (16 mg, 0.13 mmol) and the corresponding carboxylic acid
(2.86 mmol) in CH2Cl2 (4 mL) at 0 °C, under a nitrogen atmo-
sphere, DCC was added in one portion (590 mg, 2.86 mmol). The
temperature of the resulting suspension was allowed to reach r.t.
Stirring was continued until no starting material was left, as con-
firmed by TLC. The dicyclohexylurea formed was filtered and the
precipitate washed with CH2Cl2 (20 mL). The filtrate was washed
with a sat. aq solution of NaHCO3 (15 mL) and dried over Na2SO4.
Filtration and evaporation yielded the crude compounds 8a–j,
which were purified by flash chromatography on silica gel (hexane–
EtOAc, 6:4).
(5R)-3-Benzoyl-4-methyl-5-phenyl-1,3,4-oxadiazinan-2-one
(8d)
25
Yield: 87%; white crystals; mp 91–92 °C; [a]D +20.0 (c 1.03,
CHCl3).
IR (CCl4): 3067, 3032, 3004, 2800, 1777, 1753, 1709, 1602, 1453,
1278, 1251 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.48–7.29 (m, 10 H), 4.95 (dd,
2J = 11.7 Hz, 3J = 5.7 Hz, 1 H), 4.75 (dd, 2J = 11.7 Hz, 3J = 7.0 Hz,
1 H), 4.43 (m, 1 H), 3.00 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 169.94, 151.08, 135.98, 134.32,
131.97, 129.11, 128.63, 128.16, 127.96, 126.89, 67.76, 62.65,
43.96.
(5R)-3-Acetyl-4-methyl-5-phenyl-1,3,4-oxadiazinan-2-one (8a)
25
Yield: 90%; white crystals; mp 102–103 °C; [a]D +44.5 (c 1.00,
CHCl3).
MS (EI): m/z (%) = 296 (3), 161 (13), 105 (100), 77 (48), 51 (17).
IR (CCl4): 3068, 2963, 2922, 1770, 1727, 1454, 1372, 1254, 1217,
1070 cm–1.
Anal. Calcd for C17H16N2O3 (296.32): C, 68.91; H, 5.44; N, 9.45.
Found: C, 68.65; H, 5.59; N, 9.63.
1H NMR (300 MHz, CDCl3): d = 7.40–7.34 (m, 5 H), 4.84 (dd,
2J = 11.7 Hz, 3J = 5.7 Hz, 1 H), 4.66 (dd, 2J = 11.7 Hz, 3J = 7.8 Hz,
1 H), 4.35 (dd, 3J = 7.8 Hz, 3J = 5.7 Hz, 1 H), 2.80 (s, 3 H), 2.38 (s,
3 H).
(5R)-4-Methyl-5-phenyl-3-(phenylacetyl)-1,3,4-oxadiazinan-2-
one (8e)
Yield: 85%; colorless viscous oil; [a]D25 +88.3 (c 1.09, CHCl3).
13C NMR (75 MHz, CDCl3): d = 169.86, 150.27, 135.51, 129.01,
128.65, 127.04, 67.84, 62.07, 42.72, 24.80.
IR (CCl4): 3066, 3034, 3006, 2802, 1770, 1722, 1602, 1497, 1454,
1264 cm–1.
MS (EI): m/z (%) = 234 (1), 192 (90), 118 (20), 105 (15), 104 (100),
103 (11), 101 (18), 91 (13), 78 (15), 77 (18).
1H NMR (500 MHz, CDCl3): d = 7.37–7.16 (m, 10 H), 4.70 (dd,
2J = 11.4 Hz, 3J = 5.6 Hz, 1 H), 4.36 (m, 1 H), 4.26 (dd, 3J = 8.0 Hz,
Synthesis 2005, No. 15, 2578–2582 © Thieme Stuttgart · New York

PAPER
Synthesis of 1,3,4-Oxadiazinan-2-ones
2581
3J = 5.6 Hz, 1 H), 4.05 (AB system, Dn = 54.6 Hz, 2J = 15.4 Hz, 2
H), 2.75 (s, 3 H).
MS (EI): m/z (%) = 192 (12), 133 (13), 118 (57), 104 (100), 103
(53), 91 (41), 89 (26), 78 (72), 77 (85), 65 (37), 63 (35), 56 (35), 52
(24), 51 (94), 50 (50), 43 (45), 42 (92), 39 (63).
13C NMR (75 MHz, CDCl3): d = 170.83, 150.66, 135.54, 133.92,
129.38, 129.01, 128.65, 128.55, 127.09, 127.04, 67.98, 62.86,
43.24, 42.91.
Anal. Calcd for C14H18N2O3S (294.37): C, 57.12; H, 6.16; N, 9.52.
Found: C, 56.70; H, 6.02; N, 9.59.
MS (EI): m/z (%) = 311 (1), 193 (13), 192 (100), 104 (34), 91 (52),
65 (17), 43 (21).
(5R)-3-(2-Furoyl)-4-methyl-5-phenyl-1,3,4-oxadiazinan-2-one
(8i)
Yield: 90%; colorless viscous oil; [a]D25 +41.6 (c 1.00, CHCl3).
Anal. Calcd for C18H18N2O3 (310.35): C, 69.66; H, 5.85; N, 9.03.
Found: C, 69.98; H, 5.94; N, 8.92.
IR (CCl4): 3067, 3035, 3005, 2804, 1778, 1700, 1576, 1475, 1296,
1258 cm–1.
(5R)-3-(Methoxyacetyl)-4-methyl-5-phenyl-1,3,4-oxadiazinan-
2-one (8f)
25
Yield: 85%; white crystals; mp 116–117 °C; [a]D +24.9 (c 1.00,
CHCl3).
1H NMR (300 MHz, CDCl3): d = 7.52 (dd, 3J = 1.7 Hz, 4J = 0.8 Hz,
1 H), 7.42–7.30 (m, 5 H), 7.20 (dd, 3J = 3.6 Hz, 4J = 0.8 Hz, 1 H),
3
3
2
6.50 (dd, J = 3.6 Hz, J = 1.7 Hz, 1 H), 4.76 (dd, J = 11.4 Hz,
3J = 6.0 Hz, 1 H), 4.51 (dd, 2J = 11.4 Hz, 3J = 9.7 Hz, 1 H), 4.37 (dd,
3J = 9.7 Hz, 3J = 6.0 Hz, 1 H), 2.95 (s, 3 H).
IR (CCl4): 3068, 3034, 2925, 2826, 1775, 1740, 1455, 1257, 1215,
1190 cm–1.
13C NMR (75 MHz, CDCl3): d = 158.34, 151.43, 146.18, 145.94,
135.91, 129.01, 128.61, 126.62, 119.19, 112.15, 68.95, 64.80,
44.96.
1H NMR (300 MHz, CDCl3): d = 7.42–7.30 (m, 5 H), 4.90 (dd,
2J = 11.6 Hz, 3J = 5.2 Hz, 1 H), 4.78 (dd, 2J = 11.6 Hz, 3J = 6.5 Hz,
1 H), 4.35 (AB system, Dn = 60.4 Hz, 2J = 17.2 Hz, 2 H), 4.36 (dd,
3J = 6.5 Hz, 3J = 5.2 Hz, 1 H), 3.36 (s, 3 H), 2.82 (s, 3 H).
MS (EI): m/z (%) = 286 (6), 229 (9), 174 (9), 161 (45), 118 (10), 104
(11), 95 (100), 77 (10), 43 (20), 39 (31).
13C NMR (125 MHz, CDCl3): d = 169.75, 149.49, 134.99, 129.06,
128.73, 127.05, 73.09, 67.15, 60.93, 59.22, 42.25.
Anal. Calcd for C15H14N2O4 (286.28): C, 62.93; H, 4.93; N, 9.79.
Found: C, 62.92; H, 4.80; N, 10.01.
MS (EI): m/z (%) = 177 (4), 118 (31), 104 (26), 103 (19), 91 (25),
89 (12), 78 (25), 77 (41), 65 (18), 63 (16), 56 (23), 55 (10), 51 (47),
50 (22), 45 (100), 43 (28), 42 (60), 39 (29).
(5R)-3-[(2E)-Cinnamoyl]-4-methyl-5-phenyl-1,3,4-oxadiazi-
nan-2-one (8j)
Yield: 80%; colorless viscous oil; [a]D25 +4.40 (c 1.05, CHCl3).
Anal. Calcd for C13H16N2O4 (264.28): C, 59.08; H, 6.10; N, 10.60.
Found: C, 58.71; H, 5.90; N, 10.63.
IR (CCl4): 3087, 3065, 3032, 2802, 1763, 1737, 1700, 1621, 1449,
1333, 1255, 1188 cm–1.
(5R)-4-Methyl-3-(phenoxyacetyl)-5-phenyl-1,3,4-oxadiazinan-
2-one (8g)
Yield: 90%; white crystals; mp 112–114 °C; [a]D25+17.7 (c 1.00,
CHCl3).
1H NMR (300 MHz, CDCl3): d = 7.81 (d, 3J = 15.6 Hz, 1 H), 7.56–
7.34 (m, 10 H), 7.30 (d, 3J = 15.6 Hz, 1 H), 4.81 (dd, 2J = 11.5 Hz,
3J = 5.7 Hz, 1 H), 4.61 (dd, 2J = 11.5 Hz, 3J = 8.5 Hz, 1 H), 4.38 (dd,
3J = 8.5 Hz, 3J = 5.7 Hz, 1 H), 2.87 (s, 3 H).
IR (CCl4): 3068, 3033, 2966, 2799, 1777, 1742, 1600, 1495, 1257,
1191 cm–1.
13C NMR (125 MHz, CDCl3): d = 165.62, 150.56, 145.73, 135.63,
134.66, 130.44, 129.03, 128.85, 128.66, 128.37, 127.03, 117.98,
68.13, 62.85, 43.54.
1H NMR (500 MHz, CDCl3): d = 7.42–7.35 (m, 5 H), 7.25–7.17 (m,
2 H), 6.97–6.91 (m, 1 H), 6.71–6.66 (m, 2 H), 4.93 (AB system,
2
2
3
Dn = 63.0 Hz, J = 17.4 Hz, 2 H), 4.92 (dd, J = 11.7 Hz, J = 5.1
Hz, 1 H), 4.76 (dd, 2J = 11.7 Hz, 3J = 5.7 Hz, 1 H), 4.35 (dd, 3J = 5.7
Hz, 3J = 5.1 Hz, 1 H), 2.85 (s, 3 H).
MS (EI): m/z (%) = 322 (4), 132 (10), 131 (100), 104 (10), 103 (30),
76 (26), 51 (11).
Anal. Calcd for C19H18N2O3 (322.36): C, 70.79; H, 5.63. Found: C,
70.49; H, 5.70; N, 8.46.
13C NMR (75 MHz, CDCl3): d = 168.30, 157.79, 149.48, 135.10,
129.47, 129.10, 128.72, 127.11, 121.55, 114.71, 68.53, 67.09,
60.83, 42.48.
Acknowledgment
MS (EI): m/z (%) = 326 (7), 205 (35), 192 (16), 161 (30), 132 (72),
118 (30), 117 (23), 107 (21), 104 (21), 103 (14), 91 (26), 79 (16), 78
(21), 77 (100), 65 (19), 51 (33), 43 (48), 42 (36), 39 (23).
We thank the Fundação de Amparo à Pesquisa do Estado de São
Paulo (FAPESP) for financial support of this research and a fel-
lowship to A.R. We thank the Conselho Nacional de Desenvolvi-
mento Científico e Tecnológico (CNPq) for fellowships to. P.R.O.
and R.R.
Anal. Calcd for C18H18N2O4 (326.35): C, 66.25; H, 5.56; N, 8.58.
Found: C, 66.29; H, 5.54; N, 9.02.
(5R)-3-[(Ethylthio)acetyl]-4-methyl-5-phenyl-1,3,4-oxadiazi-
nan-2-one (8h)
Yield: 83%; light-yellow oil; [a]D25 +42.0 (c 1.09, CHCl3).
References
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