1
0004 J . Org. Chem., Vol. 63, No. 26, 1998
Notes
sponding 2,3-dioxytetrahydropyridines into 2-substituted
-hydroxytetrahydropyridines. Although the rationaliza-
evaporated, and the residue was chromatographed (silica gel,
Et
2
O) to yield piperidine 5 (528 mg, 77%). Recrystallization from
3
1
hexanes- Et
2
O gave white crystals, mp 154-156 °C. H NMR
tion of the oxidation processes seems problematic because
they are probably influenced by several factors such as
the nature of the oxidant, the reaction conditions, and
the stability and the substitution pattern of the dihydro-
pyridines, the experimental procedures reported may
fulfill the practical needs on this type of reactivity.
Considering the synthetic implications of the above
methodology, these results may lead to interesting trans-
formations of dihydropyridines, a class of compounds
with a relevant role in biochemistry and in natural
product synthesis.
δ_6.80_(d, J ) 2.7 Hz, 2H), 5.34 (m, J ) 8.9 and 2.7 Hz, 2H),
3
6
.73 (s, 3H), 2.13 (m, J ) 8.9 Hz, 2H), 2.06 (s, 6H), 2.00 (s,
H); C NMR δ_169.9,_169.1,_153.6,_73.9,_65.1,_53.8,_25.1,_20.8,
13
_20.5;_IR (KBr) 1748, 1735, 1732; Anal. Calcd for C15H21NO10
C, 47.98; H, 5.64; N, 3.73. Found: C, 47.86; H, 5.70; N, 3.79.
:
Meth yl cis-2,3-Dia cetoxy-1-ben zoyl-1,2,3,4-tetr a h yd r o-
p yr id in e-5-ca r boxyla te (6). Following the above experimental
procedure, diacetate 6 (70%) was obtained from dihydropyridine
1
2
d . Recrystallization from hexanes - Et O gave white crystals,
1
mp 164-166 °C. H NMR δ_7.94_(s, 1H), 7.54 (m, 5H), 6.74 (d,
J ) 3.1 Hz, 1H), 5.31 (m, 1H), 3.73 (s, 3H), 2.74 (d, J ) 19.5 Hz,
1H), 2.54 (m, J ) 19.5, 4.3 and 2.2 Hz, 1H), 2.09 (s, 3H), 2.08 (s,
1
3
3H); C NMR δ_170.3,_169.5,_168.1,_167.4,_134.1,_132.4,_131.9,
_128.7,_128.4,_106.8,_73.6,_63.7,_51.7,_21.1,_20.9,_20.7;_IR (KBr)
1756, 1742, 1702, 1689, 1636; UV (MeOH) 264 (4.16); Anal. Calcd
Exp er im en ta l Section
for C18
.30; N, 3.78.
Gen er a l Meth od for DMD Oxid a tion s. A 1.1-fold excess
7
H19NO : C, 59.83; H, 5.26; N, 3.87. Found: C, 59.99; H,
Gen er a l. All solvents were purified and dried by standard
methods. All reagents were of commercial quality from freshly
opened containers. Organic extracts were dried with anhydrous
sodium sulfate. Melting points were determined in a capillary
tube and are uncorrected. Microanalyses and HRMS were
performed by Centro de Investigaci o´ n y Desarrollo (CSIC),
Barcelona. Unless otherwise quoted, NMR spectra were recorded
5
23
of DMD solution (0.07 M) in acetone was added to a solution
of the dihydropyridine 1e-h (1 mmol) in acetone (20 mL) at 0
°
C. The progress of the reaction was monitored by TLC. When
all the starting material was consumed (ca. 5 min), the solvent
was removed under reduced pressure and the residue was
in CDCl
3
solution with TMS as an internal reference at 200,
chromatographed (neutral alumina, CH
the corresponding dioxane 8e-h .
2
Cl
2
- MeOH) to give
Dioxa n e 8e (72%). Major isomer: 1H NMR (CD
3
OD) δ 2.18
1
13
3
00, or 500 MHz ( H) and 50.3 or 75 MHz ( C). Only noteworthy
-
1
IR absortions are listed (cm ). UV spectra were obtained in
MeOH solution.
(
1
ddd, J ) 16.3, 2.7 and 1.5 Hz, 2H), 2.60 (ddd, J ) 16.3, 3.7 and
Gen er a l Meth od for m -CP BA Oxid a tion s. A solution of
.9 Hz, 2H), 3.15 (s, 6H), 3.83 (m, 2H), 4.51 (dd, J ) 2.6 and 1.5
m-CPBA (3.5 mmol) in anhydrous CH
dropwise under N atmosphere to a stirred solution of dihydro-
pyridine 1a or 2a (3 mmol) in CH Cl (50 mL) kept at -40 °C,
2
Cl
2
(25 mL) was added
13
3
Hz, 2H), 6.98 (dd, J ) 1.9 and 0.8 Hz, 2H); C NMR (CD OD)
2
δ: 24.4, 39.3, 63.9, 70.3, 80.4, 122.7, 146.0; IR (NaCl) 2189, 1630;
2
2
+
MS (EI) m/z (relative intensity) 272 (M , 8), 136 (51), 119 (100);
and stirring was continued at this temperature until no dihy-
dropyridine was detected by TLC (usually 1 h). Aqueous NaOH
UV (MeOH) 266 (4.7); HRMS (EI) mass calcd for C14
16 4 2
H N O
72.1273, found 272.1272. Minor isomer: 1H NMR (CD
2
2
3
OD) δ
(
1 M, 30 mL) was added, and the mixture was extracted with
CH Cl
(3 × 75 mL). The combined organic extracts were dried
Na SO ). The solvent was removed under reduced pressure, and
the residue was purified by column chromatography (SiO
elution with Et O) to yield pure tetrahydropyridinols 3 or 4.
.25-2.45 (m, 4H), 2.89 (s, 6H), 3.87 (m, 2H), 4.65 (d, J ) 2.6
2
2
13
3
Hz, 2H), 6.89 (s, 2H); C NMR (CD OD) δ 26.9, 41.2, 68.5, 73.7,
(
2
4
+
8
8.7, 123.2, 148.4; MS (EI) m/z (relative intensity) 272 (M , 7),
36 (39), 119 (100).
-Hyd r oxy-1-m eth yl-1,2,3,4-tetr a h yd r op yr id in e-5-ca r bo-
n itr ile (9). To a stirred solution of dioxane 8e (50 mg, 0.18
mmol) in dry CH Cl (15 mL) kept at -60 °C were added TiCl
0.35 mL, 3.17 mmol) and Et SiH (0.3 mL, 3.5 mmol), and
stirring was continued for 5 min at this temperature. Saturated
aqueous NH Cl (50 mL) and saturated aqueous Na CO (100
mL) were added, and the resulting mixture was extracted with
CH Cl
(3 × 30 mL). The combined organic layers were dried
and evaporated under reduced pressure to give a residue that
was purified by column chromatography (silica gel, CH Cl ) to
furnish tetrahydropyridine 9 (47 mg, 95%). H NMR δ 2.20 (m,
H), 2.49 (m, J ) 15.9 Hz, 1H), 2.95 (s, 3H), 3.01 (m, J ) 12.6,
2
,
1
2
3
Meth yl tr a n s-2-(3-Ch lor oben zoyloxy)-3-h yd r oxy-1,2,3,4-
tetr a h yd r op yr id in e-1-ca r boxyla te (3) (65%). Recrystalliza-
2
2
4
tion from hexanes - Et
2
O gave white crystals, mp 119-121 °C.
H NMR δ_8.06 (s, 1H), 7.98 (d, J ) 7.6 Hz, 1H), 7.52 (d, J )
.3 Hz, 1H), 7.40 (m, 1H), 6.70 (bs, 1H), 5.92 (bs, 1H), 5.17 (m,
(
3
1
7
4
2
3
1
3
1
H), 4.90 (bs, 1H), 3.81 (s, 3H), 2.45 (m, 2H), 1.65 (bs, 1H); C
NMR δ_164.5,_154.0,_134.5, 133.2, 131.4, 129.7, 129.6, 127.9,
2
2
1
1
22.6, 102.6, 73.6, 70.8, 53.4, 22.1;_IR (KBr) 3400, 1723, 1693,
625; UV (MeOH) 290 (3.93), 282 (4.06); Anal. Calcd for C14
: C, 53.94; H, 4.52; N, 4.49. Found: C, 53.76; H, 4.55; N,
14
H -
2
2
ClNO
.48.
Meth yl tr a n s-2-(3-Ch lor oben zoyloxy)-3-h yd r oxy-1,2,3,6-
tetr a h yd r op yr id in e-1-ca r boxyla te (4) (66%). Recrystalliza-
tion from hexanes - Et O gave white crystals, mp 117-119 °C.
H NMR δ_8.05 (s, 1H), 7.95 (d, J ) 7.7 Hz, 1H), 7.54 (d, J )
5
1
4
2
5.6, 2.5 and 0.9 Hz, 1H), 3.17 (m, J ) 12.6, 2.6 and 1.1 Hz, 1H),
4.19 (bs, 1H), 6.79 (d, J ) 0.9 Hz, 1H); 13C NMR δ 30.0, 42.9,
52.9, 61.9, 69.5, 123.0, 147.5; IR (NaCl) 3400, 2181, 1627; MS
2
1
+
(EI) m/z (relative intensity) 138 (M , 46), 95 (100); UV (MeOH)
7
1
6
.3 Hz, 1H), 7.39 (m, 1H), 6.16 (d, J ) 4.1 Hz, 1H), 5.95 (m,
H), 5.73 (m, J ) 10.3 Hz, 1H), 5.38 (bs, 1H), 4.03 (m, J ) 18.4,
.0 and 2.9 Hz, 1H), 3.68 (s, 3H), 3.65 (m, J ) 18.4, 8.3 and 2.4
275 (4.3).
3-Hyd r oxy-2-m eth oxy-1-m eth yl-1,2,3,4-tetr a h yd r op yr i-
d in e-5-ca r bon itr ile (10). To a stirred solution of dioxane 8e
1
3
Hz, 1H), 2.70 (bs, 1H); C NMR δ_164.5,_155.3,_134.5, 133.3,
31.2, 129.7, 129.6, 127.9, 125.9, 121.6, 72.4, 69.4, 53.1, 40.1;_IR
KBr) 3376, 1721, 1687; UV (MeOH) 280 (4.09); Anal. Calcd for
14ClNO : C, 53.94; H, 4.52; N, 4.49. Found: C, 53.88; H,
.54; N, 4.44.
Meth yl (2RS, 3RS, 5RS, 6RS)-2,3,5,6-Tetr a a cetoxyp ip -
(70 mg, 0.25 mmol) in dry CH Cl2 (15 mL) kept at 0 °C were
2
1
(
C
4
added MeOH (0.5 mL) and TFA (0.25 mL), and stirring was
continued for 5 min at this temperature. Saturated aqueous Na2-
CO3 (100 mL) was added, and the resulting mixture was
extracted with CH Cl (3 × 30 mL). The combined organic layers
14
H
5
2
2
were dried and evaporated under reduced pressure to give a
residue that was purified by column chromatography (silica gel,
er id in e-1-ca r boxyla te (5). To a stirred solution of dihydropy-
ridine 1a (255 mg, 1.8 mmol) and 4-methylmorpholine N-oxide
CH Cl -hexanes) to furnish tetrahydropyridine 10 (81 mg, 96%)
2 2
1
(535 mg, 3.9 mmol) in a mixture of acetone (2 mL) and water
as a mixture of epimers (trans:cis 3:1). H NMR δ_(trans isomer)
2.12 (m, J ) 16.6, 2.2 and 1.3 Hz, 1H), 2.40 (m, J ) 16.6, 3.8
and 1.9 Hz, 1H), 3.09 (s, 3H), 3.38 (s, 3H), 3.93 (m, 1H), 4.07
(dd, J ) 3.2 and 1.2 Hz, 1H), 6.77 (dd, 1H, J ) 2.0 and 1.0 Hz,
1H); 13C NMR δ_(trans isomer) 25.6, 42.6, 56.4, 61.8, 73.1, 89.4,
122.1, 145.2; IR (NaCl) 3420, 2190, 1632; MS (EI) m/z (relative
(1.2 mL) was added a solution of osmium tetroxide in t-BuOH
prepared according to ref 14 (1 mL), and the resulting mixture
was stirred at room temperature for 24 h. The solvent was
evaporated under reduced pressure, the residue was taken up
in Ac
at room temperature for 15 h. Et
the reaction mixture was successively washed with aqueous Na
SO (10%, 100 mL) and NaHCO (10%, 100 mL) solutions and
brine (100 mL). The organic phase was dried (Na SO ) and
2
O (4 mL) and Et
3
N (8 mL), and the mixture was stirred
+
2
O was added (100 mL), and
intensity) 168 (M , 100), 137 (95), 95 (90). UV (MeOH) 267 (4.2);
2
-
8 12 2 2
HRMS (EI) mass calcd for C H N O 168.0899, found 168.0902.
3-H yd r oxy-1-m et h yl-2-(2-m et h yl-3-in d olyl)-1,2,3,4-t et -
r a h yd r op yr id in e-5-ca r bon itr ile (11). To a stirred solution of
3
3
2
4