"Nonbiomimetic" Oxidations of Dihydropyridines

Full text of DOI:10.1021/jo980688m

J . Org. Chem. 1998, 63, 10001-10005
10001
“
Non biom im etic” Oxid a tion s of
Dih yd r op yr id in es
Sch em e 1
Rodolfo Lavilla,* Xavier Bar o´ n, Oscar Coll,
Francisco Gull o´ n, Carme Masdeu, and J oan Bosch*
Laboratory of Organic Chemistry, Faculty of Pharmacy,
University of Barcelona, 08028 Barcelona, Spain
Sch em e 2
Received April 14, 1998
Continuing our research in the development of new
1
transformations of dihydropyridines, we have recently
described some “nonbiomimetic” oxidations of these
compounds, in which the normal production of the
corresponding pyridinium salt is avoided.2 Here we
report the studies toward the dioxygenation of the
enaminic moiety present in these substrates (Scheme 1).
Very little is known about this type of reactions4 and
it was decided to study the process with a broad selection
of diversely substituted 1,4- and 1,2-dihydropyridines, 1
,3
,5
and 2 respectively. The N-methoxycarbonyl derivatives
6
1
a and 2a were prepared according to Fowler’s method.
7
Phenylsulfonyldihydropyridines 1b and 1c were formed
using Knaus’ procedure. Benzoyl derivative 1d and the
8
N-alkyl-1,4-dihydropyridines 1e-h were prepared through
reduction of the corresponding pyridinium salts with
sodium cyanoborohydride9 and sodium dithionite re-
spectively (Scheme 2).
10
The interaction of dihydropyridines with m-CPBA to
promote a formal epoxidation was tested first of all.11 On
2 2
exposure of 1a to 1 equiv of m-CPBA in CH Cl solution
*
To whom correspondence should be addressed. Phone: (3493)-
024537. Fax: (3493)4021896. E-mail: lavilla@farmacia.far.ub.es.
1) For reviews on the chemistry of dihydropyridines, see: (a) Eisner,
U.; Kuthan, J . Chem. Rev. 1972, 72, 1. (b) Stout, D. M.; Meyers, A. I.
Chem. Rev. 1982, 82, 223. (c) Sausins, A.; Duburs, G. Khim. Geterotsikl.
Soedin. 1993, 579. (d) Sausins, A.; Duburs, G. Heterocycles 1988, 27,
4
at -40 °C, the addition compound 3 was formed (65%).12,13
The process probably involves an initial oxygen transfer
from the peroxy acid to form an unstable aminoepoxide,
which is in situ regio- and stereoselectively trapped by
the m-chlorobenzoic acid present in the solution. In a
similar way, 2a reacted to afford tetrahydropyridinol 4
(66%). The rest of the dihydropyridines underwent
extensive decomposition and, in some cases, trace amounts
of the corresponding 2-acyloxytetrahydropyridin-3-ol de-
rivatives could be detected (NMR from crude reaction
mixtures), together with the biomimetic oxidation prod-
ucts (the N-alkylpyridinium salts from 1e-h ). No useful
double epoxidations were achieved, either by direct
treatment of 1a or 2a with 2 equiv of m-CPBA or by
subsequent oxidation of 3 or 4.
(
2
91. (e) Kutney, J . P. Heterocycles 1977, 7, 593. (f) Comins, D. L.;
O′Connor, S. Adv. Heterocycl. Chem. 1988, 44, 199.
2) For a preliminary report of a part of this work, see: Lavilla, R.;
Gull o´ n, F.; Bar o´ n, X.; Bosch, J . Chem. Commun. 1997, 213.
3) (a) Lavilla, R.; Coll, O.; Kumar, R.; Bosch, J . J . Org. Chem. 1998,
3, 2728. (b) Lavilla, R.; Kumar, R.; Coll, O.; Masdeu, C.; Bosch, J .,
Molins, E.; Espinosa, E. Unpublished results.
4) Some reports dealing with vicinal dioxygenation of N-alkyl-1,4-
dihydropyridines with K MoO , and O in the presence of CuSO were
(
(
6
(
2
4
2
4
not successfully reproduced in our hands: (a) Negievich, L. A.; Grishin,
O. M.; Yasnikov, A. A. Ukr. Khim. Zh. 1968, 34, 684 (Chem. Abstr.
1
969, 70, 11513) (b) Negievich, L. A.; Grishin, O. M.; Yasnikov, A. A.
Ukr. Khim. Zh. 1968, 34, 802 (Chem. Abstr. 1969, 70, 28776).
5) For a 4 + 2 cycloaddition involving N-acyl-1,2-dihydropyridines
(
and singlet oxygen, see: (a) Natsume, M.; Sekine, Y.; Ogawa, M.;
Soyagimi, H.; Kitagawa, Y. Tetrahedron Lett. 1979, 3473. (b) Ut-
sunomiya, I.; Ogawa, M.; Natsume, M. Heterocycles 1992, 33, 349. For
the osmylation of N-acyl-1,2-dihydropyridines, see: (c) Tschamber, T.;
Backenstrass, F.; Neuburger, M.; Zehnder, M.; Streith, J . Tetrahedron
The osmylation of dihydropyridines was explored next,
and substrate 1a was treated with osmium tetroxide
solution14 (catalytic) using 4-methylmorpholine N-oxide
as stoichiometric reoxidant, to afford, after the usual
acetylation, the piperidine derivative 5 as a single
1
994, 50, 1135. (d) Tschamber, T.; Rodr ´ı guez-P e´ rez, E.-M.; Wolf, P.;
Streith. J . Heterocycles 1996, 42, 669.
(
6) Fowler, F. W. J . Org. Chem. 1972, 37, 1321.
(7) The o-nitrophenylsulfonyl group was selected because of its easy
and mild cleavage; see: Fukuyama, T.; J ow, C. K.; Cheung, M.
Tetrahedron Lett. 1995, 36, 6373.
(12) For a similar reaction taking place upon an N-acyl-1,2,3,4-
tetrahydropyridine, see: Masamune, T.; Hayashi, H.; Takasugi, M.;
Fukuoka, S. J . Org. Chem. 1972, 37, 2343.
(
(
8) Knaus, E. E.; Redda, K. Can. J . Chem. 1977, 55, 1788.
9) Obika, S.; Nishiyama, T.; Tatematsu, S.; Nishimoto, M.; Mi-
yashita, K.; Imanishi, T. Heterocycles 1997, 44, 537.
10) Brewster, M. E.; Simay, A.; Czako, K.; Winwood, D.; Farag, H.;
Bodor, N. J . Org. Chem. 1989, 54, 3721.
11) For a general review on the oxidation of enamines, see: Pittaco,
G.; Valentin, E. V. In The Chemistry of Enamines; Rappoport, Z., Ed.
The Chemistry of Functional Groups, Patai, S.; Rappoport, Z., Eds.);
Wiley: Chichester, 1994; Part 2, Chapter 17.
(13) The related interaction of peracids with enol ethers has been
reported: (a) Wood, H. B., J r.; Fletcher, H. G., J r. J . Am. Chem. Soc.
1957, 79, 3234. (b) Groneberg, R. D.; Miyazaki, T.; Stylianides, N. A.;
Schulze, T. J .; Stahl, W.; Schreiner, E. P.; Suzuki, T.; Iwabuchi, Y.;
Smith, A. L.; Nicolaou, K. C. J . Am. Chem. Soc. 1993, 115, 7593.
(14) Akashi, K.; Palermo, R. E.; Sharpless, K. B. J . Org. Chem. 1978,
43, 2063.
(
(
(
1
0.1021/jo980688m CCC: $15.00 © 1998 American Chemical Society
Published on Web 12/04/1998

1
0002 J . Org. Chem., Vol. 63, No. 26, 1998
Notes
stereoisomer (77%). The stereochemical outcome of this
double dihydroxylation is in good agreement with the
previously reported osmylation of dihydropyridine 2a ,5c
in which the second oxidation takes place on the less
substituted face of the tetrahydropyridine intermediate.15
Analogously, N-benzoyl-3-substituted dihydropyridine 1d
was converted into the corresponding diacetoxy tetrahy-
dropyridine 6 (70%). Attempted dihydroxylations of N-
sulfonyl- or N-alkyldihydropyridines under the same
conditions resulted in decomposition or pyridinium salt
formation. However, small amounts of 2,3-dihydroxytet-
rahydropyridines were obtained from the osmylation of
Sch em e 3
Ta ble 1. DMD Oxid a tion Rea ction s fr om
Dih yd r op yr id in es 1
entry
dihydropyridine
product
yield (%)
1
2
3
4
1e
1f
1g
1h
8e
8f
8g
8h
72
75
69
60
1
6
1
f and 1h when a (DHQ)
2
2 2 4
PHAL - K [OsO (OH) ]
1
7
system was used, apparently suggesting that the ligand-
accelerated catalysis helps to overcome (although to a
small extent) the natural tendency of N-alkyl-1,4-dihy-
dropyridines to undergo oxidation to the corresponding
pyridinium salts. Also problematic were the aminohy-
droxylation reactions18 upon dihydropyridines 1. Only
compounds 1d and 1f were converted to the correspond-
ing 2-acetamido-3-hydroxytetrahydropyridines, although
in very low yields. For instance, compound 7 was isolated
from 1d in 5% yield, in a process that also formed traces
of the corresponding diol, whereas the products obtained
from 1f could not be isolated and were only detected from
the crude reaction mixture by NMR.
When dihydropyridine 1e was treated at room tem-
perature with a DMD solution,23 the dioxane 8e was
obtained in acceptable yield (72%), together with some
of the corresponding pyridinium salt, indicating a kinetic
competition between the two oxidation pathways. The
process can be rationalized by considering the initial
epoxidation of the enamine double bond, with subsequent
ring-opening of the oxirane ring to give a zwitterionic
species that undergoes dimerization.2
1a-c
Substrates 1f,
1
g, and 1h underwent similar transformations, affording
the corresponding dioxanes 8f - 8h in yields ranging
from 60% to 75% (dihydropyridines 1a -d and 2a afforded
low yields of unstable compounds) (Scheme 3 and Table
Looking for a reagent that could efficiently transfer an
oxygen atom to the olefin moiety of the highly reactive
N-alkyl-1,4-dihydropyridines, we became interested in
1
). In contrast, the use of dioxiranes generated in situ
1
9
the properties of dimethyldioxirane (DMD). Especially
appealing were the reports on the epoxidation of enol
ethers20 and enamines, which are sensitive substrates
difficult to oxidize by other methods. On the other hand,
it should be mentioned that a chemically related diox-
etane was involved in the “normal” (biomimetic) oxidation
of a NADH analogue.22
from 2-chlorocyclohexanone or 1,1,1-trifluoroacetone in
the presence of stoichiometric amounts of Oxone was
24
21
not satisfactory (only pyridinium salts were produced),
thus making evident the incompatibility of dihydropy-
ridines with strong oxidants such as peroxy acids. The
stereochemical analysis of 8e indicated a major isomer
with a center of symmetry, showing a cis stereochemistry
for the oxygens at C2-C3 and an anti relation between
the two tetrahydropyridine moieties.25 Minor amounts of
other isomer were isolated, probably with a syn stereo-
chemistry. The stereochemical assignments were based
(15) For a discussion about the influence of conformational solvent
effects and hydrogen-bonding in the stereocontrol of double dihydroxy-
lations, see: (a) Donohoe, T. J .; Moore, P. R.; Beddoes, R. L. J . Chem.
Soc., Perkin Trans. 1, 1997, 43. (b) Donohoe, T. J .; Moore, P. R.; Waring,
M. J .; Newcombe, N. J . Tetrahedron Lett. 1997, 38, 5027.
1
on the coupling constants in the H NMR spectra and on
(
16) Methyl cis-2,3-dihydroxy-1-methyl-1,2,3,4-tetrahydropyridine-
1
1
H- H COSY, HMQC, and NOESY experiments. Diox-
1
5
1
1
-carboxylate (6%): H NMR δ_7.27 (s, 1H), 4.60 (m, 1H), 3.88 (m,
H), 3.68 (s, 3H), 3.21 (d, J ) 5 Hz, 1H), 3.06 (s, 3H), 2.65 (dd, J )
8.3 and 4.3 Hz, 1H), 2.47 (d, J ) 5 Hz, 1H), 2.31 (dd, J ) 18.3 and 9.6
anes 8e-h were stable enough to be chromatographed
(decomposition took place to a reduced extent), spectro-
scopically characterized, and stored in the freezer under
an inert atmosphere for months.
It is well known that R-alkoxyamines can promote the
formation of iminium ions in the presence of Lewis acids
and, in this way, allow the introduction of substituents
at the nitrogen R-position through nucleophilic addition.
Accordingly, we envisaged a set of transformations of this
type to make the above nonbiomimetic oxidation of
dihydropyridines synthetically useful for the preparation
1
3
Hz, 1H); C NMR δ_168.5, 144.8, 93.8, 80.7, 67.0, 51.0, 39.6, 25.0.
Methyl cis-1-benzyl-2,3-dihydroxy-1,2,3,4-tetrahydropyridine-5-car-
1
boxylate (7%): H NMR δ_7.40-723 (m, 6H), 4.60 (m, 1H), 4.53 (d, J
15 Hz, 1H), 4.37 (d, J ) 15 Hz, 1H), 3.88 (m, 1H), 3.69 (s, 3H), 2.69
dd, J ) 18 and 4 Hz, 1H), 2.35 (m, 3H); MS (EI) m/z (relative intensity)
)
(
2
+
63 (M , 10), 245 (16), 204 (8), 91 (100).
17) See, for instance: Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless,
K. B. Chem. Rev. 1994, 94, 2483.
18) Different versions of this transformation were investigated,
(
(
following the protocols developed by Sharpless: (a) Li, G.; Chang, H.-
T.; Sharpless, K. B. Angew. Chem., Int. Ed. Engl. 1996, 35, 451. (b)
Rudolph, J .; Sennhenn, P. C.; Vlaar, C. P.; Sharpless, K. B. Angew.
Chem., Int. Ed. Engl. 1996, 35, 2810. (c) Li, G.; Angert, H. H.;
Sharpless, K. B. Angew. Chem., Int. Ed. Engl. 1996, 35, 2813. (d)
Brucko, M.; Schlingloff, G.; Sharpless, K. B. Angew. Chem., Int. Ed.
Engl. 1997, 36, 1483.
(23) DMD solutions were prepared according to Adam, W.; Bialas,
J .; Hadjiarapoglou, L. Chem. Ber. 1991, 124, 2377, and the dioxirane
content (ca. 0.07 M) was determined by iodometric titration.
(24) For the use of catalytic DMD epoxidations, see: (a) Yang, D.;
Wong, M. K.; Yip, Y. C. J . Org. Chem. 1995, 60, 3887. (b) Yang, D.;
Yip, Y. C.; Tang, M. W.; Wong, M. K.; Zheng, J . H.; Cheung, K. K. J .
Am. Chem. Soc. 1996, 118, 491. (c) Denmark, S. E.; Forbes, D. C.; Hays,
D. S.; DePue, J . S.; Wilde, R. G. J . Org. Chem. 1995, 60, 1391. (d)
Curci, R.; D′Accolti, L.; Fiorentino, M.; Rosa, A. Tetrahedron Lett. 1995,
36, 5831.
(25) .For related structures, see: (a) Koppenhoefer, B.; Winter, B.;
Bayer, E. Liebigs Ann. Chem. 1983, 1986. (b) Adam, W.; Peters, K.;
Sauter, M. Synthesis 1994, 111. (c) Agami, C.; Couty, F.; Hamon, L.;
Prince, B.; Puchot, C. Tetrahedron 1990, 46, 7003. Also see refs 12
and 21c.
(
19) (a) Crandall, J . K. In Encyclopedia of Reagents for Organic
Synthesis. Paquette, L. A., Ed. Wiley: Chichester, 1995, Vol. 3, p 2061.
(
(
b) Adam, W.; Curci, R.; Edwards, J . O. Acc. Chem. Res. 1989, 22, 205.
c) Murray, R. W. Chem. Rev. 1989, 89, 1187.
(
20) Halcomb, R. L.; Danishefsky, S. J . J . Am. Chem. Soc. 1989,
11, 6661.
21) (a) Adam, W.; Peters, E.-M.; Peters, K.; von Schnering, H.-G.;
1
(
Voerckel, V. Chem. Ber. 1992, 125, 1263. (b) Adam, W.; Ahrweiler, M.;
Paulini, K.; Reissig, H.-U.; Voerckel, V. Chem. Ber. 1992, 125, 2719.
(
c) Adam, W.; Reinhardt, D.; Reissig, H.-U.; Paulini, K. Tetrahedron
995, 51, 12257. (d) Burgess, L. E.; Gross, E. K. M.; J urka, J .
Tetrahedron Lett. 1996, 37, 3255.
22) Adam, W.; Heil, M.; Hutterer, R. J . Org. Chem. 1992, 57, 4491.
1
(

Notes
J . Org. Chem., Vol. 63, No. 26, 1998 10003
Sch em e 4a
a
Reagents and conditions: i. Et3SiH, TiCl4, THF, -60 °C, 5 min, (95%). ii. MeOH, TFA, 0 °C, 5 min, (96%, trans:cis 3:1). iii.
2
-Methylindole, TFA, 20 °C, 5 min, (84%, trans:cis 2.5:1). iv. TMSCN, TiCl4, CH2Cl2, 0 °C, 5 min, (67%; trans:cis 1.5:1). v. AllylTMS,
TiCl4, CH2Cl2, -78 °C, 5 min, then SiO2 column chromatography, (trans-13 46%, 15 7%). vi. 1-Methoxyethene, BF3‚Et2O, THF-CH2Cl2,
-60 °C, 5 min, (60%, mixture of isomers at the acetalic carbon).
(46%), together with a small amount of a bicyclic furo-
pyridine 15 (7%), which was not present in the crude
reaction mixture but eluted after the main compound on
column chromatography on silica gel. Probably, its
formation is the result of an acid-catalyzed cyclization
of the minor cis isomer (cis-13) produced in the addition
step.29 In fact, this addition - cyclization sequence can
be carried out more efficiently, thus gaining practical
access to the above-mentioned bicyclic systems. Thus, on
BF
3
3
‚0Et
2
O-promoted methoxyethene addition to dioxane
8
e, partially reduced furopyridine 14 (60%) was ob-
tained as an epimeric mixture at the acetalic carbon.
Remarkably, in sharp contrast with the above nucleo-
philic additions, the stereochemistry at the ring fusion
is cis (determined from NOE and ROESY experiments;
see Figure 1), thus suggesting that a reversible addition
of the enol ether forms a stabilized carbocation, which
would undergo intramolecular trapping by the hydroxyl
group to close the tetrahydrofuran ring. Only a cis
arrangement would favor the cyclization and, probably,
the initially formed trans cationic intermediate would
equilibrate with the more reactive cis isomer.
F igu r e 1.
of 2-substituted 3-hydroxy-1,2,3,4-tetrahydropyridines
(
see Scheme 4). The reduction of 8e with Et
presence of TiCl afforded the tetrahydropyridinol 9
95%).26 TFA-induced addition of MeOH gave the “mon-
3
SiH in the
4
(
omeric” equivalent 10 (96%) as a diastereomeric mixture,
the trans isomer being the major compound (3:1 vs the
cis isomer).27 The addition of heteroaromatics was next
investigated and, on interaction of dioxane 8e with
2
-methylindole under acid catalysis, adduct 11 (84%) was
In summary, we have described several nonbiomimetic
oxidation reactions of 1,2- and 1,4-dihydropyridines that
allow the vicinal dioxygenation of these substrates, and
we have carried out some transformations of the corre-
formed with moderate stereoselectivity (trans:cis 5:2).
The stereochemistry of both isomers was assigned with
the aid of monodimensional NOE and ROESY experi-
ments, showing the spatial connectivity depicted in
Figure 1. On the other hand, R-aminonitrile 12 (67%,
trans:cis 3:2) was prepared through TiCl
SCN addition to 8e. Allylsilane addition to the iminium
ion generated from 8e on TiCl
treatment28 gave the
expected trans-2-allyl-3-hydroxytetrahydropyridine 13
(28) For related transformations, see: (a) Kozikowski, A. P.; Park,
4
-mediated TM-
P. J . Org. Chem. 1984, 49, 1674. (b) Sakagami, H.; Kamikubo, T.;
Ogasawara, K. Chem. Commun. 1996, 1433. (c) Hartman, G. D.;
Philips, B. T.; Halczenko, W.; Springer, J . P.; Hirshfield, J . J . Org.
Chem. 1987, 52, 1136.
4
(29) Interestingly, when attempting the reaction at 0 °C the only
isolated compound (10%, NMR and MS evidence) was a bicyclic
analogue of 15, bearing a (trimethylsilyl)methyl group at C-2, thus
indicating that an intramolecular trapping of the carbocation by the
hydroxyl group had taken place instead of the usual elimination to
regenerate the double bond. For a related situation, see ref 28c.
(30) For additions or addition-cyclization sequences of enol ethers
to iminium ions, see: (a) Natsume, M.; Masashi, O. Heterocycles 1980,
14, 169. (b) Shono, T.; Matsumura, Y.; Inoue, K.; Ohmizu, H.;
Kashimura, S. J . Am. Chem. Soc. 1982, 104, 5753.
(
26) This transformation represents a two-step sequence for the anti-
Markownikoff water addition to 1,4-dihydropyridines.
27) The preferred formation of trans isomers in this type of
(
reactions may reflect the more favorable approach of the nucleophile
from the less sterically hindered face of the iminium ion, away from
the electron-rich hydroxyl group. See, for instance: Khan, S. D.; Dobbs,
K. D.; Hehre, W. J . J . Am. Chem. Soc. 1988, 110, 4602. Also see ref
2
5c.

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

Notes
J . Org. Chem., Vol. 63, No. 26, 1998 10005
1
dioxane 8e (23 mg, 0.08 mmol) in a 1:1 mixture of AcOEt -
an oil. H NMR δ 1.60 (bs, 1H), 1.95 (m, 2H), 2.30 (m, 3H), 3.00
(s, 3H), 3.95 (bs, 1H), 5.10 (m, 1H), 5.12 (m, 1H), 5.70 (m, 1H),
6.79 (s, 1H); 13C NMR δ 26.3, 35.8, 42.5, 61.8, 63.1, 76.8, 114.4,
118.8, 132.9, 146.0; IR (NaCl) 3400, 2182, 1627; MS (EI) m/z
dioxane (10 mL) at room temperature were added 2-methylindole
(
27 mg, 0.21 mmol) and TFA (5 drops), and stirring was
continued for 5 min at this temperature. Saturated aqueous Na
CO (100 mL) was added, and the resulting mixture was
2
-
+
3
(relative intensity) 178 (M , 4), 137 (19), 69 (100). UV (MeOH)
extracted with AcOEt (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,
272 (4.5); Anal. Calcd for C10
Found: C, 67.32; H, 8.07; N, 15.42. On further elution with CH
Cl - MeOH (99:1). (3a RS, 7a RS)-2,4-Dim eth yl-2,3,3a ,4,7,7a -
14 2
H N O: C, 67.41; H, 7.86; N, 15.73.
2
-
2
1
AcOEt-hexanes) to furnish trans-11 (26 mg, 60%). H NMR δ
h exa h yd r ofu r o[3,2-b]p yr id in e-6-ca r bon itr ile (15, 25 mg,
1
2
1
.33 (dd, J ) 15.6 and 6.7 Hz, 1H), 2.43 (s, 3H), 2.50 (dd, J )
5.6 and 4.0 Hz, 1H), 2.81 (s, 3H), 4.20 (m, J ) 6.7, 5.4 and 4.0
7%) was obtained as an epimeric mixture at C-2. H NMR δ_-
(major isomer) 1.26 (d, J ) 6.2 Hz, 3H), 1.78 (m, J ) 13.2, 7.7
and 5.7 Hz, 1H), 2.20-2.40 (m, 3H), 2.91 (s, 3H), 3.56 (dd, J )
Hz, 1H), 4.30 (d, J ) 5.4 Hz, 1H), 7.02 (s, 1H), 7.07-7.20 (m,
1
3
2
1
1
3
1
H), 7.33 (d, J ) 8.0 Hz, 1H), 7.47 (d, J ) 7.7 Hz, 1H), 8.10 (bs,
9.3 and 4.9 Hz, 1H), 4.23-4.35 (m, 2H), 6.72 (s, 1H); C NMR
δ_(major isomer) 21.8, 24.8, 37.7, 40.2, 58.5, 72.6, 73.4, 79.8,
123.0, 147.3; IR (NaCl) 2183, 1631; MS (EI) m/z (relative
1
3
H); C NMR δ 11.8, 28.3, 40.9, 60.6, 66.4, 69.2, 108.0, 110.6,
17.8, 119.8, 120.0, 121.6, 122.2, 134.5, 136.1, 148.5; IR (NaCl)
+
+
400, 2185, 1627; MS (EI) m/z (relative intensity) 267 (M , 34),
intensity) 178 (M , 79), 135 (100), 119 (60).
73 (100), 144 (67); UV (MeOH) 274 (4.5); HRMS (EI) mass calcd
2-Meth oxy-4-m eth yl-2,3,3a ,4,7,7a -h exa h yd r ofu r o[3,2-b]-
p yr id in e-6-ca r bon itr ile (14). To a stirred solution of dioxane
for C16
17 3
H N O 267.1372, found 267.1381. On elution with AcOEt,
1
cis -11 (10 mg, 24%) was obtained. H NMR δ 2.17 (dd, J ) 15.3
and 8.9 Hz, 1H), 2.44 (s, 3H), 2.50 (dd, J ) 15.3 and 5.0 Hz,
8e (70 mg, 0.25 mmol) in dry CH
were added BF ‚Et O (0.1 mL, 0.56 mmol) and methoxyethene
(0.15 mL, 1.1 mmol) dissolved in THF (5 mL) precooled to -78
C, and stirring was continued at -60 °C until no starting
material was detected by TLC (5 min). Saturated aqueous K
CO (100 mL) was added, and the resulting mixture was
extracted with CH Cl
2 2
Cl (30 mL) kept at -60 °C
3
2
1
7
8
1
H), 2.83 (s, 3H), 4.19 (m, 1H), 4.57 (bs, 1H), 7.00 (s, 1H), 7.06-
.18 (m, 2H), 7.33 (d, J ) 7.9 Hz, 1H), 7.52 (d, J ) 7.9 Hz, 1H),
o
1
3
.11 (bs, 1H); C NMR δ 12.2, 29.1, 41.2, 58.5, 67.3, 69.7, 104.9,
2
-
10.5, 118.7, 119.9, 120.2, 121.5, 123.5, 135.1, 135.2, 148.7; IR
3
(
NaCl) 3400, 2183, 1625; MS (EI) m/z (relative intensity) 267
2
2
(3 × 30 mL). The combined organic layers
+
(M , 34), 173 (100), 144 (66).
were dried and evaporated under reduced pressure to give a
residue that was purified by column chromatography (neutral
3
-H yd r oxy-1-m et h yl-1,2,3,4-t et r a h yd r op yr id in e-2,5-d i-
ca r bon itr ile (12). To a stirred solution of dioxane 8e (50 mg,
.18 mmol) in dry CH Cl (30 mL) kept at 0 °C were added TiCl
0.35 mL, 3.17 mmol) and TMSCN (0.6 mL, 4.3 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
alumina, CH Cl -hexanes) to furnish bicycle 14 (60 mg, 60%)
2 2
1
0
2
2
4
as a mixture of epimers at the acetalic carbon. H NMR δ_(major
epimer, 2RS, 3aSR, 7aSR) 1.97 (m, J ) 13.7, 7.5 and 2.9 Hz,
1H), 2.40 (m, 1H), 2.47 (m, 2H), 2.92 (s, 3H), 3.35 (s, 3H), 3.55
(m, 1H), 4.25 (m, 1H), 5.02 (dd, J ) 5.9 and 2.9 Hz, 1H), 6.72 (s,
(
4
2
3
1
3
1H); C NMR δ_(major epimer, 2RS, 3aSR, 7aSR) 25.5, 36.6,
2
2
40.8, 55.4, 57.1, 73.5, 79.9, 104.0, 123.1, 147.1; IR (NaCl) 2185,
+
1632; MS (EI) m/z (relative intensity) 194 (M , 22), 119 (100);
2
2
UV (MeOH) 271 (4.3); HRMS (EI) mass calcd for C10
194.1055, found 194.1060.
14 2 2
H N O
furnish dinitrile 12 (40 mg, 67%) as a mixture of epimers (trans:
1
cis 3:2). H NMR δ_(trans isomer) 2.30 (m, J ) 16.8, 2.6 and 2.3
Hz, 1H), 2.75 (m, J ) 16.8, 3.6 and 2.0 Hz, 1H), 3.08 (s, 3H),
Ack n ow led gm en t. This work was supported by the
DGICYT, Spain (project PB94-0214). Thanks are also
due to the Comissionat per Universitats i Recerca
(Generalitat de Catalunya) for Grant SGR97-0018. O.
C. thanks the “Ministerio de Educaci o´ n y Cultura”,
Spain, for a fellowship. Prof. K. B. Sharpless (Scripps
Research Institute) is thanked for helpful discussions.
3
2
7
.98 (dd, J ) 2.6 and 2.3 Hz, 1H), 4.39 (m, 1H), 6.77 (d, 1H, J )
13
.0 Hz, 1H); C NMR δ_(trans isomer) 27.2, 41.3, 52.7, 63.2,
6.3, 115.4, 120.7, 145.5; IR (NaCl) 3500, 2196, 1629; MS (EI)
+
m/z (relative intensity) 163 (M , 85), 134 (100), 107 (59); UV
(MeOH) 265 (4.8); HRMS (EI) mass calcd for C
8 9 3
H N O 163.0746,
found 163.0746.
tr a n s-2-Allyl-3-h yd r oxy-1-m eth yl-1,2,3,4-tetr a h yd r op y-
r id in e-5-ca r bon itr ile (13). To a stirred solution of dioxane 8e
(
264 mg, 0.97 mmol) in dry CH
added TiCl (0.4 mL, 3.16 mmol) and allyltrimethylsilane (0.18
mL, 1.5 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
2
Cl
2
(30 mL) kept at -78 °C were
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and characterization data for compounds 1d , 7, 8f-
4
1
13
h ; copies of the H and C NMR spectra of compounds 8e-h ,
4
9
, 10, 11, 12, 14, 15 (24 pages). This material is contained in
2
3
libraries on microfiche, immediately follows this article in the
microfilm version of the journal, and can be ordered from the
ACS; see any current masthead page for ordering information.
2
2
(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
2
Cl
2
) to furnish tetrahydropyridine 13 (160 mg, 46%) as
J O980688M