Chiral Nonracemic Synthesis and Reactivity of Two New Endocyclic Enamines in the Phenyloxazolopiperidine Series

Full text of DOI:10.1021/jo990706f

J . Org. Chem. 2000, 65, 3209-3212
3209
Ch ir a l Non r a cem ic Syn th esis a n d
Rea ctivity of Tw o New En d ocyclic
En a m in es in th e P h en yloxa zolop ip er id in e
Ser ies
David Franc¸ois, Erwan Poupon,
Marie-Christine Lallemand, Nicole Kunesch,*,† and
Henri-Philippe Husson*
UMR 8638 du CNRS associe´e a` l’Universite´ Rene´-Descartes,
Faculte´ des Sciences Pharmaceutiques et Biologiques, 4,
Avenue de l’Observatoire, 75270 Paris Cedex 06, France
F igu r e 1.
Received April 27, 1999
Sch em e 1
As part of our continuing work on bicyclic chiral
nonracemic oxazolopiperidines, we became interested in
the synthesis of analogues of building block 1,1 viz. the
R-cyano-1,4-dihydropyridine (2) and the simple oxazo-
lopiperidine (3) (Figure 1).
On the basis of the versatility of the 1,4-dihydropyri-
dine equivalent 1, for the asymmetric synthesis of a wide
range of substituted piperidines,2 we sought to elaborate
new systems which could afford a larger scope of syn-
theses targeting additionnal substituents or functions at
all the piperidine ring positions.
While compound 3 should react as a simple enamine,
compound 2 would in fact combine both the reactivity of
an R-cyanoenamine at the C-2, C-3, and C-4 carbon atoms
and that of a simple enamine at the C-5 and C-6 centers.
This postulate led us to synthesize these two building
blocks and to examine their reactivity in a preliminary
study.
A large amount of work has been devoted to the
chemistry of R-cyanoenamines due to their high reactiv-
ity3 and captodative properties.4 Cyclic R-cyanoenamines
of type 2 were recently investigated. While Meyers5
obtained compound 4 in a four-step synthesis starting
from the corresponding lactam, Grierson and Fowler
prepared compounds 56 and the racemic 67 by an in-
tramolecular Diels-Alder reaction (IMDA) of a 2-cyano-
N-alkylazadiene in a five- or three-step procedure, re-
spectively (Figure 1). Cyclic cyanoenamines similar to 4
and 5 were recently investigated and interestingly led
to the introduction of electrophiles at the C-4 carbon
atom.5,7a However, none of these building blocks permits
deprotection of the piperidine nitrogen for further N-
substitution or heterocyclization. Consequently, we were
interested in the preparation of the analogue in the
phenylglycinol series which allows elimination of the
chiral appendage.
Taking advantage of synthon 1, its lithiated anion was
reacted with tosyl cyanide to afford dicyano derivative 7
in 67% yield (Scheme 1). Several attempts using conven-
tional methods to remove one of the two cyano groups
were unsuccessful. Finally, thermolysis of derivative 7
as described for N-methyl-2,2-dicyanopiperidine8 gave a
mixture of two compounds in moderate yield. A careful
separation by column chromatography allowed the ob-
tention of pure cyanoenamine 2a as the major product
accompanied by the epimeric oxazolidine 2b, epimeric at
position 6.
The structures of the major (2a ) and minor (2b)
1
compounds were deduced from the H NMR spectra. A
correlation between H-6 and the axial protons H-7 and
H-8 was observed in the NOESY spectrum of 2b. More-
over, the chemical shift and the signal pattern of H-6
were characteristic of equatorial (2a , 4.95, dd, J ) 7 and
3.5 Hz) or axial (2b, 4.81, dd, J ) 10 and 2.5 Hz)
orientation as already described for similar derivatives.9
A simple preparation of 3 as a single diastereomer was
achieved in good yield (79%) by reductive decyanation of
1, using a large excess of Raney nickel in refluxing THF
(Scheme 1). In comparison with classical methods, such
† E-mail: kunesch@pharmacie.univ-paris5.fr.
(1) Bonin, M.; Grierson, D. S.; Royer, J .; Husson, H.-P. Org. Synth.
1992, 70, 54-59.
(2) (a) Husson, H.-P.; Royer, J . Adv. Use Synthons Org. Chem. 1995,
2, 1-68. (b) Husson, H.-P.; Royer, J . Chem. Soc. Rev. 1999, 28, 383-
394.
(3) (a) De Lombaert, S.; Lesur, B.; Ghosez, L. Tetrahedron Lett. 1982,
23, 4251-4254. (b) Ahlbrecht, H.; Dietz, M. Synthesis 1985, 417-421.
(4) (a) Viehe, H. G.; J anousek, Z.; Mere´nyi, R.; Stella, L. Acc. Chem.
Res. 1985, 18, 148-154. (b) Boucher, J .-L.; Stella, L. Tetrahedron 1985,
41, 875-887. (c) Viehe, H. G.; Mere´nyi, R.; J anousek, Z. Pure Appl.
Chem. 1988, 60, 1635-1644.
(5) (a) Schwarz, J . B.; Devine, P. N.; Meyers, A. I. Tetrahedron 1997,
53, 8795-8806. (b) Schwarz, J . B.; Meyers, A. I. J . Org. Chem. 1998,
63, 1619-1629. (c) Schwarz, J . B.; Meyers, A. I. J . Org. Chem. 1998,
63, 1732-1735.
as the use of NaBH4 or Na in liquid ammonia,11 this
10
new process permitted a very mild reductive elimination
(7) (a) Motorina, I. A.; Grierson, D. S. Tetrahedron Lett. 1999, 40,
7211-7214. (b) Motorina, I. A.; Grierson, D. S. Tetrahedron Lett. 1999,
40, 7215-7218.
(8) Baudhuin, M. The`se de Doctorat, Universite´ Catholique de
Louvain, 1989.
(9) Micouin, L. The`se de Doctorat, Universite´ Rene´-Descartes, Paris,
1995.
(6) (a) Sisti, N. J .; Zeller, E.; Grierson, D. S.; Fowler, F. W. J . Org.
Chem. 1997, 62, 2093-2097. (b) Motorina, I. A.; Fowler, F. W.;
Grierson, D. S. J . Org. Chem. 1997, 62, 2098-2105 and references
therein.
(10) Bonin, M.; Romero, J . R.; Grierson, D. S.; Husson, H.-P.
Tetrahedron Lett. 1982, 23, 3369-3372.
(11) Yamada, S.; Tomioka, K.; Koga, K. Tetrahedron Lett. 1976, 61-
64.
10.1021/jo990706f CCC: $19.00 © 2000 American Chemical Society
Published on Web 04/26/2000

3210 J . Org. Chem., Vol. 65, No. 10, 2000
Notes
Sch em e 2
of the cyano group while the oxazolidine ring remained
unchanged.
Structure 3 of the new phenyloxazolopiperidine12 ob-
tained as a single diastereomer was ascertained on the
basis of NMR. The correlations of H-2 with the axial
protons H-6 and H-7 in the 2D NOESY experiment
established the relative configuration of C-2 in respect
to H-7.13 Moreover, the coupling constant J H-2/H-3ax ) 9
Hz was in agreement with the axial position of H-2.14
Finally, the chemical shift at 2.85 ppm of the equatorial
proton H-6 was characteristic of the thermodynamically
more stable structure 3 in which both the nitrogen lone
pair and the phenyl ring contribute to the strong deshield-
ing.
Unsubstituted endocyclic enamines are very unstable
compounds. For instance, 1,2,3,4-tetrahydropyridine does
not exist as such, while the extremely reactive parent
imine is only isolated as a dimeric or trimeric form.15
Several publications16 reported attempts to overcome this
difficulty since six-membered cyclic enamines in their
monomeric form would be of great interest in organic
synthesis.17 In this context, the achiral N-(phenylmeth-
ylsilyl)-1,2,3,4-tetrahydropyridine was recently pre-
pared.18
In all respects, compound 3 constitutes a new stable
and chiral synthetic equivalent of 1,2,3,4-tetrahydro-
pyridine. Indeed, the enamine functionality (8) could be
revealed through equilibration with 3 in protic medium
or by heating (Scheme 1). Furthermore, the chiral
auxiliary can be easily removed by hydrogenolysis at the
end of the synthesis.
The access to these new related enamines 2 and 3 leads
us to report in this paper our first results concerning their
reactivity. Reaction of an enamine with diethyl acety-
lenedicarboxylate is a well-known procedure for construc-
tion of functionalized 1,2,3,4-tetrahydroazocines accord-
ing to a [2 + 2] thermal cycloaddition.19 When heated in
a polar aprotic solvent, the electron-rich carbon-carbon
double bond of the cyclic enamine reacts with the
electron-deficient alkyne to give an intermediate cy-
clobutene. Spontaneous ring opening of the unstable
cyclobutene affords ring-enlarged compounds according
to a well-investigated mechanism.20
We chose this reaction not only as an efficient method
to compare the reactivity of enamines 2a , 2b, and 3 with
that of compound 121 but also because there has been
increasing interest recently in the synthesis of eight-
membered ring systems such as azocines. This diverse
class of compounds often possesses biological activity22
and has been widely used in synthetic chemistry.23 It is
of note that this type of medium size ring nitrogen
heterocycle is not easily accessible and is interesting for
the design of conformationally restricted peptides.24
R-Cyanoenamine 2a appeared to be a very reactive
compound. Treatment with diethyl acetylenedicarboxy-
late in DMSO at 110 °C afforded in 30 min (48 h for
compound 121) a mixture of two diastereomeric cyano-
tetrahydroazocines. The major compound was isolated in
82% yield and characterized as 9 (Scheme 2). The
configuration at C-8 was assigned on the basis of the
NMR data we reported previously for analogues.21 This
reaction constitutes a very straightforward procedure for
the synthesis of chiral nonracemic tetrahydroazocines
possessing four different functionalities. R-Cyanoenamine
2b afforded 9 as the major compound under the same
reaction conditions.
Another new tetrahydroazocine, 10, was obtained in
excellent yield simply by heating 3 with diethyl acety-
lenedicarboxylate in DMSO for 3 h (Scheme 2).
In contrast to the bicyclic azocine 9, this new compound
was shown by NMR in various solvents (CDCl3, CD3OD,
DMSO-d6) to be a 6:4 mixture of two conformers. Indeed,
two singlets for the signal of H-2 at 7.77 and 7.90 ppm
were observed while the 13C NMR spectrum showed two
signals for each carbon atom. Heating a DMSO-d6 solu-
tion of 10 to 70 °C led to the coalescence of those signals
1
in the H NMR and the 13C NMR spectra.
It is well known25 that the azocine ring possesses
mostly a crown conformation, but there are also boat-
chair, chair-chair, and boat-boat conformations. In par-
ticular, this was not found in the related bicyclic deriva-
tive 9 which combines a tetrahydoazocine core and a
fused five-membered oxazolidine ring, assigning a con-
formationally restricted framework.
(12) 3 has been reported without characterization as a side reaction
product. Wong, Y.-S.; Marazano, C.; Gnecco, D.; Das, B. C. Tetrahedron
Lett. 1994, 35, 707-710.
(13) Guerrier, L.; Royer, J .; Grierson, D. S.; Husson, H.-P. J . Am.
Chem. Soc. 1983, 105, 7754-7755.
(14) Wong, Y.-S.; Marazano, C.; Gnecco, D.; Ge´nisson, Y.; Chiaroni,
A.; Das, B. C. J . Org. Chem. 1997, 62, 729-733.
(15) Scho¨pf, C.; Braun, F.; Komzak, A. Chem. Ber. 1956, 89, 1821-
1833.
(16) (a) Scully, F. E., J r. J . Org. Chem. 1980, 45, 1515-1517. (b)
De Kimpe, N.; Stevens, C. J . Org. Chem. 1993, 58, 2904-2906.
(17) Boyd, G. V. The chemistry of enamines: Heterocyclic synthesis
of enamines, Part 2; Rappoport, Z., Ed.; Wiley Interscience: New York,
1994.
(18) Hao, L.; Harrod, J . F.; Lebuis, A.-M.; Mu, Y.; Shu, R.; Samuel,
E.; Woo, H.-G. Angew. Chem., Int. Ed. 1998, 37, 3126-3129.
(19) Acheson, R. M.; Elmore, N. F. Advances in Heterocyclic Chem-
istry; Katritzky, A. R., Boulton, A. J ., Eds.; Academic Press: New York,
1978; Vol. 23, pp 263-482.
(22) (a) Andersen, R. J .; Van Soest, R. W. M.; Kong, F. In Alka-
loids: Chemical and Biological Perspectives; Pelletier, S. W., Ed.;
Elsevier Science Ltd.: Oxford, 1996; Vol. 10. (b) Vedejs, E.; Galante,
R. J .; Goekjian, P. G. J . Am. Chem. Soc. 1998, 120, 3613-3622.
(23) (a) Evans, P. A.; Holmes, A. B. Tetrahedron 1991, 47, 9131-
9166. (b) Ruder, S. M.; Norwood, B. K. Tetrahedron Lett. 1994, 35,
3473-3476. (c) Torisawa, Y.; Motohashi, Y.; Ma, J .; Hino, T.; Naka-
gawa, M. Tetrahedron Lett. 1995, 36, 5579-5580.
(24) Evans, P. A.; Holmes, A. B.; Russell, K. Tetrahedron Lett. 1992,
33, 6857-6858.
(20) Visser, G. W.; Verboom, W.; Reinhoudt, D. N.; Harkema, S.;
van Hummel, G. J . J . Am. Chem. Soc. 1982, 104, 6842-6844.
(21) Lallemand, M.-C.; Chiadmi, M.; Tomas, A.; Kunesch, N.;
Husson, H.-P. Tetrahedron Lett. 1995, 36, 2053-2056.
(25) Sutharchanadevi, M.; Murugan, R. In Eight-Membered Rings
with one Nitrogen Atom; Newkome, G. R., Ed.; Comprehensive
Heterocyclic Chemistry II, Katritzky, A. R., Rees, C. W., Scriven, E.
F. V., Eds.; Pergamon Press: New York, 1995; Vol. 9, pp 404-407.

Notes
To finalize this preliminary study of the use of building
J . Org. Chem., Vol. 65, No. 10, 2000 3211
7 (36%). Purification by flash chromatography over silica gel (85:
15 cyclohexanes-ethyl ether) gave 61 mg (35%) of R-cyano-
enamine 2a , 150 mg (14%) of R-cyanoenamine 2b, and 80 mg of
block 3 as a latent enamine, we investigated its reaction
with Michael acceptors such as methyl vinyl ketone
(MVK) to provide â-alkylated chiral nonracemic pip-
eridines or chiral annelated quinolones according to a
previously reported method.26 Reaction of 3 in MeOH
with a stoichiometric amount of MVK gave only piperi-
dine 11 (63% yield). The axial relationship between H-2
and H-3 (J H-2/H-3 ) 9 Hz) (Scheme 2) was in favor of the
configuration 2R,3R. This reaction could constitute a very
simple preparation with excellent stereocontrol of â-sub-
stituted piperidines. Furthermore, opening of the oxazo-
lidine ring is reported to afford stereocontrolled formation
of C-2,C-3 disubstituted piperidines.9
In summary, we have described an easy access to
compounds 2 and 3 which were found to be powerful
enamines by [2 + 2] cycloaddition reactions with diethyl
acetylenedicarboxylate. A further example of the enamine
reactivity of 3 was furnished by a stereocontrolled â-alky-
lation.
starting material 7. 2a : mp ) 100-104 °C (MeOH-ether); [R]20
D
) -297 (c 1, CHCl3); 1H NMR δ 1.70-1.78 (m, 1H, H-5), 2.26-
2.35 (m, 3H), 4.10 (dd, J ) 1.5, 8.5 Hz, 1H, H-8), 4.30 (dd, J )
6, 8.5 Hz, 1H, H-8), 4.72 (d, J ) 6 Hz, 1H, H-7), 4.81 (dd, J )
2.5, 10 Hz, 1H, H-6), 5.32 (brs, 1H, H-3), 7.32-7.41 (m, 5H); 13
C
NMR δ 21.2, 26.0, 61.6, 73.7, 87.4, 114.0, 115.1, 115.7, 127.7,
128.0, 128.6, 141.0; IR (film) 2223, 1669, 1608 cm-1; MS m/z 227
(M + 1)+. Anal. Calcd for C14H14N2O: C, 74.31; H, 6.24; N, 12.38.
Found: C, 74.21; H, 6.39; N, 12.21. 2b: [R]20 ) -245 (c 1,
D
CHCl3); 1H NMR δ 1.70-1.80 (m, 1H), 2.05-2.38 (m, 3H), 3.82
(dd, J ) 6.5, 8.5 Hz, 1H, H-8), 4.35 (dd, J ) 6.5, 8.5 Hz, 1H,
H-8), 4.65 (t, J ) 6.5 Hz, 1H, H-7), 4.95 (dd, J ) 3.5, 7 Hz, 1H,
H-6), 5.67 (t, J ) 4.5 Hz, 1H, H-3), 7.28-7.48 (m, 5H); 13C NMR
δ 19.0, 24.7, 64.5, 72.2, 87.8, 115.6, 118.9, 119.5, 126.7, 127.9,
128.6, 139.5; IR (film) 2223, 1670, 1610 cm-1; MS m/z 227 (M +
1)+; HRMS (CI, CH4) m/z (M + 1)+ calcd for C14H15N2O 227.1184,
found 227.1177.
P h en yloxa zolop ip er id in e (3). Compound 1 (5 g, 2.19 mmol)
was dissolved in THF (100 mL). Raney nickel (25 g, W-2, 50%
slurry in water) was added and the suspension refluxed for 20
h. The reaction mixture was then filtered on Celite with MeOH
(400 mL). The filtrate was dried over anhydrous Na2SO4 and
concentrated under vacuum to give an oily residue (4.35 g).
Compound 3 was isolated after flash chromatography on silica
gel (90:10 cyclohexanes-ether) and crystallized from cyclohexane
We are continuing our exploration of the synthetic
potential of these two useful building blocks toward
asymmetric syntheses.
(colorless crystals, 3.5 g, 79%): mp ) 38-41 °C; [R]20 ) -103
D
Exp er im en ta l Section
1
(c 1, CHCl3); H NMR δ 1.30-1.45 (m, 1H, H-4), 1.48-1.61 (m,
Gen er a l Meth od s. 1H and 13C NMR spectra of CDCl3
solutions were recorded at 300 and 75 MHz (Bruker, AC-300),
respectively. Mass spectra (low resolution) were obtained in the
chemical ionization mode with NH3 on a Nermag/Sidar V 2.3.
Fourier transform infrared absorption spectra were recorded on
a Perkin-Elmer 1600 spectrophotometer. Optical rotations were
determined at room temperature with a Perkin-Elmer 141 MC
polarimeter and are referenced to the D-line of sodium. Con-
centrations were performed under reduced pressure with a Bu¨chi
rotary evaporator. Melting points were measured with a Leica
Galen III apparatus. Starting materials and solvents were
purchased from commercial sources. Tetrahydrofuran was dried
via distillation from sodium-benzophenone ketyl. Flash chro-
matography was carried out on silica gel (20-45 µm).
3H), 1.85-1.89 (m, 1H), 1.97-2.05 (m, 2H), 2.85 (br d, J ) 10.5
Hz, 1H, H-6), 3.53 (t, J ) 8 Hz, 1H, H-7), 3.65 (t, J ) 8 Hz, 1H,
H-8), 3.68 (dt, J ) 3, 9 Hz, 1H, H-2), 4.17 (t, J ) 8 Hz, 1H, H-8),
7.26-7.40 (m, 5H); 13C NMR δ 22.5, 24.8, 30.3, 47.8, 67.1, 72.9,
94.6, 127.6, 127.7, 128.4, 138.9; MS m/z 204 (M + 1)+. Anal.
Calcd for C13H17NO: C, 76.81; H, 8.43; N, 6.89. Found: C, 76.75;
H, 8.15; N, 6.96.
2-Cya n otetr a h yd r oa zocin e (9). Diethyl acetylenedicar-
boxylate (0.1 mL, 106 mg, 0.62 mmol) was added to a solution
of R-cyanoenamine 2a (100 mg, 0.44 mmol) in dry DMSO (2 mL).
The reaction mixture was heated at 110 °C under an argon
atmosphere for 30 min. After cooling, the reaction mixture was
diluted with water (10 mL) and extracted with CH2Cl2. The
organic layer was dried over anhydrous Na2SO4 and evaporated
to dryness under reduced pressure. Purification by flash chro-
matography (1:1 cyclohexanes-ether) of the crude residue
furnished the major diastereomer as an oily product (144 mg,
2,2-Dicya n op h en yloxa zolop ip er id in e (7). To a stirred
solution of diisopropylamine (4.05 mL, 28.9 mmol) in anhydrous
THF (10 mL) at 0 °C was added n-butyllithium (2.5 M in
hexanes, 11.6 mL, 28.9 mmol) under an argon atmosphere. The
mixture was stirred at 0 °C for 30 min and then cooled at -78
°C for 20 min, at which time 2-cyanophenyloxazolopiperidine 1
(2.19 g, 9.6 mmol) in anhydrous THF (40 mL) was added
dropwise over 7 min. The solution was stirred at -78 °C for 20
min, and a solution of tosyl cyanide (3.34 g, 18.4 mmol) in
anhydrous THF (30 mL) was added dropwise. The mixture was
then stirred for 4 h at -78 °C and quenched with a saturated
aqueous solution of NH4Cl. The aqueous phase was extracted
(three times) with CH2Cl2, and the combined organic phases were
dried over anhydrous Na2SO4 and concentrated. Flash chroma-
tography of the residue (80:20 cyclohexanes-ether) provided 1.56
g (67%) of dicyano compound 7. Colorless crystals were obtained
82%): [R]20 ) +21 (c 1, CHCl3); 1H NMR δ 1.0-1.5 (m, 6H),
D
1.7-2.0 (m, 2H), 2.5-2.8 (m, 2H), 3.82 (dd, J ) 3, 9 Hz, 1H),
3.9-4.4 (m, 5H), 5.22 (dd, J ) 3, 7 Hz, 1H), 5.92 (dd, J ) 3, 9
Hz, 1H), 6.82 (dd, J ) 8, 9 Hz, 1H), 7.1-7.5 (m, 5H); 13C NMR
δ 13.7, 13.8, 23.9, 24.8, 61.0, 61.5, 66.4, 71.3, 90.2, 113.4, 113.6,
126.1, 127.9, 128.7, 131.3, 140.8, 140.9, 165.2, 165.5; IR (film)
2200, 1735, 1610, 1247 cm-1; MS m/z 397 (M + 1)+.
Tet r a h yd r oa zocin e (10). To a solution of phenyloxazolo-
piperidine 3 (1 g, 4.9 mmol) in dry DMSO (10 mL) was added
diethyl acetylenedicarboxylate (1.02 mL, 1.09 g, 6.4 mmol), and
the solution was stirred under an argon atmosphere at 110 °C
for 3 h. After cooling, the mixture was diluted with CH2Cl2 and
washed 10 times with water. After drying over anhydrous
Na2SO4 and concentration under vacuum, the crude residue (2.6
g) was purified by flash chromatography over silica gel (97:3 CH2-
from cyclohexanes-ether (80:20): mp ) 134-135 °C; [R]20
)
D
-151 (c 1, CHCl3); 1H NMR δ 1.60-1.80 (m, 2H), 2.00-2.30 (m,
3H), 2.33-2.38 (m, 1H), 3.90 (dd, J ) 7, 8.5 Hz, 1H, H-8), 4.05
(dd, J ) 7, 8.5 Hz, 1H, H-7), 4.09 (dd, J ) 3, 10.5 Hz, 1H, H-6),
4.33 (t, J ) 8.5 Hz, 1H, H-8), 7.40-7.55 (m, 5H); 13C NMR δ
19.1, 28.6, 36.4, 52.1, 64.2, 73.7, 90.4, 111.0, 112.3, 128.4, 128.8,
129.1, 137.4; IR (film) 2362, 2344 cm-1; MS m/z 254 (M + 1)+.
Anal. Calcd for C15H15N3O: C, 71.13; H, 5.97; N, 16.59. Found:
C, 70.96; H, 6.11; N, 16.41.
Cl2-MeOH) to afford compound 10 (1.71 g, 93%), as an orange
1
oil: [R]20 ) -20 (c 1, CHCl3); H NMR (mixture of isomers) δ
D
0.8-1.1 (m, 2H), 1.1-1.2 (m, 6H), 1.24-1.33 (m, 8H), 2.0-2.4
(m, 4H), 2.4-2.6 (m, 2H), 2.78 (dd, J ) 3, 14 Hz, 1H), 2.90 (dd,
J ) 3, 14 Hz, 1H), 3.25 (brs, 1H), 3.83 (dt, J ) 3, 14 Hz, 1H),
3.9-4.2 (m, 12H), 4.2-4.4 (m, 2H), 6.2-6.3 (m, 2H), 7.26-7.40
1
(m, 10H), 7.77 (s, 1H), 7.90 (s, 1H); H NMR (DMSO-d6, 70 °C)
R-Cya n oen a m in es 2a a n d 2b. Compound 7 (500 mg, 1.97
mmol) was heated at 170-190 °C under reduced pressure (20
mmHg) for 5 h. The ratio of the different compounds in the crude
residue (452 mg) was estimated by 1H NMR: 2a (48%), 2b (16%),
δ 1.02 (t, J ) 7 Hz, 3H), 1.11 (t, J ) 7 Hz, 3H), 1.15 (m, 1H),
2.26 (brm, 2H), 3.2-3.6 (m, 5H), 3.87 (m, 4H), 4.01 (q, J ) 7
Hz, 2H), 4.25 (t, J ) 6.5 Hz, 1H), 6.04 (t, J ) 8.5 Hz, 1H), 7.1-
7.3 (m, 5H), 7.59 (s, 1H); 13C NMR (mixture of isomers) δ 14.1,
17.6, 18.6, 24.9, 25.0, 42.7, 45.1, 59.7, 60.4, 60.5, 61.9, 70.9, 71.9,
92.7, 93.1, 127.4, 127.6, 128.2, 128.6, 133.9, 134.4, 134.6, 136.3,
137.1, 149.7, 150.0, 169.5, 169.6; 13C NMR (DMSO-d6, 70 °C) δ
14.3, 14.5, 18.2, 25.1, 44.9, 59.0, 59.9, 62.2, 71.3, 93.0, 128.0,
(26) (a) Stevens, R. V.; Mehra, R. K.; Zimmerman, R. L. J . Chem.
Soc., Chem. Commun. 1969, 877-878. (b) Stevens, R. V.; Hrib, N. J .
Chem. Soc., Chem. Commun. 1983, 1422-1424.

3212 J . Org. Chem., Vol. 65, No. 10, 2000
Notes
128.1, 128.8, 133.9, 134.9, 138.6, 149.5, 168.3, 168.6; IR (film)
3400, 1674, 1579, 1252 cm-1; MS m/z 374 (M + 1)+; HRMS (CI,
CH4) m/z (M + 1)+ calcd for C21H28NO5 374.1967, found
374.1974.
J ) 8 Hz, 1H), 7.25-7.45 (m, 5H); 13C NMR δ 24.8, 26.5, 29.3,
29.8, 40.5, 41.6, 47.5, 66.9, 72.9, 99.2, 127.6, 128.4, 138.9, 209.2;
IR (film) 1743 cm-1; MS m/z 274 (M + 1)+; HRMS (CI, CH4) m/z
(M + 1)+ calcd for C17H23NO2 273.1729, found 273.1732.
P ip er id in e (11). A solution of phenyloxazolopiperidine 3 (225
mg, 1.1 mmol) and MVK (77 mg, 0.09 mL, 1.1 mmol) in methanol
was refluxed for 4 h. Then the reaction mixture was concentrated
and the crude material submitted to a flash chromatography
over silica gel (85:15 cyclohexanes-ether) affording 11 as a
colorless oil (191 mg, 63%): [R]20D ) - 80 (c 1, CHCl3 ); 1H NMR
δ 0.92-1.10 (m, 1H), 1.45-1.65 (m, 4H), 1.70-2.05 (m, 3H), 2.15
(s, 3H), 2.45-2.70 (m, 2H), 2.81 (b d, J ) 11 Hz, 1H), 3.37 (d, J
) 9 Hz, 1H), 3.48 (t, J ) 8 Hz), 3.59 (t, J ) 8 Hz, 1H), 4.13 (t,
Su p p or tin g In for m a tion Ava ila ble: Su p p or tin g In -
1
for m a tion Ava ila ble: H NMR and 13C NMR spectra for all
compounds, 2D-experiments (1H-1H and/or 13C-1H) for 2a ,
1
2b, 3, and 7 and (NOESY) for 2b and 3, and H and 13C NMR
spectra at high temperature for 10. This material is available
free of charge via the Internet at http://pubs.acs.org.
J O990706F