Selective reductions of 1-methyl-4-phenyl-2-pyridone

Article abstract of DOI:10.1021/jo951529v

We have explored the reactions of 1-methyl-4-phenyl-2-pyridone (5) with various reducing agents in an effort to develop synthetic approaches to specifically deuterium-labeled 1,4-disubstituted 1,2,3,6-tetrahydropyridine analogs needed for metabolic and enzyme mechanistic studies. Reactions with NaBH₄ in CH₃OH or THF, LiAl(O-t-Bu)₃H in THF, and Al(i-Bu)₂H (DIBALH) in THF resulted in quantitative recovery of starting material. On the other hand, treatment with BH₃ in THF unexpectedly led to the formation of 4-phenylpyridine (7) in 98% yield. LiAlH₄ in THF or Et₂O and Red-Al in THF gave varying amounts of the 3,6-dihydro-2-pyridone 8 and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (1). In the presence of TiCl₃, LiAlH₄ in THF at 0°C converted 5 to 1 in 97% yield. LiB(s-Bu)₃H (L-Selectride) in THF gave exclusively the 1,4-reduction product 8. Base catalyzed isomerization of 8 provided the conjugated 5,6-dihydro-2-pyridone 4. The applications of these reactions with deuterated reagents provide insights into the reaction pathways and several avenues for the regioselective synthesis of the required deuterium-labeled compounds.

Full text of DOI:10.1021/jo951529v

J . Org. Chem. 1996, 61, 309-313
309
Selective Red u ction s of 1-Meth yl-4-p h en yl-2-p yr id on e
Ste´phane Mabic and Neal Castagnoli, J r.*
Department of Chemistry, Virginia Tech, Blacksburg, Virginia 24061
Received August 18, 1995X
We have explored the reactions of 1-methyl-4-phenyl-2-pyridone (5) with various reducing agents
in an effort to develop synthetic approaches to specifically deuterium-labeled 1,4-disubstituted
1,2,3,6-tetrahydropyridine analogs needed for metabolic and enzyme mechanistic studies. Reactions
with NaBH4 in CH3OH or THF, LiAl(O-t-Bu)3H in THF, and Al(i-Bu)2H (DIBALH) in THF resulted
in quantitative recovery of starting material. On the other hand, treatment with BH3 in THF
unexpectedly led to the formation of 4-phenylpyridine (7) in 98% yield. LiAlH4 in THF or Et2O
and Red-Al in THF gave varying amounts of the 3,6-dihydro-2-pyridone 8 and 1-methyl-4-phenyl-
1,2,3,6-tetrahydropyridine (1). In the presence of TiCl3, LiAlH4 in THF at 0 °C converted 5 to 1 in
97% yield. LiB(s-Bu)3H (L-Selectride) in THF gave exclusively the 1,4-reduction product 8. Base
catalyzed isomerization of 8 provided the conjugated 5,6-dihydro-2-pyridone 4. The applications
of these reactions with deuterated reagents provide insights into the reaction pathways and several
avenues for the regioselective synthesis of the required deuterium-labeled compounds.
In tr od u ction
As part of our mechanistic and metabolic studies on
the monoamine oxidase-catalyzed oxidation of the neu-
rotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
(MPTP, 1) leading to the corresponding dihydropyri-
dinium 2 and pyridinium 3 products,1-3 we required
synthetic routes to regiospecifically deuterium- and tri-
tium-labeled 1,4-disubstituted tetrahydropyridine deriva-
tives. The synthesis of the 6,6-d2 analog 1-6,6-d 2 has
been achieved by reduction of 1-methyl-4-phenyl-5,6-
dihydro-2-pyridone (4) with LiAlD4.4 This approach,
however, appeared to be limited in terms of the regio-
chemistry (only the 6,6-d2 analog could be prepared) and
suffered from the poor overall yield of the starting
dihydropyridone.5,6 The only other relevant literature
of our studies on the reduction of 5 with diverse boron-
and aluminum-containing hydride reagents.
report describes the preparation of racemic 1-6-d 1 via
reduction of the corresponding dihydropyridinium species
2.7,8
Resu lts
We recently developed a high yield synthesis of 1-meth-
yl-4-phenyl-2-pyridone (5)9 and therefore elected to focus
our attention on reductions of this intermediate that
could provide approaches to selectively deuterated prod-
ucts. Previous attempts to control the catalytic hydro-
genation of 5 to generate a dihydro-2-pyridone product
that might be useful for subsequent conversion to the
corresponding deuterated amine gave only the corre-
sponding 2-piperidone 6.4 Consequently, we turned our
attention to metal hydrides that might provide the
required selectivity. In this paper, we report the results
Tables 1, 2 and 3 and Schemes 1 and 2 summarize the
salient results of these studies. Only starting material
was recovered after prolonged treatment of 5 with NaBH4
in either THF or CH3OH (Table 1). On the other hand,
reaction with BH3 in THF, a well-known reagent for the
reduction of amides to amines,10 led to the consumption
of all of the starting lactam. The product isolated from
this reaction in high yield proved to be 4-phenylpyridine
1
(7), which was readily identified by comparison of its H
NMR and GC-EI mass spectra with those of an authen-
tic sample. Treatment of 5 with LiB(s-Bu)3H (L-Selec-
tride, Aldrich) in THF at -35 °C also resulted in complete
reaction but in this case led to the selective formation in
high yield of a product which displayed GC-EI mass
spectral characteristics consistent with a dihydropyridone
X Abstract published in Advance ACS Abstracts, November 15, 1995.
(1) Chiba, K.; Trevor, A.; Castagnoli, N., J r. Biochem. Biophys. Res.
Commun. 1984, 120, 574-578.
(2) Singer, T. P.; Ramsay, R. R.; McKeown, K.; Trevor, A.; Castag-
noli, N. J . J . Toxicol. 1988, 49, 17.
(3) Langston, J . W.; Irwin, I.; Langston, E. B.; Forno, L. S. Neurosci.
Lett. 1984, 48, 87.
(4) Ottoboni, S.; Caldera, P.; Trevor, A.; Castagnoli, N. J . J . Biol.
Chem. 1989, 264, 13684-13688.
(5) Wu, E.; Shinka, T.; Caldera-Munoz, P.; Yoshizumi, H.; Trevor,
A.; Castagnoli, N. J . Chem. Res. Toxicol. 1988, 1, 186-194.
(6) Mo¨hrle, H.; Weber, H. Tetrahedron 1970, 26, 2953-2958.
(7) Gessner, W.; Brossi, A.; Shen, R.-S.; Fritz, R. R.; Abell, C. W.
Helv. Chem. Acta 1984, 67, 2037-2042.
(8) Gessner, W.; Brossi, A.; Bembenek, M. E.; Fritz, R. R.; Abell, C.
W. FEBS Lett. 1986, 199, 100-102.
(9) Mabic, S.; Castagnoli, N. J . J . Labelled Comp. Radiopharm.
1995, in press.
1
structure. The H NMR spectrum clearly identified this
product as 1-methyl-4-phenyl-3,6-dihydro-2-pyridone (8).
Base- or acid-catalyzed isomerization of 8 to 4 confirmed
this assignment.
We next examined the reaction of 5 with a variety of
aluminum hydride reagents. LiAl(O-t-Bu)3H in THF and
Al(i-Bu)2H (DIBALH) in THF were without effect on the
lactam. Al(i-Bu)2H in Et2O was more reactive. All of the
(10) Lane, C. F. Chem. Rev. 1976, 76, 773-799.
0022-3263/96/1961-0309$12.00/0 © 1996 American Chemical Society

310 J . Org. Chem., Vol. 61, No. 1, 1996
Mabic and Castagnoli
Ta ble 1. Red u ction s of 1-Meth yl-4-p h en yl-3,5-d ih yd r o-2-p yr id on e (5) w ith Va r iou s Meta l Hyd r id esa
% yield
reagent
time (h)
temp (°C)
pyridone 5
dihydropyridone 8
tetrahydropyridine 1
phenylpyridine (7)
NaBH4/MeOH
NaBH4/THF
6
15
11
0.75
16
15
4
3
7
2
25
99
99
reflux
reflux
-35
reflux
reflux
25
15
25
0
BH3‚THF/THFb
L-Selectride/THFb,c
LiAl(O-t-Bu)3H/THF
DIBALH/THF
DIBALH/Et2O
Red-Al/THFd
99
99
96
95
4
5
61
32
37
75
39
30
34
25
32
27
6
3
LiAlH4/Et2O
LiAlH4/THFb
a
b
d
Yields estimated by GC-MS unless otherwise noted. Yields after purification. c L-Selectride ) Li(s-butyl)3BH. Red-Al
)
[NaAl(CH3OCH2CH2O)2H2].
Ta ble 2. Red u ction of 1-Meth yl-4-p h en yl-2-p yr id on e (5)
w ith LiAlH4 in th e P r esen ce of Tr a n sition Meta ls
Sch em e 1
% yield
temp
reagent
time
15 h
45 min
25 min
40 min
5 h
(°C)
5
8
1
NaBH4/CoCl2‚6H2O/EtOH
LiAlH4/TiCl3/THF
LiAlH4/TiCl3/THF
LiAlH4/TiCl4/THF
LiAlH4/CoCl2‚6H2O/THF
reflux
-20
0
-10
25
99
5
1
7
99
38
2
35
57
97
58
starting material was consumed after 4 h at room
temperature, and two products were produced. One of
the products formed in this reaction (39% yield) was
readily identified as the tetrahydropyridine 1 by com-
parison with the synthetic standard. The second major
product (61% yield) was characterized as the same 3,6-
dihydro-2-pyridone (8) that was obtained with L-Selec-
tride.
reductions. These reactions were complete within 45 min
at -20 to -10 °C (compared to the 6 h at 25 °C with
LiAlH4 alone) and gave a 6:4 ratio of 1 to 8. With TiCl3
at 0 °C, the tetrahydropyridine 1 was obtained in 97%
yield within 30 min, a result comparable to that reported
by Ferles who used lithium aluminum hydride in the
The reaction of 5 with other aluminum hydride reduc-
ing agents also produced mixtures of products. NaAl-
[(CH3OCH2CH2O)2H2] (Red-Al) in THF under relatively
mild conditions gave a mixture of 1, 7, 8, and starting
material. An extended reaction time or higher reaction
temperature with Red-Al led to the formation of ad-
ditional side products that were detected by GC-EIMS
which were not further characterized. Reductions of
2-pyridone derivatives with LiAlH4 have been reported
by Holik and Ferles to be a good route to the correspond-
ing 1,2,3,6-tetrahydropyridines.11-13 These workers also
noted the formation of a dihydro-2-pyridone intermediate
during the course of the reaction. In our hands, reduction
of 5 with LiAlH4 in Et2O gave mixtures of products. The
tetrahydropyridine 1 was detected early in the reaction,
and variations in temperature and stoichiometry of the
reagents did not prevent its formation. LiAlH4 in THF
gave the dihydro-2-pyridone 8 in 75% yield but even with
these optimized conditions compound 1 was a major
byproduct.
presence of AlCl3 (1 h reaction in boiling THF).13
A
summary of the reaction pathways observed with these
reductions of 5 is presented in Scheme 1.
With the dual purpose of examining deuteration pat-
terns and gaining insight into the pathways associated
with these reactions, the incorporation of deuterium into
the products generated in the LiAlH4 reaction was
investigated with the use of deuterated reagents. The
2-pyridone 5 was allowed to react at ambient tempera-
ture for 20 min with LiAlH4 or LiAlD4 in THF following
which the reaction mixtures were quenched either with
CH3OH or CD3OD (Table 3 and Scheme 2). The reaction
mixtures were analyzed by GC-EIMS, and the reduction
products (the 3,6-dihydro-2-pyridone 8 and the tetrahy-
dropyridine 1) were separated by column chromatogra-
In an attempt to enhance reactivity, the reactions with
NaBH4 and LiAlH4 were conducted in the presence of
1
phy and analyzed by H NMR spectroscopy. Treatment
with LiAlD4 in THF followed by a CH3OH workup (path
a) gave a monodeuterated dihydro-2-pyridone that was
characterized as 8-6-d 1 and a tetradeuterated tetrahy-
dropyridine that was characterized as 1-2,2,3,6-d 4. The
corresponding reaction employing LiAlH4 followed by a
CD3OD workup (path b) yielded the dideuterodihydro-
pyridone 8-3,3-d 2 and the tetrahydropyridine 1 contain-
ing no deuterium. Finally, LiAlD4 and a CD3OD workup
(path c) gave 8-3,3,6-d 3 and 1-2,2,3,6-d 4. Thus, in the
case of the dihydropyridone reduction products, the
hydride (deuteride) reagent introduced the protons (or
deuterons) at the C-6 position, while the solvent provided
the protons (or deuterons) at C-3. In the case of the
CoCl2‚6H2O,14 TiCl3,15 and TiCl4 (Table 2), transition
16
metals that are known to increase the reducing potency
of metal hydrides. The titanium chlorides enhanced
greatly the reactivity, but not the selectivity of the LiAlH4
(11) Ferles, M.; Holik, M. Collect. Czech. Chem. Commun. 1966, 31,
2416-2422.
(12) Ferles, M.; Attia, A.; Silhankova, A. Collect. Czech. Chem.
Commun. 1973, 38, 615-619.
(13) Holik, M.; Tesarova, A.; M., F. Collect. Czech. Chem. Commun.
1967, 32, 1730-1737.
(14) Chung, S. K. J . Org. Chem. 1979, 44, 1014-1016.
(15) Ashby, E.; Lin, J . J . J . Org. Chem. 1978, 43, 2567-2572.
(16) Sato, F.; Sato, S.; Sato, M. J . Organomet. Chem. 1977, 131,
C26-C28.

Selective Reductions of 1-Methyl-4-phenyl-2-pyridone
J . Org. Chem., Vol. 61, No. 1, 1996 311
Ta ble 3. Deu ter iu m In cor p or a tion Accom p a n yin g th e Red u ction of 1-Meth yl-4-p h en yl-2-p yr id on e (5) in THF
MPTP 1
dihydropyridone 8
system
d0
d1
d2
d3
d4
d0
d1
d2
d3
d4
LiAlH4/CH3OH
LiAlD4/CH3OH
LiAlH4/CD3OD
LiAlD4/CD3OD
1.00
0
1.00
0
0
0
0
0
0
0.04
0
0
0
0.10
0
0
0.86
0
1.00
0
0
0
0
0
0
0
0
0
0
0
0.96
0.03
0
0.04
0.97
0.15
0.08
0.92
0.78
0.07
Sch em e 2
when treated with BH3/THF, it may be reasonable to
propose that in this case the 1,2-reduction product 9
undergoes an alternative, intramolecular hydride trans-
fer reaction (pathway b) that is accompanied by C-N
bond scission to yield the observed 4-phenylpyridine (7)
as shown in Scheme 4. The stability of 7 may account
for the unexpected behavior of 9.
Although spectroscopic evidence17 argues that the
lactam is the energetically preferred form of the starting
material 5, the general behavior of this molecule toward
hydride reagents may be better described in terms of the
corresponding oxypyridine form. This form in general
will be favored in the presence of metallic cations because
of the increased stabilization gained through resonance
of the resulting pyridinium species 10 (Scheme 5).18-21
In this case, 1,4 attack by the various hydride reagents
examined will afford intermediate 11. The presence of
weak ions (1-5%) with m/z values corresponding to the
pyridone +30 amu (AlH3) or 33 amu (AlD3) in hydride/
deuteride reaction mixtures indicates that metal com-
plexes (such as 10) could be involved and supports the
hypothesis of a chelation of the metal to the pyridone.
Sch em e 3
The results obtained with LiAlD4 (Table 3, Scheme 2)
provide some support for this pathway. Thus, the
deuterium found at C-6 of 8 is derived exclusively from
the LiAlD4 while the protons or deuterons at C-3 are
derived from solvent. Since workup with CD3OD intro-
duces two deuterium atoms at C-3 (8-3,3,6-d 3 and 8-3,3-
d 2), we postulate the further conversion of 11 to the
bismetallic species 12 which, upon treatment with CD3-
OD, would lead to the 3,3-d2 products. The possibility
that the protons at C-3 may undergo exchange could be
ruled out since 8-3,3-d 2 was stable in the presence of
NaOH and H2O during the workup.
Sch em e 4
The second product formed in this reaction is the
tetrahydropyridine 1. This product may be formed via
the pathway 13 f 14 f 15 f 1 as shown in Scheme 5.
The results with the deuterated reagents provide some
support for this sequence. Workup of intermediate 15
(R ) D) derived from the LiAlD4 reaction with CH3OH
gave 1-2,2,3,6-d 4 rather than the tetrahydropyridine
bearing only three deuterium atoms (i.e., 1-2,6,6-d 3) that
would result from replacement of the carbon-metal bond
with H from the CH3OH. Similarly, workup of the
LiAlH4 reaction product 15 (R ) H) with CD3OD gave
the d0 product (1-d 0) rather than the monodeuterated
product (1-1-d 1). To account for these results, we propose
that the metal bonded at C-3 in intermediate 15 is
displaced by H- or D- to yield the final products observed
in the reactions. Analogous incorporation results were
observed with the LiAlH4 and LiAlD4 reductions of the
1-methyl-4-phenylpyridinium species 3 (Scheme 3). For
tetrahydropyridine reduction products the hydride (deu-
teride) reagent was the source of all newly introduced
protons (or deuterons). In order to provide additional
evidence for the pathways leading to the incorporation
patterns observed in these experiments, we also exam-
ined reduction of the pyridinium compound 3 (Scheme
3). As predicted from the above results, LiAlD4 followed
by CH3OH or CD3OD workup gave 1-2,3,6-d 3 whereas
LiAlH4 followed by CH3OH or CD3OD work-up gave 1-d 0,
that is, all newly introduced protons (deuterons) in the
tetrahydropyridine product were derived from the hy-
dride (deuteride) reagent.
Discu ssion
The conversion of the pyridone 5 to 4-phenylpyridine
(7) by BH3 was unexpected since BH3 in THF is a well-
known reagent for the reduction of amides to amines.10
The pathway for this reaction is likely to proceed via the
1,2-reduction product 9 (Scheme 4). Intermediates such
as 9 normally undergo elimination to form the corre-
sponding iminium species (pathway a); in this case, the
pyridinium compound 3. Since compound 3 is stable
(17) Klinsberg, E. Heterocyclic compounds: pyridine and derivatives;
J ohn Wiley & Sons: New York, 1962; Vol. 3.
(18) Wigfield, D. C. Tetrahedron 1979, 35, 449-462.
(19) Handel, H.; Pierre, J . L. Tetrahedron 1975, 31, 2799-2802.
(20) Handel, H.; Pierre, J . L. Tetrahedron 1975, 31, 997-1000.
(21) Pierre, J . L.; Handel, H.; Perraud, R. Tetrahedron 1975, 31,
2795-2798.

312 J . Org. Chem., Vol. 61, No. 1, 1996
Mabic and Castagnoli
Sch em e 5
hydrogenperoxide (5 mL) was added slowly followed by 3 M
NaOH (2 mL). This mixture was extracted with Et2O (3 × 20
mL), and the combined organic phase was washed with brine,
dried over MgSO4, and evaporated to give pure 8 (186 mg, 99%)
as a white solid: mp 88-89 °C; 1H-NMR (CDCl3, 270 MHz) δ
7.37 (m, 5H), 6.10 (tt, J ) 1.6, 3.4 Hz, 1H), 4.10 (dd, J ) 4.8,
3.4 Hz, 2H), 3.35 (dd, J ) 1.6, 4.8 Hz, 2H), 3.07 (s, 3H); 13C
NMR (CDCl3, 68 MHz) δ 167.6, 138.3, 132.9, 128.59, 127.9,
124.8, 116.2, 76.0, 51.2, 33.8; GC-MS (EI) m/z (rel int) 187
example, the observed formation of 1-2,3,6-d 3 from the
reaction with LiAlD4 followed by workup with CH3OH
requires that all three newly introduced atoms be derived
from the hydride reducing reagent. This incorporation
pattern was achieved only following prolonged reaction
times, suggesting that the C3-M bond, if present, is
cleaved slowly.
(100), 158 (49), 144 (53), 129 (31), 115 (54); IR (CHCl3, cm-1
)
Con clu sion
1640, 1515, 1477, 1219, 1018; UV (MeOH, nm) 250, 206. Anal.
Calcd for C12H13NO: C, 76.98; H, 7.00; N, 7.42. Found: C,
76.77; H, 7.23; N, 7.32.
In conclusion, we have exploited the selective reactivity
of various hydride reagents to achieve reductions of
1-methyl-4-phenyl-2-pyridone that can be applied to the
regioselective synthesis of deuterium-labeled 1,4-disub-
stituted 1,2,3,6-tetrahydropyridines of biological interest.
L-Selectride gives the 3,6-dihydro-2-pyridone 8 that can
be isomerized to the conjugated 5,6-dihydro-2-pyridone
4, whereas borane leads to 4-phenylpyridine 7. In
addition to dihydropyridones and phenylpyridine, the
1,2,3,6-tetrahydropyridine 1 was readily obtained by
reduction of the 2-pyridone with LiAlH4 in the presence
of TiCl3. The starting 2-pyridone, therefore, can lead to
four compounds in excellent yields depending on the
reduction system used.
1-Meth yl-4-p h en yl-5,6-d ih yd r o-2-p yr id on e (4). Alk a l-
in e Con d ition s. To a stirred solution of the 3,6-dihydro-2-
pyridone 8 (50 mg, 0.27 mmol) in 2-methyl-2-propanol (8 mL)
was added potassium tert-butoxide (105 mg, 0.94 mmol). After
the mixture was stirred for 18 h at ambient temperature, HCl
(200 µL, 37%) was added, and after the addition of water (12
mL), the reaction mixture was extracted with Et2O (3 × 15
mL). The combined organic phase was washed with water and
brine, dried over MgSO4, and evaporated under reduced
pressure to give 49 mg (98%) of pure 1-methyl-4-phenyl-5,6-
dihydro-2-pyridone (4) as a white solid. Acid ic Con d ition s.
A mixture of the 3,6-dihydro-2-pyridone 8 (50 mg, 0.27 mmol),
p-toluenesulfonic acid (160 mg, 1 mmol), and toluene (8 mL)
was heated under reflux for 16 h. After cooling, water (10 mL)
was added, and the resulting mixture was extracted with Et2O
(3 × 10 mL). The combined organic phase was washed with
water and brine, dried over MgSO4, and evaporated under
reduced pressure to give 49 mg (98%) of the dihydropyridone
4 as a white solid: mp 94-95 °C (lit.5 mp 94-95 °C); 1H-NMR
(CDCl3, 270 MHz) δ 7.53 (m, 2H), 7.49 (m, 3H), 6.30 (t, J )
1.4 Hz, 1H), 3.58 (t, J ) 7.1 Hz, 2H), 3.02 (s, 3H), 2.81 (td, J
) 1.4, 7.1 Hz, 2H); 13C NMR (CDCl3, 68 MHz) δ 165.6, 148.9,
137.5, 129.4, 128.7, 125.7, 119.9, 47.5, 34.2, 26.4; GC-MS (EI)
m/z (rel int) 187 (83), 158 (11), 144 (100), 129 (10), 115 (78);
IR (CHCl3, cm-1) 1634, 1528, 1477, 1218, 1018; UV (MeOH,
nm) 272, 260, 216, 210.
Exp er im en ta l Section
Caution: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (1)
is a known nigrostriatal neurotoxin and should be handled
using disposable gloves in a properly ventilated hood. Detailed
procedures for the safe handling of MPTP have been re-
ported.22
Gen er a l. See ref 9.
4-P h en ylp yr id in e (7). The pyridone 5 prepared following
the reported procedure9,23 (1 mmol, 185 mg) was dissolved in
anhydrous THF (15 mL), and BH3‚THF (5 mL, 1 M, 5 mmol)
was added. The reaction mixture was heated under reflux for
11 h, and after cooling, water (10 mL) was added. The mixture
was extracted with Et2O (3 × 20 mL), and the combined
organic phases were dried over MgSO4 and evaporated to give
4-phenylpyridine (7, 152 mg, 99%) which displayed properties
identical to the commercial sample.
1-Meth yl-4-p h en yl-3,6-d ih yd r o-2-p yr id on e (8). Red u c-
tion w ith L-Selectr id e. To a stirred solution of the 2-pyri-
done 5 (185 mg, 1 mmol) in THF (15 mL) maintained at -35
°C was added slowly a 1 M solution of L-Selectride in THF (2
mL, 2 mmol). After 45 min, brine (2 mL) was added, and after
the mixture was warmed to 0 °C an aqueous solution of 30%
Red u ction s w ith Red -Al a n d DIBALH were performed
under anhydrous conditions at the temperatures indicated in
Table 1, using 2 equiv of reducing agent. The reactions were
monitored by GC-EIMS. The products were not isolated.
Rea ction of 2-P yr id on e 5 w ith LiAlH4/LiAlD4. Varia-
tions in temperature, order of addition of reagents, and
reaction times were examined. The following conditions are
optimized for the best yield of 8 and were used in studies with
deuterated reagents. LiAlH4 (104 mg, 2.8 mmol) was added
all at once to a stirred solution of 2-pyridone 5 (185 mg, 1
mmol) in anhydrous THF (15 mL) at 0 °C. The reaction
mixture was stirred for 2 h at 0 °C and, after being cooled to
-78 °C, was treated dropwise with CH3OH (200 µL) and
subsequently at room temperature with 1 N NaOH (1 mL) and
then H2O (1 mL and then 10 mL). The resulting mixture was
extracted with Et2O (3 × 15 mL), and the combined organic
phase was washed with water and brine and then dried over
(22) Pitts, S. M.; Markey, S. P.; Murph, y. D. L.; Weisz, A.
Recommended practices for the safe handling of MPTP. In MPTPsA
Neurotoxin Producing a Parkinsonian Syndrome; Academic Press:
New York, 1995.
(23) Fujii, T.; Yoshifuji, S. Tetrahedron 1970, 26, 5953-5958.

Selective Reductions of 1-Methyl-4-phenyl-2-pyridone
J . Org. Chem., Vol. 61, No. 1, 1996 313
MgSO4 and evaporated under reduced pressure. The crude
extract was chromatographed (SiO2, EtOH:EtOAc:Hex, 10:40:
50) to give 1-methyl-4-phenyl-3,6-dihydro-2-pyridone (8, 134
mg, 0.75 mmol, 75%) as a white solid and the tetrahydropy-
ridine 1 as a white, low-melting solid (36 mg, 0,21 mmol, 21%).
Deu ter a tion Stu d ies. The procedures followed using the
deuterated reagents were the same as that summarized above.
The following summarizes the 1H NMR and GC-EI mass
spectral characteristics of the resulting products.
1-Meth yl-4-p h en yl-3,6-d ih yd r o-2-p yr id on e-6-d 1 (8-6-d 1):
1H-NMR (CDCl3, 270 MHz) δ 7.37 (m, 5H), 6.10 (m, 1H), 4.10
(m, 1H), 3.35 (d, J ) 4.6 Hz, 2H), 3.07 (s, 3H); GC-MS (EI)
m/z (rel int) 188 (100), 159 (41), 145 (30), 144 (43), 130 (30),
116 (44), 115 (38), 97 (16), 96 (16).
(m, 2H), 7.30 (m, 3H), 6.14 (m, 1H), 2.56 (bs, 1H), 2.47 (bs,
1H), 2.27 (s, 3H); GC-MS (EI) m/z (rel int) 177 (100), 176 (81),
155 (8), 146, (22), 145 (19), 132 (46), 117 (34), 116 (29), 100
(70), 92 (20).
Red u ction w ith LiAlH 4 a n d TiCl3. The reaction was run
under the same conditions as with LiAlH4, at 0 °C in
anhydrous THF (1 mmol of 5, 185 mg). TiCl3 (1 mmol, 154
mg) was added prior to LiAlH4. Product formation was
monitored by GC-EI mass spectrometry. After 25 min of
reaction, NaOH 1 N (1mL) was added followed by 5 mL of
water. The reaction mixture was extracted with Et2O (3 ×
15 mL), and the combined organic layers were dried over
MgSO4 and evaporated under reduced pressure. The crude
extract was purified by silica gel chromatography (EtOH:
EtOAc:Hex, 15:35:50) to give 1 (168 mg, 0.97 mmol, 97%) as a
low-melting white solid.
1-Meth yl-4-p h en yl-3,6-d ih yd r o-2-p yr id on e-3,3-d 2 (8-3,3-
1
d 2): H-NMR (CDCl3, 200 MHz) δ 7.37 (m, 5H), 6.11 (t, J )
3.4 Hz, 1H), 4.11 (d, J ) 3.4 Hz, 2H), 3.07 (s, 3H); GC-MS
(EI) m/z (rel int) 189 (100), 160 (41), 144 (25), 131 (27), 117
(23), 116 (24), 98 (25).
Ack n ow led gm en t. This work was supported by a
Lavoisier fellowship to S.M. (Ministe`re des Affaires
Etrange`res, France), by the National Institute of Neu-
rological and Communicative Disorders and Stroke (NS
28792), and by the Harvey W. Peters Center for the
Study of Parkinson’s Disease.
1-Meth yl-4-p h en yl-3,6-d ih yd r o-2-p yr id on e-3,3,6-d 3 (8-
3,3,6-d 3): 1H-NMR (CDCl3, 200 MHz) δ 7.37 (m, 5H), 6.10 (bs,
1H), 4.07 (bs, 1H), 3.05 (s, 3H); MS (EI) m/z (rel int) 190 (100),
161 (25), 146 (80),145 (63), 132 (20), 118 (52), 117 (82), 116
(55), 92 (14).
1 -M e t h y l -4 -p h e n y l -1 ,2 ,3 ,6 -t e t r a h y d r o p y r i d i n e -
2,3,6,6-d 4 (1-2,2,3,6-d 4): 1H-NMR (DMSO-d6, 270 MHz) δ 7.43
J O951529V