Synthesis of 3-Substituted 4-Piperidinones via a One-Pot Tandem Oxidation-Cyclization-Oxidation Process: Stereodivergent Reduction to 3,4-Disubstituted Piperidines

Article abstract of DOI:10.1021/jo0357418

A novel approach to 3-substituted 4-piperidinones is described. The one-pot tandem oxidation-cyclization-oxidation of unsaturated alcohols 1a-e by PCC or PCC and trifluoromethanesulfonic acid affords piperidinones 2a-e in good yield. Reduction of 2a-e by

Full text of DOI:10.1021/jo0357418

SCHEME 1. On e-P ot Ta n d em
Syn th esis of 3-Su bstitu ted 4-P ip er id in on es
via a On e-P ot Ta n d em
Oxid a tion -Cycliza tion -Oxid a tion of Un sa tu r a ted
Alcoh ols 1 to P ip er id in on es 2 by P CCa
Oxid a tion -Cycliza tion -Oxid a tion P r ocess:
Ster eod iver gen t Red u ction to
3,4-Disu bstitu ted P ip er id in es
Perdip S. Bahia and J ohn S. Snaith*
School of Chemistry, The University of Birmingham,
Edgbaston, Birmingham, B15 2TT, United Kingdom
j.s.snaith@bham.ac.uk
Received November 27, 2003
Abstr a ct: A novel approach to 3-substituted 4-piperidino-
nes is described. The one-pot tandem oxidation-cyclization-
oxidation of unsaturated alcohols 1a -e by PCC or PCC and
trifluoromethanesulfonic acid affords piperidinones 2a -e in
good yield. Reduction of 2a -e by L-Selectride gives the
corresponding cis 3,4-disubstituted piperidines with diaster-
eomeric ratios of >99:1. By contrast, reduction of 2a -e by
Al-isopropoxydiisobutylalane gives the trans products with
diastereomeric ratios of up to 99:1.
a
Aldehyde 3 and piperidine 4 are nonisolated intermediates.
The importance of the piperidine ring system in
natural products1 and synthetic pharmaceuticals2 has
resulted in the development of a large number of syn-
thetic approaches to these heterocycles.3 Nevertheless,
the variety of functionality and substitution patterns
found in piperidine targets continues to drive the search
for new methodologies.4
Piperidinones frequently serve as versatile intermedi-
ates in the synthesis of functionalized piperidines. We
envisaged a concise route whereby unsaturated alcohols
1 were converted into 3-substituted 4-piperidinones 2, the
key step being the formation of the C3-C4 bond via a
one-pot tandem oxidation-cyclization-oxidation by PCC
(Scheme 1). Tandem oxidation-cyclization reactions by
PCC to form six-membered rings were first reported by
Corey;5 application to the construction of heterocycles has
not been explored.
F IGURE 1. Cyclization precursors 1a -f.
described.6 Alcohol 1f was prepared by the same route
in an overall yield of 67%.
The tandem cyclization process was initially attempted
with PCC without any additives (Table 1). Treatment of
the alcohols 1c and 1e with 2.5 equiv of PCC led smoothly
to the piperidinones 2c and 2e within 24 h. In the other
cases reaction stopped at the corresponding aldehyde 3,
with subsequent cyclization-oxidation being extremely
slow. Presumably the strain imposed on the double bonds
by the five- and seven-membered rings in 1c and 1e
increases the reactivity of these alkenes toward cycliza-
tion. In an effort to accelerate the remaining cyclizations,
we increased the number of equivalents of PCC and
extended the reaction time. Alcohols 1a , 1b, and 1d were
found to cyclize under the extremely forcing conditions
of 15 equiv of PCC for 10 days, affording the piperidino-
nes 2a , 2b, and 2d , respectively. Alcohol 1f resisted even
these conditions, most likely as a result of the less
electron rich monosubstituted double bond.
Clearly such conditions were unacceptable, and so we
sought alternative methods to accelerate the process.
Initial oxidation to the aldehyde was rapid, and it
appeared that the rate-limiting step was cyclization to
the piperidine 4 via a carbonyl-ene type process.
Since such carbonyl-ene reactions are known to be
catalyzed by Brønsted acids, we explored the addition of
various acids to the reaction mixture. Unfortunately, the
addition of either concentrated hydrochloric acid or
The cyclization precursors 1a -e (Figure 1) were syn-
thesized in two steps from 3-aminopropanol as previously
(1) (a) Findlay, J . A. In The Alkaloids; Brossi, A., Ed.; Academic
Press: London, UK, 1985; Vol. 26, pp 89-183. (b) Pinder, A. R. Nat.
Prod. Rep. 1986, 3, 171-180. (c) Pinder, A. R. Nat. Prod. Rep. 1987,
4, 527-537. (d) Pinder, A. R. Nat. Prod. Rep. 1989, 6, 67-78. (e) Pinder,
A. R. Nat. Prod. Rep. 1990, 7, 447-455. (f) Pinder, A. R. Nat. Prod.
Rep. 1992, 9, 491-504.
(2) Between J uly 1988 and December 1998 over 12 000 piperidines
were mentioned in clinical and preclinical studies. See: Watson, P.
S.; J iang, B.; Scott, B. Org. Lett. 2000, 2, 3679-3681.
(3) For recent reviews see: (a) Laschat, S.; Dickner, T. Synthesis
2000, 1781-1813. (b) Weintraub, P. M.; Sabol, J . S.; Kane, J . M.;
Borcherding, D. R. Tetrahedron 2003, 59, 2953-2989.
(4) (a) Kuethe, J . T.; Comins, D. L. Org. Lett. 1999, 1, 1031-1033.
(b) Souers, A. J .; Ellman, J . A. J . Org. Chem. 2000, 65, 1222-1224. (c)
Amat, M.; Perez, M.; Llor, N.; Bosch, J .; Lago, E.; Molins, E. Org. Lett.
2001, 3, 611-614. (d) Harris, J . M.; Padwa, A. Org. Lett. 2002, 4, 2029-
2031. (e) Hu, X. E.; Kim, N. K.; Ledoussal, B. Org. Lett. 2002, 4, 4499-
4502. (f) Shu, C.; Liebeskind, L. S. J . Am. Chem. Soc. 2003, 125, 2878-
2879. (g) Legault, C.; Charette, A. B. J . Am. Chem. Soc. 2003, 125,
6360-6361.
(5) (a) Corey, E. J .; Ensley, H. E.; Suggs, J . W. J . Org. Chem. 1976,
41, 380-381. (b) Corey, E. J .; Boger, D. L. Tetrahedron Lett. 1978, 19,
2461-2464.
(6) Williams, J . T.; Bahia, P. S.; Snaith, J . S. Org. Lett. 2002, 4,
3727-3730.
10.1021/jo0357418 CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/03/2004
3226
J . Org. Chem. 2004, 69, 3226-3229

TABLE 1. Cycliza tion s of Alcoh ols 1a -e
TABLE 2. Red u ction of 4-P ip er id in on es 2a -e
yield (%)b
2a -f
yield (%)c
6a -e
entry alcohol PCC equiva time (h)
acidc
entry ketone reducing agenta time (h) 6:7b
1
2
3
4
5
6
7
8
9
1c
1e
1a
1b
1d
1f
1b
1b
1a
1b
1d
1f
2.5
2.5
15
15
15
15
2.5
2.5
5
5
5
24
24
62
65
64
62d
71
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2a
2b
2c
2d
2e
L-Selectride
L-Selectride
L-Selectride
L-Selectride
L-Selectride
iBu2AlOiPr
iBu2AlOiPr
iBu2AlOiPr
iBu2AlOiPr
iBu2AlOiPr
3
3
3
3
3
6
6
6
6
6
99:1
99:1
99:1
99:1
99:1
1:99
1:99
2:98
4:96
1:99
85
82d
86
70
79
79
74d
70
73
87
240
240
240
240
24
24
24
24
24
e
-
f
-
HCl
H2SO4
CF3SO3H
CF3SO3H
CF3SO3H
CF3SO3H
f
-
61
10
11
12
67d
59
10
e
5
24
-
a
L-Selectride reductions performed in tetrahydrofuran at -78
i
b
°C; Bu2AlOiPr reductions performed in toluene at 25 °C. Ratio
a
b
Reactions performed in CH2Cl2 at 25 °C. Isolated yields
determined by HPLC of crude reaction product. c Isolated yields
following chromatography. c 1.5 equiv. Formed as a 2:1 mixture
d
d
of E:Z isomers. e Aldehyde obtained. f Carboxylic acid 5 was the
following chromatography. Formed as a 2:1 mixture of E:Z
isomers.
sole product.
tion of a 2,3-disubstituted 4-piperidinone to set the cis
stereochemistry between positions 3 and 4 in the total
synthesis of Dienomycin-C.
sulfuric acid to a solution of 1b and PCC resulted in over-
oxidation to the carboxylic acid 5, without any cyclization
occurring. Happily, changing the acid to trifluoromethane-
sulfonic acid resulted in an acceleration of the desired
cyclization reaction without any of the competing car-
boxylic acid formation. Thus, treatment of alcohols 1a ,
1b, and 1d with PCC (5 equiv) and trifluoromethane-
sulfonic acid (1.5 equiv) in dichloromethane for 24 h gave
piperidinones 2a , 2b, and 2d as the sole product in each
case, in isolated yields of 59-67% after chromatography.
The less electron rich 1f afforded only the corresponding
aldehyde under these conditions.
Support for the mechanism proposed in Scheme 1 came
from the isolation of small amounts (<5%) of the inter-
mediate piperidines on two occasions, during the prepa-
ration of 2b and 2e, when the reaction was stopped too
soon. Simply extending the reaction time resulted in
complete conversion to the piperidinones.
Comins10 has used K-Selectride for the stereoselective
reduction of 2-substituted 4-piperidinones to the ther-
modynamically less stable isomer. Treatment of piperi-
dinones 2a -e with L-Selectride resulted in complete
conversion to the cis-3-substituted 4-hydroxypiperidines
6a -e, with diastereomeric ratios determined by HPLC
in excess of 99:1 (Table 2).
The products were isolated as crystalline solids after
chromatography. Single crystals of 6a were grown from
petroleum ether and ethyl acetate, and X-ray analysis
confirmed the cis relationship between the two substit-
uents (Figure 2).
Methods for the reduction of six-membered cyclic
ketones to the thermodynamically more stable stereoi-
somer are rather less well developed.
Cha and Kwon11 recently reported a new method for
the reduction of cyclic ketones to the thermodynamically
more stable alcohols using a diethyl ether solution of Al-
isopropoxydiisobutylalane, a reagent readily prepared by
the addition of 2-propanol to diisobutylaluminum hy-
dride. The authors propose that the reduction proceeds
through a Meerwein-Ponndorf-Verley (MPV)-type mech-
anism, supported by the fact that the proportion of the
thermodynamically more stable alcohol increases with
time. The stereocontrol is good to excellent, although a
drawback is that long reaction times are required to
achieve this, typically between 5 and 7 days.
With the piperidinones in hand, we went on to explore
their stereoselective reduction to 4-hydroxypiperidines.
A number of cis- and trans-3,4-disubstituted piperidines
have potent biological activity,7 and so we sought condi-
tions which would allow us to access both stereoisomers.
Methods for the reduction of six-membered cyclic ketones
to the thermodynamically less stable stereoisomer are
well developed, with the Selectride reagents of Brown
most notable among the methods for achieving this
transformation.8 Troin9 employed the L-Selectride reduc-
(7) (a) J acobsen, P.; Labouta, I. M.; Schaumburg, K.; Falch, E.;
Krosgaard-Larsen, P. J . Med. Chem. 1982, 25, 1157-1162. (b) Thomas,
J . B.; Atkinson, R. N.; Rothman, R. B.; Fix, S. E.; Mascarella, S. W.;
Vinson, N. A.; Xu, H.; Dersch, C. M.; Lu, Y. F.; Cantrell, B. E.;
Zimmerman, D. M.; Carroll, F. I. J . Med. Chem. 2001, 44, 2687-2690.
(c) The pharmaceutical Paroxetine is a 3,4-disubstituted piperidine;
for a recent synthesis see: J ohnson, T. A.; Curtis, M. D.; Beak, P. J .
Am. Chem. Soc. 2001, 123, 1004-1005.
(8) Brown, H. C.; Krishnamurthy, S. J . Am. Chem. Soc. 1972, 94,
7159-7161.
(9) Ripoche, I.; Bennis, K.; Canet, J . L.; Gelas, J .; Troin, Y.
Tetrahedron Lett. 1996, 37, 3991-3992.
The rates of MPV reductions have been reported to
exhibit significant solvent effects,12 being fastest in
nonpolar solvents and slowest in solvents such as ether
(10) Brooks, C. A.; Comins, D. L. Tetrahedron Lett. 2000, 41, 3551-
3553.
(11) Cha, J . S.; Kwon, O. O. J . Org. Chem. 1997, 62, 3019-3020.
(12) (a) Giacomelli, G.; Menicagli, R.; Lardicci, L. J . Org. Chem.
1973, 38, 2370-2376. (b) Knauer, B.; Krohn, K. Liebigs Ann. 1995,
677-683.
J . Org. Chem, Vol. 69, No. 9, 2004 3227

146.4, 206.1; MS (electrospray) m/z 316 (100%, [M + Na]+). Anal.
Calcd for C15H19NO3S: C, 61.41; H, 6.53; N, 4.78. Found: C,
61.3; H, 6.3; N, 4.6.
3-[(3-E t h ylp en t -2-en yl)(t olu en e-4-su lfon yl)a m in o]p r o-
p a n oic Acid (5). Concentrated hydrochloric acid (0.044 mL, 0.45
mmol) was added to a suspension of pyridinium chlorochromate
(0.32 g, 1.5 mmol) in CH2Cl2 (10 mL), which was then stirred
for 5 min before being cooled to 0 °C. The N-alkylated sulfona-
mide 1b (0.098 g, 0.3 mmol) in CH2Cl2 (5 mL) was then added
in one portion to the reaction mixture. After the mixtue was
warmed to room temperature and stirred for 24 h, NaHSO4 (0.89
g) and ether (15 mL) were added, then the solution was
vigorously stirred for 15 min. After filtering through silica, the
residue was washed with ether (100 mL), dried over MgSO4, and
concentrated in vacuo. Flash column chromatography of the
colorless oil (silica; eluent 1:3 ethyl acetate:petroleum ether)
afforded 3-[(3-ethylpent-2-enyl)(toluene-4-sulfonyl)amino]pro-
panoic acid (5) (0.068 g, 67%) as a colorless oil: Rf 0.29; IR 2969,
1713, 1600, 1342, 1160 cm-1; 1H NMR (300 MHz, CDCl3) δ 0.87-
0.95 (m, 6H), 1.94-2.05 (m, 4H), 2.42 (s, 3H), 2.69-2.73 (m 2H),
3.35 (t, J ) 7.5 Hz, 2H), 3.84 (d, J ) 7.0 Hz, 2H), 4.90 (t, J ) 6.7
Hz, 1H), 7.30 (d, J ) 8.1, 2H), 7.69 (d, J ) 8.1, 2H); 13C NMR
(75 MHz, CDCl3) δ 13.2, 14.0, 23.4, 24.2, 29.8, 35.1, 43.6, 47.0,
117.5, 128.2, 130.6, 138.1, 144.7, 149.2, 177.9; MS (electrospray)
m/z 362 (100%, [M + Na]+).
F IGURE 2. ORTEP representation of 6a ; ellipsoids are drawn
at the 30% probability level.
and THF, which are capable of acting as donor ligands
to the aluminum.
Typ ica l P r oced u r e for th e L-Selectr id e Red u ction :
P r ep a r a tion of (3R*,4S*)-3-Isop r op en yl-1-(tolu en e-4-su l-
fon yl)p ip er id in -4-ol (6a ). L-Selectride (1 M solution in THF,
0.157 mL, 0.157 mmol) was added to 2a (46 mg, 0.157 mmol) in
THF (20 mL) at -78 °C. The reaction mixture was stirred at
-78 °C for 3 h and then allowed to warm to room temperature
before being hydrolyzed with water (4 mL) and ethanol (15 mL).
The organoborane was oxidized by stirring it along with 6 M
NaOH (10 mL) and 30% hydrogen peroxide (15 mL) at room
temperature for 1 h. The organic phase was separated, and the
aqueous layer was extracted with ether (3 × 20 mL). The
combined organic phases were washed with brine (20 mL), dried
over MgSO4, and concentrated in vacuo. Purification by flash
column chromatography (silica; eluent 2:1 petroleum ether:ethyl
acetate) afforded (3R*,4S*)-3-isopropenyl-1-(toluene-4-sulfonyl)-
piperidin-4-ol (6a ) (39 mg, 85%) as a white crystalline solid: mp
89-91 °C (from petroleum ether/ethyl acetate); Rf 0.36; IR 3519,
Paralleling these findings, we found the production of
trans-piperidin-4-ols 7 to be sluggish in ether. In an effort
to accelerate the reductions, we adapted the Cha and
Kwon procedure to use toluene as the solvent. The change
in solvent was found to markedly increase the rate of
reaction. Thus, treatment of piperidinones 2a -e with Al-
isopropoxydiisobutylalane (1 equiv) in toluene for 6 h led
to formation of the trans-3-substituted 4-hydroxypip-
eridines 7a -e, with diastereomeric ratios of between 96:4
and 99:1 (HPLC) and with isolated yields of 70-87% after
chromatography (Table 2).
In summary, we have discovered a concise synthesis
of 3-substituted 4-piperidinones via the tandem oxida-
tion-cyclization-oxidation of simple precursors. Reduc-
tion of the piperidinones can be controlled by appropriate
choice of reducing agent to afford either the cis- or trans-
3,4-disubstituted piperidines with high diastereoselec-
tivity. Application to the synthesis of more complex
molecules is currently under investigation and will be
reported in due course.
1
2920, 2904, 1651, 1597, 1447, 1323, 1304, 1157 cm-1; H NMR
(500 MHz, CDCl3) δ 1.50 (br s, 1H), 1.77 (s, 3H), 1.81-1.95 (m,
2H), 2.37 (d, J ) 12.1 Hz, 1H), 2.42 (s, 3H), 2.55-2.62 (m, 2H),
3.55-3.59 (m, 2H), 3.96 (d, J ) 2.2 Hz, 1H), 4.58 (s, 1H), 4.96
(s, 1H), 7.31 (d, J ) 8.1 Hz, 2H), 7.64 (d, J ) 8.1 Hz, 2H); 13C
NMR(125 MHz, CDCl3) δ 21.5, 22.8, 31.1, 40.5, 43.5, 46.7, 63.0,
112.2, 127.6, 129.6, 133.4, 143.4, 143.8; MS (CI) m/z 296 ([M +
H]+, 100%), 278 (4), 257 (5), 189 (8), 143 (13), 124 (15), 105 (4),
79 (11). Anal. Calcd for C15H21NO3S: C, 60.99; H, 7.17; N, 4.74.
Found: C, 61.0; H, 7.1; N, 4.6.
P r ep a r a tion of DIBAOiP r in Tolu en e. Isopropyl alcohol
(0.81 mL, 10.5 mmol) was added dropwise to diisobutylauminium
hydride (1 M solution in toluene, 10 mL, 10 mmol) at 0 °C. After
the evolution of hydrogen had ceased, the reagent solution was
stirred at room temperature for 1 h to give a solution of DIBAOi-
Pr (0.93 M) in toluene.
Typ ica l P r oced u r e for DIBAOiP r Red u ction : P r ep a r a -
tion of (3R*,4R*)-3-Isop r op en yl-1-(tolu en e-4-su lfon yl)p i-
p er id in -4-ol (7a ). DIBAOiPr (0.93 M solution in toluene, 0.169
mL, 0.157 mmol) was added to 2a (46 mg, 0.157 mmol) in toluene
(10 mL) and the reaction mixture was stirred at room temper-
ature for 24 h. Then 3 M HCl (1.5 mL) and ether (10 mL) were
added, and the mixture was allowed to stir for 30 min, after
which 3 M NaOH (5 mL) was added, and this solution was
allowed to stir for 1 h. The organic layer was separated, the
aqueous phase was extracted with ether (3 × 20 mL), and the
combined organic phases were washed with brine, dried over
MgSO4, and concentrated in vacuo. Purification by flash column
chromatography (silica; eluent 2:1 petroleum ether:ethyl acetate)
afforded (3R*,4R*)-3-isopropenyl-1-(toluene-4-sulfonyl)piperidin-
4-ol (7a ) (37 mg, 79%) as a white crystalline solid: mp 149-151
°C (from petroleum ether/ethyl acetate); Rf 0.24; IR 3391, 2920,
Exp er im en ta l Section
Typ ica l P r oced u r e for th e Ta n d em Oxid a tion -Cycliza -
tion : P r ep a r a tion of 3-Isop r op en yl-1-(tolu en e-4-su lfon yl)-
p ip er id in -4-on e (2a ). Triflic acid (0.08 mL, 0.9 mmol) was
added to a suspension of pyridinium chlorochromate (0.65 g, 3.0
mmol) in CH2Cl2 (15 mL), which was then stirred for 5 min
before being cooled to 0 °C. The N-alkylated sulfonamide 1a (0.18
g, 0.6 mmol) in CH2Cl2 (5 mL) was then added in one portion to
the reaction mixture. After the mixture was warmed to room
temperature and stirred for 24 h, NaHSO4 (1.78 g) and ether
(25 mL) were added, then the solution was vigorously stirred
for 15 min. After filtering through silica, the residue was washed
with ether (200 mL), dried over MgSO4, and concentrated in
vacuo. Flash column chromatography of the colorless oil (silica;
eluent 1:3 ethyl acetate:petroleum ether) afforded 3-isopropenyl-
1-(toluene-4-sulfonyl)piperidin-4-one (2a ) (0.11 g, 61%) as a white
crystalline solid: mp 82-83 °C; Rf 0.40; IR 2924, 1721, 1598,
1342, 1166 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.72 (s, 3H), 2.44
(s, 3H), 2.55-2.60 (m, 2H), 3.04-3.23 (m, 3H), 3.63-3.71 (m,
2H), 4.90 (s, 1H), 5.01-5.03 (m, 1H), 7.35 (d, J ) 8.1 Hz, 2H),
7.68 (d, J ) 8.1 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 22.8,
23.0, 41.2, 47.6, 50.9, 57.7, 116.5, 128.8, 131.2, 134.9, 140.9,
3228 J . Org. Chem., Vol. 69, No. 9, 2004

2904, 1647, 1597, 1458, 1334, 1304, 1157 cm-1 1H NMR (500
;
Ack n ow led gm en t. We thank the Engineering and
Physical Sciences Research Council (studentship to
P.S.B.) and the University of Birmingham for financial
support.
MHz, CDCl3) δ 1.58-1.68 (m, 1H), 1.71 (s, 3H), 1.85 (br s, 1H),
2.01-2.06 (m, 1H), 2.17-2.27 (m, 2H), 2.37 (dt, J ) 2.8, 12.4
Hz, 1H), 2.43 (s, 3H), 3.44 (dt, J ) 4.5, 10.1 Hz, 1H), 3.75-3.77
(m, 1H), 3.81-3.86 (m, 1H), 4.89 (s, 1H), 5.01 (s, 1H), 7.32 (d, J
) 8.0 Hz, 2H), 7.64 (d, J ) 8.0 Hz, 2H); 1H NMR (125 MHz,
CDCl3) δ 20.6, 21.5, 32.5, 45.0, 48.8, 51.6, 69.4, 114.7, 127.6,
129.7, 133.6, 142.4, 143.6; MS (CI) m/z 296 ([M + H]+, 100%),
278 (4), 247 (5), 189 (5), 143 (10), 124 (8), 79 (4), 69 (10). Anal.
Calcd for C15H21NO3S: C, 60.99; H, 7.17; N, 4.74. Found: C,
61.0; H, 7.1; N, 4.6.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and full characterization for piperidinones 2a -e and
piperidine-4-ols 6a -e and 7a -e, as well as the CIF file for
6a . This material is available free of charge via the Internet
at http://pubs.acs.org.
J O0357418
J . Org. Chem, Vol. 69, No. 9, 2004 3229