Synthesis of aryl-substituted piperidines by superacid activation of piperidones

Article abstract of DOI:10.1021/jo990454i

Diarylpiperidines (8-12) may be prepared in good to excellent yields (80-99%) by the reaction of piperidones (3d-h) with benzene and the Bronsted superacid, trifluoromethanesulfonic acid (CF₃-SO₃H, TfOH). Tropinone (6) and quinuclidone (7) also react in good yields with benzene in TfOH to give the condensation products (13 and 14). Ketal and acetal derivatives also give condensation products (8 and 24) upon reaction with C₆H₆ in TfOH. The conversion of 3g to 11 is sensitive to both acid quantity and acid strength; a mechanism is proposed for the conversion that invokes dicationic intermediates.

Full text of DOI:10.1021/jo990454i

6702
J . Org. Chem. 1999, 64, 6702-6705
Syn th esis of Ar yl-Su bstitu ted P ip er id in es by Su p er a cid Activa tion
of P ip er id on es
Douglas A. Klumpp,* Manuel Garza, Andre J ones, and Saray Mendoza
Department of Chemistry, California State Polytechnic University, 3801 West Temple Avenue,
Pomona, California, 91768
Received March 12, 1999
Diarylpiperidines (8-12) may be prepared in good to excellent yields (80-99%) by the reaction of
piperidones (3d -h ) with benzene and the Bronsted superacid, trifluoromethanesulfonic acid (CF3-
SO3H, TfOH). Tropinone (6) and quinuclidone (7) also react in good yields with benzene in TfOH
to give the condensation products (13 and 14). Ketal and acetal derivatives also give condensation
products (8 and 24) upon reaction with C6H6 in TfOH. The conversion of 3g to 11 is sensitive to
both acid quantity and acid strength; a mechanism is proposed for the conversion that invokes
dicationic intermediates.
In tr od u ction
ring system 3d is the most reactive toward nucleophilic
attack by H2O or thiols. In a similar respect, Yang and
co-workers exploited the field effects in 4-oxopiperidinium
salts in their studies of electrophilic dioxirane epoxidizing
agents such as 4.8 These results suggested that piperi-
dones might generate reactive dicationic electrophiles by
diprotonation in superacidic solution.
The concept of superelectrophilic activation was first
advanced by Olah in order to explain the reactivities of
some electrophiles in superacid solution.1 Superelectro-
philic activation may occur when a cationic electrophile
reacts with a Bronsted or Lewis acid to give a dicationic,
superelectrophile. Superelectrophilic activation has been
proposed in the Friedel-Crafts-type reactions of 1,2-di-
carbonyl groups,2 aldehydes,3 nitriles,4 and other sys-
tems.5 We recently reported our studies of the trifluoro-
methanesulfonic acid (CF3SO3H, TfOH)-catalyzed con-
densation of 3-pyridinecarboxaldehyde (1) with deacti-
vated aromatic compounds (eq 1) and the observation of
dication 2 by low-temperature NMR.6a The results with
1 provided a demonstration of the reactivity of dicationic
electrophiles and suggested that protonation of a strong,
adjacent base site can activate an electrophilic functional
group, such as a carboxonium ion.6b
If reactive electrophiles can be generated from piperi-
dones, then it should be possible to synthesize aryl-
substituted piperidines by Friedel-Crafts chemistry.
Piperidine compounds possess a variety of biological
activities.9 The aryl-substituted piperidines have been of
particular interest because of their strong interaction
with monoamine receptors associated with the central
nervous system.10 There have been some reports of the
preparation of aryl-substituted piperidines from piperi-
dones in AlCl3-benzene solution,11 and several reports
have appeared in which intramolecular electrophilic
aromatic substitution involving piperidones was ac-
complished with strong Bronsted acids.12 In this paper,
we describe the trifluoromethanesulfonic acid-catalyzed
Seto and co-workers recently described the electrostatic
field effects related to the nucleophilic attack on ketones
3a -d .7 Among the series, they found that the piperidone
(1) Olah, G. A. Angew. Chem., Int. Ed. Engl. 1993, 32, 2, 767.
(2) (a) Klumpp, D. A.; Yeung, K. Y.; Prakash, G. K. S.; Olah, G. A.
Synth. Lett. 1998, 918. (b) Klumpp, D. A.; Yeung, K. Y.; Prakash, G.
K. S.; Olah, G. A. J . Org. Chem. 1998, 63, 4481. (c) Yamazaki, T.; Saito,
S.-i.; Ohwada, T.; Shudo, K. Tetrahedron Lett. 1995, 36, 5749.
(3) (a) Olah, G. A.; Rasul, G.; York, C.; Prakash, G. K. S. J . Am.
Chem. Soc. 1995, 117, 11211. (b) Saito, S.; Ohwada, T.; Shudo, K. J .
Am. Chem. Soc. 1995, 117, 11081.
(8) Yang, D.; Yip, Y.-C.; J iao, G.-S.; Wong, M.-K. J . Org. Chem. 1998,
63, 8952.
(9) (a) Rubiralta, M.; Giralt, E.; Diez, A. Piperidine; Elsevier: New
York, 1991. (b) Numuta, A.; Ibuka, T. In The Alkaloids; Brossi, A.,
Ed.; Academic Press: New York, 1987; Vol. 31, Chapter 6, pp 193-
315.
(10) (a) Giringauz, A. Medicinal Chemistry; Wiley-VHC: New York,
1997; pp 169-174. (b) Smith, M. P.; J ohnson, K. M.; Zhang, M.;
Flippen-Anderson, J . L.; Kozikowski, A. P. J . Am. Chem. Soc. 1998,
120, 9072. (c) Russ, H.; Pindur, U.; Przunutek, H. J . Neural Transm.
1986, 65(3-4), 157. (d) Neuser, D.; Stasch, J . P.; Witteller, M.; Kuhn,
W.; Gerlach, M.; J utzi, P.; Przuntek, H. Eur. J . Pharmacol. 1983, 87,
315. (e) Thomas, J . B.; Gigstad, K. M.; Fix, S. E.; Burgess, J . P.; Cooper,
J . B.; Mascarella, S. W.; Cantrell, B. E.; Zimmerman, D. M.; Carroll,
F. I. Tetrahedron Lett. 1999, 40, 403.
(4) Sato, Y.; Yato, M.; Ohwada, T.; Saito, S.; Shudo, K. J . Am. Chem.
Soc. 1995, 117, 3037.
(5) (a) Olah, G. A.; Klumpp, D. A.; Neyer, G.; Wang, Q. Synthesis
1996, 321. (b) Klumpp, D. A.; Baek, D. N.; Prakash, G. K. S.; Olah, G.
A. J . Org. Chem. 1997, 62, 6666. (c) Olah, G. A.; Wang, Q.; Neyer, G.
Synthesis 1994, 276. (d) Saito, S.; Sato, Y.; Ohwada, T.; Shudo, K. J .
Am. Chem. Soc.. 1994, 116, 2312. (e) Yokoyama, A.; Ohwada, T.; Shudo,
K. J . Org. Chem. 1999, 64, 611.
(6) (a) Klumpp, D. A.; Lau, S., in press. (b) Ohwada, T.; Yamagata,
N.; Shudo, K. J . Am. Chem. Soc. 1991, 113, 1364.
(7) Conroy, J . L.; Sanders, T. C.; Seto, C. T. J . Am. Chem. Soc. 1997,
119, 4285.
(11) (a) Chem. Abstr. 1973, 78, 124458. (b) German Patents:
2139084, 1936452. (c) Schaefer, H.; Hackmack, G.; Eistetter, K.;
Krueger, U.; Menge, H. G.; Klosa, J . Arzneim.-Forsch. 1984, 34, 233.
(12) Takeda, M.; May, E. L. J . Med. Chem. 1970, 13, 1223.
10.1021/jo990454i CCC: $18.00 © 1999 American Chemical Society
Published on Web 08/13/1999

Synthesis of Aryl-Substituted Piperidines
J . Org. Chem., Vol. 64, No. 18, 1999 6703
Ta ble 1. Resu lts fr om th e Rea ction s of P ip er id on es
3d -h a n d Heter ocycles 6 a n d 7 w ith Ben zen e in CF 3SO3H
is up to 100 times stronger acid than H2SO4,14 and when
3g is reacted with C6H6 in H2SO4, no condensation
reaction is seen. When 3g is reacted with C6H6 and either
1.0 or 3.0 equiv of TfOH, complex product mixtures are
produced. However, reaction of 3g with C6H6 and 9.0
equiv of TfOH gives 11 as the exclusive product in 80%
yield (eq 4). Cyclohexanone 3a was also reacted with
benzene in excess TfOH (30 equiv). No products are
detected from reaction with benzene, although a small
amount of the aldol condensation product can be detected
(eq 5).
A mechanism for the conversion of 3g to 11 is proposed
in Scheme 1. In superacidic TfOH, an equilibrium is
a
3d , 3g, and 7 were reacted as the hydrated hydrochloride salt.
condensations of piperidones and related systems with
aromatic compounds to give diarylpiperidines. We also
propose a mechanism in which reactive dications are
generated.
Sch em e 1
Resu lts a n d Discu ssion
When piperidones 3d -h are reacted with C6H6 in
TfOH,13 the condensation products 8-12 are formed in
good to excellent yields (Table 1). In addition to the
piperidones, the bicyclic systems of tropinone 6 and
quinuclidone 7 also condense with C6H6 in TfOH to give
products 13 and 14, respectively. Ketone 7 reacts with
substituted arenes such as chlorobenzene and alkylben-
zenes. In the case of chlorobenzene, the condensation
occurs regioselectively at the para position (eq 2), while
in the case of toluene, the condensation gives the mixture
of regioisomers (eq 3). Ketone 7 was also reacted with
nitrobenzene and TfOH at 80 °C, but no condensation
products were observed.
established between protonated intermediates. Given the
dependence of the condensation reaction on acid quantity
and acid strength, this suggests that the dication 16 is
generated in the superacid. Intermediate 16 is suf-
ficiently electrophilic to react with benzene leading to the
condensation product 11.15 Under less acidic conditions,
16 is not formed in high enough concentration for the
condensation reaction to occur at a significant rate and
The condensation reaction has been found to be sensi-
tive to both acid strength and acid quantity. Triflic acid
(14) Olah, G. A., Prakash, G. K. S., Sommer, J . In Superacids;
Wiley: New York, 1985.
(15) Shudo, K.; Ohwada, T. In Stable Carbocation Chemistry;
Prakash, G. K. S., Schleyer, P. v. R., Eds.; Wiley: New York, 1997; pp
525-548.
(13) (a) For a review of TfOH chemistry, see: Stang, P. J .; White,
M. R. Aldrichim. Acta 1983, 16, 15. (b) TfOH may be quantitatively
recycled; for a procedure, see: Booth, B. L.; El-Fekky, T. A. J . Chem.
Soc., Perkin Trans. 1 1979, 2441.

6704 J . Org. Chem., Vol. 64, No. 18, 1999
Klumpp et al.
other reactions take place. Support for the proposed
mechanism was obtained from reaction of the substituted
piperidine 17 with C6H6 in TfOH (eq 6). In accord with
the proposed mechanism, 17 gives the expected product
(8) in good yield. When 17 was reacted with TfOH and
chlorobenzene, compounds 8, 18, and 19 are the only
major products (eq 7; formed in a ratio of 1.0:9.3:12.2,
respectively). Similarly, compound 8 reacts with TfOH
and chlorobenzene to give unreacted 8 and products 18
and 19 (ratio: 1.0:9.0:9.9). Compound 19 must be pro-
duced from the loss of the phenyl group(s). This suggests
that the condensation of piperidones occurs with at least
one reversible electrophilic aromatic substitution step.
reactions.18 This well-known condensation reaction of
aldehydes or ketones generally occurs only with activated
arenes such as phenols or alkylbenzenes. Although
cyclohexanone (3a ) is extensively protonated in TfOH,14
it does not react with benzene in a hydroxyalkylation
reaction in TfOH. Heterocycles 3d -h , 6, and 7 are
considerably more reactive than 3a as electrophiles in
TfOH. We propose that the origin of this enhanced
reactivity is in the base site located at the nitrogen and
that the protonated nitrogen activates the electrophilic
carboxonium group. This activation may arise from
inductive effects or by through-space electrostatic effects.
In accord with Olah’s concept of superelectrophilic aci-
vation, this further illustrates the reactivity of dicationic
electrophilies.
In addition to the reaction steps described in Scheme
1, the piperidone systems also undergo rapid, acid-
catalyzed keto-enol tautomerizations.16 Compounds 3e
and 7 were reacted with C6D6 in deuterated triflic acid,
TfOD (eqs 8 and 9). Both condensation reactions were
accompanied by nearly complete incorporation of deute-
rium at the R-positions to give products 20 and 21
(deuterium is not incorporated at the bridgehead position
of product 21). Moreover when 3e is dissolved in TfOD
without C6D6, incorporation of deuterium in the R-posi-
tions occurs quantitatively.
Con clu sion
Diarylpiperidones are compounds that have been of
interest as drugs in the treatment of various neurological
disorders. We have found the diarylpiperidines are
formed in good to excellent yields by the reaction of
piperidones with arenes in trifluoromethanesulfonic acid
(CF3SO3H, TfOH). We propose that the condensation
reactions occur through reactive dicationic intermediates.
Exp er im en ta l Section
Piperidones 3d -k and compounds 6, 7, 16, 22, and 23 were
purchased from Aldrich and used as received. Trifluoromethane-
sulfonic acid was purchased from 3M Co. and distilled under
a dry, inert atmosphere immediately prior to its use. Benzene
was dried with sodium prior to use. High-resolution mass
spectra were recorded at the Mass Spectrometry Facility at
the University of California, Riverside.
Gen er a l P r oced u r e for th e P r ep a r a tion of Dia r ylp i-
p er id in es. A 0.2 g portion of the piperidone (or related
compounds 6, 7, 22, and 23) was dissolved or suspended in 2
mL of dry C6H6, and 2 mL of triflic acid was added.19 The
solution was stirred at room temperature for at least 3 h, after
which the mixture was poured over several grams of ice. The
aqueous solution was then made basic by addition of NaOH,
and the products were extracted into CHCl3. The organic
solution was then washed with H2O and brine, dried with
MgSO4, and concentrated in vacuo.
4,4-Dip h en ylp ip er id in e (8): 1H NMR (300 MHz, CHCl3)
δ, ppm 2.52 (t, J ) 3.9 Hz, 4H), 3.08 (t, J ) 4.5, 4H), 7.18-
7.30 (m, 6 H), 7.36 (m, 4 H); 13C NMR (75 MHz, CHCl3) δ,
ppm 35.0, 42.3, 44.4, 126.3, 126.8, 128.3, 128.7; EI MS 237
(M+); HRMS calcd for C17H19N 237.1518, found 237.1519.
4,4-Dip h en yl-N-p r op ylp ip er id in e (9): 1H NMR (300
MHz, CHCl3) δ, ppm 0.96 (t, J ) 7.2 Hz, 3H), 1.60 (m, 2H),
In addition to the condensations involving piperidones,
tropinone, and quinuclidone, related ketal and acetal
compounds react with C6H6 in TfOH. The ketal derivative
of 4-piperidone (22) reacts with C6H6 in TfOH to give the
condensation product 8 as the major product in about
50% yield (eq 10), while the acetal 23 gives the condensa-
tion product 24 in 75% yield (eq 11). The acetal and ketal
groups are both cleaved in the superacid to yield elec-
trophiles capable of reacting with C6H6. If an analogy is
made with the condensations involving piperidones, these
results suggest that dicationic carboxonium ions are
involved in the formation of 8 and 24.17
(18) Hofmann, J . E.; Schriesheim, A. In Friedel-Crafts and Related
Reaction; Olah, G. A., Ed.; Wiley: New York, 1964; Vol 2, pp 597-
640.
The condensations of the nitrogen heterocycles 3d -h ,
6, and 7 with arenes are examples of hydroxyalkylation
(19) When the piperidone hydrochloride salts are reacted in TfOH,
a significant amount of gas pressure is generated (presumably HCl
gas). These reactions were done in a flask fitted with an outlet for gas
pressure.
(16) Rappoport, Z. The Chemistry of Enols; Wiley: New York, 1990.
(17) Fukuzawa, S.; Tsuchimoto, T.; Hiyama, T. J . Org. Chem. 1997,
62, 151.

Synthesis of Aryl-Substituted Piperidines
J . Org. Chem., Vol. 64, No. 18, 1999 6705
2.31 (m, 2H), 2.52-2.68 (broad s, 8 H), 7.18-7.25 (m, 4 H),
7.34-7.37 (m, 6H); 13C NMR (75 MHz, CHCl3) δ, ppm 12.0,
20.2, 36.2, 44.7, 50.6, 60.1, 125.6, 127.2, 128.2, 128.3; EI MS
279 (M+); HRMS calcd for C20H25N 279.1987, found 279.1989.
4,4-Dip h en yl-N-ben zylp ip er id in e (10): 1H NMR (300
MHz, CHCl3) δ, ppm 2.42-2.56 (m, 8 H), 3.40 (s, 2H), 7.10-
7.16 (m, 4 H), 7.23-7.34 (m, 11H); 13C NMR (75 MHz, CHCl3)
δ, ppm 36.2, 44.7, 50.7, 63.3, 125.6, 127.0, 127.2, 128.2, 128.3,
3,3-Bis(4-ch lor op h en yl)-1-a za bicyclo[2.2.2]octa n e (15):
1H NMR (300 MHz, CHCl3) δ, ppm 1.56 (m, 2H), 1.65 (m, 2H),
2.78 (m, 4H), 2.87 (m, 1H), 3.84 (s, 2H), 7.04-7.09 (m, 2H),
7.19-7.30 (m, 6H); 13C NMR (75 MHz, CHCl3) δ, ppm 23.2,
28.7, 47.0, 58.6, 125.4, 126.6, 128.3, 148.3; EI MS 331 (M+);
HRMS calcd for C19H19Cl2N 331.0895, found 331.0896.
N-P r op yl-4,4-b is(p en t a d eu t er iop h en yl)-3,3,5,5-t et r a -
d eu ter iop ip er id in e (19): 1H NMR (300 MHz, CHCl3) δ, ppm
0.86 (t, J ) 7.2 Hz, 3H), 1.50 (m, 2H), 2.22 (m, 2H) 2.50 (s,
4H); 13C NMR (75 MHz, CHCl3) δ, ppm 12.0, 20.2, 35.4, 50.5,
50.5, 60.9, 125.4, 127.1, 127.8, 128.1; EI MS 293 (M+); HRMS
calcd for C20H11D14N 293.2866, found 293.2855.
3,3-Bis(p en t a d eu t er iop h en yl)-2,2-d id eu t er o-1-a za b i-
cyclo[2.2.2]octa n e (20): 1H NMR (300 MHz, CHCl3) δ, ppm
1.56 (m, 2H), 1.65 (m, 2H), 1.97 (m, 2H), 2.43 (m, 1H), 2.79
(m, 2H); 13C NMR (75 MHz, CHCl3) δ, ppm 23.4, 25.6, 28.7,
39.6, 46.9, 125.0, 126.5, 127.7, 128.0; EI MS 275 (M+); HRMS
calcd for C19H9D12N 275.2427, found 275.2418.
128.3, 129.2, 138.7; EI MS 327 (M+); HRMS calcd for C24H25
327.1987, found 327.1985.
N
3,3-Diph en yl-N-eth ylpiper idin e (11): 1H NMR (300 MHz,
CHCl3) δ, ppm 1.23 (t, J ) 7.5 Hz, 3H), 1.62 (m, 2H), 2.35 (m,
2H), 2.47-2.58 (m, 4H), 2.94 (s, 2H), 7.16-7.22 (m, 2H), 7.28-
7.38 (m, 4H); 13C NMR (75 MHz, CHCl3) δ, ppm 11.8, 22.4,
35.5, 46.3, 52.6, 54.3, 62.5, 125.5, 127.6, 127.9; EI MS 265 (M+);
HRMS calcd for C19H23N 265.1831, found 265.1818.
3,3-Dip h en yl-N-ben zylp ip er id in e (12): 1H NMR (300
MHz, CHCl3) δ, ppm 1.68 (m, 2H), 2.40 (m, 2H), 2.58 (m, 2H),
3.00 (m, 2H), 3.64 (s, 2H), 7.20-7.28 (m, 2H), 7.33-7.38 (m,
8H), 7.43-7.47 (m, 5H); 13C NMR (75 MHz, CHCl3) δ, ppm
22.3, 35.4, 46.6, 54.2, 63.2, 63.5, 125.6, 127.0, 127.8, 127.9,
N-(2,2-Dip h en yleth yl)p ip er id in e (24): 1H NMR (300
MHz, CHCl3) δ, ppm 1.36 (m, 2H), 1.48 (m, 4H), 2.39 (m, 4H),
2.95 (d, J ) 7.2 Hz, 2H), 4.23 (t, J ) 7.2 Hz, 1H), 7.13-7.26
(m, 10H); 13C NMR (75 MHz, CHCl3) δ, ppm 24.4, 25.9, 48.8,
54.9, 64.5, 126.1, 128.2, 128.3, 144.3; EI MS 98 (M - 167);
HRMS(DCI/NH3) calcd for C19H25N (MH+) 266.1909, found
266.1897.
128.1, 129.3, 138.6; EI MS 327 (M+); HRMS calcd for C24H25
327.1987, found 327.1987.
N
3,3-Dip h en yl-N-m eth yl-8-a za bicyclo[3.2.1]octa n e (13):
1H NMR (300 MHz, CHCl3) δ, ppm 1.48 (m, 2H), 1.82 (m, 2H),
2.42 (s, 3H), 2.61 (m, 2H), 3.07 (m, 2H), 3.39 (m, 2H), 7.40-
7.14 (m, 2H), 7.21-7.26 (m, 4H), 7.30-7.41 (m, 2H), 7.66-
7.69 (m, 2H); 13C NMR (75 MHz, CHCl3) δ, ppm 24.2, 39.0,
39.3, 42.2, 61.0, 124.6, 125.0, 125.4, 125.5, 126.7, 127.8, 127.9,
128.2; EI MS 277 (M+); HRMS calcd for C20H23N 277.1831,
found 277.1844.
Ack n ow led gm en t. Financial support from the Na-
tional Institutes of Health (SO6GM53933-0251) is grate-
fully acknowledged. The assistance of Mr. Siufu Lau is
appreciated. We also thank the reviewers for their
suggestions and comments.
3,3-Dip h en yl-1-a za bicyclo[2.2.2]octa n e (14): 1H NMR
(300 MHz, CHCl3) δ, ppm 1.66 (m, 4H), 2.86 (m, 4H), 2.95 (m,
1H), 3.93 (s, 2H), 7.06-7.16 (m, 2H), 7.18-7.30 (m, 8 H); 13C
NMR (75 MHz, CHCl3) δ, ppm 22.5, 28.5, 45.9, 46.7, 57.9,
125.7, 126.4, 128.5, 147.5; EI MS 263 (M+); HRMS calcd for
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for compounds 8-15, 20, 21, and 24. This material is
available free of charge via the Internet at http://pubs.acs.org.
C
19H21N 263.1674, found 263.1675.
J O990454I