CAN-mediated rearrangement of 4-benzhydrylidenepiperidines

Article abstract of DOI:10.1016/j.tetlet.2006.09.068

Several 1-substituted phenyl-(4-phenylpiperidin-4-yl)methanones are synthesized in modest overall yields starting from the reaction of different 1-substituted 4-benzhydrylidenepiperidines via CAN-mediated rearrangement. This facile strategy was also used to synthesize meperidine analog.

Full text of DOI:10.1016/j.tetlet.2006.09.068

Tetrahedron Letters 47 (2006) 8347–8350
CAN-mediated rearrangement of 4-benzhydrylidenepiperidines
Meng-Yang Chang,a,* Tsun-Cheng Wu,a Chun-Yu Linb and Ching-Yi Hunga
aDepartment of Applied Chemistry, National University of Kaohsiung, Kaohsiung 811, Taiwan
bDepartment of Chemistry, National Sun Yat-Sen University, Kaohsiung 804, Taiwan
Received 1 September 2006; revised 12 September 2006; accepted 15 September 2006
Available online 5 October 2006
Abstract—Several 1-substituted phenyl-(4-phenylpiperidin-4-yl)methanones are synthesized in modest overall yields starting from
the reaction of different 1-substituted 4-benzhydrylidenepiperidines via CAN-mediated rearrangement. This facile strategy was also
used to synthesize meperidine analog.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Among various cerium(IV) complexes, cerium ammo-
nium nitrate (CAN) is one of the most important oxi-
dants in organic synthesis, as it is sufficiently stable in
different solvents and is commercially available.1 It
was invented by Smith et al. in 1936 and explored exten-
sively in the organic reactions of industries and acade-
mia fields.1a This reagent has been reviewed for
reactions involving carbon–carbon, carbon–nitrogen,
carbon–sulfur, carbon–selenium, carbon–halogen, and
other carbon–heteroatom bond formations.1 Represen-
tative examples include oxidative addition, photooxida-
tion, nitration, and deprotection etc.2–6 Due to the
numerous advantages associated with this eco-friendly
compound, CAN has been explored as a powerful
reagent for different reactions. Many research groups
successfully developed various useful transformations
by the application of this reagent.
Ar
Ar
Ar OH
(1) CAN, NaN3
NH
(1) OsO4
2
O
(2) CAN
(ref. 7a)
(2) H2, Pd/C
(ref. 7b)
NH
Ts
N
Ts
N
Ts
Scheme 1.
For investigating the CAN-mediated rearrangement,
several 1-substituted 4-benzhydrylidenepiperidines 2a–f
(a, R = MeSO2; b, R = PhSO2; c, R = p-TolSO2; d,
R = EtCO; e, R = PhCO; f, R = BnOCO) were chosen
as the starting materials and prepared via N-acylation
of phenyl-piperidin-4-yl-methanone (1)8 with different
acid chlorides in CH2Cl2 at 0 ꢁC, Grignard addition
with phenylmagnesium bromide reagent in THF at
ꢀ78 ꢁC, and subsequent dehydration with BF3–OEt2
in CH2Cl2 at rt.
Recently, we developed two straightforward strategies
toward CAN-mediated oxidative cleavage of cis-4-aryl-
3,4-dihydroxypiperidines and CAN-mediated oxidative
addition of 4-aryl-1,2,5,6-tetrahydropyridines with
sodium azide and followed by hydrogenation
(Scheme 1).7a,b In order to address this issue, the
CAN-mediated rearrangement of 4-benzhydrylidene-
piperidines was explored.
With several compounds 2a–f in hand, CAN-mediated
rearrangement in CH3CN at rt without nitrogen system
was examined.9 To explore the generality of this reac-
tion, the results of investigations were presented in
Scheme 2. The total synthetic procedure could be mon-
itored by TLC until the reaction was complete at rt for
ca. 3 h. The structure of compound 3c was determined
by single-crystal X-ray analysis as shown in Diagram 1.
The transformation is an efficient rearrangement with a
facile operation procedure, which is governed by the
stability of tertiary radical, and the introduction of
molecular oxygen takes place. How is the oxidative re-
arrangement of compounds 2a–f initiated by CAN?
Mechanically it is not clear if the reaction follow the
Keywords: Cerium ammonium nitrate; 4,4-Bisphenylmethylenepiperi-
dines; Rearrangement; Phenyl-(4-phenyl-piperidin-4-yl)methanones;
Meperidine.
*
Corresponding author. Tel.: +886 7 5919464; fax: +886 7 5919348;
e-mail: mychang@nuk.edu.tw
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.09.068

8348
M.-Y. Chang et al. / Tetrahedron Letters 47 (2006) 8347–8350
Ph
Ph
Ph
Ph
Ph
O
Ph
Ph
O
Ph
+
O
S
Ph
O
1) RCl
Me
N
CAN
O
CAN
Ph
2) PhMgBr
N
S
N
S
Me
N
H
N
R
N
R
3) BF -OEt
Ph
3
2
O
Me
O
O
2a
I
II
1
2a, R=MeSO (52%)
3a, 65%
3b, 63%
3c, 60%
3d, 60%
3e, 53%
3f, 60%
2
2b, R=PhSO (58%)
2
2c, R=p-TolSO (54%)
2
O
S
O
O
O
OH
O
2d, R=EtCO (58%)
2e, R=PhCO (55%)
2f, R=BnOCO (50%)
Me
N
Me
N
O
2
O
O S
Ph
Ph
Ph
Ph
Scheme 2.
III
IV
Ph
O
S
Ph
O
Me
N
O
O
Ph
N
S
Me
Ph
O
O
3a
V
Scheme 3.
Although a great number of 4-aroyl-4-arylpiperidines
and their derivatives with this specific substitution
pattern are of particular interest, more significant efforts
toward the development of new methods are needed.10
The exhibited methodology could provide a new route
for the preparation of various 4-aroyl-4-arylpiperidines
in search of useful compounds with potential biological
activities.10c
Diagram 1. X-ray crystallography of compound 3c.
same pathway as shown in Scheme 3. However, the ini-
tial event may be considered to be the formation of the
cation radical I from model substrate 2a. Benzylic radi-
cal II can trap molecular oxygen leading peroxyradical
III and the latter can abstract hydrogen from the solvent
and eliminate hydroxide radical to form hydroperoxide
IV and oxyradical V. Next, compounds 3a–f were pro-
vided by the bond migration of intermediate V.
To reinvestigate the applicability of the facile reaction,
we had tried to study compound 4.11 Compound 4 is a
key precursor for preparing meperidine. Meperidine
can serve as an atypical l-opioid agonist at monoamine
transporters and was initially found to be selective for
the serotonin transporter over the dopamine.12 As
shown in Scheme 4, the treatment of ketone 3f with
m-chloroperoxybenzoic acid and sodium carbonate
and followed by hydrogenolysis yielded aminoacid 4.
According to the recent literature reports,2d,f Nair and
his coworkers had developed a series of CAN-mediated
reaction with molecular oxygen. The possible reaction
mechanism involving different supporting experimental
data was proposed well. With the literature reports
and our results, we have to envision that molecular oxy-
gen plays an important role to promote the occurrence
of rearrangement reactions by CAN.
Upon the treatment of three unsymmetrical compounds
6a (Ar = 2-MePh), 6b (Ar = 3-MeOPh) and 6c (Ar = 4-
FPh) with CAN, the inseparated mixture was obtained
in 62%, 60%, and 56% yields with nearly 2:1–3:1 ratios
by 1H NMR spectral analysis. Based on the results,
the poor regioselectivity was provided between phenyl
group and aryl group with donating and withdrawing
For enhancing the reaction diversity, reaction solvents
(methanol or t-butanol), reaction additives (sodium
azide and lithium thiomethoxide) and other conditions
(with or without nitrogen system) were tested under
the CAN-mediated reaction. But unsatisfied results
(lower yields or complex products) were yielded. In this
letter, the present methodology was an optimum
reaction condition among the tested conditions by us.
Briefly, the best condition for this facile operation
reaction is room temperature within 3 h in dry MeCN
without nitrogen or argon system.
Ph
OH
OH
Ph
O
Ph
O
O
O
Ph
O
MCPBA, Na CO
2
H , Pd/C
2
3
(56%)
(79%)
N
N
N
H
OBn
3f
OBn
5
4
Scheme 4.

M.-Y. Chang et al. / Tetrahedron Letters 47 (2006) 8347–8350
8349
2006, 62, 7293; (j) Duan, Z.; Xuan, X.; Li, T.; Yang, C.;
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group during the rearrangement process. In our technol-
ogy, we cannot separate the three pairs of regioisomers
such that the correct structures of 4-aroyl-4-phenyl-
piperidines and 4-benzoyl-4-arylpiperidines cannot be
determined. We had also tried to study a number of
reaction conditions (e.g., prolonged reaction time and
elevated temperature) for increasing the regiochemical
selectivity, which provided unsatisfactory results.
Although the synthetic application is decreased, the
present work is complementary to existing methodol-
ogy.
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Ph
Ph
Ar
Ph
Ar
O
O
CAN
+
N
Ms
N
Ms
N
Ms
ð1Þ
6a, Ar=2-MePh
6b, Ar=3-MeOPh
6c, Ar=4-FPh
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1996, 24, 1.
In conclusion, we have developed a straightforward
method for synthesizing 1-substituted phenyl-(4-phen-
ylpiperidin-4-yl)methanones via the CAN-mediated
rearrangement of different 1-substituted 4-benzhydryl-
idenepiperidines. A key precursor of meperidine was
also prepared by the simple operation. Currently studies
are in progress in this direction.
6. (a) Bull, S. D.; Davies, S. G.; Mulvaney, A. W.; Prasad,
R. S.; Smith, A. D.; Fenton, G. Chem. Commun. 2000,
337; (b) Ates, A.; Gautier, A.; Leroy, B.; Plancher, J.-
Acknowledgments
´
M.; Quesnel, Y.; Marko, I. E. Tetrahedron Lett. 1999,
´
40, 1799; (c) Marko, I. E.; Ates, A.; Augustyns, B.;
The authors would like to thank the National Science
Council (NSC-95-2113-M-390-003-MY2) of the Repub-
lic of China for financial support.
Gautier, A.; Quesnel, Y.; Turet, L.; Wiaux, M. Tetra-
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References and notes
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1. (a) Smith, G. F.; Sullivan, V. R.; Frank, G. Ind. Eng.
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9. CAN-mediated rearrangement of olefins 2a–f into com-
pounds 3a–f is as follows: A solution of ceric ammonium
nitrate (CAN, 2.2 g, 2.0 mmol) in CH3CN (10 mL) was
added dropwise to a solution of olefins 2a–f (1.0 mmol) in
dry CH3CN (5 mL) at rt under open system condition.
The reaction mixture was stirred at rt for 1 h. Water
(1 mL) was added to the reaction mixture and the solvent
was concentrated. The residue was extracted with AcOEt
(3 · 20 mL). The combined organic layers were washed
with brine, dried, filtered and evaporated to afford crude
product. Purification on silica gel (hexane/AcOEt = 4/1–
2/1) afforded compounds 3a–f. For compound 3a: 1H
NMR (500 MHz, CDCl3) d 7.41–7.31 (m, 8H), 7.27–7.24
(m, 2H), 3.69 (d, J = 12.5 Hz, 2H), 2.84 (dt, J = 1.5,
2. (a) Kobayashi, K.; Umakoshi, H.; Hayashi, K.; Mori-
kawa, O.; Konishi, H. Chem. Lett. 2004, 1588; (b) Lee, Y.
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Paolobelli, A. B.; Ruzziconi, R.; Lupattelli, P.; Scafato, P.;
Spezzacatena, C. J. Org. Chem. 1999, 64, 3364; (d) Nair,
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Lett. 2006, 47, 487; (i) Ko, S.; Yai, C.-F. Tetrahedron

8350
M.-Y. Chang et al. / Tetrahedron Letters 47 (2006) 8347–8350
12.0 Hz, 2H), 2.75 (s, 3H), 2.67 (d, J = 12.5 Hz, 2H), 2.19
(125 MHz, CDCl3) d 203.20, 170.36, 142.13, 137.13,
133.86, 131.86, 129.58, 129.38 (2·), 128.87 (2·), 128.41
(2·), 128.18 (2·), 127.61, 126.83 (2·), 125.94 (2·), 54.08,
45.26, 39.49, 36.31, 33.96; HRMS (ESI) m/z calcd for
C25H24NO2 (M++1) 370.1807, found 370.1810. For com-
pound 3f: (rotamer): 1H NMR (500 MHz, CDCl3) d 7.43–
7.23 (m, 15H), 5.13 (br s, 2H), 4.07–3.99 (m, 2H), 3.11–
2.95 (m, 2H), 2.55 (d, J = 13.0 Hz, 2H), 2.11–1.92 (m, 2H);
13C NMR (125 MHz, CDCl3) d 203.35, 155.25, 142.38,
137.35, 136.71, 131.71, 129.30 (2·), 128.81 (2·), 128.42
(2·), 128.11 (2·), 127.91, 127.77 (2·), 127.48, 125.95 (2·),
67.01, 53.77, 41.26 (2·), 35.19, 34.28; HRMS (ESI)
m/z calcd for C26H26NO3 (M++1) 400.1913, found
400.1913.
(dt, J = 4.5, 12.0 Hz, 2H); 13C NMR (125 MHz, CDCl3) d
203.01, 141.96, 136.81, 132.04, 129.44 (2·), 129.98 (2·),
128.25 (2·), 127.72, 125.82 (2·), 53.21, 43.41 (2·), 34.56
(2·), 34.41; HRMS (ESI, M++1) calcd for C19H22NO3S
344.1320, found 344.1323. For compound 3b: 1H NMR
(500 MHz, CDCl3) d 7.73 (d, J = 7.5 Hz, 2H), 7.63–7.60
(m, 1H), 7.53 (t, J = 7.5 Hz, 2H), 7.40–7.30 (m, 6H), 7.19–
7.17 (m, 4H), 3.69 (d, J = 12.5 Hz, 2H), 2.61 (d,
J = 12.0 Hz, 2H), 2.47 (dt, J = 2.0, 12.0 Hz, 2H), 2.17
(dt, J = 4.0, 12.0 Hz, 2H); 13C NMR (125 MHz, CDCl3) d
202.95, 141.91, 136.95, 136.02, 132.73, 131.81, 129.35 (2·),
129.99 (2·), 128.69 (2·), 128.12 (2·), 127.64, 127.51 (2·),
125.76 (2·), 53.07, 43.59 (2·), 34.31 (2·); HRMS (ESI,
M++1) calcd for C24H24NO3S 406.1477, found 406.1481.
For 3c: 1H NMR (500 MHz, CDCl3) d 7.60 (d, J = 8.0 Hz,
2H), 7.41–7.31 (m, 8H), 7.20–7.18 (m, 4H), 3.68 (dt,
J = 3.0, 13.5 Hz, 2H), 2.60 (d, J = 13.5 Hz, 2H), 2.46 (s,
3H), 2.45 (td, J = 1.5, 13.5 Hz, 2H), 2.17 (td, J = 4.0,
13.5 Hz, 2H); 13C NMR (125 MHz, CDCl3) d 203.08,
143.51, 142.05, 137.06, 133.15, 131.84, 129.66 (2·), 129.40
(2·), 128.78 (2·), 128.16 (2·), 127.67, 127.62 (2·), 125.83
(2·), 53.18, 43.63 (2·), 34.39 (2·), 21.57; HRMS (ESI,
M++1) calcd for C25H26NO3S 420.1633, found 420.1632.
Single-crystal X-ray diagram: the crystal of compound 3c
was grown by slow diffusion of AcOEt into a solution of
compound 3c in CH2Cl2 to yield, colorless prism. The
compound crystallizes in the monoclinic crystal system.
10. For the synthesis and biological activities of 4-aroyl-4-
arylpiperidines, see: (a) Watanabe, Y.; Usui, H.; Koba-
yashi, S.; Yoshiwara, H.; Shibano, T.; Tanaka, T.;
Morishima, Y.; Yasuoka, M.; Kanao, M. J. Med. Chem.
1992, 35, 189; (b) Rhoden, J. B.; Bouvet, M.; Izenwasser,
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Med. Chem. 2005, 13, 5623; (c) Lindsley, C. W.; Zhao, Z.;
Leister, W. H.; O’Brien, J.; Lemaire, W.; Williams, D. L.,
Jr.; Chen, T.-B.; Chang, R. S. L.; Burno, M.; Jacobson,
M. A.; Sur, C.; Kinney, G. G.; Pettibone, D. J.; Tiller, P.
R.; Smith, S.; Tsou, N. N.; Duggan, M. E.; Conn, P. J.;
Hartman, G. D. ChemMedChem 2006, 1, 807; (d) Lyle, R.
E.; Lyle, G. G. J. Am. Chem. Soc. 1954, 76, 3536; (e) Ong,
H. H.; Angew, M. N. J. Heterocycl. Chem. 1981, 18, 815.
11. (a) Nagarathnam, D.; Wetzel, J. M.; Miao, S. W.; Marza-
badi, M. R.; Chiu, G.; Wong, W. C.; Hong, X.; Fang, J.;
Forray, C.; Branchek, T. A.; Heydorn, W. E.; Chang, R. S.
L.; Broten, T.; Schorn, T. W.; Gluchowski, C. J. Med.
Chem. 1998, 41, 5320; (b) Stevenson, G. I.; MacLeod, A.
M.; Huscroft, I.; Cascieri, M. A.; Sadowski, S.; Baker, R. J.
Med. Chem. 1995, 38, 1264; (c) Auberson, Y. P.; Bischoff,
S.; Moretti, R.; Schmutz, M.; Veenstra, S. J. Bioorg. Med.
Chem. Lett. 1998, 8, 65; (d) Stevenson, G. I.; Huscroft, I.;
MacLeod, A. M.; Swain, C. J.; Cascieri, M. A.; Chicchi, G.;
Graham, M. I.; Harrison, T.; Kelleher, F. J.; Kurtz, M.;
Ladduwahetty, T.; Merchant, K. J.; Metzger, J. M.;
MacIntyre, D. E.; Sadowski, S.; Sohal, B.; Owenset, A. P.
J. Med. Chem. 1998, 41, 4623; (e) Zhu, J.; Pottorf, R. S.;
Player, M. R. Tetrahedron Lett. 2006, 47, 7267.
˚
˚
space group P2(1), a = 12.430(3) A, b = 6.1974(13) A,
3
˚
˚
c = 14.688(3) A, V = 1042.1(4) A , Z = 4, dcalcd
=
,
2.674 mg/m3, 0.365 mmꢀ1
absorption coefficient
F(000) = 888, 2h range (1.51–28.36ꢁ); R indices (all data):
1
R1 = 0.0658, wR2 = 0.1007. For compound 3d: H NMR
(500 MHz, CDCl3) d 7.45–7.21 (m, 10H), 4.44 (br d, J =
13.5 Hz, 1H), 3.70 (br d, J = 13.5 Hz, 1H), 3.31 (t,
J = 12.5 Hz, 1H), 2.73 (t, J = 12.5 Hz, 1H), 2.62 (br
d, J = 13.5 Hz, 1H), 2.53 (br d, J = 13.5 Hz, 1H), 2.32 (q,
J = 7.5 Hz, 2H), 2.12 (dt, J = 3.5, 13.5 Hz, 1H), 1.83 (dt,
J = 3.5, 13.5 Hz, 1H), 1.12 (t, J = 7.5 Hz, 3H); 13C NMR
(125 MHz, CDCl3) d 203.23, 172.28, 142.19, 137.11,
131.79, 129.30 (2·), 128.83 (2·), 128.12 (2·), 127.52,
125.88 (2·), 53.91, 42.94, 38.83, 36.40, 33.55, 26.40, 9.45;
HRMS (ESI) m/z calcd for C21H24NO2 (M++1) 322.1807,
found 322.1806. For compound 3e (rotamer): 1H NMR
(500 MHz, CDCl3) d 7.43–7.31 (m, 13H), 7.27–7.23 (m,
2H), 4.57–4.54 (m, 1H), 3.67–3.64 (m, 1H), 3.31–3.27
(m, 1H), 3.01–2.96 (m, 1H), 2.66–2.61 (m, 1H), 2.54–2.51
(m, 1H), 2.26–2.22 (m, 1H), 1.88–1.84 (m, 1H); 13C NMR
12. (a) Lomenzo, S. A.; Izenwasser, S.; Gerdes, R. M.; Katz,
J. L.; Kopajtic, T.; Trudell, M. L. Bioorg. Med. Chem.
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