CAN-mediated oxidative cleavage of 4-aryl-3,4-dihydroxypiperidines

Article abstract of DOI:10.1016/j.tetlet.2006.02.039

A CAN-mediated oxidative cleavage of 4-aryl-3,4-dihydroxypiperidines 2Aa-Be to β-amino carbonyl compounds 3Aa-Be and 4Aa-Be in different ratios is described. This facile strategy was also used to synthesize racemic fluoxetine (5).

Full text of DOI:10.1016/j.tetlet.2006.02.039

Tetrahedron Letters 47 (2006) 2565–2568
CAN-mediated oxidative cleavage of
4-aryl-3,4-dihydroxypiperidines
Meng-Yang Chang,a,* Chun-Yu Lina,b and Chun-Li Paib
aDepartment of Applied Chemistry, National University of Kaohsiung, Kaohsiung 811, Taiwan
bDepartment of Chemistry, National Sun Yat-Sen University, Kaohsiung 804, Taiwan
Received 19 January 2006; revised 31 January 2006; accepted 8 February 2006
Available online 24 February 2006
Abstract—A CAN-mediated oxidative cleavage of 4-aryl-3,4-dihydroxypiperidines 2Aa–Be to b-amino carbonyl compounds 3Aa–
Be and 4Aa–Be in different ratios is described. This facile strategy was also used to synthesize racemic fluoxetine (5).
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
mic coerulescine, horsfiline, and baclofen as shown in
Figure 1.7
CAN (cerium ammonium nitrate) was invented by
Smith et al. in 1936 and explored extensively in organic
reactions in the industry and academia fields.1 Represen-
tative examples include oxidative addition,2 oxidation,3
photooxidation,4 nitration,5 and deprotection,6 etc.
Many research groups successfully developed various
useful transformations by application of this reagent.
Very recently, we developed an easy and straightforward
strategy toward 4-aryl-1,2,5,6-tetrahydropyridines and
explored the related applications for synthesizing race-
The letter presents CAN-mediated transformation of
4-aryl-3,4-dihydroxypiperidines, which provides a new
and convenient method for the preparation of 2-amino-
ethyl (b-amino) arylketones. The b-amino carbonyl
framework is structurally similar to that of known b-
amino acid derivatives. The multiple potential biological
activities of these similar structures have attracted many
efforts from synthetic chemists. Development of a
general and novel procedure for b-amino carbonyl
R
NH
Ar=C6H5
CO2H
R=H, coerulescine
R=OMe, horsfiline
ref. 7a
O
N
N
Ar
Cbz
Me
Cl
Cl
N
Cbz
ref. 7b
baclofen
Ar=4-ClC6H4
HO2C
NH2
N
Cbz
Figure 1.
Keywords: 4-Hydroxypiperidine; 4-Aryl-3,4-dihydroxypiperidines; b-Amino carbonyl compounds; Cerium ammonium nitrate; Fluoxetine.
*
Corresponding author. Tel.: +(886) 7 591 9464; fax: +(886) 7 591 9348; e-mail: mychang@nuk.edu.tw
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.02.039

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M.-Y. Chang et al. / Tetrahedron Letters 47 (2006) 2565–2568
compounds provides an expedient entry point due to the
importance of this structural motif in organic
chemistry.8,9
+
Ar
Ar
Ar
OH
OH
OH
OH
CAN
OH
N
R
N
R
N
R
I
II
2
2. Results and discussion
Ar
Ar
Ar
O
OO
OH
OOH
O
OH
2
OH
4-Aryl-3,4-dihydroxypiperidines 2 (a, Ar = C6H5; b,
Ar = 4-FC6H4; c, Ar = 4-ClC6H4; d, Ar = 4-MeOC6H4;
e, Ar = 3-MeOC6H4) were prepared by the concise five-
step protocol from 4-hydroxypiperidine (1) (N-benzyl-
oxycarbonylation or tosylation, Jones oxidation, Grig-
nard addition, Lewis acid-mediated dehydration, and
dihydroxylation).7 Thus diols 2 were yielded by the
recrystallizations in modest yields. Then, CAN-medi-
ated oxidative cleavage of diols 2 was investigated in
the next step. Two b-amino arylketones 3 and 4 were
provided in different ratios (2:1–3:1) at refluxed tempera-
ture for 30 min as shown in Scheme 1.10
N
R
N
R
N
R
III
IV
V
Ar
Ar
Ar
CAN
OH
O
O
O
O
O
N
R
N
R
H
VII
N
R
VI
VIII
Ar
Ar
Ar
O
2
O
O
O
O
O
CHO
But, the oxidative cleavage of model substrate 2Aa was
unsuccessful on the other commercial available reagents
(e.g., lead tetraacetate and sodium periodate) at refluxed
temperature for 30 min. The difference between CAN
and other reagents was not clear. These results repre-
sented the interesting reaction types for different 4-aryl
groups of 3,4-dihydroxypiperidines. The experimental
results also gave similar data and are summarized in
Table 1.
N
R
N
R
NH
R
4
IX
3
Scheme 2.
How is the oxidative cleavage of compounds 2 initiated
by CAN in acetonitrile? Mechanically it is not clear if
the reaction follows the same pathway as shown in
Scheme 2.2a However, the initial event may be consid-
ered to be the formation of the cation radical I from
2. Benzylic radical II can trap molecular oxygen leading
the peroxyradical III and the latter can abstract hydro-
gen from the solvent and eliminate hydroxide radical to
form the hydroperoxide IV and oxyradical V. Interme-
diate VIII can be generated via bond cleavage of V,
hydrogen abstraction of VI, and oxidative addition of
VII in the presence of excess CAN. Next, compounds
3 are provided by the repeated treatment of VIII with
molecular oxygen and CAN-mediated bond cleavage
of IX. In situ hydrolysis of compounds 3 is further pro-
vided to form compounds 4 in different ratios.
OH
O
1) RCl, Et N
3
1) ArMgBr
2) Jones ox.
R=Cbz or Ts
2) BF -OEt
3
2
N
H
N
R
3) OsO , NMO
4
1
Ar
Ar
Ar
OH
OH
CAN, MeCN
O
O
+
CHO
N
R
2
N
R
3
NH
R
0.1N LiOH
(aq)
4
Furthermore, treatment of diols 2 with CAN did not
cause oxidative cleavage reaction at room temperature.
The reaction must be heated to increase reaction rate.
If the reaction was refluxed over 2 h, the desired prod-
ucts 3 and 4 slowly disappeared and a complex mixture
resulted. The overall reaction progress was monitored
by TLC. Therefore, the best condition for this CAN-
mediated reaction is refluxed temperature within
30 min in acetonitrile.
Scheme 1.
Table 1. CAN-mediated oxidative cleavage of diols 2Aa–Be
Entry
2, (R, Ar), yielda
3, yieldb,c
4, yieldb,c
(%)
(%)
(%)
1
2
3
4
5
6
7
2Aa, (Cbz, C6H5), 64
2Ab, (Cbz, 4-FC6H4), 64
2Ba, (Ts, C6H5), 58
2Bb, (Ts, 4-FC6H4), 52
2Bc, (Ts, 4-ClC6H4), 56
2Bd, (Ts, 4-MeOC6H4), 58
2Be, (Ts, 3-MeOC6H4), 61
3Aa, 54
3Ab, 58
3Ba, 52
3Bb, 55
3Bc, 52
3Bd, 49
3Be, 50
4Aa, 18
4Ab, 28
4Ba, 18
4Bb, 27
4Bc, 20
4Bd, 24
4Be, 25
We had also tried to study the CAN-mediated oxidative
cleavage of 4-alkyl (methyl and ethyl functional group)
3,4-dihydroxypiperidine, but the complex products were
provided in similar condition. Although the synthetic
application is decreased, the present work is comple-
mentary to existing the methodology. We believe the
4-aryl functional group of diols 2 is an important substi-
tuent, which provides a stable benzylic radical in the ini-
tial process of oxidative cleavage.
a All yields were based on compound 1 confirmed.
b The product ratio was adjusted based on isolated products.
c All yields were based on compound 2 confirmed.

M.-Y. Chang et al. / Tetrahedron Letters 47 (2006) 2565–2568
2567
Supplementary data
F C
3
O
1) LAH, THF
O
Experimental procedures and photocopies of 1H and
13C NMR (CDCl3) spectral data for compounds 3Aa–
Be, 4Aa–Be, and 5 were supported. Supplementary data
associated with this article can be found, in the online
version, at doi:10.1016/j.tetlet.2006.02.039.
NHCbz
NHCH
HCl
2) NaH, DMSO,
3
then 4-ClC H CF
3
6
4
) HCl
3
(aq)
fluoxetine-HCl (5)
4Aa
(three steps 52%)
Scheme 3.
References and notes
With the results in hand, the next focus was to examine
the conversion from compounds 3 into 4. Treatment of
compounds 3 with aqueous lithium hydroxide solution
was successfully yielded compounds 4 in nearly quanti-
tative yields.11 The present work can increase the overall
yields for the preparation of compounds 4. Based on the
experimental simplicity, the preparation of compound
4Aa was also conducted in a multigram scale (10 mmol)
with 46% overall yield. Thus enough amounts of com-
pound 4Aa were provided for synthesizing racemic flu-
oxetine by the simple two-step procedure with CAN-
mediated reaction of model substrate 2Aa and basic
hydrolysis of compound 3Aa.
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Racemic fluoxetine, marketed under the trade name
Prozacꢁ, has recently surpassed the $3 billions mark in
annual scales. Fluoxetine offers the potential for treat-
ment of additional indications such as anxiety, alcohol-
ism, chronic pain, headache, obsessive disorders, sleep
disorders, and bulimia. Due to its biological and phar-
macological importance, there have been several reports
on the total synthesis of fluoxetine.12
As shown in Scheme 3, racemic fluoxetine hydrochloride
(5) was successfully accomplished by reduction of
compound 4Aa with lithium aluminum hydride in
tetrahydrofuran, etherification with 4-chlorobenzotrifluo-
ride and sodium hydride in dimethylsulfoxide, and
subsequent hydrolysis with aqueous hydrochloric acid
solution in 52% yield.12a,13 Finally, an easy and novel
approach for total synthesis of racemic fluoxetine (5)
from 4-hydroxypiperidine (1) has been explored.
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3. Conclusion
In conclusion, we explore a CAN-mediated transforma-
tion of diols 2 to two 2-aminoethyl arylketone deriva-
tives 3 and 4 with different ratios and utilize the
method to achieve the synthesis of racemic fluoxetine
(5). We are currently studying the scope of this process
as well as additional applications of this approach to
the synthesis of various potential biological activities
of compounds using 4-hydroxypiperidine (1) as the
starting material.
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.-M.;
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1999, 40, 5613; (d) DattaGupta, A.; Singh, R.; Singh, V.
K. Synlett 1996, 69.
Acknowledgment
The authors would like to thank the National Science
Council (NSC 94-2113-M-390-001) of the Republic of
China for financial support.
7. (a) Chang, M. Y.; Pai, C. L.; Kung, Y. H. Tetrahedron
Lett. 2006, 47, 855; (b) Chang, M. Y.; Pai, C. L.; Kung, Y.
H. Tetrahedron Lett. 2005, 46, 8463.

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Tetrahedron Lett. 2002, 43, 5435; (e) Xu, C.; Yuan, C.
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R. A.; Kumar, P. Tetrahedron Lett. 2002, 43, 4425; (g)
Robertson, D. W.; Krushinski, J. H.; Fuller, R. W.;
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Tetrahedron: Asymmetry 2004, 15, 3955; (m) Kamal, A.;
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2002, 13, 2039; (n) Brown, A.; Carlyle, I.; Clark, J.;
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10. CAN-mediated conversion of diols 2 into b-amino aryl-
ketones 3 and 4 is as follows: CAN (220 mg, 0.4 mmol)
was added to a solution of diols 2 (0.1 mmol) in
acetonitrile (10 mL) at rt. The reaction mixture was stirred
at refluxed temperature for 30 min. Water (1 mL) was
added to the reaction mixture and the solvent was
concentrated under reduced pressure. The residue was
extracted with ethyl acetate (3 · 10 mL). The combined
organic layers were washed with brine, dried, filtered, and
evaporated to afford crude product under reduced
pressure. Purification on silica gel (hexane/ethyl acetate
= 4/1–2/1) afforded b-amino arylketones 3 and 4 in
different ratios (see Table 1). Representative data for 3Aa:
1H NMR (500 MHz, CDCl3) d 9.25 (s, 1H), 7.92–7.90 (m,
2H), 7.59–7.55 (m, 1H), 7.47–7.44 (m, 2H), 7.40–7.36 (m,
5H), 5.32 (s, 2H), 4.11 (t, J = 7.5 Hz, 2H), 3.24 (t,
J = 7.5 Hz, 2H); 13C NMR (125 MHz, CDCl3) d 190.52,
162.64, 153.71, 136.34, 134.49, 133.37, 128.92, 128.80 (2·),
128.65 (2·), 128.54 (2·), 127.99 (2·), 69.05, 36.84, 36.82;
HRMS (ESI) m/z calcd for C18H18NO4 (M++1) 312.1236,
13. Synthesis of fluoxetine hydrochloride (5) is as follows:
Lithium aluminum hydride (38 mg, 1.0 mmol) was added
to a solution of compound 4Aa (70 mg, 0.25 mmol) in
tetrahydrofuran (10 mL) at rt. The reaction mixture was
heated at refluxed temperature for 3 h. After completion
of the reaction as indicated by the TLC, the reaction
mixture was cooled to rt and ethyl acetate (5 mL) was
slowly added. The mixture was filtered through a short
plug of Celite. Water (10 mL) was added to the reaction
mixture and extracted with ethyl acetate (3 · 10 mL). The
combined organic layers were washed with brine, dried,
filtered, and evaporated to afford crude product under
reduced pressure. Without further purification, sodium
hydride (20 mg, 60%, 0.5 mmol) was added to a solution
of the resulting amino alcohol in dimethyl sulfoxide
(2 mL) at rt. The reaction mixture was heated at 60 ꢂC
for 1 h. A solution of 4-chlorobenzotrifluoride (90 mg,
0.5 mmol) in dimethylsulfoxide (0.5 mL) was added to the
reaction mixture at 60 ꢂC and the resultant mixture was
heated for 1 h at 100 ꢂC. After completion of the reaction
as indicated by the TLC, the reaction mixture was cooled
to rt. Water (10 mL) was added to the reaction mixture
and extracted with ether (3 · 10 mL). The combined
organic layers were washed with brine, dried, filtered,
and evaporated to afford crude product under reduced
pressure. Aqueous hydrochloric acid solution (2 N,
0.5 mL) was added to the crude product in ether (5 mL)
at rt. The resulting white solid was filtered and washed
with ether (3 · 10 mL) to give compound 5 (52%, 45 mg).
1H NMR (300 MHz, CDCl3) d 9.68 (br s, 2H), 7.41 (d,
J = 9.0 Hz, 2H), 7.35–7.25 (m, 5H), 6.89 (d, J = 8.7 Hz,
2H), 5.46 (dd, J = 4.5, 8.1 Hz, 1H), 3.12 (br s, 2H), 2.62 (t,
J = 5.4 Hz, 3H), 2.53–2.44 (m, 2H). The NMR spectral
data of compound 5 were in accordance with those
reported in the literature.12a
1
found 312.1235. For 4Aa: H NMR (500 MHz, CDCl3) d
7.95 (d, J = 7.5 Hz, 2H), 7.59 (t, J = 7.5 Hz, 1H), 7.47 (t,
J = 7.5 Hz, 2H), 7.37–7.30 (m, 5H), 5.41 (br s, 1H), 5.09
(s, 2H), 3.63 (dd, J = 6.0, 12.0 Hz, 2H), 3.24 (t, J = 5.5 Hz,
2H); 13C NMR (125 MHz, CDCl3) d 199.15, 156.40,
136.48 (2·), 133.47, 128.68 (2·), 128.48, 128.06, 128.02
(2·), 128.00 (3·), 69.63, 38.49, 35.89; HRMS (ESI) m/z
calcd for C17H18NO3 (M++1) 284.1287, found 284.1288.
11. Conversion of compounds 3 to 4 is as follows: Aqueous
lithium hydroxide (0.1 N, 1 mL) solution was added to a
solution of compounds 3 (0.05 mmol) in tetrahydrofuran
(3 mL). The reaction mixture was heated at refluxed
temperature for 1 h. It was then cooled to rt, acidified with
aqueous hydrochloric acid solution (2 N, 5 mL) and
extracted with ether (3 · 10 mL). The combined organic
layers were evaporated under reduced pressure to afford
crude product under reduced pressure. Purification on
silica gel (hexane/ethyl acetate = 4/1–2/1) afforded com-
pounds 4 in nearly quantitative yields.
12. Synthesis of fluoxetine (5), see: (a) Miles, W. H.; Fialco-
witz, E. J.; Halstead, E. S. Tetrahedron 2001, 57, 992; (b)
Kumar, A.; Ner, D. H.; Dike, S. Y. Tetrahedron Lett.