A concise and stereoselective synthesis of (+/-)-erythro-methylphenidate

Article abstract of DOI:10.1016/S0040-4039(03)00420-9

A concise and stereoselective synthesis of racemic erythro-methylphenidate (1) is described. The coupling reaction between piperidine-2-thione (3) and 2-bromo-2-phenylmethylacetate (4) afforded the β-enaminocarbonyl compound 2 in 60% yield by a modified Eschenmoser sulfide contraction reaction. In most cases the bicyclic thiazolidinone 5 was produced. Diastereoselective reduction of 2 in the presence of borohydrydes furnished the (+/-)-erythro-methylphenidate in good yields with dr >95%.

Full text of DOI:10.1016/S0040-4039(03)00420-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 2923–2926
A concise and stereoselective synthesis of
(+/−)-erythro-methylphenidate
Dennis Russowsky* and Brenno Amaro da Silveira Neto
Instituto de Qu´ımica, Universidade Federal do Rio Grande do Sul, Av. Bento Gonc¸alves, 9500, 91501-970 Porto Alegre, Brazil
Received 10 February 2003; accepted 12 February 2003
Abstract—A concise and stereoselective synthesis of racemic erythro-methylphenidate (1) is described. The coupling reaction
between piperidine-2-thione (3) and 2-bromo-2-phenylmethylacetate (4) afforded the b-enaminocarbonyl compound 2 in 60% yield
by a modified Eschenmoser sulfide contraction reaction. In most cases the bicyclic thiazolidinone 5 was produced. Diastereoselec-
tive reduction of 2 in the presence of borohydrydes furnished the (+/−)-erythro-methylphenidate in good yields with dr >95%.
© 2003 Elsevier Science Ltd. All rights reserved.
The
(+/−)-threo-methylphenidate
hydrochloride
thesis of (2S,2%S)-erythro-methylphenidate was recently
(Ritalin®), is an indirect catecholamine agonist,1 and is
the drug treatment of choice for the attention deficit/
hyperactivity disorder (AD/HD),2 one of the most com-
mon behavioral disorders of childhood which affects
5–10% of the general population.3 The activity of
Ritalin® promotes an enhancement of the cognitive
performance in both adults and children diagnosed with
AD/HD.4 Although Ritalin® is available in the market
as the racemate, the (2R,2%R)-(+)-threo-methylphenidate
has been reported to be up to 38 times5 more active
than (2S,2%S)-(−)-threo-methylphenidate and several
racemic6–9 and chiral10–13 synthesis of threo-methyl-
phenidate were reported previously.
published by Prashad and co-workers.16
Due to this fact and relating to our interest in the
synthesis of b-aminocarbonyl compounds17,18 we would
like to communicate in this paper our approach to the
synthesis of (+/−)-erythro-methylphenidate 1 applying a
new concise stereoselective synthetic strategy.
We envisaged obtaining 1 based on a stereoselective
reduction of a b-enaminocarbonyl compound 2 which
is readily accessible by the Eschenmoser sulfide contrac-
tion reaction19,20 (Scheme 1).
The needed piperidine-2-thione (3) was prepared in 91%
yield after reaction of piperidine-2-one with Lawesson
reagent.21 The bromoester 4 was obtained by sterifica-
tion and subsequent a-bromination22 of 2-phenylacetic
acid in 71% overall yield after purufication by horizon-
tal destilation at reduced pressure. Next, the condensa-
tion reaction of compounds 3 and 4 was carried out
under the Eschenmoser sulfide contraction reaction
Although the erythro-methylphenidate exhibits very few
therapeutic properties and toxic hypertensive effects,14
the stereoselective synthesis of the erythro-isomer can be
helpful due to the possibility of resolution and epimeriza-
tion of the erythro-isomer.2,15 This approach was used
early in the original synthesis of (+/−)-threo-
methylphenidate. Close to this, an enantioselective syn-
Scheme 1. The retrosynthetic analysis of 1 based on the eschemoser sulfide contraction reaction.
* Corresponding author. Tel.: +55-51-33166284; fax: +55-51-33167304; e-mail: dennis@iq.ufrgs.br
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00420-9

2924
D. Russowsky, B. A. da Sil6eira Neto / Tetrahedron Letters 44 (2003) 2923–2926
In our first attempt to carry out the condensation of
compounds 3 and 4 by the usual Eschenmoser protocol
we were able to isolate the b-enaminocarbonyl compound
2 in 42% yield along with 20% yield of a second product
which was identified as the bicyclic thiazolidinone 5
(Scheme 2).
protocol to provide the key intermediate b-enaminocar-
bonyl compound 2 (Table 1).
The classical conditions to carry out this reaction gener-
ally employ CH2Cl2 as the solvent, Et3N as the base and
excess of Ph3P as the sulfur scavenger. Other tertiary
amines and phosphorous thiophiles23 are reported in the
literature as being effective, as well as reaction performed
in the absence of a thiophile.24
The products 2 and 5 were separated and purified by
column chromatography and their 1H and 13C NMR and
IR spectra are in accordance with the proposed struc-
tures.32 The formation of a thiazolidinones was recently
reported in the literature by Padwa33 and Michael34 for
analogous reactions and the factors controlling its forma-
tion are not yet clear. The geometry of the double bond
in 2 was shown to be Z by the analysis of the NOE
experiment: irradiation of allylic protons of the piperidine
ring at l 2.10 showed a 5.30% increment in the ortho-
hydrogens of the phenyl ring. Attempting to achieve the
best yields of compound 2 and to avoid the formation
of thiazolidinone 5, we carried out the reaction under
various different conditions employing three different
thiofiles and a set of bases. The results are summarized
in Table 1.
While trisubstituted b-enaminocarbonyl compounds are
readily prepared starting from thiolactams and a-bro-
moesters under the usual protocol, the tetrasubstituted
derivatives, such as 2, require carefully controlled condi-
tions to avoid undesired side reactions.25,26 The main
examples in the literature to prepare the tetrasubstituted
b-enaminocarbonyl compounds are limited to the
employment of a secondary a-triflates27,28 or a-bromo-
carbonyl reagent with a second electron withdrawing
group (CN, COR, CO2R, NO2) attached to the a-car-
bonyl carbon.29–31
Table 1. Reaction conditions and yields of compounds 2
and 5 via Scheme 2
We observed that different amounts of Ph3P as the
thiophile in the reaction using Et3N as the base did not
produce a significative change in the proportion of 2 and
5 and the yields were essentially the same (Table 1, entries
1–3). The use of n-Bu3P caused a small decrease in the
yield of thiazolidinone 5 (Table 1, entry 4) and no
products were observed employing (EtO)3P as the thio-
phile (Table 1, entry 5). Changing from Et3N to DBU
(Table 1, entry 6) caused a decrease in the formation of
product 2 and an increase in the yield of 5. With these
initial results, we decided to monitor the reaction course
byGCanalysis. Inthefirsthourofreaction, itwaspossible
to detect the formation of compounds 2 and 5 and partial
consumption of piperidine-2-thione, even in the absence
of base and thiophile.
Entry
Base (2.0
equiv.)
Thiophile (no. equiv.)
Yield (%)
2
5
1
2
3
4
Et3N
Et3N
Et3N
Et3N
Ph3P (4.0)
Ph3P (2.0)
Ph3P (1.0)
n-Bu3P (2.0)
42
46
45
44
–
20
21
20
16
–
5
Et3N
(EtO)3P (2.0)
6
7
8
9
10
11
12
13
14
15
DBU
Et3N
Py
DMAP
DABCO
DIPEA
DBN
TMEDA
DBU
Ph3P (2.0)
35
6
41
25
11
4
12
12
13
21
–
–
–
–
–
–
–
–
–
–
13
27
32
41
41
46
60
20
We supposed that a competitive side reaction would form
the thiazolidinone 5 from the initially formed thioalkyl-
ated salt 620 (pathway B) and the addition of a base could
enhance the yield of compound 2 (pathway A) by the
current accepted mechanism of the Eschenmoser sulfide
contraction reaction14 (Scheme 3).
KOt-Bu
35
Scheme 2. The Eschenmoser sulfide contraction reaction. Reagents and conditions: (a) (i) CH2Cl2, rt, 24 h; (ii) Et3N (2.0 equiv.),
rt, then; (iii) Ph3P (2.0 equiv.), rt, 18 h.
Scheme 3. Formation of products 2 and 5 from the intermediate salt 6.

D. Russowsky, B. A. da Sil6eira Neto / Tetrahedron Letters 44 (2003) 2923–2926
2925
Scheme 4. Reduction of the b-enaminoester 2.
Table 2. Reduction reaction of b-enaminoester 2
Entry
Reducing agent
Conditions
Solvent
erythro:threo (%)
Yield (%)
1
2
3
4
5
6
PtO2
NaBH4
NaCNBH3
NaHB(OAc)3
NaHB(OAc)3
Mg
HClO4, 1 atm H2, rt
MeOH
CH3CN
CH3CN
CH3CN
CH3CN
MeOH
80:20
96:4
96:4
96:4
93:7
85:15
90
91
90
89
72
40
AcOH, rt
HCl, rt
AcOH, rt
rt
60°C
Reduction of 2 with NaBH4/AcOH was ineffective but
performing the reaction in presence of CH3CN as sol-
vent afforded the erythro-isomer 1 in dr 96:4 in 91%
yield after chromatography (Table 2, entry 2). High
diastereoselectivity was also observed using NaCNBH3/
HCl40 as the reducing agent (Table 2, entry 3). For the
NaHB(OAc)3/AcOH41 (Table 2, entry 4) the reaction
shows dr 96:4 to the erytho-isomer 1 in a relative good
yield, and this reducing agent is effective (Table 2, entry
5) even in the absence of acetic acid (dr 93:7 and 72%
yield). Metalic magnesium in MeOH42 was also tested,
but reduction of 2 occurred in poor yield of erythro-1
in dr 85:15 (Table 2, entry 6).
The addition of 2 equiv. of Et3N without subsequent
addition of a thiophile afforded 2 in only 6% yield and
5 in 25% yield (Table 1, entry 7). In this way, a set of
available tertiary amines as bases was investigated. In
all cases a variable ratio of compounds 2 and 5 was
observed (Table 1, entries 8–14) and the use of KOt-Bu
furnished the compound 5 as a major product (entry
15). Interestingly, the best yield of compound 2 (60%)
was achieved when DBU was employed in the absence
of a thiophile (Table 1, entry 14) in which thiazolidi-
none 5 was not isolated. We believe that these results
can be closely related with both the bulkiness and the
basicity of employed bases but a rationale for this
competition remains unclear.
In conclusion, we have described a novel, concise, and
stereoselective strategy for the synthesis of (+/−)-ery-
thro-methylfenidate 1 in three steps from piperidine-2-
one in 52% overall yield through the modified
Eschenmoser sulfide contraction reaction. Interestingly,
the thiazolidinone 5 is concurrently formed in variable
amounts depending on the reaction conditions and an
investigation of the reaction mechanism for its forma-
tion is underway.
With product 2 in hand, the next step was the reduction
of the double bond to obtain the corresponding b-
aminoester derivative 1 (Scheme 4). Attempts to carry
out the hydrogenation in the presence of 5% Pd–C35 (1
atm) and 10% Pd–C (1, 5 and 15 atm) as well as
Pd(OH)2 (5 atm) were not effective to reduce the com-
pound 2.
The utilization of PtO2 and PtO2/AcOH (1 atm) also
did not afford the reduced product. However, when the
reaction was carried out in the presence of PtO2/
Acknowledgements
HClO4 the (+/−)-erythro-methylphenidate37 (1) was
36
formed in 90% yield as a 80:20 mixture (Table 2, entry
1).
This work was sponsored by grants from CNPq and
FAPERGS. Professors B. M. S. Tenius, M. N. Eberlin
and R. A. Pilli for their collaboration and helpfull
discussions are acknowledged. B.A.S.N. acknowledges
CAPES for the fellowship.
The relative configuration of the reduced product was
1
inferred by comparing the spectral data of H and 13C
NMR reported in the literature.12 The diastereoiso-
meric ratio was determined by gas chromatography and
1H NMR analysis of the crude mixture and showed
essentialy the same results. Trying to improve stereose-
lectivity, we tried to use a general methodology based
on reduction by metal-hydrides. Owing to low elec-
trophilicity, enaminocarbonyls show poor reactivity
toward hydrides.38 Sodium borohydride–carboxylic
acid is, however, an effective reducing agent for enam-
ines and for the N-alkylation of the relative amines.39
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