The influence of the ring size of thiolactams in the Eschenmoser coupling reaction in presence of DBU. Formation of bicyclic thiazolidinones or thioimines

Article abstract of DOI:10.1016/j.tetlet.2003.12.049

The different behaviors of pyrrolidin-2-thione and piperidin-2-thione under a modified Eschenmoser sulfur contraction reaction protocol using DBU as base was observed. The pyrrolidin-2-thione 1b follows the expected reaction course, leading to thioimines

Full text of DOI:10.1016/j.tetlet.2003.12.049

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 1437–1440
The influence of the ring size of thiolactams in the Eschenmoser
coupling reaction in presence of DBU. Formation of
bicyclic thiazolidinones or thioiminesq
Dennis Russowsky* and Brenno Amaro da Silveira Neto
ꢀ
Instituto de Quımica, Universidade Federal do Rio Grande do Sul, Av. Bento Gonßcalves 9500, Porto Alegre 91501-970, Brazil
Received 2 October 2003; revised 9 December 2003; accepted 10 December 2003
Abstract—The different behaviors of pyrrolidin-2-thione and piperidin-2-thione under a modified Eschenmoser sulfur contraction
reaction protocol using DBU as base was observed. The pyrrolidin-2-thione 1b follows the expected reaction course, leading to
thioimines 5a–d, which can be transformed subsequently into the respective by action of a thiophile, while the piperidin-2-thione
leads to the formation of bicyclic thiazolidinones 4b–d in moderate to good yields. The b-enaminocarbonyl compound 11 was
hydrogenated to afford the respective five-membered analogue of methylphenidate 12.
Ó 2003 Elsevier Ltd. All rights reserved.
The exo-cyclic enamines, are useful building blocks for
the synthesis of natural products.1 The Eschenmoser
sulfide contraction reaction2 is an elegant way to pre-
pare this special class of compounds and it is an
important tool in organic synthesis.3 This methodology
has been successfully applied as a key pathway in many
synthetic strategies addressed to the synthesis of natural
products, notably in the synthesis of alkaloids.4–8
While N-secondary or N-tertiary trisubstituted b-en-
aminocarbonyl compounds are readily prepared under
classical conditions, the tetrasubstituted derivatives need
carefully controlled conditions.12;13 Secondary a-triflate-
esters14;15 are required in the cases where pyrrolidine
thiolactams were involved. The principal examples to
prepare the N-secondary tetrasubstituted exo-cyclic
b-enaminocarbonyl compounds from piperidine thio-
lactams use a a-bromocarbonyl reagent with a second
electron withdrawing substituent groups (CN,16 COR or
CO2R17) attached to the a-carbonyl carbon.
The Eschenmoser sulfide contraction reaction, also
called the Eschenmoser coupling reaction,9 occurs when
a thiolactam condenses with an a-bromocarbonyl com-
pound in the presence of a base and a sulfur scavenger,
leading to the respective b-enaminocarbonyl derivative.
The classical conditions generally employ a tertiary
amine (Et3N) as the base and a phosphine (Ph3P-thio-
phile) as the sulfur scavenger, although other tertiary
amines and phosphorous thiophiles10 have been
reported as being effective, as well as reactions per-
formed in the absence of a thiophile.11
In connection with our interest in the synthesis of
b-aminocarbonyl compounds,18;19 we have recently
applied the Eschenmoser coupling reaction to synthesize
the b-enaminoester 3a as the key intermediary in the
synthesis of ( )-erythro-methylphenidate. The reaction
of the piperidin-2-thione (1a) with the a-bromoester 2a,
under the Eschenmoser protocol, produced 3a and a
variable quantity of the unexpected thiazolidinone 4a,
depending on the base employed (Scheme 1). However,
3a was obtained as a sole product when the reaction was
carried using DBU (2 equiv) as base and in the absence
of Ph3P as a thiophile.20
Keywords: Eschenmoser coupling reaction; Thiazolidinones; Methyl-
phenidate derivatives; DBU.
q Supplementary data associated with this article can be found in the
online version, at doi:10.1016/j.tetlet.2003.12.049
* Corresponding author. Tel.: +55-51-3316-62-84; fax: +55-51-3316-
73-04; e-mail: dennis@iq.ufrgs.br
In attempt to generalize this modified Eschenmoser
protocol to prepare the N-secondary tetrasubstituted
b-enaminocarbonyls, we would like to disclose here, our
results regarding the different behaviors observed for the
0040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.12.049

1438
D. Russowsky, B. A. da Silveira Neto / Tetrahedron Letters 45 (2004) 1437–1440
corresponding b-enaminoesters but gave the thiazolid-
inones 4b–d in good yields (entries 5–7).
O
Base
Br
OMe
+
N
H
S
Thiophile
Ph
It should be noted that in all performed examples, the
formation of the b-enaminocarbonyl compound was
only observed when the R1 substituent groupis phenyl
groupand the change of DBU by Et 3N was not effective
to promote the condensation and the starting materials
were totally recovered.
1a
2a
S
Ph
CO2Me
Ph
+
N
H
N
4a
O
3a
Scheme 1. Formation of b-enaminocarbonyl 3a and the thiazolidinone
4a.
Next, we carried out the reactions of pyrrolidine-thione
1b (n ¼ 1) with the bromoesters 2a–d under the same
reaction conditions. In all cases, we did not observe the
formation of either b-enaminocarbonyls or the thiazol-
idinones but rather the respective thioimines 5a–d21
were obtained in high yields (Table 1, entries 8–11),
independent of the nature of the R1 group.
reactions of thiolactams 1a (n ¼ 2) and 1b (n ¼ 1) with
the a-bromoesters 2a–d (Scheme 2).
As previously mentioned, the reaction of piperidine-
thione 1a (R1 ¼ Ph) with the bromoester 2a in presence
of 2 equiv of Et3N or DBU and 2 equiv of Ph3P (see
Table 1, entries 1 and 2, respectively) or Et3N in absence
of Ph3P (entry 3) afforded a mixture of the enamino
compound 3a and the thiazolidinone 4a. On the other
hand, when the reaction was carried out with DBU in
absence of Ph3P (entry 4), only the enaminocarbonyl
compound 3a was obtained in 60% yield.
The structures of the b-enaminoester 3a, as well as of the
thiazolidinones 4a–d and thioimines 5a–d were in
accordance with their 1H NMR, 13C NMR, and IR
spectral data.22
The unexpected formation of thiazolidinones in the
Eschenmoser coupling reaction was recently reported
independently by Padwa et al.23 and Michael et al.24 for
analogous compounds but the factors controlling their
formation are not clear yet.
Based on these results, we decided to investigate a pos-
sible general method for the preparation of alkylated
secondary tetrasubstituted b-enaminoesters carrying out
the condensations of the piperidine-thione 1a and the
a-bromoesters 2b–d (R1 ¼ Me, n-Pr, and n-Bu, respec-
tively) by this modified Eschenmoser coupling reaction
protocol.
In an earlier report, Lhommet and co-workers,25 trying
to prepare the tetrasubstituted b-enaminocarbonyls,
observed a different behavior of N-tertiary five and six-
membered ring thiolactams in the Eschenmoser cou-
pling reaction. The authorÕs explanation for the different
course of this reaction is that the potentially acidic
hydrogen Hb in the initially formed thionium salt 6 is
abstracted preferentially by the base when n ¼ 2, giving
To our surprise, the reactions of 1a with the bromoesters
2b–d (R1 ¼ alkyl), in the presence of 2 equiv of DBU did
not undergo the extrusion of the sulfur atom to give the
CO2R2
S
(n)
1a
1b
R1
DBU
R1
CO2R2
R1
DBU
S
N
+
R1
+
N
H
N
S
CH2Cl2
CH2Cl2
N
CO2R2
Br
2a-d
O
H
1a (n=2)
1b (n=1)
4a-d
3a
5a-d
Scheme 2. Eschenmoser sulfide contraction reaction.
Table 1. Compounds 3a, 4a–d, and 5a–d by Scheme 2
Entry
Thiolactam
Bromoester
R1
Base
Products
Yield (%)
R2
1
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
2a
2a
2a
2a
2b
2c
2d
2a
2b
2c
2d
Ph
Ph
OMe
Et3Na
DBUa
Et3N
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
3a(46):4a(21)
3a(35):4a(41)
3a(6):4a(25)
67
76
31
60
72
85
89
91
87
92
94
2
OMe
OMe
OMe
OMe
OEt
3
Ph
Ph
4
3a
4b
4c
4d
5a
5b
5c
5d
5
Me
n-Pr
n-Bu
Ph
6
7
OEt
8
OMe
OMe
OEt
9
Me
n-Pr
n-Bu
10
11
OEt
a Reaction performed with 2 equiv of Ph3P.

D. Russowsky, B. A. da Silveira Neto / Tetrahedron Letters 45 (2004) 1437–1440
1439
the tetrahydrothieno[2,3-b]pyridin-3(2H)-one (7). On the
Ph
Ph3P
Ph
other hand, when n ¼ 1, the hydrogen Ha is abstracted
and the expected b-enaminocarbonyl 8 is produced
(Scheme 3).
N
H
CH2Cl2
reflux, 18h
S
5a
CO2Me
N
CO2Me
11
H2 /PtO2
100 atm
H
CO2Me
Although our examples are restricted to N-secondary
thiolactams, this rationale can be extended to our
studied cases. Based on the currently accepted mecha-
nism of the Eschenmoser coupling reaction,3 the first
stepis the thio-alkylation reaction that gives the thio-
nium cation 9a (n ¼ 1) or 9b (n ¼ 2), which have three
potentially acidic hydrogens: Hc, Hd, and He. In the
second step, the first equivalent of DBU abstracts
preferentially the more acidic Hc hydrogen and the
thioimines 5a–d (n ¼ 1) and 10a–d (n ¼ 2) were formed.
In this step, the thioimines 5a–d were sufficiently stable
N
Ph
H
12
Scheme 5. Synthesis of methylphenidate analogue 12.
sulfide contraction also does not occurred in absence of
a thiophile. In this way, we performed the reactions of
compounds 5a–d with Ph3P (4 equiv) in CHCl3 under
reflux for 18 h. In only one case, the compound 5a fur-
nished the respective b-enaminocarbonyl compound 11
in 86% yield as a unique Z stereoisomer26 (Scheme 5).
1
to be isolated and characterized by H NMR and IR,
while 10a–d were not detected. Next, the second equiv-
alent of the base abstracts the acidic benzylic hydrogen
He in 10a (R1 ¼ Ph) giving the corresponding b-enamino-
carbonyl 3a through the usual accepted mechanism with
subsequent sulfide extrusion (Scheme 4).
The direct Eschenmoser coupling reaction of pyrrol-
idine-thione 1b with the bromoester 2a in presence of
DBU (2 equiv) and Ph3P (4 equiv) was also proceeded
and we were able to isolate the respective b-enamino-
carbonyl derivative 11 in 75% yield after purification by
chromatography. Finally, due to the interest in the
synthesis of analogues of methylphenidate,27;28 the
compound 11 was tentatively hydrogenated under
H2/PtO2 at various H2 pressures and the reaction was
only completed by the utilization of 100 atm of H2 which
afforded the five-membered ring analogue of methyl-
phenidate 12 in 95% yield (see Scheme 5) as a single
isomer.29
The allylic hydrogen Hd seems to become more acidic
than He in intermediaries 10b–d, when the R1 sub-
stituent groupis an alkyl group, and is preferentially
abstracted by the base leading to the exclusive formation
of thiazolidinones 4b–d by a subsequent intramolecular
cyclization (see Scheme 4).
For the reactions of N-secondary five-membered ring
thiolactam 1b the DBU is not sufficiently basic to
abstract the allylic hydrogen Hd in the thioimines 5a–d.
In addition, the normal course of the Eschenmoser
In conclusion, the formation of N-secondary tetrasub-
stituted b-enaminocarbonyl compounds or bicyclic
thiazolidinones promoted by DBU from piperidine-thi-
ones or pyrrolidine-thiones depends on the nature of the
R1 groupof the bromoester, the strength and/or the
bulkiness of the employed tertiary amine, and the size of
the thiolactam ring.
Hb
Abstraction
of Ha
Abstraction
of Hb
Ha
(n)
CO2R2
R1
+
Br-
S
N
n= 1
n= 2
6
Me
O
R1
1
R
N
CO2R2
Supplementary material
S
N
Me
8
7
Me
1
Supplementary material includes the H NMR and 13C
NMR spectra and data of compounds 3a, 4a, 5a, 11,
and ( )-erythro-12. The supplementary data is available
online with the paper in ScienceDirect.
Scheme 3. Reaction carried out by Lhommet.
Hd
Hd
S
He
He
(n)
(n)
CO2R2
CO2R2
Hc
+
Br-
S
9
Abstraction
N
N
R1
R1
Hc
n=1 - 5a-d
Acknowledgements
He
n=2 - 10a-d
Abstraction
Hd
Abstraction
This work was sponsored by grants from Conselho
ꢀ
Nacional de Desenvolvimento Cientifico e Tecnologico
~
Estado do Rio Grande do Sul (FAPERGS). The Co-
S
ꢁ
(CNPq) and Fundaßcao de Amparo a Pesquisa do
1
R
Ph
N
N
H
CO2R2
~
ꢀ
ordenaßcao de Aperfeißcoamento de Pessoal de Nıvel
Superior (CAPES) is acknowledged for the fellowship
(B.A.S.N.). We are in debt with Professor L. C. Dias for
the helpful suggestions.
O
4a-d
3a
Scheme 4. Possible pathways to the formation of compounds 3a, 4a–d,
and 5a–d.

1440
D. Russowsky, B. A. da Silveira Neto / Tetrahedron Letters 45 (2004) 1437–1440
22. Spectral data for compounds 3a: 1H NMR (200 MHz,
References and notes
CDCl3): d (ppm) 9.72 (br s, 1H), 7.34–7.10 (m, 5H), 3.55
(s, 3H), 3.51–3.33 (m, 2H), 2.10 (t, J ¼ 6:6 Hz, 2H), 1.79–
1.68 (m, 2H), 1.63–1.54 (m, 2H); 13C NMR (50 MHz,
CDCl3): d (ppm) 170.3, 161.3, 152.9, 138.1, 132.3, 127.8,
94.4, 50.4, 41.4, 27.7, 22.3, 19.9; IR (KBr): m 3344, 3046,
2926, 1581. Spectral data of compound 4a: 1H NMR
(300 MHz, CDCl3): d (ppm) 7.45–7.31 (m, 5H), 5.06 (s,
1H), 4.92 (t, J ¼ 4:3 Hz, 1H), 3.75–3.67 (m, 2H), 2.42 (dd,
J ¼ 15:6, 5.9 Hz, 2H), 1.95–1.83 (m, 2H); 13C NMR
(75 MHz, CDCl3): d (ppm) 170.8, 137.5, 129.8, 128.2, 98.1,
51.1, 42.1, 22.5, 20.4; IR (neat): m 3061, 2928, 2849, 1696,
1645, 1387. Spectral data of compound 5a: 1H NMR
(200 MHz, CDCl3): d (ppm) 7.55–7.27 (m, 5H), 5.55 (s,
1H), 3.89–3.81 (m, 2H), 3.72 (s, 3H), 2.66–2.56 (m, 2H),
1.99 (qt, J ¼ 7.6 Hz, 2H); 13C NMR (50 MHz, CDCl3): d
(ppm) 170.9, 170.7, 134.9, 128.8, 128.4, 128.3, 60.8, 53.9,
37.9, 23.5; IR (neat): m 3063, 2951, 1740, 1693, 1594.
23. Padwa, A.; Beall, L. S.; Heidelbaugh, T. M.; Liu, B.;
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the ortho-hydrogens of the phenyl ring. Spectral data for
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8.61–8.42 (br s, 1H), 7.28–7.15 (m, 5H), 3.60 (s, 3H), 3.58
(t, J ¼ 7.4 Hz, 2H), 2.42 (t, J ¼ 7.4 Hz, 2H), 1.90 (qt,
J ¼ 7.1 Hz 2H); 13C NMR (50 MHz, CDCl3): d (ppm)
169.9, 165.5, 138.3, 131.4, 127.7, 125.8, 92.5, 50.5, 47.3,
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29. Based on our previous report (see Ref. 20) we attributed
the relative stereochemistry of compound 12 as being
analogue to the erythro-methylphenidate. Spectral data of
compound 12: 1H NMR (200 MHz, CDCl3): d (ppm)
7.36–7.26 (m, 5H), 6.16 (br s, 1H), 4.14 (s, 1H), 3.69 (s,
3H), 3.55–3.30 (m, 2H), 2.35–1.87 (m, 4H); 13C NMR
(50 MHz, CDCl3): d (ppm) 171.4, 133.6, 128.9, 128.8,
128.5, 62.9, 52.8, 52.3, 46.8, 28.4, 23.4; IR (neat): m 3022,
2935, 1735, 1453, 1161.