Studies on the Eschenmoser coupling reaction and insights on its mechanism. Application in the synthesis of Norallosedamine and other alkaloids

Article abstract of DOI:10.1016/j.tet.2009.01.081

The conditions of the Eschenmoser coupling reaction were studied. The formation of the α-thioiminium ion was achieved faster in the presence of an additive (NaI) and dry chloroform as the preferred solvent. The developed conditions were used for the second part of the reaction (the sulfur extrusion itself). The present protocol avoids the formation of byproducts, which were previously described as a major drawback to be overcome. Electrospray ionization tandem mass spectrometry was used to characterize some aspects (intermediates) of the first step of the reaction mechanism. Some reduction conditions were properly tested and the selected conditions were applied to the synthesis of the natural alkaloid Norallosedamine and other derivatives.

Full text of DOI:10.1016/j.tet.2009.01.081

Tetrahedron 65 (2009) 2484–2496
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Studies on the Eschenmoser coupling reaction and insights on its mechanism.
Application in the synthesis of Norallosedamine and other alkaloids
, ,
,
Brenno A.D. Neto a y, Alexandre A.M. Lapis b, Alinne B. Bernd c, Dennis Russowsky d
*
*
a Laboratory of Medicinal and Technological Chemistry, University of Brasilia (IQ-UnB), Brasilia, DF, Brazil
b Universidade Federal do Pampa, Unipampa, Bage´, RS, Brazil
c Laboratory of Molecular Catalysis, Chemistry Institute, UFRGS, Porto Alegre, RS, Brazil
d
´
ˆ
´
Departamento Quımica Organica, Instituto de Quımica, UFRGS, Porto Alegre, RS, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
The conditions of the Eschenmoser coupling reaction were studied. The formation of the a-thioiminium
Received 29 September 2008
Received in revised form 14 January 2009
Accepted 15 January 2009
ion was achieved faster in the presence of an additive (NaI) and dry chloroform as the preferred solvent.
The developed conditions were used for the second part of the reaction (the sulfur extrusion itself). The
present protocol avoids the formation of byproducts, which were previously described as a major
drawback to be overcome. Electrospray ionization tandem mass spectrometry was used to characterize
some aspects (intermediates) of the first step of the reaction mechanism. Some reduction conditions
were properly tested and the selected conditions were applied to the synthesis of the natural alkaloid
Norallosedamine and other derivatives.
Available online 27 January 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
The Sedamine alkaloids family14–17 (Fig. 2) is responsible for
a number of therapeutic effects, e.g., control of anxiety. This class of
The Eschenmoser coupling reaction1 (sulfide contraction re-
action/sulfur extrusion reaction) is a general and distinct method
for the preparation of
treating a secondary or tertiary thioamide 1 with a suitable elec-
trophile component;2 normally, an
-bromocarbonyl system 2
(Scheme 1). Sulfur extrusion as a method to effect carbon–carbon
(C]C) bond formation was first observed by Knott3 in his in-
vestigation of sulfur-containing chromophores. Later, a mechanism
proceeding through an episulfide intermediate, followed by the
extrusion of the sulfur atom, was proposed to explain his obser-
vations (see Scheme 1).4 The sulfide contraction as a synthetic tool
was developed and implemented by Albert Eschenmoser and ap-
plied in the total synthesis of Vitamin B12.5,6 Tertiary thioamides
are the substrates of preference to perform the Eschenmoser cou-
pling reaction, especially due to the formation of a more reactive
alkaloids is extracted from both Sedum and Lobelia (Indian tobacco)
species and their properties18,19 and synthesis20–29 have been par-
tially reviewed.30 These systems have long been known to exhibit
interesting biological properties. Lobelia inflata has been used for
memory enhancement. Additionally, it displays other useful prop-
erties.31 For instance, the crude extract of Indian tobacco species
has been used for treatment of respiratory illnesses such as asthma,
bronchitis, and pneumonia.32 As little is known about the biological
properties of this class,33 the development of new synthetic routes
is interesting in order to allow new structure–activity relationship
studies.
b-enaminocarbonyl compounds 3 upon
a
In relation to our interest in the Eschenmoser coupling re-
action10,34 and to our interest in biologically active heterocyclic
systems,35–39 we report in the current manuscript our study on the
Eschenmoser coupling reaction conditions, the reductions tests
a-thioiminium intermediate. However, the possibility of byproduct
(and conditions) to form b-aminocarbonyl compounds from
formation is very likely, as described before by Eschenmoser et al.,7
others8,9 and us10 (Fig. 1), mainly due to the influence of the thio-
lactam ring size.11–13 In consequence, there is a need of more uni-
versal conditions for carrying out the sulfide contraction reaction
using secondary or tertiary thioamides.
Eschenmoser’s adducts, a new approach to the synthesis of Nor-
allosedamine (and other alkaloids) applying the methodology de-
scribed herein, and an electrospray (tandem) mass spectrometry
study on the Eschenmoser coupling reaction mechanism.
2. Results and discussion
* Corresponding authors. Tel.: þ55 61 37994567; fax: þ55 61 32734149.
E-mail address: brenno.ipi@gmail.com (B.A.D. Neto).
Present address: Campus Universita´rio Darcy Ribeiro, CEP 72.919-970, PO Box
Initially, we examined the conditions to perform the
iminium salt formation using thiolactams 5a–d and -bromo-
carbonyl compound 6 (Scheme 2). The best results can be seen in
a-thio-
y
a
´
15003, Brasılia, DF, Brazil.
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.01.081

B.A.D. Neto et al. / Tetrahedron 65 (2009) 2484–2496
2485
Eschenmoser coupling reaction
H
N
OH
N
OH
R1
R3
R2
S
O
O
N
R1
X
R3
R5
N
R5
+
R2
R4
(+/-)-Norallosedamine
H
(+/-)-Allosedamine
R4
3
1
2
N
N
OH
OH
X = Cl, Br, I, OTf
Mechanism (first step)
_
X+
(+/-)-Norsedamine
(+/-)-Sedamine
R1
R2
S
R1
R3
R2
R1
R2
S
+
..
X
R4
N
N
N
Figure 2. Sedamine alkaloid family.
+
O
R5
R4
_
R3
R3
S
R5
O
requiring a long time for the reaction to take place (see Tables S1
and S2 in Supplementary data).
Mechanism (second step)
R2
N
Despite the addition of NaI, it was not possible to observe imi-
nium formation upon treatment of thiolactam 5d with 6b,c (Table 1,
entries 12 and 15). Although it seems a simple alkylation reaction
(SN2), to the best of our knowledge, the use of thiolactam 5d in the
Eschenmoser coupling reaction to obtain tetra-substituted olefins
has not been achieved so far. When 5d is treated with iodomethane
no S-alkylated product is formed. Methylation of thiolactam 5c
using iodomethane was reported,41 but the same reaction using 5d
was carried out under drastic conditions: dimethylsulfate (alky-
lating agent) and 5d in solventless conditions and heating.42
R1
R2
+
R4
R1
R4
_
N
X
R5
R3
R5
S
R3
H
O
O
sulfur
extrusion
base
R3 R4
_
R3 R4
R1
R5
R1
R5
+
N
R2
S
S
N
R2
Therefore, it was expected that the a-thioiminium salt formation
O
O
described in Scheme 2 using the thiolactam 5d would not be ach-
ieved. Many attempts to solve this problem were performed by us
without success (see Table S3 in Supplementary data). However,
Scheme 1. Eschenmoser coupling reaction and its proposed mechanism.
initial conditions to form the
a-thioiminium salt in the Eschen-
Table 1 (also see Supplementary datadTables S1 and S2dfor
complete data). Solvent such as benzene, diethyl ether, THF, and
1,4-dioxane gave poor conversion requiring long reaction time.
It is clear from the data in Table 1 that the use of NaI as the
moser coupling reaction was achieved (Table 1, entries 7–11 and
13–14) in a short time and with high conversion using the other
thiolactams (5a–c). Electrospray (tandem) mass spectrometry ex-
periments confirmed the importance of an appropriate solvent
selection, especially to avoid the formation of byproducts, as will be
discussed at the end of the current report.
Sulfur extrusion in the Eschenmoser coupling is often a difficult
transformation.1 Some have described the use of three different
solvents during the reaction course43 and others the use of reflux
conditions with xylene.44 Nevertheless, the high boiling tempera-
ture of xylene and the inconvenience of using three solvents are
drawbacks that were easily overcome by just using chloroform as
solvent during all reaction courses. The second step requires the
addition of thiophile and of a base, not necessarily in this order.
Dual reagents (base and thiophile in the same structure) have been
developed.4,7 Although sometimes it is necessary to add first the
base followed by thiophile addition43 and, in some cases, the op-
posite order45 is necessary to avoid byproduct formation.8 We ob-
served that actually, it depends mainly on whether a secondary or
tertiary thioamide was used and on whether a mono- or di-
additive (1.1–2.0 equiv) results in a beneficial effect on the a-thio-
iminium salt formation, allowing a faster thiolactam consumption.
Polar and aprotic solvents such as acetonitrile and chloroform gave
the best results. However, it has been described that the salt for-
mation occurs in equilibrium and it is reversible.40 The use of
chloroform gives an advantage in that the formed salt precipitates
in the media avoiding the reversibility of its formation. This re-
versibility has been described by others.40 Acetonitrile was capable
of dissolving all tested systems (including the thioiminium salt).
The use of a polar and protic solvent (ethanol) favored the bicyclic
formation previously described by Eschenmoser et al.7 (see Fig. 2)
and it will be discussed in due course of the manuscript. The use of
both less polar and non-polar solvents gave poor salt formation,
CH2CO2Me
substituted
a-halocarbonyl compound was used.
N
S
S
RO2C
N
First, we decided to perform the synthesis of tri-substituted b-
enaminocarbonyl compounds using Eschenmoser coupling re-
action (Scheme 3) and the results are summarized in Table 2.
Ph
Bn
Reported by
Roth and Eschenmoser
(reference 7)
Reported by
Shiosaki and Rapoport
(reference 8)
The bromine-containing
a-halocarbonyl 6e was synthesized
according to a previous report.46,47 All compounds 8a–d were
synthesized in good yield using the Eschenmoser coupling reaction
(64–86%) as isolated products. Compounds 8a–d were equally
isolated as single isomers (determined by GC analysis and con-
firmed using cycle-NOE experimentsdFig. 3).
O
S
R
R
N
S
N
O
The synthesis of tetra-substituted
b-enaminocarbonyl com-
Bn
Reported by
Russowsky and Neto
(reference 10)
pounds normally presents some drawbacks.48 Therefore, we de-
cided to carry out the synthesis of these derivatives as seen in
Scheme 4.
Reported by
Marchand and Lhommet
(reference 9)
Compound 6c was easily synthesized in two steps from
an esterification reaction of phenylacetic acid followed by an
Figure 1. Examples of characterized byproducts during Eschenmoser coupling
reaction.

2486
B.A.D. Neto et al. / Tetrahedron 65 (2009) 2484–2496
S
(n)
(n)
S
P
S
MeO
P
S
S
O
OMe
N
N
R1
R1
Lawesson's reagent
5a n = 1, R1 = H (92%)
5b n = 1, R1 = Bn (90%)
5c n = 2, R1 = H (91%)
5d n = 2, R1 = Bn (91%)
4a n = 1, R = H
4b n = 1, R = Bn
4c n = 2, R = H
4d n = 2, R = Bn
PhH
or PhMe
Reflux
R
(n)
(n)
R2
O
+
S
N
S
N
Br
R2
R1
O
solvent
R1
7a n = 1, R = H, R1 = H, R2 = OEt
7b n = 1, R = H, R1 = Bn, R2 = OEt
7c n = 2, R = Ph, R1 = H, R2 = OMe
7d n = 2, R = Ph, R1 = Bn, R2 = OMe
7e n = 2, R = Me, R1 = H, R2 = OMe
7f n = 2, R = Me, R1 = Bn, R2 = OMe
7g n = 2, R = H, R1 = H, R2 = Ph
+
R
(additive)
5a n = 1, R1 = H
5b n = 1, R1 = Bn
5c n = 2, R1 = H
5d n = 2, R1 = Bn
6a R = H, R2 = OEt
6b R = Me, R2 = OMe
6c R = Ph, R2 = OMe
6d R = H, R2 = Ph
Scheme 2. Thiolactams synthesis and a-thioiminium formation.
O
a
-bromination with NBS. The geometry of the double bond of
compound 8e was determined comparing it with previous reports
from literature49 (Table 3). All tetra-substituted
-enaminocarbonyl
(n)
(n)
O
S
NaI
R
N
R1
N
R1
b
Br
Ph3P
H
+
R
compounds were obtained as single isomers using the developed
conditions described here. Normally, mixtures are obtained.50 The
implementation of the methodology resulted in clean conversion to
the tetra-substituted alkene as a single geometric isomer, which is
an improvement to the existing methods (in good yieldsd76% for
8e and 69% for 8f). Compound 8g was obtained in only 45% yield.
However, it can be obtained as a single compound by changing the
reaction conditions. We have already partially described the in-
fluence of ring size (five- and six-membered ring) of thiolactams in
the Eschenmoser coupling reaction in the formation of bicyclic
thiazolidinones 9 or thioimines.10 Our attempts to optimize the
reaction conditions for the selective formation of 8g are summa-
rized in Table 4.
Et3N
5a n = 1, R1 = H
5b n = 1, R1 = Bn
5c n = 2, R1 = H
5d n = 2, R1 = Bn
8a n = 1, R1 = Bn, R = OEt
8b n = 1, R1 = Bn, R = Ph
8c n = 1, R1 = H, R = Xp*
8d n = 2, R1 = H, R = Ph
6a R = OEt
6d R = Ph
6e R = Xp*
CHCl3
Xp* = (S)-5-(phenylmethyl)-2-oxazolidinone
Scheme 3. Synthesis of tri-substituted -enaminocarbonyl compounds.
b
Table 2
Tri-substituted
b-enaminocarbonyl compounds
Entry Thiolactam
a
-Bromocarbonyl
Product
Yield (%)
5
n
R1 6 R
8 n R1
R
The geometry of the double bond for the single isomers 8f,g
(determined by GC analysis) was confirmed using cycle-NOE ex-
periments (Fig. 4).
1
2
3
b
b
b
1
1
1
Bn a OEt
Bn b Ph
a 1 Bn OEt
b 1 Bn Ph
83
86
Bn e (S)-5-(Phenylmethyl) c 1 Bn (S)-5-(Phenylmethyl) 80
-2-oxazolidinone -2-oxazolidinone
d Ph d 2 H Ph
4
c
2
H
64
Table 1
Conditions for
a
-thioiminium formationa
O
O
H
Entry Thiolactam
Additive Solvent
(equiv)
a
-Brominecarbonyl
Iminium (7)
formationb (h)
5
n
R1
6
R
R2
O
N
N
H
H
H
1
2
3
4
5
6
7
8
a
b
a
b
a
b
c
d
a
b
c
d
c
b
d
c
1
1
1
1
1
1
2
2
1
1
2
2
2
1
2
2
H
Bn
H
Bn
H
Bn
H
Bn
H
Bn
H
Bn
H
Bn
Bn
H
d
d
d
d
MeCN
MeCN
CHCl3
CHCl3
a
a
a
d
a
d
a
d
c
H
H
H
H
OEt
OEt
OEt
Ph
18
24
18
22
16
18
12
18
18
18
18
d
18
18
d
15
H
9,85
H
H
NOE
irradiation at
δ = 4,68 ppm
irradiation at
4,03
4,35
NOE
NOE
δ = 5,90 ppm
8b
NaI (2.0) MeCN
NaI (1.5) MeCN
NaI (2.0) CHCl3
NaI (1.5) CHCl3
NaI (1.1) CHCl3
NaI (1.1) CHCl3
NaI (1.1) CHCl3
NaI (2.0) CHCl3
NaI (1.1) CHCl3
NaI (1.1) CHCl3
NaI (1.1) CHCl3
NaI (2.0) CHCl3
H
H
OEt
Ph
8a
H
H
OEt
Ph
6,51
H
NOE
H
9
Ph
Ph
Me
Ph
Ph
Me
Me
H
OMe
OMe
OMe
OMe
OMe
OMe
OMe
Ph
Ha
O
H
10
11
12
13
14
15
16
c
b
c
9,54
H
NOE
N
N
H
N
Hb
H
O
irradiation at
δ = 5,59 ppm
c
O
O
b
b
d
H
irradiation at
δ = 6,36 ppm
8d
6,23
Hb
NOE
8c
a
Determined by GC (consumption of thiolactam).
Time to iminium formation.
b
Figure 3. Cycle-NOE experiments of systems 8a–d.

B.A.D. Neto et al. / Tetrahedron 65 (2009) 2484–2496
2487
We clearly see that by using DBU (the strongest amine base
tested) as the base and without the presence of thiophile, we can
obtain compound 8g as the only product of the Eschenmoser
coupling reaction (Table 4, entry 16). Increasing the thiophile
concentration, also increased byproduct formation 9a (Table 4,
entries 1–8).
O
O
S
NaI
N
OMe
N
Et3N / Ph3P
OMe
O
+
Me
CHCl3
Br
6b
5b
8e
In order to gain insights into the application of the described
methodology, we decided to use different commercially available
NaI
Et3N / Ph3P
a-bromocarbonyl compounds to expand the methodology (Scheme
S
N
H
+
N
H
OMe
5, Table 5).
CHCl3
Br
6c
O
OMe
5a
8f
S
R1
6c NaI
Ph
N
H
N
H
N
Et3N / Ph3P
CHCl3
N
+
S
O
OR2
O
9a
O
8h-j
R1
H
O
OMe
OR2
5c
DBU
8g
N
H
+
S
Br
CHCl3
Scheme 4. Synthesis of tetra-substituted b-enaminocarbonyl compounds 8e–g.
6f R1 = Me; R2 = Me
6g R1 = n-Pr; R2 = Et
6h R1 = n-Bu; R2 = Et
S
5c
R1
N
Table 3
Spectroscopic data for 8e
O
9b-d
Scheme 5. Reaction of thiolactam 5c with compounds 6f–h.
Compound
13C NMR (
d ppm)
C]O
N–C]C
C]C–C]O
8e Za
8e Ea
8e
167.4
169.3
169.8
159.9
162.7
163.1
86.4
88.7
88.9
Table 5
Reaction of thiolactam 5c with compounds 6f–h
a
From literature.49
Entry
a
-Halocarbonyl
8h–j (%)
9b–d (%)
6f–h
R1
R2
1
2
3
f
g
h
Me
n-Pr
n-Bu
Me
Et
Et
d
d
d
9b (88)
9c (91)
9d (94)
Table 4
Used conditions and formation of compounds 8g and 9a
Entry
Base (equiv)
Thiophile (equiv)
8g (%)
9a (%)
Conversion (%)
1
2
3
4
5
6
7
8
Et3N (2.00)
Et3N (2.00)
Et3N (2.00)
Et3N (2.00)
Et3N (2.00)
DBU (2.00)
d
Ph3P (4.00)
Ph3P (2.00)
Ph3P (1.00)
n-Bu3P
(EtO)3P
Ph3P (2.00)
Ph3P (4.00)
n-Bu3P (4.00)
d
d
d
d
d
d
d
d
d
42
46
45
44
d
35
28
28
13
6
27
32
41
41
46
60
20
20
21
20
16
d
41
25
23
11
25
4
12
12
13
21
d
35
62
67
65
60
d
Instead of the desired tetra-substituted
b-enamine 8h–j for-
mation, we observed a complete conversion of reactants into con-
densation products 9b–d. At first glance, the result obtained seems
to be surprising. However, the high yields obtained forming ex-
clusively compounds 9b–d (88–94% of isolated yields) can be
explained in terms of the acidity of the hydrogen atoms in the in-
termediate thioimine analogues, as will be discussed. Nevertheless,
before a more precise conclusion, the reactions were carried out
using thiolactam 5a to gain information on how the systems be-
haved under the developed conditions. Scheme 6 describes the
reactions.
76
53
51
24
31
31
44
53
54
67
60
55
d
9
Py (2.00)
10
11
12
13
14
15
16
17
Et3N (2.00)
DMAP (2.00)
DABCO (2.00)
DIPEA (2.00)
DBN (2.00)
TMEDA (2.00)
DBU (2.00)
KO-t-Bu
(2.00)
DBU (1.10)
O
R1
N
18
d
31
5
36
R1
OR2
OR2
S
DBU
S
N
H
+
Br
O
CHCl3
6c R1 = Ph; R2 = Me
6f R1 = Me; R2 = Me
6g R1 = n-Pr; R2 = Et
6h R1 = n-Bu; R2= Et
10a R1 = Ph; R2 = Me
10b R1 = Me; R2 = Me
10c R1 = n-Pr; R2 = Et
10d R1 = n-Bu; R2= Et
5a
5,47
3,24
NOE
NOE
3,85
5,30
NOE
NOE
H
H
Scheme 6. Reaction of thiolactam 5a with compounds 6e–h.
HH
H
H
H
O
H
H
H
N
H
N
H
The results are summarized in Table 6.
H
8f
H
8g
Using a five-membered thiolactam, instead thiazolidinone 9, we
obtained and characterized exclusively the intermediates thioimine
10a–d in high isolated yields (89–91%). We observed the formation
of 10b, but it was shown to be a very unstable product, precluding
its full spectroscopic characterization.
O
OMe
OMe
irradiation at
irradiation at
δ = 2,11 ppm
δ = 2,42 ppm
Figure 4. Cycle-NOE experiments of systems 8f,g.

2488
B.A.D. Neto et al. / Tetrahedron 65 (2009) 2484–2496
Table 6
groups (Me, n-Pr, n-Bu) in the other derivatives 10c,d resulted in
a less acidic -proton slated for abstraction and the consequence
was decomposition of the thioimine intermediates under sulfur
extrusion reaction conditions. It is worth noting that when isolating
10a, the use of triphenylphosphine alone is enough to promote the
contraction of the system to form 8f (Table 7, entry 3).
Reaction of thiolactam 5a with compounds 6e–h
a
Entry
a
-Halocarbonyl 6e–h
R1
R2
10a–d (%)
1
2
3
4
c
f
g
Ph
Me
n-Pr
n-Bu
Me
Me
Et
a (93)
b (d)
c (89)
d (91)
h
Et
Much effort was put into trying to rationalize the main results
obtained using five- and six-membered thiolactams 5a,c under the
developed conditions (CHCl3 and DBU as base), and we had all data
necessary to rationalize the observed events. In Scheme 8 we can
visualize the events according to the ring size, qualitative intrinsic
acid character of hydrogen atoms slated for abstraction, and con-
ditions used to promote the Eschenmoser coupling reaction.
Once we could visualize all events and had the data relative to
the developed conditions and the difference in behavior of five- and
six-membered rings, we could explain the results in terms of the
acidity of the hydrogen atoms in the intermediates, as seen in
Scheme 9.
Table 7
Sulfur extrusion reaction and conditions in attempt to form systems 8f,k,l
Entry
R1
R2
Steps
Intermediates
10a,c,d (%)
Conditions
8f,k,l (%)
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Me
Me
Me
n-Pr
n-Pr
n-Pr
n-Bu
n-Bu
n-Bu
Me
Me
Me
Me
Me
Me
Et
Et
Et
Et
Et
1
1
2
1
1
1
1
1
2
1
1
2
Not isolated
Not isolated
Isolated (93%)
Not isolated
Not isolated
Not isolated
Not isolated
Not isolated
Isolated (89%)
Not isolated
Not isolated
Isolated (91%)
Et3N/Ph3P
DBU/Ph3P
DBU then Ph3P
Et3N/Ph3P
DBU/Ph3P
DBU then Ph3P
Et3N/Ph3P
DBU/Ph3P
DBU then Ph3P
Et3N/Ph3P
DBU/Ph3P
8f (69)
8f (77)
8f (86)
Decomposition
Decomposition
Decomposition
Decomposition
Decomposition
Decomposition
Decomposition
Decomposition
Decomposition
9
R1
N
10
11
12
OR2
S
not acid
Et
DBU then Ph3P
Hb
(Ha is not in an appropriate
Ha
O
angle with C=N bound)
_
We treated thioimine intermediates under different conditions
(Table 7) to obtain the respective -enaminocarbonyl compound
(Scheme 7). The presence of an electron withdrawing group in in-
termediate 10a allows the hydrogen abstraction to precede the
sulfur extrusion. However, the presence of electron donating
B
b
R1
N
Ha
N
OR2
S
S
_
Hb
Ha
Hb
R1
B
O
Ha
_
O
OR2
B
N
R1
R1
R1 = donating group or electron withdrawing group
OR2
N
H
S
Scheme 9. Possible pathways to hydrogen abstraction in thioimine intermediates.
OR2
O
O
8f R1 = Ph; R2 = Me
8k R1 = n-Pr; R2 = Et
8l R1 = n-Bu; R2= Et
10a R1 = Ph; R2 = Me
10c R1 = n-Pr; R2 = Et
10d R1 = n-Bu; R2= Et
In the five-membered ring, Ha is in a position that renders the
hydrogen non-acidic because of its angle relative to the C]N
bond that does not favor its abstraction by the base allowing the
corresponding enamine formation. On the other hand, Hb
Scheme 7. Sulfur extrusion of systems 10a,c,d.
O
(n)
R1
OR2
Br
S
N
+
H
6c R1 = Ph; R2 = Me
6f R1 = Me; R2 = Me
6g R1 = n-Pr; R2 = Et
5a n = 1
5c n = 2
6h R1 = n-Bu; R2= Et
CHCl3 DBU
n = 1
n = 2
R1 = electron
withdrawing
R1 = electron
donating
N
R1
S
OR2
R1
S
N
N
H
O
O
Ph3P
10a R1 = Ph; R2 = Me
10b R1 = Me; R2 = Me
10c R1 = n-Pr; R2 = Et
10d R1 = n-Bu; R2= Et
OR2
9b R1 = Me
9c R1 = n-Pr
9d R1 = n-Bu
O
(no base)
8g
CHCl3
R1 = electron
withdrawing
R1 = electron
donating
N
H
decomposition
OMe
O
8f
Scheme 8. Rationalization of the obtained results using five- and six-membered thiolactams 5a,c and DBU as base. Formation of thioimines 10a–d intermediates and thiazoli-
dinones 9b–d.

B.A.D. Neto et al. / Tetrahedron 65 (2009) 2484–2496
2489
displays a very acidic nature, especially in the situation where R1
is an electron withdrawing group (phenyl in the case of 10a).
When R1 is an electron donating group, the outcome is a drastic
decrease in the acidity of Hb. The net result is that under the
reaction conditions (strong basic media), the thioimine 10 de-
composes and no sulfur extrusion takes place. In the six-mem-
bered ring, both Ha and Hb are slated for abstraction due to
conformational aspects of the system (see Scheme 9, below). It is
clear from our results that when R1 is an electron withdrawing
group the acidic character of Hb is considerably higher than Ha,
and the expected sulfur reaction pathway takes place naturally.
However, when R1 is an electron donating group, we clearly
observed a higher acidity character of Ha, and its abstraction
leads to a nucleophilic enamine, which undergoes spontaneous
cyclization forming, in an exclusive manner, the corresponding
a very good choice for selective reduction of the C]C double bond.
Using PtO2 and catalytic amounts of acetic acid, no reductions were
observed. However, using catalytic amounts of a stronger acid
(HClO4) and small H2 pressure (1–3 atm) we could observe partial
reduction (C]C reduction) in all tested compounds 8a–g (Table 8,
entries 4, 8, 12, 16, 20, 23–27, 32, and 33).
It is important to note that the use of borohydrides led to
a higher stereoselectivity during the reduction of the C]C double
bond than hydrogenations. A possible explanation to the described
selection may have its origin in the mechanism of the reduction, as
proposed in the great work of Palmieri et al.51,52 The proposed
mechanism previously reported by this group explains the selec-
tivity, however it has some aspects that differ in kind to our
proposition (see Scheme 11 for a plausible catalytic cycle).
It is believed that the mixture NaBH4 and acetic acid leads to an
in situ generation of the reducing agent NaH(OAc)3 that reduces an
iminium–enol intermediate. The reduction leads preferentially to
erythro derivatives, as seen in Scheme 11.
bicyclic thiazolidinones 9. As
a consequence, thioimine in-
termediates with the six-membered ring are not observed, only
byproducts 9.
Once we could tune the synthesis of some
b
-enaminocarbonyl
It is important to highlight that the proposition seen in Scheme
11 can explain either catalytic amounts of acid acting in the system
to form the iminium–enol intermediate slated for reduction and
cases where the chosen acid act as solvent (media) and reagent, as
described in the case of the reducing system NaBH4/AcOH.
Under catalytic acid conditions using different borohydrides, the
reduction can be explained as follows: first, the tautomeric imi-
nium–enol specie is formed by protonation. The available borate
complexes in the oxygen and the hydride is transferred reducing
the C]N double bond in the iminium carbon. After, a protonation
in the enol carbon takes place, restoring the C]O double bond and
compounds, we decided to investigate the partial and/or total re-
duction of those systems. Both catalytic hydrogenations and hy-
dride reductions were tested under different conditions (Scheme
10, Table 8).
Many other methods were tested without success to partial
and/or total reduction of
b-enaminocarbonyl compounds (see
Table S4 in Supplementary data to access all experiments). It is
noteworthy that partial reduction (C]C only) occurs preferentially
in all cases. And, as will be discussed, in only one case the total
reduction (C]C and C]O reductions) takes place under the tested
conditions.
releasing both the reduced b-aminocarbonyl compound and the
The reduction using borohydrides was shown to be a good
acid, allowing a new catalytic cycle to start.
methodology to access
actions were fast and clean. The use of NaBH4 and AcOH was very
effective in reducing
-enaminocarbonyl compounds51,52 derived
b
-aminocarbonyl compounds 11. All re-
The reduction of compound 8c is of special importance, mainly
due to a presence of a chiral inductor in the ester moiety ((S)-5-
phenylmethyl-2-oxazolidinone). In all cases (Table 8, entries 9–12)
b
from tertiary thioamide (R1¼Bn) yet ineffective toward secondary
thioamide derivatives. Indeed, for tertiary thioamide derivatives, it
was shown to be the best method tested (Table 8, entries 1, 5, and
9). On the other hand, commercially available NaBH(OAc)3 was the
least effective for promoting C]C reduction (Table 8, entries 3, 7, 11,
14, 19, 29, and 30), despite the fact that it could also reduce sec-
ondary thioamide derivatives. NaBH3CN/HCl was shown to be
a good combination for partial reduction of the tested systems. In
all cases the yields were very good (Table 8, entries 2, 6, 10, 13, 18,
21, and 28).
we observed a 1:1 mixture of diastereoisomers in the reduced b-
aminocarbonyl compound 11c. The results associated with the
previous knowledge of cycle-NOE experiments performed in its
precursor (8c) indicate that the stereogenic center is far from the
double bond, resulting in no chiral induction during the reduction
(see Fig. 3).
Reducing compounds 8f and 8g we obtain, respectively, a five-
and six-membered ring (the five-membered analogue and methyl-
phenidate), which is an indirect catecholamine agonist,53 and is the
drug treatment of choice for attention deficit/hyperactivity disor-
der,54 one of the most common behavioral disorders in children
and which affects 5–10% of the general population.55
Catalytic hydrogenations were equally tested using all
b-
enaminocarbonyl derivatives 8a–g. When we used Pd-containing
catalysts under many different conditions (see Table S4 in Sup-
plementary data), no partial hydrogenation could be observed.
Nevertheless, the use of platinum derivatives showed these to be
Compound 11f had its stereochemistry determined by com-
paring its NMR data with a previous report in literature.56 However,
the most important is compound 11g, which suffers
O
OH
R2
O
(n)
(n)
(n)
R2
R2
+
N
R1
N
R1
N
R1
R
R
R
β-enaminocarbonyl
β-aminocarbonyl
γ -aminoalcohol
8a n = 1, R1 = Bn, R = H, R2 = OEt
8b n = 1, R1 = Bn, R = H, R2 = Ph
8c n = 1, R1 = Bn, R = H, R2 = Xp*
8d n = 2, R1 = H, R = H, R2 = Ph
8e n = 1, R1 = Bn, R = Me, R2 = OMe
8f n = 1, R1 = H, R = Ph, R2 = OMe
11a n = 1, R1 = Bn, R = H, R2 = OEt
11b n = 1, R1 = Bn, R = H, R2 = Ph
11c n = 1, R1 = Bn, R = H, R2 = Xp*
11d n = 2, R1 = H, R = H, R2 = Ph
12a n = 1, R1 = Bn, R = H, R2 = H
12b n = 1, R1 = Bn, R = H, R2 = Ph
12c n = 1, R1 = Bn, R = H, R2 = H
12d n = 2, R1 = H, R = H, R2 = Ph
11e n = 1, R1 = Bn, R = Me, R2 = OMe 12e n = 1, R1 = Bn, R = Me, R2 = H
11f n = 1, R1 = H, R = Ph, R2 = OMe
12f n = 1, R1 = H, R = Ph, R2 = H
8g n = 2, R1 = H, R = Ph, R2 = OMe 11g n = 2, R1 = H, R = Ph, R2 = OMe 12g n = 2, R1 = H, R = Ph, R2 = H
Xp* = (S)-5-(phenylmethyl)-2-oxazolidinone
Scheme 10. Reduction of b-enaminocarbonyl compounds 8a–g.

2490
B.A.D. Neto et al. / Tetrahedron 65 (2009) 2484–2496
Table 8
b-Enaminocarbonyl compounds (8a–g) reductions and conditions
Entry
8
Conditions
11 (%)
12 (%)
erythro:threob (11)
n
R1
R
R2
1
2
3
4
5
6
7
8
a
a
a
a
b
b
b
b
c
c
c
c
d
d
d
d
e
e
e
e
f
f
f
f
f
f
f
g
g
g
g
g
g
1
1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
H
H
H
H
Bn
Bn
Bn
Bn
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
Me
Me
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
OEt
OEt
OEt
OEt
Ph
Ph
Ph
Ph
NaBH4/AcOH
88
75
71
85
89
72
72
86
99
74
73
88
75
71
9
87
92
98
71
81
70
62
35
60
68
91
99
90
89
72
40
45
90
d
d
d
d
d
d
d
d
d
d
d
d
d
d
60
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
NaBH3CN/HCla
NaBH(OAc)3
d
d
a
a
a
a
a
PtO2 (1 atm H2)/HClO4
NaBH4/AcOH
d
d
NaBH3CN/HCla
NaBH(OAc)3
d
d
PtO2 (1 atm H2)/HClO4
NaBH4/AcOH
d
9c
10c
11c
12c
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
Xp
*
Xp
*
Xp
*
Xp
*
Ph
Ph
Ph
Ph
d
NaBH3CN/HCla
NaBH(OAc)3
d
d
PtO2 (1 atm H2)/HClO4
NaBH3CN/HCla
NaBH(OAc)3
d
d
d
NaBH4/EtOH
d
PtO2 (1 atm H2)/HClO4
NaBH4/AcOH
d
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
97:3
95:5
95:5
85:15
99:1
99:1
99:1
99:1
99:1
99:1
99:1
96:4
96:4
93:7
85:15
80:20
80:20
NaBH3CN/HCla
NaBH(OAc)3
PtO2 (1 atm H2)/HClO4
NaBH3CN/HCla
NaBH(OAc)3
PtO2 (30 atm H2)/HClO4ad24 h
PtO2 (50 atm H2)/HClO4ad24 h
PtO2 (70 atm H2)/HClO4ad24 h
PtO2 (100 atm H2)/HClO4ad18 h
PtO2 (130 atm H2)/HClO4ad18 h
NaBH3CN/HCla
NaBH(OAc)3
NaBH(OAc)3/AcOH
Mg/MeOHdreflux
PtO2 (3 atm H2)/HClO4
d
a
a
PtO2 (5 atm H2)/HClO4
Xp
*
¼(S)-5-(phenylmethyl)-2-oxazolidinone.
Catalytic amounts of acid.
Determined by GC analysis.
a
b
c
Diastereoisomeric ratio determined by GC (z1:1 in all cases).
NR1R4
R3
O
R2
R
-enaminocarbonyl
compound
NaBH4
AcOH
NR1R4
R3
O
+NR1R4
R3
H
R2
O
H+
R
-aminocarbonyl
NaBH(OAc)3
(or hydride donor)
R2
compound
R
MBHL3 - hydride donor,
where M is the metal and
L is the ligand
iminium-enol
OAc
AcO
H
H
B
AcO
OAc
+
+O
NR1R4
O
B
H
_
NR1R4
O
H
R3
R2
R3
R2
R
R
OAc
NR1R4
AcO
O
B
R2
R3
R
Scheme 11. Proposed mechanism to acid-catalyzed hydride reduction. (Based on previous literature reports.51,52
)

B.A.D. Neto et al. / Tetrahedron 65 (2009) 2484–2496
2491
epimerization57 leading to threo-isomer, which is commercially
available as RitalinÒ. This specific drug is sold as the racemate and it
is synthesized using the erythro-epimer.34 The data for both iso-
mers are available in the literature56,58 allowing an easy attribution
The methods described here allow us to a directly obtain of the
desired intermediate 11d. The reduction of 8d using the reducing
systems NaBH3CN/HCl and NABH(OAc)3 led directly to 11d, mark-
ing the formal synthesis of Sedamine derivatives (Table 8, entries 13
and 14). Nevertheless, in this case, the use of catalytic hydrogena-
tion (PtO2/HClO4 and H2 1 atmdTable 8, entry 16) gave a better
yield (87%) of the desired intermediate.
for the formed b-aminocarbonyl 11g as seen in Tables 9 and 10.
Table 9
1H NMR of compound 11g
Due to our interest in studying the reduction of
b-enamino-
carbonyl systems, we decided to investigate the total reduction of
molecule 8d. Since all methods led only to partial reduction of
tested compounds, we decided to use NaBH4/EtOH as the reducing
Hb
Hb
Ha
Ha
N
H
N
H
system. The combination resulted in the total reduction of
enaminocarbonyl with the formation of only one isomer: Nor-
allosedamine 12d ( -aminoalcohol) in a good yield (Scheme 13,
b-
CO2Me
erythro-methylphenidate
CO2Me
threo-methylphenidate
g
Methylphenidate
threoa
1H NMR (
d
¼ppm and J¼Hz)
Table 8, entry 15). We could also observe in 9% yield the b-ami-
nocarbonyl 11d (Table 8, entry 15).
7.29
3.44 (d, 1Ha,
J¼9.9)
2.69 (dt, 1Hb, J¼3.0 e 12.0)
2.93 (d, 1Hb, J¼12.3)
(m, 5H)
7.42–7.20
(m, 5H)
7.44–7.28
(m, 5H)
erythroa
3.48 (d, 1Ha,
J¼10.2)
OH
O
H
11g
3.48 (d, 1Ha,
J¼10.1)
2.92 (d, 1Hb, J¼12.4)
N
H
NaBH4
EtOH
N
H
N
H
+
Data from literature.56,58
a
O
11d
8d
Noralosedamina 12d
Scheme 13. Synthesis of Norallosedamine.
The developed method allowed the synthesis of the natural al-
kaloid in only three steps with good overall yield. The stereo-
chemistry of compound 12d was confirmed comparing the NMR
data previously reported to Sedamine alkaloids59,61–63 (Table 11).
The data confirms the stereochemistry attributed to compound
12d was correctly assigned to the natural alkaloid Norallosedamine.
Finally, we present the results using electrospray (tandem) mass
spectrometry to study the Eschenmoser coupling reaction’s first
step. To gain insights into the mechanism of the reaction we
monitored it online by electrospray ionization (tandem) mass
spectrometry.64,65 Note that ESI-MS and ESI-MS/MS have been
shown to be a suitable technique to study reaction mechanisms via
the interception and structural characterization of key ionic in-
termediates.66–69 Our group has used successfully this fast and
sensitive technique in the study of other reactions.37,39 The gentle
transfer to the gas phase allowed us to have a good idea of how the
species are behaving during Eschenmoser coupling reaction.
First, we tested the reaction using mixtures of thiolactam 5a and
Table 10
13C NMR of compound 11g
C6
C6
C5
C7
C5
C7
C8
C3
C3
C8
N
H
N
H
C4
C4
CO2Me
CO2Me
C2
C1
C2
C1
threo-methylphenidate
erythro-methylphenidate
Methylphenidate
13C NMR (
d
¼ppm)
C2
C1
C3
C4
C8
C5
C6
C7
threoa
erythroa
11g
173.8
173.1
172.9
58.8
59.0
59.2
58.7
58.3
58.1
51.9
51.9
51.8
46.8
47.0
46.9
29.9
31.0
30.9
26.1
25.7
25.6
24.3
24.4
24.5
a
Data from literature.56,58
Tables 9 and 10 clearly show that the reduction of compound 8g
leads directly to erythro-isomer, independent of the chosen re-
ducing agent.
a-halocarbonyl compound 6d in a polar and protic solvent
(MeOHdFig. 5A). A second experiment was performed with a polar
and aprotic solvent (MeCNdFig. 5B) in order to analyze how the
reaction behaves under different solvents influence.
It is important to point out that in a polar and protic solvent
(MeOH) we could observe the presence of a m/z 202 ion that was
attributed as a byproduct previously described by Eschenmoser
et al..7 ESI(þ)MS/MS of the signal (Fig. 5C) shows its fragmentation
pattern and it is coherent with the proposed structure exhibiting
signals of m/z 174, 134, 105, and 91. The structures of these signals
are seen in Figure 5. On the other hand, when using a polar and
Studying the reduction of b-enaminocarbonyl 8d we envisioned
the possibility of a formal synthesis of the Sedamine alkaloid family
and the total synthesis of one stereoisomer from this family by the
total reduction of compound 8d. The partial reduction of the mol-
ecule would lead directly to
b-aminocarbonyl compound 11d,
which is the formal synthesis of all four isomers (Scheme 12).59,60
4c
3 steps
OH
OH
H
H
Table 11
Data for Sedamine derivatives
N
N
H
Zn(BH)2
LiEt3BH
O
Compound
1H NMR
d
J (Hz),
HO–C–H
13C NMR
(ppm)
d
Me
N
H
Norsedamine
Sedamine
(ppm), HO–C–H
Norallosedaminea
Norsedaminea
Allosedaminea
Sedaminea
5.05
4.92
5.13
4.90
5.02
dd, J¼7.4 and 3.8
dd, J¼10.8 and 2.7
dd, J¼10.5 and 3.3
dd, J¼10.6 and 2.8
dd, J¼8.6 and 4.2
71.6
75.5
71.8
75.0
71.3
OH
H
OH
H
11d
N
N
H
Me
12d
Norallosedamine
Alosedamine
a
Data from literature.59,61–63
Scheme 12. Formal synthesis of four Sedamine alkaloid family isomers.

2492
B.A.D. Neto et al. / Tetrahedron 65 (2009) 2484–2496
202
A
B
S
N
+
220
220
Ph
Ph
S
S
N
H
N
H
+
+
O
O
+
+
S
S
N
N
105
105
H
H
H
H
134
102
102
50
75 100 125 150 175 200 225 250 275 300
m/z
50
75 100 125 150 175 200 225 250 275 300
m/z
C
D
105
O+
S
202
N
+
.
Ph
S
S
N
H
+
SH
N
H
+
O
+
134
220
+
S
N
S
+
N
114
H
H
174
102
H2C=N
91
91
60
80
100
120
140
160
180
200
60
90
120
150
180
210
m/z
m/z
Figure 5. ESI(þ)MS and ESI(þ)MS/MS of the Eschenmoser coupling reaction first step. (A) ESI(þ)/MS of a mixture of thiolactam 5a and
a-halocarbonyl 6d in methanol solution. (B)
ESI(þ)/MS of a mixture of thiolactam 5a and -halocarbonyl 6d in MeCN solution. (C) ESI(þ)MS/MS of ion of m/z 202. (D) ESI(þ)MS/MS of ion of m/z 220.
a
aprotic solvent, no signal of m/z 202 was observed. The main signal
(m/z 220dFig. 5B) was structurally characterized and its ESI(þ)MS/
MS was collected (Fig. 5D). The set of fragmentation displays signal
of m/z 114, 105, and 91, that were attributed to the species seen in
Figure 5D. The mass experiments clearly show that to perform the
thioiminium ion formation in the first step, a polar and aprotic
solvent is preferred.
were carried out under an argon or nitrogen atmosphere in oven-
dried resealable Schlenk tubes. All new compounds were fully
characterized after purification. NMR spectra were recorded on
Varian Inova 300 MHz or Varian Gemini 200 MHz spectrometers.
Infrared spectra were registered on a Bomem B-102 spectrometer.
Melting points were measured on a 12000 PL-DSC apparatus at
a heating rate of 5 ꢀC/min or in an Electrothermal IA9000 Melting
Point apparatus.
In summary, we demonstrate that the Eschenmoser coupling
reaction is an efficient and elegant method for the construction of
b
-enaminocarbonyl systems. In the first step, the use of a polar and
3.2. General procedure for the synthesis of thiolactams
derivatives 5a–d
aprotic solvent avoids byproduct formation and the use of an ad-
ditive (NaI) consistently reduces the required time for thioiminium
formation. Electrospray (tandem) mass spectrometry experiments
confirm the importance of an appropriate solvent selection to thi-
oiminium formation without byproduct formation. The use of
a strong base (such as DBU) to form tetra-substituted derivatives
helps the proton abstraction and the sulfur extrusion itself.
Reducing systems such as NaBH4/AcOH and PtO2/H2 resulted in
To a 50 mL flask were added 2.5 mmol of lactams 4a–d, 20 mL of
benzene or toluene, and 1.25 mmol of Lawesson’s reagent. The re-
action was refluxed for 4 h and the solvent was removed under
reduced pressure. The crude products were purified by chroma-
tography column eluted with n-hexane/ethyl acetate mixtures.
b
-aminocarbonyl (partially reduced) compounds in high yields. The
3.2.1. Thiolactam 5a
1H NMR (200 MHz, CDCl3):
d ppm 9.24–9.12 (br, 1H), 3.68 (t,
developed methodology allowed the synthesis of methylphenidate
analogue, RitalinÒ, and Norallosedamine. Thus, it opens up a new
avenue for other alkaloid syntheses.
J¼7.3 Hz, 2H), 2.92 (t, J¼7.9 Hz, 2H), 2.22 (qt, J¼7.6 Hz, 2H). 13C NMR
(50 MHz, CDCl3):
d
ppm 205.2, 49.6, 43.2, 22.6. FTIR (KBr, cmꢁ1):
2946, 2884, 1535, 1294, 1113. Mp¼114.6–115.8; literature7 114.0–
116.0. Anal. Calcd for C4H7NS: C, 47.49; H, 6.97; N, 13.85. Found: C,
47.52; H, 6.99; N, 13.95.
3. Experimental
3.1. General
3.2.2. Thiolactam 5b
All commercial chemicals were purchased from Acros or Aldrich
and used without further purification. All air/wet sensible reactions
1H NMR (200 MHz, CDCl3):
d ppm 7.30 (s, 5H), 4.98 (s, 2H), 3.59
(t, J¼7.3 Hz, 2H), 3.10 (t, J¼7.9 Hz, 2H), 2.00 (qt, J¼7.6 Hz, 2H). 13C

B.A.D. Neto et al. / Tetrahedron 65 (2009) 2484–2496
2493
NMR (50 MHz, CDCl3):
d
ppm 201.5, 131.9, 128.6, 128.1, 127.8, 53.8,
was stirred for 24 h and the volatiles were removed under reduced
pressure. The products were purified by a chromatography column
eluted with n-hexane/ethyl acetate gradient.
51.1, 41.8, 19.3. FTIR (KBr, cmꢁ1): 3021, 2985, 1592, 1511, 1303.
Mp¼70.2–71.8; literature70 70.0–71.0. Anal. Calcd for C11H13NS: C,
69.07; H, 6.85; N, 7.32. Found: C, 69.10; H, 7.01; N, 7.40.
3.5.1.
b
-Enaminocarbonyl compound 8a
ppm 7.32–7.15 (m, 5H), 4.68 (s, 1H),
3.2.3. Thiolactam 5c
1H NMR (200 MHz, CDCl3):
d
1H NMR (200 MHz, CDCl3):
d
ppm 9.60–9.06 (br, 1H), 3.36–3.2
4.34 (s, 2H), 4.08 (q, J¼7.1 Hz, 2H), 3.33 (t, J¼6.9 Hz, 2H), 3.22 (t,
(m, 2H), 2.93–2.87 (m, 2H), 1.90–1.70 (m, 4H). 13C NMR (50 MHz,
J¼7.8 Hz, 2H), 1.95 (qt, J¼7.5 Hz, 2H), 1.22 (t, J¼7.1 Hz, 3H). 13C NMR
CDCl3):
d
ppm 200.8, 43.7, 38.4, 19.9, 19.3. FTIR (KBr, cmꢁ1): 2859,
(50 MHz, CDCl3): d ppm 164.9, 135.8, 128.5, 127.2, 126.9, 78.2, 58.0,
1571, 1321, 1114. Mp¼92.1–92.8; literature71 87–93. Anal. Calcd for
52.2, 49.8, 32.4, 20.9, 14.5. FTIR (KBr, cmꢁ1): 3013, 2918, 1657, 1592,
1085, 1027. Mp¼61.8–62.9; literature70 62.0–63.0. Yield 83%. Anal.
Calcd for C15H19NO2: C, 73.44; H, 7.81; N, 5.71. Found: C, 73.51; H,
7.90; N, 5.79.
C5H9NS: C, 52.13; H, 7.87; N, 12.16. Found: C, 52.19; H, 7.94; N, 12.23.
3.2.4. Thiolactam 5d
1H NMR (200 MHz, CDCl3):
d ppm 7.31 (s, 5H), 5.32 (s, 2H), 3.34
(t, J¼7.9 Hz, 2H), 3.08 (t, J¼6.1 Hz, 2H), 1.88–1.63 (m, 4H). 13C NMR
3.5.2. b-Enaminocarbonyl compound 8b
(50 MHz, CDCl3):
d
ppm 200.4, 135.2, 128.4, 127.4, 57.1, 49.0, 41.6,
1H NMR (200 MHz, CDCl3):
d ppm 7.85–7.20 (m, 10H), 5.90 (s,
22.0, 20.3. FTIR (KBr, cmꢁ1): 3023, 2956, 1592, 1508, 1299.
Mp¼67.7–69.1; literature72 68.0–69.0. Anal. Calcd for C12H15NS: C,
70.20; H, 7.36; N, 6.82. Found: C, 70.14; H, 7.23; N, 6.77.
1H), 4.51 (s, 2H), 3.53–3.40 (m, 4H), 2.05 (qt, J¼7.4 Hz, 2H). 13C NMR
(50 MHz, CDCl3): d ppm 187.9, 167.4, 141.9, 135.5, 130.2, 128.9, 127.9,
127.7,127.1, 86.8, 52.6, 50.3, 33.8, 20.9. FTIR (KBr, cmꢁ1): 3022, 2949,
2870, 1620, 1576, 1543, 1475, 1219. Mp¼57.1–58.3. Yield 86%. Anal.
Calcd for C19H19NO: C, 82.28; H, 7.81; N, 5.71. Found: C, 82.33; H,
7.89; N, 5.79.
3.3.
a-Halocarbonyl compound 6c
In a 100 mL flask were added methyl phenylacetate (6.17 g;
41.1 mmol), 30 mL of CCl4, NBS (8.1 g; 45.3 mmol), and benzoyl
peroxide 70% (0.1 g; 0.41 mmol). The reaction was refluxed for 4 h.
The formed succinimide was filtered off and the crude product was
3.5.3.
b
-Enaminocarbonyl compound 8c
ppm 7.40–7.22 (m, 10H), 6.36 (s,
1H NMR (300 MHz, CDCl3):
d
1H), 4.73–4.68 (m, 1H), 4.47 (s, 2H), 4.06–3.96 (m, 2H), 3.44 (t,
J¼7.0 Hz, 2H), 3.34 (dd, J¼16.0 and 14.0 Hz, 1H), 2.75 (dd, J¼12.0
and 10.0 Hz, 1H), 2.01 (qt, J¼7.5 Hz, 2H). 13C NMR (50 MHz, CDCl3):
distilled at 1 mmHg/115 ꢀC affording methyl-
a-bromophenylace-
tate 6c in 84% yield as a colorless liquid.
1H NMR (200 MHz, CDCl3):
d
ppm 7.56–7.52 (m, 2H), 7.37–7.34
ppm
d ppm 167.7, 165.3, 154.2, 136.2, 135.4, 129.5, 128.7, 128.6, 127.8,
(m, 3H), 5.36 (s, 1H), 3.78 (s, 3H). 13C NMR (50 MHz, CDCl3):
d
127.7, 126.8, 79.7, 65.3, 55.3, 52.5, 50.5, 38.6, 33.8, 20.8. FTIR (KBr,
168.7, 135.6, 129.2, 128.8, 128.6, 53.3, 46.5. FTIR (neat, cmꢁ1): 3023,
2859, 1731, 1594, 1464, 1368. Anal. Calcd for C9H9BrO2: C, 47.19; H,
3.96. Found: C, 47.24; H, 3.99.
cmꢁ1): 3019, 2944, 2861, 1642, 1592, 1205. [
a
]
þ10.1 (c 1.01, eth-
D
anol). Mp¼153.2–154.4. Yield 80%. Anal. Calcd for C16H18N2O3: C,
67.12; H, 6.34; N, 9.78. Found: C, 67.19; H, 6.40; N, 9.87.
3.4.
a
-Halocarbonyl compound 6e
3.5.4.
b
-Enaminocarbonyl compound 8d
ppm 11.78–1.59 (br, 1H), 7.92–7.78
1H NMR (200 MHz, CDCl3):
d
Under inert atmosphere conditions, (S)-4-benzyl-2-oxazolidi-
none (1.0 g, 5.64 mmol) was dissolved in dry THF (18 mL) and the
solution was cooled at ꢁ78 ꢀC. To this solution was added a solution
(m, 7H), 7.42–7.31 (m, 4H), 5.59 (s, 1H), 3.46–3.28 (m, 2H), 2.50 (t,
J¼6.1 Hz, 2H), 1.91–1.68 (m, 4H). 13C NMR (50 MHz, CDCl3):
d ppm
187.0, 165.7, 140.6, 130.1, 128.0, 126.7, 90.3, 41.0, 28.9, 22.2, 19.3. FTIR
(KBr, cmꢁ1): 3042, 2928, 1606, 1528, 1335, 1289. Mp¼96.4–97.5.
Yield 64%. Anal. Calcd for C13H15NO: C, 77.58; H, 7.51; N, 6.96.
Found: C, 77.67; H, 7.61; N, 7.05.
of n-BuLi 2 M (2.82 mL) and
a-bromoacetylbromide (0.55 mL,
6.20 mmol). The reaction was stirred for 10 min at ꢁ78 ꢀC and
30 min at room temperature. After, the solvent was removed under
reduced pressure. The crude product was dissolved in CH2Cl2 and
washed with aqueous saturated ammonium chloride solution. The
organic phase was dried, filtered off, and the solvent removed. The
product was purified by chromatography column eluted with n-
hexane/ethyl acetate mixture to afford 6c in 86% yield.
3.6. General procedure for the synthesis of tetra-substituted
enaminocarbonyl compounds 8e–g and compound 9a
In a 50 mL flask, under argon atmosphere, to a solution of
compound 5a–c (2.62 mmol) in dry chloroform (6 mL) were added
NaI (2.62 mmol) and compound 6b (7.86 mmol). The reaction was
stirred for 24 h at room temperature. After this period the reaction
temperature was raised to reflux and a solution of triphenylphos-
phine (5.24 mmol) and triethylamine (5.24 mmol) in dry chloro-
form (6 mL) was added dropwise. The system was kept at this
temperature and under stirring for 18 h. The solvent was removed
and compounds 8e, 8f or 8g (also compound 9a obtained as un-
desired product) were obtained pure after purification by chro-
matography column eluted with n-hexane/ethyl acetate gradient.
1H NMR (200 MHz, CDCl3):
d ppm 7.39–7.20 (m, 5H), 4.76–4.64
(m, 1H), 4.53 (s, 2H), 4.32–4.20 (m, 2H), 3.32 (dd, J¼3.2 and 14.0 Hz,
1H), 2.80 (dd, J¼9.5 and 14.0 Hz, 1H). 13C NMR (50 MHz, CDCl3):
d
ppm 165.8, 152.9, 134.7, 129.3, 128.9, 127.4, 66.6, 55.3, 37.4, 28.3.
]
[
a
D ꢁ75.1 (c 2.30, CH2Cl2); literature46 (enantiomer) þ75.4 (c 2.30,
CH2Cl2). Anal. Calcd for C12H12BrNO3: C, 48.34; H, 4.06; N, 4.70.
Found: C, 48.28; H, 4.13; N, 4.78.
3.5. General procedure for the synthesis of tri-substituted
enaminocarbonyl compounds 8a–d
b-
In a 50 mL flask, in an argon atmosphere, thiolactams 5a–
d (0.79 mmol) was dissolved in 2 mL of dry chloroform. To the
3.6.1.
1H NMR (200 MHz, CDCl3):
3.68 (s, 3H), 3.29 (t, J¼7.1 Hz, 2H), 3.12 (t, J¼7.1 Hz, 2H), 1.96–1.88
b
-Enaminocarbonyl compound 8e
d
ppm 7.31–7.18 (m, 5H), 4.97 (s, 1H),
solution were added dry NaI (0.87 mmol) and the
a-halo com-
pounds 6a, 6d or 6e. The reaction was stirred for 18 h at room
temperature. After this period were added triphenylphosphine
(1.58 mmol) and triethylamine (1.58 mmol) in this order to the
protected nitrogen compounds. To the unprotected compounds the
additions were performed in the inverse order. The reaction system
(m, 5H). 13C NMR (50 MHz, CDCl3):
d ppm 170.3, 163.9, 138.2, 129.3,
127.2, 126.9, 89.6, 54.6, 52.3, 50.1, 34.8, 21.8, 14.7. FTIR (KBr, cmꢁ1):
3015, 2978, 2943, 1674, 1577, 1427, 1275. Mp¼62.1–62.8. Yield 76%.
Anal. Calcd for C15H19NO2: C, 73.44; H, 7.81; N, 5.71. Found: C,
73.50; H, 7.89; N, 5.78.

2494
B.A.D. Neto et al. / Tetrahedron 65 (2009) 2484–2496
3.6.2.
b
-Enaminocarbonyl compound 8f
ppm 8.61–8.42 (br, 1H), 7.28–7.15
(m, 5H), 3.60 (s, 3H), 3.58 (t, J¼7.5 Hz, 2H), 1.90 (qt, J¼7.1 Hz, 2H).
this period and kept in this condition an additional hour. The sol-
vent was removed and the crude products purified by chroma-
tography column eluted with n-hexane/ethyl acetate gradient.
1H NMR (200 MHz, CDCl3):
d
13C NMR (50 MHz, CDCl3):
d ppm 169.9, 165.5, 138.2, 131.4, 127.6,
125.7, 92.5, 50.5, 47.3, 32.2, 22.1. FTIR (KBr, cmꢁ1): 3044, 2925, 1581,
1489, 1238. Mp¼113.5–114.5. Yield 90%. Anal. Calcd for C13H15NO2:
C, 71.87; H, 6.96; N, 6.45. Found: C, 71.97; H, 7.04; N, 6.55.
3.8.1. Thioimine compound 10a
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 (m, 2H). 13C
NMR (50 MHz, CDCl3): d ppm 170.9, 170.7, 134.8, 128.8, 128.4, 128.3,
3.6.3.
b
-Enaminocarbonyl compound 8g
ppm 9.82–9.63 (br, 1H), 7.34–7.10
60.7, 52.9, 52.1, 37.9, 23.5. FTIR (neat, cmꢁ1): 3063, 2951, 1740, 1693,
1594. Yield 93%. Anal. Calcd for C14H19NO2S: C, 63.37; H, 7.22; N,
5.28. Found: C, 63.44; H, 7.31; N, 5.36.
1H NMR (200 MHz, CDCl3):
d
(m, 5H), 3.55 (s, 3H), 3.40–3.33 (m, 2H), 2.11 (t, J¼6.5 Hz, 3H), 1.74
(qt, J¼5.8 Hz, 2H), 1.63–1.54 (m, 2H). 13C NMR (50 MHz, CDCl3):
d
ppm 170.2, 161.3, 138.1, 132.2, 127.8, 125.9, 94.4, 50.4, 41.3, 27.7,
3.8.2. Thioimine compound 10c
22.2, 19.0. FTIR (KBr, cmꢁ1): 3043, 2926, 1581, 1485, 1257.
Mp¼114.1–115.0. Yield 60%. Anal. Calcd for C14H17NO2: C, 72.70; H,
7.41; N, 6.06. Found: C, 72.78; H, 7.48; N, 6.13.
1H NMR (200 MHz, CDCl3):
d
ppm 4.42 (t, J¼7.3 Hz, 1H), 4.20 (q,
J¼7.1 Hz, 2H), 3.83 (t, J¼7.2 Hz, 2H), 2.60 (t, J¼7.4 Hz, 2H), 2.06–1.78
(m, 4H), 1.45 (st, J¼7.2 Hz, 2H), 1.27 (t, J¼7.1 Hz, 3H), 0.94 (t,
J¼7.2 Hz, 3H). 13C NMR (50 MHz, CDCl3):
d ppm 172.2, 170.6, 61.3,
3.6.4. Thiazolidinone compound 9a
60.7, 47.2, 38.3, 34.1, 23.5, 20.4, 14.1, 13.7. FTIR (neat, cmꢁ1): 3023,
2859, 1731, 1594, 1464, 1368. Yield 89%. Anal. Calcd for C12H23NO2S:
C, 58.74; H, 9.45; N, 5.71. Found: C, 58.81; H, 9.53; N, 5.80.
1H NMR (200 MHz, CDCl3):
d ppm 7.38 (m, 5H), 5.03 (s, 1H), 4.92
(t, J¼4.3 Hz, 1H), 3.71 (m, 2H), 2.28 (m, 2H), 1.9 (m, 2H). 13C NMR
(50 MHz, CDCl3):
d ppm 10.8, 137.4, 129.1, 128.7, 128.2, 128.1, 98.1,
51.0, 42.0, 22.5, 20.4. FTIR (neat, cmꢁ1): 3061, 2928, 2849, 1696,
1645, 1387, 1253. Anal. Calcd for C13H13NOS: C, 67.50; H, 5.66; N,
6.06. Found: C, 67.55; H, 5.74; N, 6.13.
3.8.3. Thioimine compound 10d
1H NMR (200 MHz, CDCl3):
d
ppm 4.40 (t, J¼7.3 Hz, 1H), 4.20 (q,
J¼7.3 Hz, 2H), 3.83 (t, J¼7.2 Hz, 2H), 2.60 (t, J¼7.4 Hz, 2H), 2.06–1.80
(m, 4H), 1.42–1.34 (m, 4H), 1.27 (t, J¼7.1 Hz, 3H), 0.90 (t, J¼7.1 Hz,
3.7. General procedure for the synthesis of compounds 9b–d
3H). 13C NMR (50 MHz, CDCl3):
d ppm 171.9, 170.2, 61.0, 60.5, 47.1,
38.1, 31, 28.9, 23.5, 22.1, 13.9, 13.6. FTIR (neat, cmꢁ1): 2957, 2865,
1736, 1594, 1464. Yield 91%. Anal. Calcd for C13H25NO2S: C, 60.19; H,
9.71; N, 5.40. Found: C, 60.27; H, 9.81; N, 5.49.
To a solution of thiolactam 5c (0.87 mmol) in dry chloroform
(5 mL) was added
a-bromoesters 6f–h (0.96 mmol) and the re-
action was stirred for 24 h at room temperature. After this period,
DBU (1.83 mmol) was added and the stirring was kept for an ad-
ditional 20 h. After this period, the reaction was warmed to reflux
temperature for 1 h and the solvent removed. The crude product
was purified by chromatography column eluted with n-hexane/
ethyl acetate gradient.
3.9. General procedure for the synthesis of b-
enaminocarbonyl compound 8f from compound 10a
In a 50 mL flask, under argon atmosphere, to a solution of
compounds 10a and 10c,d (2.62 mmol) in dry chloroform (6 mL)
were added base (5.24 mmol) (Et3N or DBU) and triphenylphos-
phine (5.24 mmol). The reaction was stirred for 18 h at reflux
temperature. The solvent was removed and compound 8f was
obtained pure after purification by chromatography column eluted
with n-hexane/ethyl acetate gradient.
3.7.1. Thiazolidinone compound 9b
1H NMR (200 MHz, CDCl3):
d
ppm 4.82 (t, J¼4.1 Hz, 1H), 4.01 (q,
J¼7.3 Hz, 1H), 3.72–3.52 (m, 2H), 2.25–2.13 (m, 2H), 1.93–1.83 (m,
2H), 1.57 (d, J¼7.5 Hz, 3H). 13C NMR (50 MHz, CDCl3):
d ppm 172.8,
130.9, 97.9, 41.9, 41.8, 22.9, 20.8, 19.9. Yield 88%. Unstable to per-
form elementary analysis.
3.9.1.
1H NMR (200 MHz, CDCl3):
(m, 5H), 3.60 (s, 3H), 3.58 (t, J¼7.5 Hz, 2H), 1.90 (qt, J¼7.1 Hz, 2H).
b
-Enaminocarbonyl compound 8f
d
ppm 8.61–8.42 (br, 1H), 7.28–7.15
3.7.2. Thiazolidinone compound 9c
1H NMR (200 MHz, CDCl3):
d
ppm 4.82 (t, J¼4.3 Hz, 1H), 3.97
13C NMR (50 MHz, CDCl3):
d ppm 169.9, 165.5, 138.2, 131.4, 127.6,
(dd, J¼3.7 and 9.3 Hz, 1H), 3.67–3.57 (m, 2H), 2.20–1.27 (m, 4H),
125.7, 92.5, 50.5, 47.3, 32.2, 22.1. FTIR (KBr, cmꢁ1): 3044, 2925, 1581,
1489, 1238. Mp¼113.5–114.5. See Table 7 for the yield. Anal. Calcd
for C13H15NO2: C, 71.87; H, 6.96; N, 6.45. Found: C, 71.97; H, 7.04; N,
6.55.
0.94 (t, J¼7.3 Hz, 3H). 13C NMR (50 MHz, CDCl3):
d ppm 172.1, 131.2,
97.3, 47.6, 41.5, 35.8, 22.3, 20.2, 20.1, 13.4. Yield 91%. Anal. Calcd for
C10H15NOS: C, 60.88; H, 7.66; N, 7.10. Found: C, 60.97; H, 7.75; N,
7.20.
3.10. Reductions of b-enaminocarbonyl compounds 8a–g
3.7.3. Thiazolidinone compound 9d
1H NMR (200 MHz, CDCl3):
d
ppm 4.81 (t, J¼4.2 Hz, 1H), 3.96
3.10.1. Method A: NaBH4/AcOH
To a solution of NaBH4 (7.56 mg, 0.2 mmol) in glacial acetic acid
(10 mL) was added b-enaminocarbonyl compound (0.40 mmol) at
0 ꢀC. The solution was stirred for 30 min at room temperature. Af-
ter, CH2Cl2 (30 mL) was added and the organic phase was washed
with saturated sodium carbonate, dried, and filtered off. The sol-
vent was removed and the crude products purified by chroma-
tography column eluted with n-hexane/ethyl acetate gradient.
(dd, J¼3.7 and 9.3 Hz, 1H), 3.65–3.60 (m, 2H), 2.24–1.26 (m, 5H),
0.91 (t, J¼6.6 Hz, 3H). 13C NMR (50 MHz, CDCl3):
d
ppm 171.9, 131.1,
97.1, 47.7, 41.4, 33.4, 28.9, 22.3, 22.0, 20.1, 13.7. Yield 94%. Anal. Calcd
for C11H17NOS: C, 62.52; H, 8.11; N, 6.63. Found: C, 62.63; H, 8.20; N,
6.71.
3.8. General procedure for the synthesis of thioimines 10a–d
To a solution of thiolactam 5a (0.99 mmol) in dry chloroform
3.10.2. Method B: NaCNBH3/HCl
(5 mL) was added
a
-bromoesters 6c–h (1.09 mmol) and the re-
To a solution of b-enaminocarbonyl compound (0.22 mmol),
action was kept under stirring for 24 h. After this period, DBU
(2.08 mmol) was added and the reaction was stirred for 20 h more
at room temperature. The temperature was raised to reflux after
NaBH3CN (0.33 mmol) and bromo-cresol 1% m/m (as the indicator)
in MeCN (2 mL) were added dropwise a methanolic solution of HCl
(1 M). The addition was stopped when the solution became yellow.

B.A.D. Neto et al. / Tetrahedron 65 (2009) 2484–2496
2495
The reaction was stirred for 30 min at room temperature. After this
period dichloromethane (10 mL) was added and the organic layer
was neutralized with an aqueous solution of NaHCO3, separated,
dried over MgSO4, and the solvent removed. The crude product was
purified by chromatography column eluted with n-hexane/ethyl
acetate gradient.
128.5, 128.4, 128.2, 128.1, 127.0, 60.7, 58.9, 53.9, 43.9, 31.3, 22.3. FTIR
(neat, cmꢁ1): 3060, 3028, 2927, 1684, 1450, 1367, 1207. Yield: 89%
(method A), 72% (method B), 72% (method C), 86% (method D).
Anal. Calcd for C19H21NO: C, 81.68; H, 7.58; N, 5.01. Found: C, 81.77;
H, 7.69; N, 5.11.
3.13.
b-Aminocarbonyl compound 11c
3.10.3. Method C: NaBH(OAc)3
To a solution of
b-enaminocarbonyl compound (0.22 mmol) in
1H NMR (200 MHz, CDCl3):
d ppm 7.32–7.17 (m, 10H), 4.73–4.51
dry MeCN (3 mL) was added NaBH(OAc)3 (0.66 mmol). The reaction
was stirred for 24 h at room temperature. Acetonitrile was removed
under reduced pressure and the system was dissolved in CH2Cl2
(10 mL). The organic phase was neutralized using an aqueous sat-
urated solution of NH4Cl, dried over MgSO4, and the solvent re-
moved. The crude product was purified by chromatography column
eluted with n-hexane/ethyl acetate gradient.
(m, 1H), 4.14–3.99 (m, 3H), 3.47–3.24 (m, 3H), 3.07–2.87 (m, 2H),
2.80–2.73 (m, 1H), 2.23–2.12 (m, 1H), 1.74–1.62 (m, 2H). 13C NMR
(75 MHz, CDCl3): d ppm 171.9, 171.8, 153.2, 139.6, 139.5, 135.2, 129.2,
128.8, 128.6, 128.5, 128.0, 127.2, 126.6, 66.0, 65.9, 60.3, 60.2, 58.7,
58.6, 55.0, 53.8, 53.7, 40.9, 40.8, 37.8, 31.1, 30.9, 22.3. FTIR (neat,
cmꢁ1): 3028, 2922, 2794, 1784, 1697, 1452, 1387, 1354, 1211. Yield:
99% (method A), 74% (method B), 73% (method C), 88% (method D).
Anal. Calcd for C23H26N2O3: C, 72.99; H, 6.92; N, 7.40. Found: C,
73.06; H, 6.99; N, 7.48.
3.10.4. Method D: PtO2/HClO4
In a 50 mL Schlenk were added the
pound (0.40 mmol), methanol (10 mL) PtO2 (1 mol %), and an
aqueous solution of HClO4 (70%) (30 L). The system was degassed,
charged with H2 (1 atm) and stirred for 24 h. The organic phase was
filtered off, neutralized using an aqueous solution of Na2CO3 and
the solvent was removed to afford the desired product in a good
purity without any additional purification process.
b-enaminocarbonyl com-
3.14.
b-Aminocarbonyl compound 11d
m
1H NMR (200 MHz, CDCl3):
5.18–5.06 (br, 1H), 3.17–3.02 (m, 3H), 2.82–2.54 (m, 1H), 1.87–1.74
(m, 1H), 1.69–1.58 (m, 2H), 1.31.52–1.20 (m, 4H). 13C NMR (50 MHz,
d ppm 7.96 (m, 2H), 7.81–7.52 (m, 3H),
CDCl3): d ppm 199.2, 137.0, 133.5, 128.9, 128.3, 53.0, 46.4, 44.7, 31.9,
25.3, 24.4. FTIR (neat, cmꢁ1): 3060, 2929, 1682, 1448, 1292. Yield:
75% (method B), 87% (method D), 9% (method E). Anal. Calcd for
C13H17NO: C, 76.81; H, 8.43; N, 6.89. Found: C, 76.88; H, 8.51; N, 6.97.
3.10.5. Method E: NaBH4/EtOH
To a solution of b-enaminocarbonyl compound (0.74 mmol) in
ethanol (5 mL) was added sodium borohydride (1.48 mmol). The
reaction was kept under stirring for 1 h at room temperature and
additional 48 h at reflux. After, HCl (2 N solution in water) was
added and the organic compounds extracted with CH2Cl2. The or-
ganic layer was dried, filtered, and the solvent removed. The crude
oil was purified by chromatography column eluted with n-hexane/
ethyl acetate gradient.
3.15.
b-Aminocarbonyl compound 11e
1H NMR (200 MHz, CDCl3):
d
ppm 7.34–7.21 (m, 5H), 4.12 (d,
J¼12.9 Hz, 1H), 3.69 (s, 3H), 3.19 (d, J¼12.9 Hz, 1H), 2.90–2.69 (m,
3H), 2.11 (dd, J¼8.6 and 17.3 Hz, 1H), 1.95–1.81 (m, 2H), 1.70–1.26
(m, 2H), 1.22 (d, J¼6.7 Hz, 3H). 13C NMR (50 MHz, CDCl3):
d ppm
175.7, 139.9, 128.5, 128.0, 126.6, 66.5, 59.2, 54.3, 51.2, 42.1, 27.1, 22.5,
14.0. FTIR (neat, cmꢁ1): 3026, 2949, 2875, 1736, 1689, 1454, 1196.
Yield: 92% (method A), 98% (method B), 71% (method C), 81%
(method D). Anal. Calcd for C15H21NO2: C, 72.84; H, 8.56; N, 5.66.
Found: C, 72.88; H, 8.61; N, 5.70.
3.10.6. Method F: Mg/MeOH
To a solution of b-enaminocarbonyl compound (0.22 mmol) in
dry methanol (5 mL), magnesium (2.20 mmol) was carefully added
under stirring. The reaction was warmed to reflux temperature and
kept for 72 h. The solvent was removed and the crude oil was
dissolved in CH2Cl2 (5 mL). The organic phase was washed two
times with 2 N HCl solution, dried over MgSO4, and the solvent was
removed to afford a crude product. The purification was made by
chromatography column eluted with n-hexane/ethyl acetate
gradient.
3.16. Methylphenidate analogue 11f
1H NMR (200 MHz, CDCl3):
(br, 1H), 4.14 (s, 1H), 3.69 (s, 3H), 3.43–3.40 (m, 3H), 2.35–1.87 (m,
d ppm 7.36–7.26 (m, 5H), 6.28–6.05
4H). 13C NMR (50 MHz, CDCl3):
d ppm 217.4, 133.5, 128.9, 128.8,
128.5, 62.8, 52.8, 46.8, 28.4, 23.4. FTIR (neat, cmꢁ1): 3022, 2935,
1735, 1453, 1161. Yield: 70% (method B), 62% (method C), 99%
(method D, 130 atm of H2 pressure). Anal. Calcd for C13H17NO2: C,
71.21; H, 7.81; N, 6.39. Found: C, 71.30; H, 7.90; N, 6.47.
3.11.
b-Aminocarbonyl compound 11a
1H NMR (200 MHz, CDCl3):
d
ppm 7.35–7.22 (m, 5H), 4.13 (q,
J¼7.1 Hz, 2H), 4.02 (d, J¼13.2 Hz, 1H), 3.37 (d, J¼12.9 Hz, 1H), 3.39–
2.93 (m, 2H), 2.70 (dd, J¼8.8 and 15.0 Hz, 1H), 2.40 (dd, J¼8.8 and
15.0 Hz, 1H), 2.31–2.22 (m, 1H), 2.14–2.02 (m, 1H), 1.82–1.59 (m,
3.17. Methylphenidate 11g
3H), 1.25 (t, J¼7.1 Hz, 3H). 13C NMR (50 MHz, CDCl3):
d
ppm 172.2,
1H NMR (200 MHz, CDCl3):
d ppm 7.44–7.28 (m, 5H), 3.64 (s,
138.8, 128.9, 128.2, 126.9, 60.8, 60.2, 58.5, 53.8, 39.6, 30.8, 22.1, 14.2.
FTIR (neat, cmꢁ1): 3029, 2964, 2929, 1734, 1454, 1244. Yield: 88%
(method A), 75% (method B), 71% (method C), 85% (method D).
Anal. Calcd for C15H21NO2: C, 72.84; H, 8.56; N, 5.66. Found: C,
72.91; H, 8.67; N, 5.73.
3H), 3.48 (d, J¼10.1 Hz, 1H), 3.16–3.06 (m, 1H), 2.92 (d, J¼12.4 Hz,
1H), 2.50 (dt, J¼3.1 and 11.1 Hz, 1H), 1.83–1.23 (m, 6H). 13C NMR
(50 MHz, CDCl3):
d ppm 172.9, 135.6, 128.8, 128.6, 127.9, 59.2, 58.1,
51.8, 46.9, 30.9, 25.6, 24.5. FTIR (neat, cmꢁ1): 3022, 2935, 1735,
1453, 1161. Yield: 90% (method B), 89% (method C), 90% (method D,
5 atm of H2 pressure), 40% (method F). Anal. Calcd for C14H19NO2: C,
72.07; H, 8.21; N, 6.00. Found: C, 72.10; H, 8.24; N, 6.03.
3.12.
b-Aminocarbonyl compound 11b
1H NMR (200 MHz, CDCl3):
d
ppm 7.94–7.90 (m, 2H), 7.60–7.21
3.18. Norallosedamine 12d
(m, 2H), 4.00 (d, J¼12.9 Hz, 1H), 3.43 (d, J¼12.9 Hz, 1H), 3.36 (t,
J¼6.2 Hz, 2H), 3.22–2.93 (m, 3H), 2.33–2.07 (m, 2H), 1.84–1.78 (m,
In
a 25 mL sealed flask, to a solution of compound 8d
2H). 13C NMR (50 MHz, CDCl3):
d ppm 199.4, 137.1, 133.0, 128.9,
(0.74 mmol) in EtOH (5 mL) were added 1.48 mmol of NaBH4. The

2496
B.A.D. Neto et al. / Tetrahedron 65 (2009) 2484–2496
27. Liguori, A.; Ottana, R.; Romeo, G.; Sindona, G.; Uccella, N. Chem. Ber. 1989, 122,
2019–2020.
28. Tufariello, J. J.; Ali, S. A. Tetrahedron Lett. 1978, 19, 4647–4650.
29. Wakabayashi, T.; Watanabe, K.; Kato, Y.; Saito, M. Chem. Lett. 1977, 223–228.
30. Ferraris, D. Tetrahedron 2007, 63, 9581–9597.
31. Kang, B.; Chang, S. Tetrahedron 2004, 60, 7353–7359.
32. Bisai, A.; Singh, V. K. Tetrahedron Lett. 2007, 48, 1907–1910.
33. Raghavan, S.; Rajender, A. Tetrahedron 2004, 60, 5059–5067.
34. Russowsky, D.; Neto, B. A. D. Tetrahedron Lett. 2003, 44, 2923–2926.
35. (a) Neto, B. A. D.; Lapis, A. A. M.; Mancilha, F. S.; Vasconcelos, I. B.; Thum, C.;
Basso, L. A.; Santos, D. S.; Dupont, J. Org. Lett. 2007, 9, 4001–4004; (b) Pinto, A.
C.; Lapis, A. A. M.; da Silva, B. V.; Bastos, R. S.; Dupont, J.; Neto, B. A. D. Tetra-
hedron Lett. 2008, 49, 5639–5641; (c) Czekster, C. M.; Lapis, A. A. M.; Souza, G.
H. M. F.; Eberlin, M. N.; Basso, L. A.; Santos, D. S.; Dupont, J.; Neto, B. A. D.
Tetrahedron Lett. 2008, 49, 5914–5917.
reaction was stirred for 48 h at reflux temperature. A solution of HCl
(2 N) was added to neutralize the media. The mixture was extracted
with CH2Cl2. The organic solvent was separated and removed and
compound 12d was obtained pure after purification by chroma-
tography column eluted with n-hexane/ethyl acetate/methanol
gradient.
1H NMR (200 MHz, CDCl3):
d ppm 7.39–7.16 (m, 5H), 5.02 (dd,
J¼8.6 and 4.2 Hz, 1H), 3.21–2.73 (m, 2H), 2.89–2.71 (m, 1H), 2.46–
2.32 (m, 1H), 2.30–1.98 (m, 3H), 1.75–1.59 (m, 4H). 13C NMR
(50 MHz, CDCl3):
d ppm 143.9, 128.6, 127.7, 125.4, 71.2, 56.9, 52.9,
39.9, 26.6, 22.8, 20.4. Mp¼91.4–92.9; literature 92.0–93.0. Yield:
60% Anal. Calcd for C13H19NO: C, 76.06; H, 9.33; N, 6.82. Found: C,
76.11; H, 9.39; N, 6.88.
36. Pilli, R. A.; Robello, L. G.; Camilo, N. S.; Dupont, J.; Lapis, A. A. M.; Neto, B. A. D.
Tetrahedron Lett. 2006, 47, 1669–1672.
37. (a) Santos, L. S.; Neto, B. A. D.; Consorti, C. S.; Pavam, C. H.; Almeida, W. P.;
Coelho, F.; Dupont, J.; Eberlin, M. N. J. Phys. Org. Chem. 2006, 19, 731–736; (b)
Lapis, A. A. M.; Neto, B. A. D.; Scholten, J. D.; Nachtigall, F. M.; Eberlin, M. N.;
Dupont, J. Tetrahedron Lett. 2006, 47, 6775–6779.
Acknowledgements
38. Neto, B. A. D.; Lopes, A. S.; Wust, M.; Costa, V. E. U.; Ebeling, G.; Dupont, J.
Tetrahedron Lett. 2005, 46, 6843–6846.
CAPES, CNPq for partial financial support. The authors are in
debt to Professors J. Dupont and V.E.U. Costa for helpful sugges-
tions. We also thank Roxzana Sudo (USA) for a critical reading of the
manuscript.
39. (a) Godoi, M. N.; Costenaro, H. S.; Kramer, E.; Machado, P. S.; Montes, D.;
Marcelo, G.; Russowsky, D. Quim. Nova 2005, 28, 1010–1013; (b) Andrade, C. K.
Z.; Rocha, R. O.; Russowsky, D.; Godoi, M. N. J. Braz. Chem. Soc. 2005, 16, 535–
539; (c) Russowsky, D.; Lopes, F. A.; Da Silva, V. S. S.; Canto, K. F. S.; Montes
D’Oca, M. G.; Godoi, M. N. J. Braz. Chem. Soc. 2004, 15, 165–169.
40. Ireland, R. E.; Brown, F. R. J. Org. Chem. 1980, 45, 1868–1880.
41. Michael, J. P.; Zwane, M. I. Tetrahedron Lett. 1992, 33, 4755–4758.
42. Jain, S.; Jain, R.; Singh, J.; Anand, N. Tetrahedron Lett. 1994, 35, 2951–2954.
43. Louwrier, S.; Ostendorf, M.; Tuynman, A.; Hiemstra, H. Tetrahedron Lett. 1996,
37, 905–908.
Supplementary data
Supplementary data including Tables and NMR spectra is
available for the current article. Supplementary data associated
with this article can be found in the online version, at doi:10.1016/
j.tet.2009.01.081.
44. Pinnick, H. W.; Chang, Y. H. J. Org. Chem. 1978, 43, 4662–4663.
45. Bachi, M. D.; Breiman, R.; Meshulam, H. J. Org. Chem. 1983, 48, 1439–1444.
46. Evans, D. A.; Weber, A. E. J. Am. Chem. Soc. 1987, 109, 7151–7157.
47. Gage, J. R.; Evans, D. A. Org. Synth. 1990, 68, 77–82.
48. Gerasyuto, A. I.; Hsung, R. P. J. Org. Chem. 2007, 72, 2476–2484.
49. Marchand, P.; Fargeaubellassoued, M. C.; Bellec, C.; Lhommet, G. Synthesis 1994,
1118–1120.
References and notes
50. Marchand, P.; Bellassoued, M. C.; Bellec, C.; Lhommet, G. Synth. Commun. 1994,
24, 2577–2584.
1. Shiosaki, K. Comprehensive Organic Synthesis: The Eschenmoser Coupling Re-
action; Pergamon: Oxford, 1993; Vol. 2.
51. Cimarelli, C.; Palmieri, G. J. Org. Chem. 1996, 61, 5557–5563.
52. Bartoli, G.; Cimarelli, C.; Marcantoni, E.; Palmieri, G.; Petrini, M. J. Org. Chem.
1994, 59, 5328–5335.
53. Mehta, M. A.; Owen, A. M.; Sahakian, B. J.; Mavaddat, N.; Pickard, J. D.; Robbins,
T. W. J. Neurosci. 2000, 20.
54. Swanson, J. M.; Lerner, M.; Williams, L. N. Engl. J. Med. 1995, 333 944–944.
55. Swanson, J. M.; Sergeant, J. A.; Taylor, E.; Sonuga-Barke, E. J. S.; Jensen, P. S.;
Cantwell, D. P. Lancet 1998, 351, 429–433.
56. Matsumura, Y.; Kanda, Y.; Shirai, K.; Onomura, O.; Maki, T. Tetrahedron 2000, 56,
7411–7422.
2. Michael, J. P.; Accone, C.; de Koning, C. B.; van der Westhuyzen, C. W. Beilstein
J. Org. Chem. 2008, 4, art. 5.
3. Knott, E. B. J. Chem. Soc. 1955, 916–917.
4. Shiosaki, K.; Fels, G.; Rapoport, H. J. Org. Chem. 1981, 46, 3230–3234.
5. Sorensen, E. J.; Nicolauo, K. C. Classics in Total Synthesis; VCH: Weinheim, 1996.
6. Riether, D.; Mulzer, J. Eur. J. Org. Chem. 2003, 30–45.
7. Roth, M.; Dubs, P.; Gotschi, E.; Eschenmoser, A. Helv. Chim. Acta 1971, 54,
710–734.
8. Petersen, J. S.; Fels, G.; Rapoport, H. J. Am. Chem. Soc. 1984, 106, 4539–4547.
9. Marchand, P.; Bellec, C.; FargeauBellassoued, M. C.; Nezry, C.; Lhommet, G.
Heterocycles 1996, 43, 63–70.
10. Russowsky, D.; Neto, B. A. D. Tetrahedron Lett. 2004, 45, 1437–1440.
11. Michael, J. P.; de Koning, C. B.; San Fat, C.; Nattrass, G. L. Arkivoc 2002, 62–77.
12. Michael, J. P.; de Koning, C. B.; van der Westhuyzen, C. W.; Fernandes, M. A.
J. Chem. Soc., Perkin Trans. 1 2001, 2055–2062.
13. David, O.; Fargeau-Bellassoued, M. C.; Lhommet, G. Tetrahedron Lett. 2002, 43,
3471–3474.
14. Fustero, S.; Jimenez, D.; Moscardo, J.; Catalan, S.; del Pozo, C. Org. Lett. 2007, 9,
5283–5286.
15. Yadav, J. S.; Reddy, M. S.; Rao, P. P.; Prasad, A. R. Synthesis 2006, 4005–4012.
16. Raghavan, S.; Rajender, A. Tetrahedron Lett. 2004, 45, 1919–1922.
17. Angoli, M.; Barilli, A.; Lesma, G.; Passarella, D.; Riva, S.; Silvani, A.; Danieli, B.
J. Org. Chem. 2003, 68, 9525–9527.
18. Adamkova, S.; Frebort, I.; Sebela, M.; Pec, P. J. Enzyme Inhib. 2001, 16, 367–372.
19. Kim, J. H.; Thart, H.; Stevens, J. F. Phytochemistry 1996, 41, 1319–1324.
20. Felpin, F. X.; Lebreton, J. Tetrahedron Lett. 2002, 43, 225–227.
21. Poerwono, H.; Higashiyama, K.; Takahashi, H. Heterocycles 1998, 47, 263–270.
22. Ghiaci, M.; Adibi, M. Org. Prep. Proced. Int. 1996, 28, 474–477.
23. Oppolzer, W. Gazz. Chim. Ital. 1995, 125, 207–213.
57. Rometsch, R. U.S. Patent 2,838,519, June 10, 1958.
58. Davies, H. M. L.; Hansen, T.; Hopper, D. W.; Panaro, S. A. J. Am. Chem. Soc. 1999,
121, 6509–6510.
59. Pilli, R. A.; Dias, L. C. Synth. Commun. 1991, 21, 2213–2229.
60. Pilli, R. A.; Russowsky, D.; Dias, L. C. J. Chem. Soc., Perkin Trans. 1 1990,
1213–1214.
61. Hootele, C.; Halin, F.; Thomas, S.; Tourwe, D. Tetrahedron 1985, 41, 5563–5568.
62. Halin, F.; Slosse, P.; Hootele, C. Tetrahedron 1985, 41, 2891–2897.
63. Mancuso, V.; Hootele, C. Tetrahedron Lett. 1988, 29, 5917–5918.
64. Neto, B. A. D.; Ebeling, G.; Goncalves, R. S.; Gozzo, F. C.; Eberlin, M. N.; Dupont, J.
Synthesis 2004, 1155–1158.
65. Neto, B. A. D.; Santos, L. S.; Nachtigall, F. M.; Eberlin, M. N.; Dupont, J. Angew.
Chem., Int. Ed. 2006, 45, 7251–7254.
66. Eberlin, M. N. Eur. J. Mass Spectrom. 2007, 13, 19–28.
67. Santos, L. S.; Rosso, G. B.; Pilli, R. A.; Eberlin, M. N. J. Org. Chem. 2007, 72,
5809–5812.
68. Milagre, C. D. F.; Milagre, H. M. S.; Santos, L. S.; Lopes, M. L. A.; Moran, P. J. S.;
Eberlin, M. N.; Rodrigues, J. A. R. J. Mass Spectrom. 2007, 42, 1287–1293.
69. Neto, B. A. D.; Alves, M. B.; Lapis, A. A. M.; Nachtigall, F. M.; Eberlin, M. N.;
Dupont, J.; Suarez, P. A. Z. J. Catal. 2007, 249, 154–161.
24. Oppolzer, W.; Deerberg, J.; Tamura, O. Helv. Chim. Acta 1994, 77, 554–560.
25. Oppolzer, W. Pure Appl. Chem. 1994, 66, 2127–2130.
26. Ozawa, N.; Nakajima, S.; Zaoya, K.; Hamaguchi, F.; Nagasaka, T. Heterocycles
1991, 32, 889–894.
70. Michael, J. P.; Hosken, G. D.; Howard, A. S. Tetrahedron 1988, 44, 3025–3036.
71. Goel, O. P.; Krolls, U. Synthesis 1987, 162–164.
72. Raucher, S.; Klein, P. J. Org. Chem. 1981, 46, 3558–3559.