Reactivity and diastereoselectivity of Michael additions of amines to achiral α,β-unsaturated thioamides

Article abstract of DOI:10.1016/S0040-4020(01)00849-3

Heterocyclic, aliphatic amines add to acyclic and cyclic α,β-unsaturated thioamides yielding β-amino-functionalized derivatives. In the case of cyclic acceptors, the formation of both kinetic and thermodynamically controlled products is observed. Tailorin

Full text of DOI:10.1016/S0040-4020(01)00849-3

TETRAHEDRON
Pergamon
Tetrahedron 57 :2001) 8705±8718
Reactivity and diastereoselectivity of Michael additions of amines
to achiral a,b-unsaturated thioamides
a,p
Jacek G. Sosnicki, Tadeusz S. Jagodzinski and Poul Erik Hansen
a
b
Â
Â
a
Â
Institute of Fundamental Chemistry, Technical University of Szczecin, Al. Piastow 42, PL-71065 Szczecin, Poland
bDepartment of Life Sciences and Chemistry, Roskilde University, P.O. Box 260, DK-4000 Roskilde, Denmark
Received 11 April 2001; revised 23 July 2001; accepted 16 August 2001
AbstractÐHeterocyclic, aliphatic amines add to acyclic and cyclic a,b-unsaturated thioamides yielding b-amino-functionalized deriva-
tives. In the case of cyclic acceptors, the formation of both kinetic and thermodynamically controlled products is observed. Tailoring of cis or
trans products is thus possible. A mechanism for the addition to cyclic acceptors is proposed and evidence presented to support it. Ease of
addition is studied in relation to the structure of the acceptors. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
addition. The broad spectrum of applied acceptors has also
allowed us to inspect the factors in¯uencing the reactivity.
The great utility of Michael addition reactions in organic
synthesis is well documented.1,2 During the last two decades
a,b-unsaturated thioamides have been recognized as good
Michael acceptors. They form C±C bonds in reactions with
C-nucleophiles such as alkyllithiums, alkylmagnesiums,3,4
lithium enolates5 and nitromethane in the presence of base
catalyst.6 Reactions with heteronucleophiles have been only
sparingly studied.7 The diastereoselectivity of Michael addi-
tion reactions to a,b-disubstituted acceptors is an important
feature. A series of papers concerning diastereoselectivity of
addition of amines to electron de®cient cyclic ole®ns, e.g.
1-nitrocyclopentenes,8 1-nitrocyclohexenes,9 substituted 30-
enesulfones10 or 30-enenitriles11 describe different diaster-
eoselection, depending on the type of acceptor and amine.
2. Results and discussion
2.1. Synthesis
Piperidine, morpholine and pyrrolidine led to stable
products in reaction with tertiary acyclic thioamides 1j±l
:Scheme 1) while only six-membered amines :piperidine
or morpholine) gave stable compounds with cyclic and
acyclic secondary thioamides 1a±i :Schemes 1 and 2).
Addition of pyrrolidine to secondary thioamides resulted
in unstable adducts :identi®ed by TLC). The products
were subsequently decomposed in a presumably retro-
Michael reaction during puri®cation. Diethylamine did not
undergo addition to the thioamides studied. Except for 1a
and d, the reactions were conducted without solvent using
neat thioamides 1b,c,e±n and a 5±10-fold excess of amine
in order to achieve complete conversion. In the case of 1a
and d, a smaller excess of piperidine was used and the
reaction was conducted in etheral or alcoholic solution,
respectively, using freshly prepared thioamide acceptors
1a :crude) or d :carefully puri®ed) due to their instability.
The adducts were obtained in good to moderate yields and
only regioselective 1,4-addition was observed. Yields and
reaction conditions are given in Table 1.
Recently, we reported the diastereoselective Michael
addition of nitrogen and sulphur nucleophiles to chiral
6-substituted a,b-unsaturated d-thiolactams.12 Owing to
the synthetic value of thioamides as synthons,13 we decided
to investigate the addition of amines to 2-, 3-substituted
acyclic and cyclic secondary and tertiary a,b-unsaturated
thioamides other than thiolactams. As donors, we selected
heterocyclic, aliphatic amines :piperidine, morpholine,
pyrrolidine), diethylamine and as acceptors, various substi-
tuted secondary and tertiary thioamides, derivatives of
acrylic- :1a), cinnamic- :1b,c,j), crotonic- :1e,k),
methacrylic- :1d,l), 1-cyclohexene- :1f,g,m) and 1-cyclo-
pentene- :1h,i,n) carboxylic acids. Applying achiral cyclic
acceptors, 1f±n, we examined the diastereoselectivity of the
The most interesting results were obtained using cyclic
thioamides 1f±i,m,n as starting materials. In this case,
dependence on reactivity and diastereoselectivity of
addition on the ring size, the character of thioamide moiety
as well as the nucleophilicity and basicity of amine was
observed :Scheme 2, Table 1). In general, the reactions
were conducted at room temperature but for less reactive
Keywords: Michael addition; a,b-unsaturated thioamides; s-cis/s-trans
conformation; Z/E con®guration; reactivity; FMO-theory; diastereoselectivity.
Corresponding author; e-mail: sosnicki@carbon.tuniv.szczecin.pl
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020:01)00 849-3

Â
J. G. Sosnicki et al. / Tetrahedron 57 52001) 8705±8718
8706
Scheme 1.
thioamides, a temperature of 808C was applied. Both the
tertiary thioamides 1m and n were not reactive, producing
only traces of the products after 40days at room tempera-
ture as well as when kept at 808C for 5 days. The reactions
conducted at room temperature showed that among both
pairs of secondary thioamides 1f,g and 1h,i N-Ph substituted
derivatives, 1f,h were more reactive than their N-Bn analogs
1g,i :Table 1). Analogously, 1-cyclopentene derivatives 1h,i
were more reactive, respectively, to their 1-cyclohexene
analogs 1f,g. Moreover in this case, different stereoselec-
tivity was observed. The course of the reaction using cyclic
thioamides was followed by 1H NMR spectroscopy. Thus in
the reaction of N-phenyl 1-cyclohexenecarboxythioamide
:1f) with piperidine for seven days only the trans isomer
:Scheme 2, Table 1, entry 9) was formed in good yield,
while its N-benzyl analog :1g), which reacted much more
slowly :48 days), led to a 90:10 mixture of cis/trans isomers,
respectively, in a total yield of 19% :Scheme 2 and Table 1,
entry 12). Both reactions showed no variation in time in
the diastereomer distribution in the crude mixture. It
should be noted that the pure products 2gp!t) and 2gp!c)
remained unchanged upon treatment with piperidine after
40days.
In the case of 1-cyclopentenecarboxythioamides 1h and i,
the formation of cis/trans mixtures and further enrichment
of the trans isomer was observed :Table 1). Only in the case
of the reaction between 1i and morpholine, the ratio of trans
and cis isomers were slightly changed :Table 1, entry 17)
while in all other cases :Table 1, entries 14±16), the isomer-
ization reaction was fast enough to lead to single trans
isomers after an appropriate time at room temperature.
Treatment of a previously formed mixture lead to preferred
formation of trans adducts as observed in the reactions
Scheme 2.

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J. G. Sosnicki et al. / Tetrahedron 57 52001) 8705±8718
8707
Table 1. Yield and the reaction conditions of addition of amines to a,b-unsaturated thioamides
Entry
Substrate
Aminea/solvent
Molar
ratio of
thioamide/amine
Temperature
:8C)
Reaction
time
Adductsa
:diastereomeric
ratio),b
yield :%)
1
2
3
4
5
6
7
8
9
1a
1b
1b
1c
1c
1d
1e
1e
1f
p/diethyl ether
p/neat
m/neat
p/neat
m/neat
p/methanol
p/neat
m/neat
1:1.2
1:8
1:8
1:8
1:8
1:2
1:8
1:8
1:1020
202 h
2024 h
2024 h
2024 h
2024 h
206 h
2020
2ap, 64
2bp, 89
2bm, 83
2cp, 85
2cm, 87
2dp, 74
2ep, 72
2em, 92
2fp!t)/2fp!c)
:100:0)c
:100:0) 77
2fp!t)/2fp!c)
ca :50:50)c
:100:0) 82
2fm!t)/2fm!c)
:43:57)c
h
h
2020
p/neat
1 day
7 days
10
11
1f
1f
p/neat
1:2080
1:1080
2 h
24 h
m/neat
14 h
82 h
:90:10)
6 days
:.95:5) 82
2gp!t)/2gp!c)
:10:90)c
12
13
1g
1g
p/neat
p/neat
1:1020
1:1080
20 days
48 days
:10:90)c 19
2gp!t)/2gp!c)
ca :30:70)c
ca :75:25)c
:100:0)c 39
2hp!t)/2hp!c)
:55:45)
24 h
72 h
7 days
14
15
16
17
1h
1h
1i
p/neat
m/neat
p/neat
m/neat
1:5
1:5
1:5
20
20
20
20
1.5 h
20 h
:100:0) 90
2hm!t)/2hm!c)
:59:41)
:.99:1) 73
2ip!t)/2ip!c)
:58:42)
:.99:1) 69
2im!t)/2im!c)
:31:69)
20h
64 h
3 days
11 days
1i
1:5
20days
Then 1:10The3nd8a0ys
:93:7) 84
18
19
20
21
22
23
24
1j
1j
1j
1k
1k
1k
1l
p/neat
m/neat
5 da1y:s1020
2jp 72
2jm 46
2jpy 66
2kp 78
2km 72
2kpy 88
2lp 43
5 da1y:s1020
5 da1y:s1020
20 1:1020
20 1:1020
20 1:1020
4 da1y:s1020
py/neat
h p/neat
h m/neat
h py/neat
p/neat
a
p: piperidine; m: morpholine; py: pyrrolidine, :t): trans; :c): cis.
The ratio of diastereoisomers was estimated by H NMR spectra of crude reaction mixture after evaporation of amine.
Substrate present.
b
c
1
between thioamides, derivatives of 1-cyclohexene-
carboxylic acid and morpholine :1f, Table 1, entry 11)
and piperidine :1f,g, Table 1, entries 10and 13, respec-
tively) conducted at 808C. It should be emphasized that in
the case of the reaction of 1g with piperidine, the tempera-
ture conditions changed the ratio of the ®nal products from
10% trans/90% cis :208C) to 100% trans :808C). For
preparative reasons and because of considerable problems
in separation of diastereoisomers, the reaction was
prolonged at room temperature :Table 1, entries 14±17) or
heated at 808C :Table 1, entries 11, 13 and 17) in order to
obtain the pure thermodynamically stable trans-isomer.
:1H, 13C, 13C DEPT) and 2D :1H, 1H COSY, 13C, 1H COSY,
1H, 1H NOESY) NMR spectra. Adducts derived from
secondary thioamides showed in CDCl3 solution, six-
membered quasi heterocyclic rings due to the strong
N±H´´´N hydrogen bond formation :Schemes 1 and 2).
N-benzyl and morpholinyl substituents caused formation
of weaker hydrogen bonding relative to the N-phenyl and
piperidinyl substituted analogs as judged from NH chemical
shifts. The con®guration of 2fp!t), 2fm!t), 2gp!t), 2gp!c),
2hp!t), 2hm!t), 2ip!t) and 2im!t) were based on coupling
constants between H-2 and H-3 protons. Spectra of 2fp!t)
and 2fm!t) were broad at room temperature and therefore
were recorded at a lower temperature :240K) and a
Lorentzian to Gaussian resolution enhancement was
applied :Fig. 1). In the case of 2fp!t), these operations
allowed observation of two similar triplets of doublets :td,
2.2. Structural assignment
The structures of all compounds were elucidated using 1D

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J. G. Sosnicki et al. / Tetrahedron 57 52001) 8705±8718
8708
Figure 1. The con®guration, conformation of 2fp!t), 2fm!t), 2gp!t), 2gp!c) and parts of the Gaussian to Lorentzian resolution enhanced spectra of compounds
2fp!t) :240K, upper-left), 2fm!t) :240K, upper-right) and 2gp!t) :300 K, lower).
J1±2ˆ10.6 Hz, J3ˆ3.6 Hz; td, J1±2ˆ10.5 Hz, J3ˆ2.9 Hz)
acceptor. Among the reactions studied, the reactions using
cyclic thioamide 1f±i gave the most interesting results. In
order to rationalize the experimental observations, the struc-
tures of all thioamide acceptors, except 1a,d :not stable
belonging to H-2; H-3, respectively :Fig. 1).
For 2fm!t), one triplet of doublets was seen, while the
second one was overlapped. Two large and one small
coupling constants indicate their trans relationship in anti-
periplanary :diaxially) orientations and allowed assignment
of the con®guration as trans :Fig. 1). A trans con®guration
was also found for 2gp!t) based on the spectra recorded at
300 K :Fig. 1). In the case of 2gp!c), signal multiplicities of
the diagnostic protons H-2 :brs), H-3 :dt, J1±2ˆ3.8 Hz,
J3ˆ11.4 Hz) established the con®guration as cis. The lack
of couplings at H-2 showed that this proton has to be
equatorial and accordingly the thioamide group is axial.
Two small and one large coupling constants at H-3 indicate
its axial position and an equatorial orientation of the piper-
idine substituent :Fig. 1). For 2hp!t), 2hm!t), 2ip!t), 2im!t),
the trans con®guration was based on the presence of almost
symmetrical multiplets :quartets) belonging to H-2 and H-3
1
1
compounds) were examined using H, H NOESY spectra.
The existence of s-cis/s-trans conformations :secondary and
tertiary thioamides) and Z/E con®guration :secondary thio-
amide) was taken into consideration. :Recently we demon-
strated that 1H, 1H NOESY spectra are suitable for
elucidation of s-cis/s-trans conformation in a,b-unsaturated
compounds.14) Subsequently, for such estimated structures,
optimization and calculation of frontier molecular orbital
energies :LUMO/HOMO) were performed using the semi-
empirical PM3 method.15 The results of the NOESY struc-
tural analysis and the calculations are presented in Table 2.
The results based on NOESY spectra showed that b-substi-
tuted derivatives :1b,c,e,j,k) are planar or almost planar and
the s-cis conformation and the Z con®guration :secondary
thioamides) predominate in these cases. These results are in
agreement with the calculated low value of the CvC±CvS
dihedral angles. In the series of a-substituted and a,b-
disubstituted compounds, the picture is more complicated.
Judging by the magnitude of NOE effects :Table 2,
integration), we could conclude that CvC±CvS dihedral
angles are close to 908 :1f±h,l±n). These observations are
also supported by PM3 calculations. Unexpectedly, in the
case of 1i contrary to the perpendicular orientation along
1
in the H spectra and on the non-existence of NOE effects
between these protons in the H, H NOESY spectra.
1
1
2.3. Structure and reactivity of the thioamide acceptors
The experimental data showed that the success of the addi-
tion of heterocyclic amines to a,b-unsaturated thioamides
depends both on the type of amine and on the type of

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J. G. Sosnicki et al. / Tetrahedron 57 52001) 8705±8718
8709
CvC±CvS bonds found by calculation, NOESY spectra
indicated rather planar orientation.
derivatives support the mechanism, as the N-phenyl deriva-
tive has a much more acidic NH group.
As far as frontier molecular orbital :FMO) calculations are
concerned, the energies for the LUMO :Table 2) are parallel
to the reactivity :Table 1). This observation for the present
Michael additions is in agreement with data found by ab
initio calculations for other conjugated acceptors, e.g.
alkenones.1 For the thioamide acceptors, some structural
dependence on LUMO level should be pointed out. The
most striking is that the presence of a phenyl ring at nitrogen
as well as at the b-position decreases the energy of the
LUMO presumably because of the phenyl group conjuga-
tion. This effect is generally greater for N-phenyl derivatives
than for b-phenyl substituted compounds and makes the
N-phenyl thioamides more reactive. Moreover for non-
aromatic tertiary, and N-benzyl secondary derivatives, the
lower LUMO is seen for structures with planar CvC±CvS
bonds, e.g. LUMO of planar 1e is 20.93 eV while the
LUMO of the non-planar 1g is higher, 20.67 eV :Table
2). The same effect is observed for 1k and l. Another factor,
which could in¯uence the reactivity, is the formation of
NH´´´N hydrogen bonds between acceptor and donor :inter-
molecular system) and in the products :intramolecular
system). This assumption could explain the higher reactivity
of the N-phenyl derivative 1f towards piperidine compared
to its N-benzyl analog 1g due to more acidic N-hydrogen in
1f as well as the higher reactivity of piperidine with respect
to morpholine, which the latterÐas mentioned aboveÐ
formed weaker NH´´´H bonds in the products. Compounds
1m and n having the highest LUMO energies, the largest
steric factors :molecules are not planar) and no possibility of
NH:thioamide)´´´N:amine) bond formation are not very
reactive.
3. Conclusions
The study has shown that addition of heterocyclic, aliphatic
amines to a,b-unsaturated thioamides is a convenient
method to obtain b-functionalized thioamides, which
could be subsequently transformed to other type of
compounds, e.g. by reduction to diamines or by hydrolysis
to b-aminoacids. Furthermore, the low LUMO energy of
acceptors, gained by planarity and/or aromatic substituents,
and NH´´´N hydrogen bonding are factors in¯uencing the
reactivity of the addition. These factors and the possibility
of basic isomerization towards thermodynamically favored
products can be used to obtain selectively uncommon trans-
1,2-disubstituted aminocarbocycles.
4. Experimental
Melting points were determined on a Boetius hot stage
apparatus and are uncorrected. Infrared spectra were taken
1
with a Specord M80instrument. H, 13C NMR spectroscopic
measurements were performed on a Bruker DPX 400
spectrometer equipped with an 5 mm 1H/BB-inverse probe-
head, operating at 400.13 and 100.62 MHz with a digital
resolution of 0.12 and 0.97 Hz per point for H and 13C,
1
respectively. Low temperature spectra were recorded in
CDCl3. TMS was used as internal reference in all measure-
ments. Two-dimensional spectra were acquired using
standard Bruker software. Heteronuclear correlation :13C,
1H COSY) was optimized for a coupling 145 Hz. In H,
1
1H NOESY experiments, the mixing time between 0.9±
1.1 s were applied. Enhanced resolution spectra were
obtained by Lorentzian to Gaussian transformation
:LBˆ22.5, GBˆ0.64) using Bruker software for PC.
Mass spectra :70eV) were recorded with a HP 6890
:Hewlett±Packard) GCMS spectrometer equipped with a
mass detector HP 5973. Silica gel :0.04±0.063 mm,
Merck) was used for preparative column chromatography.
Elemental analyses were performed on EuroEA 3000 series,
EuroVector CHNS-O Elemental Analyser. All compounds
gave satisfactory elemental analysis :C, H, N, S).
2.4. Stereoselectivity of addition to cyclic acceptorsÐ
mechanism
The obtained results clearly indicated that the mechanism of
addition of amines to the conjugated thioamides consists of
a slow, rate determining addition of amine followed by rapid
protonation of the intermediate carbanion from the same
side :syn-addition, trans-product, Scheme 2, path b) or
from the opposite side :anti-addition, cis-product, Scheme
2, path a). In the beginning of the reaction, the anti-addition
process is preferred over the syn because of lower steric
hindrance between incoming proton :H1) and CH2-11
fragment of cyclohexane ring :derivative of 1-cyclo-
hexenecarboxylic acids) as well as the amine ring :deriva-
tive of 1-cyclohexene- and 1-cyclopentenecarboxylic
acids). This is the picture seen for 1-p-tolylsulfonylcyclo-
hexene16 and is supported by the trans/cis mixture :10:90)
of 2gp!t)/2gp!c) :Table 1, entry 12) :non-isomerizating at
room temperature) and the predominance of cis isomers in
the beginning of the other reactions :Table 1, entries 11, 13
and 17). The kinetically controlled step is followed by basic
isomerization :Scheme 2), which led to the thermodynami-
cally more stable trans-products :Table 1). The calculations
of heat of formations of cis and trans diastereoisomers
:Table 3) support that trans-products are more stable than
cis-isomers. The progress of the isomerization seems to be
dependent on basicity of the amine used. The much more
facile isomerization of the N-phenyl compared to N-benzyl
4.1. Synthesis of a,b-unsaturated thioamides !starting
materials)
Thioamides 1b,c,e±g,i±n were prepared from the corre-
sponding amides according to a standard procedure using
Lawesson reagent in re¯uxing benzene in a molar ratio of
0.55:1 :Lawesson reagent/amide).17 The oxygen±sulphur
exchange was completed after 1±4 h :established by
TLC). Products were twice chromatographed on silica gel
using n-hexane/ethyl acetate :8:2) as eluent.
The thioamides, 1b: mp 138±1398C from ethyl acetate±n-
hexane :lit.18 1348C), 1c: mp 118±1198C from acetonitrile
:lit.19 115±1168C), 1d: mp 45±538C from n-hexane, lit.4
:This compound is not a stable semisolid even when kept
in the refrigerator.) 1f: mp 82±858C from ethyl acetate±n-
hexane :lit.4 858C), 1k: oil :lit.7 348C) are known compounds.

Table 2. NOESY and PM3 analysis data
Acceptor
1b
1c
1e
1f
Conformation and
con®guration based on
NOESY spectra
SˆC-CˆC planar :s-cis) SˆC-N :Z)
SˆC-CˆC planar :s-cis) SˆC-N :Z)
SˆC-CˆC planar :s-cis)
SˆC-N :Z)
SˆC-CˆC perpendicular
SˆC-N :Z)
Diagnostic NOEs
diagonal signalÐNOE
effecta
NHÐH-2000:10.7), H-2 :20.2);
H-2ÐH-2 :24.1), NH :14.0);
H-3ÐH-200 :18.1)
NHÐH-2 :8.5), CH2 :6.5);
H-2ÐNH :10.8), H-200 :11.1);
H-3ÐH-200 :9.1)
NHÐH-2 :4.4), CH2 :3.1);
H-2ÐNH :7.7), CH3 :3.4);
H-3ÐCH3 :8.0)
NHÐH-20 :1.6), H-2 :2.6),
CH2-6 :3.5); H-2ÐNH :3.2),
CH2-3 :7.9)
PM3 calculation
LUMO :eV)
HOMO :eV)
CvC±CvS dihedral
angle :deg)
21.45
28.53
0.5
21.29
28.57
3.5
20.93
28.54
0.6
21.05
28.52
93.5
Acceptor
1g
1h
1i
1j
Conformation and
con®guration based on
NOESY spectra
SˆC-CˆC almost perpendicular
SˆC-N :Z)
SˆC-CˆC perpendicular
SˆC-N :Z)
SˆC-CˆC planar :s-cis)
SˆC-N :Z)
CˆC-CˆS planar :s-cis)
Diagnostic NOEs
diagonal signalÐNOE
answera
NHÐCH2Ph :6.2), H-2 :1.7),
CH2-6 :7.8); H-2ÐNH :3.3),
CH2-3 :7.0)
NHÐH-20 :2.3), H-2 :2.0),
CH2-5 :7.2); H-2ÐNH :2.0), CH2-3
:4.3)
NHÐCH2Ph :3.6), CH2-5 :17.4);
H-2ÐCH2-3 :1.8)
H-2ÐCH-200 :6.8), CH2-50 :11.1);
H-3ÐCH-200 :5.6)
PM3 calculation
LUMO :eV)
HOMO :eV)
CvC±CvS dihedral
angle :deg)
20.67
28.54
97.8
21.12
28.55
2115
20.77
28.53
2112
21.08
28.46
235.5

Table 2 :continued)
Acceptor
1k
1l
1m
1n
Conformation and
con®guration based on
NOESY spectra
CˆC-CˆS planar :s-cis)
CˆC-CˆS perpendicular
CˆC-CˆS perpendicular
CˆC-CˆS almost perpendicular
Diagnostic NOEs
diagonal signalÐNOE
effecta
H-2ÐCH2-60 :7.8); H-3ÐCH3 :11.2);
CH3ÐCH2-20 :4.5),
CH2-60 :5.9), H-3cis :4.2);
CH2-50 Ð CH3 :7.7), CH2-10 :238.0)b
H-2ÐCH2-20 :2.6), CH2-50 :3.9),
CH2-3 :5.7); CH2-20 ÐH-2 :0.8),
CH2-6 :1.9), CH2-3 :2.4)
CH2-50 ÐH-2 :1.6), CH2-6 :3.2),
CH2-3 :4.0)
H-2ÐCH2-20 :0.5), CH2-50 :3.4),
CH2-3 :2.8); CH2-50 ÐCH2-20
:21.7)b, H-2 :0.9)
CH2-60 ÐCH2-20 :235.0)b, H-2 :4.4)
PM3 calculation
LUMO :eV)
HOMO :eV)
CvC±CvS dihedral
angle :deg)
20.93
28.43
22.0
20.69
28.51
293.6
20.52
28.44
93.5
20.53
28.44
289.9
a
Integrations of signals, calibrated relative to perturbed signals :value-100), are given in the parenthesis.
Exchange process takes place.
b

Table 3. Heat of formation :kcal/mol) of cis and trans isomers of alicyclic compounds calculated by PM3 method
2fp RˆPh, nˆ1, XˆCH2
2fm RˆPh, nˆ1, XˆO
2gp RˆBn, nˆ1, XˆCH2
2hp RˆPh, nˆ0 , XˆCH2
2ip RˆBn, nˆ0 , XˆCH2
2im RˆBn, nˆ0 , XˆO
trans !t)
cis !c)
28.99a
32.64b
29.96c
3.64
2.88a
7.07b
3.56c
4.19
22.57a
26.22b
23.22c
3.65
33.86
36.32
28.07
29.39
1.89
3.70
D:Hcis2Htrans
)
2.46
1.32
1.81
0.97
0.68
0.65
a
Calculation performed for Hax-2, Hax-3 oriented chair conformation of cyclohexane.
Calculation performed for Heq-2, Hax-3 oriented chair conformation of cyclohexane.
Calculation performed for Hax-2, Heq-3 oriented chair conformation of cyclohexane.
b
c

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J. G. Sosnicki et al. / Tetrahedron 57 52001) 8705±8718
8713
4.1.1. !E) But-2-enethioic acid benzylamide !1e). Re¯ux
3 h, yield 64%. Pale yellow solid, mp 63±658C from ethyl
acetate/n-hexane [Found: C, 68.99; H, 6.82; N, 7.15; S,
17.01. C11H13NS requires C, 69.07; H, 6.85; N, 7.32; S,
16.76%]; nmax:KBr pellet) 3286, 3036, 1654, 1536, 1392,
1346, 1184, 956, 738, 696 cm21; dH :400.1 MHz, CDCl3)
1.86 :3H, dd, Jˆ6.9, 1.6 Hz, CH3), 4.88 :2H, d, Jˆ5.3 Hz,
CH2N), 6.23 :1H, dq, Jˆ14.8, 1.6 Hz, H-2), 7.00 :1H, dq,
Jˆ14.8, 6.9 Hz, H-3), 7.26±7.38 :5H, m, C6H5), 7.41 :1H,
brs, NH); dC :100.6 MHz, CDCl3) 18.05 :q, CH3), 49.87 :t,
CH2N), 128.07, 128.31, 128.89, 136.25 :C6H5), 132.06 :d,
C-2), 140.96 :d, C-3), 196.18 :s, CvS); m/z :EI, 70eV) 191
:82, M1), 176 :74), 143 :50), 106 :38), 91 :100), 85 :19), 65
:22%).
4.1.5. !E) 2-Methyl-1-piperidin-1-yl-propenethione !1l).
:Re¯ux 4 h, yield 54%. Pale yellow oil [Found: C, 63.77;
H, 9.01; N, 8.65; S, 19.02. C9H15NS requires C, 63.85; H,
8.93; N, 8.27; S, 18.94%]; nmax:liquid ®lm) 2936, 2856,
1632, 1490, 1440, 1246, 1226, 1136, 1008, 896 cm21; dH
:400.1 MHz, CDCl3) 1.61±1.65 :2H, m, CH2), 1.65±1.80
:4H, m, 2CH2), 2.05 :3H, s, CH3), 3.73 :2H, t, Jˆ5.3 Hz,
CH2-60), 4.22 :2H, brs, CH2-20), 4.87 :1H, s, vCHH), 4.92
:1H, t, Jˆ1.4 Hz, vCHH); dC :100.6 MHz, CDCl3) 22.48
:q, CH3), 24.40, 25.36, 27.04 :each t, 3CH2), 49.43, 52.25
:each t, CH2NCH2), 111.66 :t, vCH2), 146.96 :s, C-2),
200.73 :s, CvS); m/z :EI, 70 eV) 169 :100, M1), 154
:13), 136 :16), 135 :15), 127 :11), 94 :14), 86 :26), 85
:25), 84 :30%).
4.1.2. Cyclohex-1-enecarbothioic acid benzylamide !1g).
Re¯ux 4.5 h, yield 83%. Pale yellow plates, mp 78±808C
from ethyl acetate/n-hexane [Found: C, 72.82; H, 7.69; N,
6.05; S, 14.00. C14H17NS requires C, 72.68; H, 7.41; N,
6.05; S, 13.86%]; nmax:KBr pellet) 3260, 2932, 1630,
1524, 1324, 1184, 966, 736, 696 cm21; dH :400.1 MHz,
CDCl3) 1.56±1.62 :2H, m, CH2-4), 1.65±1.72 :2H, m,
CH2-5), 2.12±2.20:2H, m, CH 2-3), 2.41±2.48 :2H, m,
CH2-6), 4.89 :2H, d, Jˆ5.2 Hz, CH2N), 6.55±6.58 :1H,
4.1.6. Cyclohex-1-enyl-pyrrolidin-1-yl-methanethione
!1m). Re¯ux 3 h, yield 80%. White plates, mp 83±848C
from ethyl acetate/n-hexane [Found: C, 67.87; H, 9.01; N,
6.90; S, 16.10. C11H17NS requires C, 67.64; H, 8.77; N,
7.17; S, 16.42%]; nmax:KBr pellet) 2928, 1484, 1474,
1450, 1216 cm21; dH :400.1 MHz, CDCl3) 1.58±1.67 :2H,
m, CH2-4), 1.67±1.76 :2H, m, CH2-5), 1.95±2.05 :4H, m,
CH2-30, CH2-40), 2.07±2.15 :2H, m, CH2-3), 2.28±2.35
:2H, m, CH2-6), 3.62 :2H, t, Jˆ6.5 Hz, CH2-50 0), 3.82
:2H, t, Jˆ6.7 Hz, CH2-20), 5.66 :1H, septet, Jˆ1.8 Hz,
vCH); dC :100.6 MHz, CDCl3) 21.57, 22.38, 24.49,
24.65, 26.26, 27.39 :each t, 6CH2), 52.47, 52.56 :each t,
CH2-20, CH2-50), 124.20:d, CH-2), 141.96 :s, C-1),
199.65 :s, CvS); m/z :EI, 70 eV) 195 :100, M1), 166
:26), 162 :32), 153 :16), 152 :33), 139 :27), 134 :34), 126
:21), 120:18), 70:18%).
m, vCH), 7.27±7.40:5H, m, C H5), 7.45 :1H, brs, NH);
6
dC :100.6 MHz, CDCl3) 21.49 :t, CH2-4), 22.35 :t, CH2-5),
25.66 :t, CH2-3), 26.93 :t, CH2-6), 50.11 :t, CH2N), 128.07,
128.28, 128.96, 136.44 :C6H5), 132.06 :d, vCH), 140.29 :s,
C-1), 200.52 :s, CvS); m/z :EI, 70 eV) 231 :100, M1), 202
:11), 198 :26), 189 :20), 188 :29), 175 :40), 156 :25), 126
:15), 106 :15), 91 :60), 79 :14), 77 :9%).
4.1.3. Cyclopent-1-enecarbothioic acid benzylamide !1i).
Re¯ux 4 h, yield 63%. Pale yellow solid, mp 74±758C from
ethyl acetate/n-hexane [Found: C, 71.99; H, 6.84; N, 6.55;
S, 15.01. C13H15NS requires C, 71.84; H, 6.96; N, 6.44; S,
14.75%]; nmax:KBr pellet) 3220, 1520, 1340, 696 cm21; dH
:400.1 MHz, CDCl3) 1.99 :2H, quintet, Jˆ7.4 Hz, CH2-4),
2.43±2.53 :2H, m, CH2-3), 2.62±2.70:2H, m, CH 2-5), 4.89
:2H, d, Jˆ5.3 Hz, CH2N), 6.65±6.68 :1H, m, vCH-2),
7.26±7.38 :5H, m, C6H5), 7.47 :1H, brs, NH); dC
:100.6 MHz, CDCl3) 23.43 :t, CH2-4), 32.92 :t, CH2-5),
33.46 :t, CH2-3), 49.71 :t, NCH2), 128.01, 128.18, 128.89,
4.1.7. Cyclopent-1-enyl-pyrrolidin-1-yl-methanethione
!1n). Re¯ux 1.5 h, yield 82%. Yellow oil [Found: C,
66.00; H, 8.12; N, 7.75; S, 17.70. C10H15NS requires C,
66.25; H, 8.34; N, 7.73; S, 17.69%]; nmax:liquid ®lm)
2952, 1468, 1446, 1328, 1260cm 21; dH :400.1 MHz,
CDCl3) 1.90±2.09 :6H, m, CH2-4, CH2-30, CH2-40),
2.46±2.52 :2H, m, CH2-3), 2.72±2.80:2H, m, CH 2-5),
3.66 :2H, t, Jˆ6.3 Hz, CH2-50), 3.86 :2H, t, Jˆ6.7 Hz,
CH2-20), 5.78±5.82 :1H, m, vCH); dC :100.6 MHz,
CDCl3) 23.03, 24.35, 26.30 :each t, CH2-4, CH2-30, CH2-
40), 33.58 :t, CH2-3), 36.30:t, CH 2-5), 52.84, 52.90:each t,
CH2-50, CH2-20), 129.68 :d, vCH), 145.60:s, C-1), 194.34
:s, CvS); m/z :EI, 70 eV) 181 :100, M1), 166 :11), 152
:35), 148 :26), 139 :35), 120:66), 112 :23), 111 :17), 94
:12), 70:25%).
136.40:C H5), 138.72 :d, CH-2), 144.71 :s, C-1), 194.26
6
:s, CvS); m/z :EI, 70 eV) 217 :100, M1), 188 :39), 184
:27), 175 :66), 156 :18), 112 :15), 106 :17), 91 :59), 65
:21%).
1
4.1.4. !E) 3-Phenyl-1-pyrrolidin-1-yl-propenethione !1j).
Re¯ux 3.5 h, yield 60%. Orange solid, mp 146±1478C from
ethyl acetate/n-hexane [Found: C, 72.09; H, 7.03; N, 6.63;
S, 14.71. C13H15NS requires C, 71.84; H, 6.96; N, 6.44; S,
14.75%]; nmax:KBr pellet) 2968, 1628, 1480, 1448, 972,
760, 696 cm21; dH :400.1 MHz, CDCl3) 1.97±2.17 :4H,
dm, CH2-30,CH2-40), 3.80:2H, t, Jˆ6.9 Hz, CH2-50), 3.99
:2H, t, Jˆ6.9 Hz, CH2-20), 7.04 :1H, d, Jˆ15.1 Hz, vCH-
2), 7.30±7.39 :3H, m, C6H5), 7.53±7.56 :2H, m, C6H5), 8.01
:1H, d, Jˆ15.1 Hz, vCH-3); dC :100.6 MHz, CDCl3)
24.16, 26.27 :each t, CH2-30,CH2-40), 50.79, 54.10 :each t,
CH2-50,CH2-20), 125.01 :d, CH-2), 128.01, 128.82, 129.67,
135.52 :C6H5), 144.15 :d, CH-3), 190.54 :s, CvS); m/z :EI,
70 eV) 217 :100, M1), 184 :12), 156 :21), 147 :36), 130
:12), 115 :46), 103 :11), 70 :45%).
Not previously published H, 13C NMR and MS spectro-
scopic data for 1d,f,k were as follows:
4.1.8. 2-Methyl-N-phenyl-thioacrylamide !1d). dH
:400.1 MHz, CDCl3) 2.19 :3H, s, CH3), 5.25 :1H, s,
vCHH), 5.50:1H, s, vCHH), 7.25 :1H, t, Jˆ7.3 Hz,
C6H5), 7.38 :2H, t, Jˆ7.8 Hz, C6H5), 7.67 :2H, brs, C6H5),
8.94 :1H, brs, NH); dC :100.6 MHz, CDCl3) 21.66 :q, CH3),
115.3 br :t, vCH2), 123.30, 126.81, 128.78, 138.34 :C6H5),
148.34 br :s, C-2), 199.38 :s, CvS); m/z :EI, 70eV) 177
:79, M1), 176 :100), 162 :6), 144 :31), 110 :22), 109 :10),
106 :12), 104 :10), 85 :54), 77 :31%).
4.1.9. Cyclohex-1-enecarbothioic acid phenylamide !1f).
Re¯ux 2.5 h, yield 55%. dH :400.1 MHz, CDCl3) 1.60±1.79

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J. G. Sosnicki et al. / Tetrahedron 57 52001) 8705±8718
8714
:4H, m, CH2-4, CH2-5), 2.21 :2H, brs, CH2-3), 2.55 :2H,
brs, CH2-6), 6.54 :1H, brs, vCH), 7.24 :1H, t, Jˆ7.5 Hz,
C6H5), 7.37 :2H, t, Jˆ8.0Hz, C 6H5), 7.63 :2H, brs, C6H5),
8.85 :1H, brs, NH); dC :100.6 MHz, CDCl3) 21.49 :t, CH2-
4), 22.43 :t, CH2-5), 25.68 :t, CH2-3), 27.25 :t, CH2-6),
123.98, 126.74, 128.91, 142.06 :C6H5), 131.19 :d, vCH),
138.74 br :s, C-1), 200.16 br :s, CvS); m/z :EI, 70eV) 217
:100, M1), 216 :86), 188 :12), 184 :84), 156 :8), 125 :48),
92 :21), 77 :30%).
25 cm3 portions of diethyl ether. The combined organic
layers were dried with anhydrous Na2SO4, ®ltered and
0.99 g :11.5 mmol) of piperidine was added in one portion.
After 2 h, the diethyl ether was evaporated in vacuo and to
oily residue 10cm 3 of benzene was added. After 1 day, the
precipitated urea :as a result of reaction of unconsumed
phenyl isothiocyanate and piperidine) was ®ltered off and
the solvent was removed from the mother-liquid in vacuo.
The residue material chromatographed on silica gel with
CHCl3/CH3OH solution :changing the ratio of components
from 99:1 to 96:4), yielded 1.54 g :64.5%) of dark yellow
oil, which solidi®ed on treatment with hexane. The solid
was recrystallized from hexane.
4.1.10. !E) 1-Piperidin-1-yl-but-2-ene-1-thione !1k).
Re¯ux 2.5 h, 75%. dH :400.1 MHz, CDCl3) 1.60±1.78 :6
H, m, CH2-30, CH2-40, CH2-50), 1.88 :3H, dd, Jˆ6.8, 1.6 Hz,
CH3), 3.74±3.80:2H, m, CH -60), 4.27 :2H, brs, CH2-20),
2
6.47 :1H, dd, Jˆ14.8, 1.6 Hz, vCH-2), 6.77 :1H, dq,
Jˆ14.8, 6.8 Hz, vCH-3); dC :100.6 MHz, CDCl3) 14.48
:q, CH3), 24.21, 25.44, 26.68 :each t, 3CH2), 51.41, 51.48
:each t, CH2NCH2), 130.11 :d, CH-2), 140.32 :d, CH-3),
194.89 :s, CvS); m/z :EI, 70eV) 169 :99, M 1), 154
:100), 136 :8), 121 :32), 85 :32), 84 :54), 68 :20%).
4.2.1. N-Phenyl-3-piperidin-1-yl-thiopropionamide !2ap).
Pale yellow needles, mp 63±658C from n-hexane [Found: C,
68.01; H, 8.08; N, 11.35; S, 13.11. C14H20N2S requires C,
67.70; H, 8.12; N, 11.28; S, 12.91%]; nmax:KBr pellet)
3100±2400 br, 2932, 1632, 1570, 1492, 1406, 1120, 1104,
910, 756 cm21; dH :400.1 MHz, CDCl3) 1.55 :2H, brs, CH2-
7), 1.68 :4H, quintet, Jˆ5.7 Hz, CH2-6, CH2-8), 2.58 :4H,
brs, CH2-5, CH2-9), 2.74±2.77 :2H, m, CH2-3), 3.04±3.07
:2H, m, CH2-2), 7.22 :1H, tt, Jˆ7.4, 1.2 Hz, C6H5), 7.40
:2H, t, Jˆ7.5 Hz, C6H5), 7.86 :2H, dd, Jˆ8.7, 1.2 Hz,
C6H5), 13.49 :1H, brs, NH); dC :100.6 MHz, CDCl3)
24.05 :t, CH2-7), 26.09 :t, CH2-6, CH2-8), 42.06 :t, CH2-
2), 53.49 :t, CH2-5, CH2-9), 56.29 :t, CH2-3), 122.36,
125.97, 128.76, 139.62 :C6H5), 201.89 :s, C-1); GCMS-
decomposition :retro-Michael addition).
4.1.11. Cyclopent-1-enecarbothioic acid phenylamide
!1h).
A
solution of 1-bromocyclopentene :0.55 g,
3.7 mmol) in THF :6 cm3) was cooled to 278 8C and
2.2 equiv. of t-BuLi :5.7 cm3, 1.5 M in pentane) was
added over 5 min. The yellowish suspension was stirred at
2788C for 10min and PhNCS :1.2 equiv., 0.61 g,
4.5 mmol) was added dropwise over 5 min. The stirring
was continued for further 5 min. at 2788C and then allowed
to warm to 258C during 1 h. The solution was quenched by
addition of a saturated ammonium chloride solution
:10cm 3). The cooling bath was removed and the solution
was allowed to warm to room temperature. Extracted with
diethyl ether :80cm 3), separated and the organic phase was
dried :MgSO4), ®ltered and concentrated in vacuo. The
crude product puri®ed by column chromatography on silica
:n-hexane/ethyl acetateˆ9:1) and crystallized from the
same solvents gave yellow crystalline product in 70%.
4.3. Preparation of 2bp, 2bm, 2cp, 2cm, 2dp, 2ep, 2em,
2fp!t), 2fm!t), 2gp!t), 2gp!c), 2hp!t), 2hm!t), 2ip!t),
2im!t), 2jp, 2jm, 2jpy, 2kp, 2km, 2kpy, 2lp: general
procedure
To 2 mmol of a,b-unsaturated thioamide, an excess of
appropriate amine was added :Table 1). If the crystalline
thioamide were poorly soluble, the suspension was slightly
warmed. In the case of 2dp, 5 cm3 MeOH was added. The
reaction mixture was left standing at room temperature over
the required period :see Table 1) and 20cm 3 hexane :2bp,
2cp, 2cm, 2em) or 5 cm3 acetonitrile :2bm) was added. The
mixture was kept at 2208C for 1±2 days. The crystalline
product was ®ltered, dried and recrystallized. In all other
cases, an amine was evaporated under low pressure
:0.1 mmHg) at room temperature and the residue was
treated with n-hexane. Crystalline product formed was
®ltered off, dried and recrystallized or chromatographed.
Compounds 2jm, 2dp, 2ep, 2km, 2gp!t)/2gp!c) 2im!t)
were puri®ed by column chromatography on silica gel
using CHCl3 or CHCl3/MeOHˆ97:3 :2kpy) as eluent.
Mp 74±768C from ethyl acetate/n-hexane [Found: C, 71.01;
H, 6.82; N, 7.05; S, 15.57. C12H13NS requires C, 70.89; H,
6.45; N, 6.89; S, 15.77%]; nmax:KBr pellet) 3236, 1604,
1516, 1356, 696 cm21; dH :400.1 MHz, CDCl3) 2.03 :2H,
quintet, Jˆ7.5 Hz, CH2-4), 2.46±2.56 :2H, m, CH2-3), 2.79
:2H, brs, CH2-5), 6.66 :1H, brs, vCH-2), 7.25 :1H, t,
Jˆ7.4 Hz, 40-H), 7.39 :2H, t, Jˆ7.7 Hz, H-30, H-50), 7.66
:2H, brd, Jˆ6.51 Hz, H-20, H-60), 8.75 :1H, brs, NH); dC
:100.6 MHz, CDCl3) 23.45 :t, CH2-4), 33.55 :t, CH2-5),
33.67 :t, CH2-3), 124.03, 126.78, 128.98, 138.47 :C6H5),
137.60:d, CH-2), 146.40:s, C-1), 193.60:brs, C vS); m/z
:EI, 70eV) 203 :82, M 1), 202 :100), 170 :39), 136 :10), 111
:77), 110:22), 94 :11), 77 :32), 67 :27%).
4.3.1. 3,N-Diphenyl-3-piperidin-1-yl-thiopropionamide
!2bp). Pale yellow solid, mp 112±1148C from acetonitrile
[Found: C, 73.95; H, 7.40; N, 8.60; S, 9.94. C20H24N2S
requires C, 74.03; H, 7.46; N, 8.63; S, 9.88%]; nmax:KBr
pellet) 3100±2400 br, 2936, 2824, 1608, 1594, 1564, 1492,
1408, 1120, 740 cm21; dH :400.1 MHz, CDCl3) 1.39 :2H,
brs, CH2), 1.56±1.76 :1H, m, CHH), 2.35 :2H, brs, C5H10N),
2.71 :2H, brs, C5H10N), 3.16 :1H, dd, Jˆ17.3, 2.3 Hz,
2-CHH), 3.67 :1H, dd, Jˆ17.3, 12.1 Hz, 2-CHH), 4.13
:1H, dd, Jˆ12.1, 2.3 Hz, 3-CH), 7.13 :2H, brdd, Jˆca
6.2, ca 2.0Hz, C 6H5), 7.24 :1H, t, Jˆ7.5 Hz, C6H5),
4.2. Addition of amines to a,b-unsaturated thioamides:
preparation of 2ap
To an ice-cooled :08C) solution of phenyl isothiocyanate
1.3 g :9.6 mmol) in dry THF :25 cm3), 10.5 mmol of vinyl
magnesium chloride in hexane was added dropwise via
syringe under stirring. Stirring was continued for 1 h at
08C and 0.5 h at room temperature. The resulting product
was hydrolyzed at 08C with an excess of 20% solution of
ammonium chloride in water and extracted twice with

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J. G. Sosnicki et al. / Tetrahedron 57 52001) 8705±8718
8715
7.31±7.38 :3H, m, C6H5), 7.42 :2H, t, Jˆ7.5 Hz, C6H5),
7.90:2H, d, Jˆ6.5 Hz, C6H5), 13.78 :1H, brs, NH); dC
:100.6 MHz, CDCl3) 24.1 :CH2), 26.4 :CH2), 46.2 :C-2),
49.4 :CH2NCH2), 67.7 :C-3), 122.7, 126.0, 128.0, 128.1,
128.6, 128.8, 139.6 :2C6H5), 201.3 :C-1); GCMS-decom-
position :retro-Michael addition).
11.03; S, 12.13. C15H22N2S requires C, 68.65; H, 8.45; N,
10.68; S, 12.22%]; nmax:KBr pellet) 3000±2300 br, 2932,
1594, 1570, 1496, 1364, 710 cm21; dH :400.1 MHz, CDCl3)
1.41 :3H, d, Jˆ7.0Hz, CH 3), 1.48±1.59 :2H, m, CH2-7),
1.59±1.75 :4H, m, CH2-6, CH2-8), 2.45 :2H, brs,
CH2NCH2), 2.54 :1H, dd, Jˆ13.0, 3.2 Hz, CHH-3), 2.69
:1H, dd, Jˆ13.0, 10.6 Hz, CHH-3), 2.72 :2H, brs,
CH2NCH2), 2.82±2.91 :1H, m, CH-2), 7.21 :1H, t,
Jˆ7.5 Hz, C6H5), 7.39 :2H, t, Jˆ7.7 Hz, C6H5), 7.78 :2H,
d, Jˆ7.7 Hz, C6H5), 13.45 :1H, brs, NH); dC :100.6 MHz,
CDCl3) 19.19 :q, 2-CH3), 23.97 :t, CH2-7), 26.16 :t, 2CH2),
41.76 :d, CH-2), 54.09 br :t, CH2NCH2), 63.87 :t, CH2-3),
122.89, 125.85, 128.74, 139.90:C 6H5), 206.87 :s, C-1); m/z
:EI, 70eV) 262 :5, M 1), 229 :22), 98 :100), 84 :9%).
4.3.2. 3-Morpholin-4-yl-3,N-diphenyl-thiopropionamide
!2bm). Pale yellow solid, mp 134±1368C from acetonitrile
[Found: C, 69.54; H, 6.72; N, 8.47; S, 9.44. C19H22N2OS
requires C, 69.90; H, 6.79; N, 8.58; S, 9.82%]; nmax:KBr
pellet) 3100±2500 br, 2852, 1620, 1566, 1492, 1400,
1116 cm21; dH :400.1 MHz, CDCl3) 2.48 :2H, brs,
CH2N), 2.70±2.78 :2H, m, CH2N), 3.22 :1H, dd, Jˆ17.0,
2.6 Hz, CHH-2), 3.66 :1H, dd, Jˆ17.0, 11.3 Hz, CHH-2),
3.78 :4H, m, CH2OCH2), 4.13 :1H, dd, Jˆ11.3, 2.6 Hz,
CH-3), 7.14 :2H, brd, Jˆca 7.8 Hz, C6H5), 7.25 :1H, t,
Jˆ7.1 Hz, C6H5), 7.32±7.45 :5H, m, C6H5), 7.85 :2H, d,
Jˆ7.8 Hz, C6H5), 13.01 :1H, br. s, NH); dC :100.6 MHz,
CDCl3) 56.6 :t, C-2), 48.7 br :t, CH2NCH2), 67.1 :t,
CH2OCH2), 67.7 :d, C-3), 122.7, 126.4, 128.4, 128.5
128.6, 129.0, 134.6, 139.3 :2C6H5), 200.9 :s, C-1);
GCMS-decomposition :retro-Michael addition).
4.3.6. N-Benzyl-3-piperidin-1-yl-thiobutyramide !2ep).
Colourless oil [Found: C, 69.74; H, 8.45; N, 10.03; S,
11.13. C16H24N2S requires C, 69.52; H, 8.75; N, 10.13; S,
11.60%]; nmax:liquid ®lm) 3000±2400 br, 2964, 2932, 2852,
1406, 1262, 1112, 740, 700 cm21; dH :400.1 MHz, CDCl3)
0.92 :3H, d, Jˆ6.6 Hz, CH3), 1.00±1.27 :6H, m, 3CH2),
2.15±2.26 :2H, brs, CH2N), 2.50±2.76 :2H, brs, CH2N),
2.76±2.91 :2H, m, CH2-2), 2.99±3.17 :1H, m, CH-3),
4.68±4.78 :2H, m, CH2Ph), 7.24±7.42 :5H, m, C6H5),
12.26 :1H, brs, NH); dH :100.6 MHz, CDCl3) 12.58 :q,
4.3.3. N-Benzyl-3-phenyl-3-piperidin-1-yl-thiopropion-
amide !2cp). White needles, mp 125±1278C from aceto-
nitrile [Found: C, 75.19; H, 7.57; N, 8.57; S, 9.19.
C21H26N2S requires C, 74.51; H, 7.74; N, 8.28; S, 9.47%];
CH3), 24.17 :t, CH2), 25.46 :t, 2CH2), 46.20:t, CH -2),
2
48.04 br :t, 2CH2N), 50.50 :t, CH2Ph), 58.66 :d, CH-3),
127.92, 128.71, 128.78, 136.60:C H5), 202.13 :s, C-1);
6
n
max:KBr pellet) 3150±2400 br, 2940, 1556, 1442, 768, 708,
m/z :EI, 70eV) 276 :10, M 1), 243 :11), 191 :27), 176
:22), 143 :15), 112 :100), 91 :48%).
700 cm21; dH :400.1 MHz, CDCl3) 1.09 :6H, brs, CH2-6,
CH2-7, CH2-8), 2.09 :2H, brs, CH2NCH2), 2.48 :2H, brs,
CH2NCH2), 3.08 :1H, dd, Jˆ17.4, 2.4 Hz, CHH-2), 3.52
:1H, dd, Jˆ17.4, 12.1 Hz, CHH-2), 3.97 :1H, dd, Jˆ12.1,
2.3 Hz, CH-3), 4.74±4.84 :2H, m, CH2Ph), 7.06 :2H, brdd,
Jˆ7.8, 1.8 Hz, C6H5), 7.25±7.42 :8H, m, 2C6H5), 12.14
:1H, brs, NH); dC :100.6 MHz, CDCl3) 23.89 :t, CH2-7),
25.55 :t, CH2NCH2), 43.95 :t, CH2-2), 49.19 br :t,
CH2NCH2), 50.71 :t, CH2Ph), 67.55 :d, CH-3), 127.87,
128.04, 128.48, 128.79, 128.87, 134.90, 136.59 :2C6H5),
202.04 :s, C-1); GCMS-decomposition :retro-Michael
addition).
4.3.7. N-Benzyl-3-morpholin-4-yl-thiobutyramide !2em).
White solid, mp 78±808C from n-hexane/ethyl acetate
[Found: C, 64.90; H, 8.02; N, 9.80; S, 11.41. C15H22N2OS
requires C, 64.71; H, 7.96; N, 10.06; S, 11.52%]; nmax:KBr
pellet) 3000±2500 br, 1546, 1438, 1410, 1114, 896, 750,
704 cm21; dH :400.1 MHz, CDCl3) 0.99 :3H, d, Jˆ6.6 Hz,
CH3), 2.28±2.34 :2H, m, CH2N), 2.57±2.62 :2H, m, CH2N),
2.85 :2H, d, Jˆ11.1 Hz, CH2-2), 3.03 :1H, sextet,
Jˆ6.6 Hz, CH-3), 3.21 :2H, brs, CH2O), 3.28 :2H, brs,
CH2O), 4.68±4.77 :2H, m, CH2Ph), 7.28±7.41 :5H, m,
C6H5), 11.68 :1H, brs, NH); dC :100.6 MHz, CDCl3)
12.94 :q, CH3), 46.05 :t, CH2-2), 47.59 br :t, CH2NCH2),
50.62 :t, CH2Ph), 58.42 :d, CH-3), 66.47 :t, CH2OCH2),
128.3, 128.7, 128.99, 136.57 :C6H5), 201.82 :s, C-1); m/z
:EI, 70eV) 278 :15, M 1), 245 :7), 191 :8), 176 :8), 143 :5),
114 :100), 91 :26%).
4.3.4. N-Benzyl-3-morpholin-4-yl-3-phenyl-thiopropion-
amide !2cm). White solid, mp 111±1138C from acetonitrile
[Found: C, 70.28; H, 6.99; N, 8.05; S, 9.46. C20H24N2OS
requires C, 70.55; H, 7.10; N, 8.23; S, 9.42%]; nmax:KBr
pellet) 3300±2500 br, 2964, 2936, 2852, 1552, 1440, 1116,
996, 708 cm21; dH :400.1 MHz, CDCl3) 2.21 :2H, brs,
CH2N), 2.51 :2H, brs, CH2N), 3.11 :1H, dd, Jˆ17.0,
2.8 Hz, CHH-2), 3.21 :2H, brs, CH2O), 3.29 :2H, brs,
CH2O), 3.50:1H, dd, Jˆ17.0, 11.3 Hz, CHH-2), 3.97 :1H,
dd, Jˆ11.3, 2.8 Hz, CH-3), 4.75±4.77 :2H, m, CH2Ph), 7.07
:2H, brd, Jˆ6.1 Hz, C6H5), 7.25±7.41 :8H, m, 2C6H5),
11.35 :1H, brs, NH); dC :100.6 MHz, CDCl3) 44.34 :t,
CH2-2), 48.43 br :t, CH2NCH2), 50.75 :t, CH2Ph), 66.43
:t, CH2OCH2), 67.63 :d, CH-3), 128.21, 128.32, 128.46,
128.73, 129.03, 134.67, 136.44, :2C6H5), 201.63 :s, C-1);
m/z :EI, 70eV) 340:11, M 1), 307 :5), 255 :9), 253 :12), 176
:100), 91 :35%).
4.3.8. trans 2-Piperidin-1-yl-cyclohexanecarbothioic acid
phenylamide [2fp!t)]. Yellow solid, mp 118±1208C from
acetonitrile [Found: C, 71.41; H, 8.70; N, 9.37; S, 11.01.
C18H26N2S requires C, 71.47; H, 8.66; N, 9.26; S, 10.60%];
n
max:KBr pellet) 3252, 2928, 1598, 1496, 1368, 1192, 756,
688 cm21; dH :400.1 MHz, CDCl3, 220K) 1.15±1.42 :5H,
m, CHH-7, H-10ax, CHH-11, CHH-12, H-13ax), 1.43±1.67
:2H, m, CHH-6, CHH-8), 1.68±1.95 :5H, m, CHH-6, CHH-
7, CHH-8, CHH-11, CHH-12), 2.03 :1H, brd, Jˆ9.8 Hz,
H-13eq), 2.32 :1H, t, Jˆ11.4 Hz, H-5ax), 2.57 :1H, t,
Jˆ9.8 Hz, H-2ax), 2.65±2.83 :2H, m, CH2-9), 2.88 :1H, t,
Jˆ10.1 Hz, H-3ax), 3.00 :1H, brd, Jˆ10.0 Hz, H-5eq), 3.12±
3.25 :1H, m, H-10eq), 7.31 :1H, t, Jˆ6.8 Hz, C6H5), 7.48
:2H, t, Jˆ8.0Hz, C 6H5), 7.60:2H, d, Jˆ7.6 Hz, C6H5),
15.65 :1H, s, NH); dC :100.6 MHz, CDCl3 220K) 23.30
4.3.5. 2-Methyl-N-phenyl-3-piperidin-1-yl-thiopropion-
amide !2dp). Pale yellow needles, mp 66±678C from
n-hexane/ethyl acetate [Found: C, 68.54; H, 8.45; N,

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J. G. Sosnicki et al. / Tetrahedron 57 52001) 8705±8718
8716
:t, CH2-13), 24.01, 25.14, 26.31 :each t, CH2-7, CH2-11,
CH2-12), 25.66 br :t, CH2-8), 26.39 br :t, CH2-6), 34.47 :t,
CH2-10), 44.44 br :t, CH2-5), 48.62 :d, CH-2), 51.27 br :t,
CH2-9), 67.16 :d, CH-3), 123.81, 126.30, 128.85, 139.28
:C6H5), 206.84 :s, CvS); dC :100.6 MHz, CDCl3 300 K)
23.70, 24.38, 25.57, 26.37, 26.62 :each t, 6CH2), 34.90:t,
CH2-10), 48.34 br :t, CH2-5,9), 50.29 :d, CH-2), 67.58 :t,
CH-3), 123.75, 126.03, 128.73, 139.94 :C6H5), 206.95 :s,
CvS); m/z :EI, 70eV) 302 :35, M 1), 269 :100), 217 :28),
216 :24), 186 :31), 184 :52), 124 :73), 98 :36), 84 :77), 77
:42), 41 :24%).
H-3ax), 3.07 :1H, brd, Jˆca 9.8 Hz, H-10eq), 4.77 :2H, q,
Jˆ14.9 Hz, CH2Ph), 7.27±7.38 :5H, m, C6H5), 12.84 :1H,
brs, NH); dC :100.6 MHz, CDCl3) 23.62 :t, CH2-11), 24.14
:t, CH2-7), 25.33 :t, 2CH2), 25.53, 26.51 :each t, CH2-12,
CH2-13), 34.35 :t, CH2-10), 48.29 br :t, 2CH2N), 48.89 :d,
CH-2), 50.96 :t, CH2Ph), 67.60:d, CH-3), 127.75, 128.73,
128.96, 136.82 :C6H5), 206.66 :s, C-1); m/z :EI, 70eV) 316
:71, M1), 283 :100), 225 :27), 192 :49), 166 :21), 151 :17),
150:18), 124 :80), 111 :26), 98 :25), 96 :17), 91 :85), 84
:46%).
4.3.12. trans 2-Piperidin-1-yl-cyclopentanecarbothioic
acid phenylamide [2hp!t)]. White needles, mp 127±
1288C from acetonitrile [Found: C, 70.49; H, 8.54; N,
9.75; S, 11.21. C17H24N2S requires C, 70.79; H, 8.39; N,
9.71; S, 11.12%]; nmax:KBr pellet) 3000±2400 br, 2940,
1596, 1564, 1498, 1396, 1374, 696 cm21; dH :400.1 MHz,
CDCl3) 1.50±1.80 :10H, m, CH 2-6, CH2-7, CH2-8, CH2-11,
CH2-12), 2.06±2.30 :2H, dm, CH2-10), 2.57 :2H, brs,
CH2N), 2.77 :2H, brs, CH2N), 2.92 :1H, quartet,
Jˆ10.4 Hz, CHb -2), 3.12 :1H, quartet, Jˆ10.4 Hz, CHa-
3), 7.20:1H, t, Jˆ7.4 Hz, C6H5), 7.39 :2H, t, Jˆ8.3 Hz,
C6H5), 7.84 :2H, dd, Jˆ8.3, 0.8 Hz, C6H5), 13.02 :1H, brs,
NH); dC :100.6 MHz, CDCl3) 20.79, 22.0 :each t, CH2-11,
CH2-12), 24.50:t, CH 2-7), 26.57 :t, 2CH2), 29.30:t,
CH2-10), 49.37 :t, CH2NCH2), 50.86 :d, CH-2), 70.66 :d,
CH-3), 122.56, 125, 73, 128.73, 139.84 :C6H5), 205.58 :s,
C-1); m/z :EI, 70eV) 288 :18, M 1), 255 :82), 201 :59), 202
:75), 124 :100), 111 :59), 34 :52%).
4.3.9. trans 2-Morpholin-4-yl-cyclohexanecarbothioic
acid phenylamide [2fm!t)]. Pale yellow needles, mp
135±1408C from n-hexane/ethyl acetate [Found: C, 67.32;
H, 7.90; N, 9.02; S, 10.51. C17H24N2OS requires C, 67.07;
H, 7.95; N, 9.20; S, 10.53%]; nmax:KBr pellet) 3000±2300
br, 2936, 2852, 1450, 1414, 1114, 764, 692 cm21; dH
:400.1 MHz, CDCl3) 1.23±1.35 :3H, m, CHH-11, CHH-
12, CHH-13), 1.44 :1H, q, Jˆ13.0Hz, H-10 ax), 1.83±2.04
:3H, m, CHH-11 CHH-12 CHH-13), 2.54±2.65 :3H, m,
CH-2, CH2N), 2.81±2.91 :4H, m, CH-3, CH2N, H-10eq),
3.69±3.79 :4H, m, CH2OCH2), 7.24 :1H, t, Jˆ7.4 Hz,
C6H5), 7.40:2H, t,
Jˆ7.6 Hz, C6H5), 7.66 :2H, d,
Jˆ7.6 Hz, C6H5), 12.75 :1H, brs, NH); dC :100.6 MHz,
CDCl3) 23.82, 25.44, 26.38 :each t, CH2-11, CH2-12,
CH2-13), 34.47 :t, CH2-10), 47.80 br :t, CH2NCH2), 52.52
br :d, CH-2), 67.00 :d, CH-3), 67.30 :t, CH2OCH2), 123.86,
126.46, 128.90, 139.41 :C6H5), 207.14 :s, CvS); m/z :EI,
70eV) 304 :41, M 1), 271 :100), 218 :9), 186 :32), 184 :32),
178 :18), 152 :17), 126 :32), 100 :18), 77 :16%).
4.3.13. trans 2-Morpholin-4-yl-cyclopentanecarbothioic
acid phenylamide [2hm!t)]. White solid, mp 138±1418C
from acetonitrile [Found: C, 66.02; H, 7.65; N, 9.70; S,
10.85. C16H22N2OS requires C, 66.17; H, 7.64; N, 9.65; S,
11.04%]; nmax:KBr pellet) 3000±2500 br, 2848, 2828, 1630,
1570, 1488, 1398, 1118, 760, 692 cm21; dH :400.1 MHz,
CDCl3) 1.60±1.73 :2H, m, CH2-11), 1.73±1.85 :2H, m,
4.3.10. cis 2-Piperidin-1-yl-cyclohexanecarbothioic acid
benzylamide [2gp!c)]. White solid, mp 91±928C from
n-hexane [Found: C, 72.29; H, 9.04; N, 8.75; S, 10.01.
C19H28N2S requires C, 72.10; H, 8.92; N, 8.85; S,
10.13%]; nmax:KBr pellet) 3000±2300 br, 2928, 1554,
1424, 1382, 1332, 764, 704 cm21; dH :400.1 MHz,
CDCl3) 0.95±1.33 :14H, m, 6CH2, H-13ax, H-12ax), 1.39
:1H, tt, Jˆ13.3, 3.9 Hz, H-10ax), 1.48 :1H, dt Jˆ13.3,
3.2 Hz, H-11eq), 1.55 :1H, quintet of t, Jˆ13.2, 3.4 Hz,
H-11ax), 1.79 :1H, brs, H-12eq), 1.92 :1H, brs, H-13eq),
2.40:4H, brs, 2CH 2N), 2.44 :1H, dt, Jˆ11.4, 3.8 Hz,
H-3ax), 3.05 :1H, brs, H-2eq), 3.12 :1H, dm, Jˆ13.3 Hz,
H-10eq), 4.73±4.83 :2H, m, CH2Ph), 7.27±7.35 :5H, m,
C6H5), 12.95 :1H, brs, NH); dC :100.6 MHz, CDCl3)
21.40:t, CH 2-11), 23.94 :t, CH2-7), 25.24 :t, CH2-13),
25.52 :t, 2CH2), 25.55 :t, CH2-12), 30.87 :t, CH2-10),
44.72 :d, CH-2), 50.32 br :t, CH2NCH2), 50.95 :t,
CH2Ph), 66.90:d, CH-3), 127.75, 128.72, 136.80:C 6H5),
204.22 :s, C-1); m/z :EI, 70eV) 316 :58, M 1), 283 :100),
231 :24), 225 :17), 192 :42), 150:13), 151 :13), 124 :65),
111 :19), 98 :19), 91 :62), 84 :33%).
CH2-12), 2.14±2.30:2H, m, CH -10), 2.63±2.68 :2H, m,
2
NCH2), 2.79±2.84 :2H, m, CH2N), 2.93 :1H, dd, Jˆ10.1,
8.7 Hz, CHb -2), 3.20:1H, dd, Jˆ10.1, 8.7 Hz, CHa -3),
3.77±3.86 :4H, m, CH2OCH2), 7.22 :1H, t, Jˆ7.4 Hz,
C6H5), 7.40:2H, t,
Jˆ7.7 Hz, C6H5), 7.81 :2H, d,
Jˆ7.7 Hz, C6H5), 12.39 :1H, brs, NH); dC :100.6 MHz,
CDCl3) 21.24 :t, CH2-11), 22.51 :t, CH2-12), 29.74 :t,
CH2-10), 48.78 br :t, CH2NCH2), 51.19 :d, CH-2), 67.38
:t, CH2OCH2), 70.44 :d, CH-3), 122.60, 126.03, 128.88,
139.56 :C6H5), 205.41 :s, CvS); m/z :EI, 70eV) 290:12,
M1), 257 :49), 203 :13), 202 :13), 164 :14), 152 :8), 139 :7),
126 :100), 111 :10), 77 :13%).
4.3.14. trans 2-Piperidin-1-yl-cyclopentanecarbothioic
acid benzylamide [2ip!t)]. White solid, mp 90±918C
from n-hexane [Found: C, 71.28; H, 8.70; N, 9.11; S,
10.41. C18H26N2S requires C, 71.47; H, 8.66; N, 9.26; S,
10.60%]; nmax:KBr pellet) 3050±2500 br, 2932, 2856,
2816, 1546, 1408, 1158, 472 cm21; dH :400.1 MHz,
CDCl3) 1.06±1.37 :6H, m, 3CH2), 1.52±1.71 :4H, m,
CH2-11, CH2-12), 2.00±2.08 :1H, m, CHH-10), 2.09±2.39
:m, 3H, CH2N, CHH-11), 2.49±2.52 :2H, brs, CH2N), 2.78
:1H, quartet, Jˆ9.3 Hz, CHb -2), 2.97 :1H, quartet,
Jˆ9.3 Hz, CHa-3), 4.69±4.79 :2H, m, CH2Ph), 7.29±7.38
:5H, m, C6H5), 11.43 :1H, brs, NH); dC :100.6 MHz,
CDCl3) 20.60, 21.78 :each t, CH2-11, CH2-12), 24.31, :t,
4.3.11. trans 2-Piperidin-1-yl-cyclohexanecarbothioic
acid benzylamide [2gp!t)]. White solid, mp 97±1008C
from hexane [Found: C, 72.02; H, 8.66; N, 9.03; S, 10.21.
C19H28N2S requires C, 72.10; H, 8.92; N, 8.85; S, 10.13%];
n
max:KBr pellet) 3204, 2932, 1538, 1452, 1262, 1102, 804,
698 cm21; dH :400.1 MHz, CDCl3) 1.00±1.31 :9H, m,
CH2-6, CH2-7, CH2-8, H-10ax, H-12ax, H-13ax), 1.72±1.89
:3H, m, H-11eq, H-12eq, H-13eq), 2.25 :2H, brs, CH2N),
2.40±2.51 :1H, m, H-2ax), 2.53±2.70:3H, m, CH 2N,

Â
J. G. Sosnicki et al. / Tetrahedron 57 52001) 8705±8718
8717
CH2), 25.82 :t, 2CH2), 29.24 :t, CH2-10), 49.24 :d, CH-2),
49.50br :t, CH NCH2), 50.34 :t, CH2Ph), 70.59 :d, CH-3),
127.84, 128.61, 128.75, 136.75 :C6H5), 206.30 :s, CvS);
m/z :EI, 70eV) 302 :33, M 1), 269 :53), 217 :50), 211 :25),
175 :34), 152 :13), 150 :11), 137 :16), 124 :100), 84 :39%).
4.3.18. 3-Phenyl-1,3-dipyrrolidin-1-yl-propane-1-thione
!2jpy). White solid, mp 67±698C from n-hexane [Found:
C, 71.06; H, 8.54; N, 9.90; S, 10.99. C17H24N2S requires
C, 70.79; H, 8.39; N, 9.71; S, 11.12%]; nmax:KBr pellet)
2948, 2780, 1492, 1448, 1256, 1132, 706 cm21; dH
:400.1 MHz, CDCl3) 1.40±1.52 :1H, m, CHH-30), 1.56±
1.70:1H, m, C HH-20), 1.70±183 :6H, m, 2CH2, CHH-20,
CHH-30), 2.53±2.66 :5H, m, CH2NCH2, CHH-40), 3.09 :1H,
dd, Jˆ12.0, 10.0 Hz, CHH-2), 3.24±3.30:1H, m, CH H-40),
3.37 :1H, dd, Jˆ12.0, 4.2 Hz, CHH-2), 3.45±3.52 :1H, m,
CHH-10), 3.69±3.76 :1H, m, CHH-10), 3.98 :1H, dd,
Jˆ10.0, 4.2 Hz, CH-3), 7.20±7.29 :3H, m, C6H5), 7.44
:2H, brd, Jˆ6.6 Hz, C6H5); dC :100.6 MHz, CDCl3) 23.56
:t, 2CH2), 24.10:t, CH 2-30), 26.08 :t, CH2-40), 50.74 :t, CH2-
50), 51.28 :t, CH2-2), 52.99 :t, CH2NCH2), 53.60:t, CH 2-20),
71.81 :d, CH-3), 127.39, 127.91, 127.99, 142.07 :C6H5),
196.90:s, C-1); GCMS-decomposition :retro-Michael
addition).
2
4.3.15. trans 2-Morpholin-4-yl-cyclopentanecarbothioic
acid benzylamide [2im!t)]. White solid, mp 95±978C
from n-hexane [Found: C, 67.05; H, 7.98; N, 8.92; S,
10.30. C17H24N2OS requires C, 67.07; H, 7.95; N, 9.20; S,
10.53%]; nmax:KBr pellet) 3116, 3050±2600 br, 1550, 1414,
1334, 1114, 872, 706 cm21; dH :400.1 MHz, CDCl3) 1.58±
1.75 :4H, m, CH2-11, CH2-12), 2.01±2.20 :1H, m, CHH-
10), 2.21±2.26 :1H, m, CHH-10), 2.31±2.50 :2H, m,
CH2N), 2.50±2.66 :2H, m, CH2N), 2.79 :1H, quartet,
Jˆ9.1 Hz, CHb -2), 3.05 :1H, quartet, Jˆ9.1 Hz, CHa -3),
3.19±3.41 :4H, m, CH2OCH2), 4.69±4.79 :2H, m,
CH2Ph), 7.27±7.40:5H, m, C H5), 10.74 :1H, brs, NH);
6
dC :100.6 MHz, CDCl3) 21.07 :t, CH2-11), 22.49 :t, CH2-
12), 29.73 :t, CH2-10), 48.64 br :t, CH2NCH2), 49.78 :d,
CH-2), 50.43 :t, CH2Ph), 66.77 :t, CH2OCH2), 70.47 :d,
CH-3), 128.17, 128.62, 128.96, 136.71 :C6H5), 206.24 :s,
CvS); m/z :EI, 70eV) 304 :48, M 1), 271 :42), 213 :21),
178 :27), 164 :12), 154 :19), 152 :12), 139 :17), 127 :30),
126 :100), 91 :59%).
4.3.19. 1,3-Dipiperidin-1-yl-butane-1-thione !2kp). White
solid, mp 68±708C from n-hexane [Found: C, 66.07; H,
10.57; N, 11.05; S, 12.31. C14H26N2S requires C, 66.09;
H, 10.30; N, 11.01; S, 12.60%]; nmax:KBr pellet) 2932,
2852, 2800, 1502, 1264 cm21; dH :400.1 MHz, CDCl3)
1.13 :3H, d, Jˆ6.7 Hz, CH3), 1.39±1.45 :2H, m, CH2),
1.52±1.58 :2H, m, CH2), 1.58±1.75 :6H, m, 3CH2), 2.45±
2.55 :4H, m, 2CH2N), 2.85±2.94 :1H, m, CHH-2), 3.08±
3.19 :2H, m, CHH-2, CH-3), 3.69±3.83 :2H, m, NCH2),
4.23±4.35 :2H, m, NCH2); dC :100.6 MHz, CDCl3) 15.08
:q, CH3), 24.13, 24.79, 25.41 :each t, 3CH2), 26.43 :t,
2CH2), 27.01 :t, CH2), 46.68 :t, CH2-2), 49.74 :t,
CH2NCH2), 51.29, 51.73 :each t, CH2-20, CH2-60), 60.38
:d, CH-3), 201.16 :s, C-1); GCMS-decomposition :retro-
Michael addition).
4.3.16. 3-Phenyl-3-piperidin-1-yl-1-pyrrolidin-1-yl-pro-
pane-1-thione !2jp). Yellow solid, mp 113±1158C from
n-hexane/ethyl acetate [Found: C, 71.08; H, 8.44; N, 9.18;
S, 10.60. C18H26N2S requires C, 71.47; H, 8.66; N, 9.26; S,
10.60%]; nmax:KBr pellet) 2932, 1476, 1448, 1266, 1204,
776, 712 cm21; dH :400.1 MHz, CDCl3) 1.35±1.47 :2H, m,
CH2), 1.50±1.62 :4H, m, 2CH2), 1.62±1.78 :2H, m, CH2),
1.78±1.92 :2H, m, CH2), 2.38±2.57 :4H, m, 2CH2), 2.96±
3.16 :2H, m, CH2-40), 3.42 :1H, dd, Jˆ12.7, 5.6 Hz, CHH-
2), 3.45±3.52 :1H, m, CHH-2), 3.53±3.63 :1H, m, CHH-10),
3.77±3.82 :1H, m, CHH-10), 4.21 :1H, dd, Jˆ8.1, 5.6 Hz,
CH-3), 7.20±7.30 :3H, m, C6H5), 7.36 :2H, brd, Jˆ7.0Hz,
C6H5); dC :100.6 MHz, CDCl3) 24.16 :t, CH2-20), 24.45 :t,
CH2-7), 26.15 :t, CH2-30), 26.22 :t, 2CH2), 47.71 :t, CH2-40),
50.83 :t, CH2-2), 52.21 :t, CH2NCH2), 53.77 :t, CH2-10),
71.25 :d, CH-3), 127.25, 127.91, 128.47, 140.28 :C6H5);
GCMS-decomposition :retro-Michael addition).
4.3.20. 3-Morpholin-4-yl-1-piperidin-1-yl-butane-1-thione
!2km). Yellow oil [Found: C, 61.09; H, 9.18; N, 10.75; S,
12.31. C13H24N2OS requires C, 60.89; H, 9.43; N, 10.93; S,
12.51%]; nmax:liquid ®lm) 2936, 1492, 1442, 1260,
1116 cm21
; dH :400.1 MHz, CDCl3) 1.14 :3H, d,
Jˆ6.6 Hz, CH3), 1.65±1.77 :6H, m, 3CH2), 2.56±2.60
:4H, m, 2CH2N), 2.88 :1H, dd, Jˆ13.0, 8.5 Hz, CHH-2),
3.12 :1H, dd, Jˆ13.0, 4.9 Hz, CHH-2), 3.14±3.25 :1H, m,
CH-3), 3.65±3.78 :6H, m, CH2OCH2, CH2N), 4.25±4.31
4.3.17.
3-Morpholin-4-yl-3-phenyl-1-pyrrolidin-1-yl-
:2H, m, CH2N); dC :100.6 MHz, CDCl3) 14.80:q, CH ),
3
propane-1-thione !2jm). Yellow oil [Found: C, 67.34; H,
7.94; N, 8.95; S, 10.51. C17H24N2OS requires C, 67.07; H,
7.95; N, 9.20; S, 10.53%]; nmax:KBr pellet) 2952, 2848,
2800, 1500, 1448, 1120, 880, 708 cm21; dH :400.1 MHz,
CDCl3) 1.54±1.74 :2H, m, CHH-30, CHH-20), 1.74±1.86
:2H, m, CHH-30, CHH-20), 2.52 :4H, brt, Jˆ4.1 Hz,
CH2NCH2), 2.82±2.89 :1H, m, CHH-40), 2.97 :1H, dd,
Jˆ12.5, 9.1 Hz, CHH-2), 3.31±3.42 :2H, m, CHH-2,
CHH-40), 3.47±3.58 :1H, m, CHH-10), 3.62±3.80:5H, m,
CHH-10, CH2OCH2), 4.12 :1H, dd, Jˆ9.1, 4.1 Hz, CH-3),
7.23±7.37 :3H, m, C6H5), 7.39 :2H, d, Jˆ8.2 Hz, C6H5); dC
:100.6 MHz, CDCl3) 24.09 :t, 2CH2-20), 26.09 :t, CH2-30),
47.74 :t, CH2-2), 50.80 :t, CH2-40), 51.64 :t, CH2NCH2),
53.73 :t, CH2-10), 67.16 :t, CH2OCH2), 71.08 :d, C-3),
127.57, 128.10, 128.38, 140.00 :C6H5), 197.13 :s, C-1);
m/z :EI, 70eV) 304 :11, M 1), 271 :14), 219 :20), 217
:30), 176 :100), 174 :24), 147 :14), 128 :24), 115 :17), 91
:11), 70:14%).
24.10, 25.40, 26.99 :each t, 3CH2), 46.41 :t, CH2-2),
49.03 :t, CH2NCH2), 51.30, 51.76 :each t, CH2NCH2),
60.03 :d, CH-3), 67.29 :t, CH2OCH2), 200.44 :s, CvS);
m/z :EI, 70eV) 256 :11, M 1), 223 :9), 169 :9), 154 :11),
114 :100), 84 :11%).
4.3.21. 1-Piperidin-1-yl-3-pyrrolidin-1-yl-butane-1-thione
!2kpy). Brown oil [Found: C, 65.06; H, 9.94; N, 11.85; S,
13.22. C13H24N2S requires C, 64.95; H, 10.06; N, 11.65; S,
13.34%]; nmax:liquid ®lm) 2936, 2856, 1488, 1442, 1264,
1148, 1010 cm21; dH :400.1 MHz, CDCl3) 1.19 :3H, d,
Jˆ6.0Hz, CH 3), 1.52±1.83 :10H, m, 5CH2), 2.69 :4H,
brs, 2CH2N), 2.98 :1H, dd, Jˆ13.6, 10.8 Hz, CHH-2),
3.11±3.21 :2H, m, CH-3, CHH-2), 3.75±3.86 :2H, m,
CH2N), 4.26±4.36 :2H, m, CH2N); dC :100.6 MHz,
CDCl3) 17.64 :q, CH3), 23.44 :t, 2CH2N), 24.12, 25.45,
26.90:t, 3CH 2), 47.58 :t, CH2-2), 50.68 :t, 2CH2N),
51.40, 51.72 :t, CH2NCH2), 58.96 :d, CH-3), 199.90:s,

Â
J. G. Sosnicki et al. / Tetrahedron 57 52001) 8705±8718
8718
CvS); m/z :EI, 70eV) 240:5, M 1), 207 :5), 169 :20), 154
:23), 98 :100), 97 :28), 84 :19), 69 :15), 56 :10), 41 :15%).
5. Tamaru, Y.; Harada, T.; Yoshida, Z.-i. J. Am. Chem. Soc.
1979, 101, 1316±1318.
Â
6. Sosnicki, J. G.; Liebscher, J. Synlett 1996, 1117±1118.
4.3.22. 2-Methyl-1,3-dipiperidin-1-yl-propane-1-thione
!2lp). White solid, mp 55±568C from n-hexane [Found: C,
66.08; H, 10.31; N, 10.72; S, 12.28. C14H26N2S requires C,
66.09; H, 10.30; N, 11.01; S, 12.60%]; nmax:KBr pellet)
2936, 2852, 1485, 1468, 1284, 1258, 1238 cm21; dH
:400.1 MHz, CDCl3) 1.23 :3H, d, Jˆ6.5 Hz, CH3), 1.30±
:6H, m, CH2-30, CH2-40, CH2-50), 2.30±2.41 :4H, m,
CH2NCH2), 2.44 :1H, dd, Jˆ12.7, 6.5 Hz, CHH-3), 2.77
:1H, dd, Jˆ12.7, 6.5 Hz, CHH-3), 3.26 :1H, sextet,
Jˆ6.5 Hz, CH-2), 3.72±3.88 :2H, m, CH2-60), 4.20±4.27
:1H, m, CHH-20), 4.32±4.48 :1H, m, CHH-20); dC
:100.6 MHz, CDCl3) 20.32 :q, CH3), 24.37, 24.52, 25.45
:each t, 3CH2), 26.18 :t, 2-CH2), 27.26 :t, CH2), 40.25 :d,
CH-2), 50.59, 51.87 :each t, 2NCH2), 55.43 :t, CH2NCH2),
66.34 :t, CH2-3), 207.68 :s, CvS); m/z :EI, 70eV) 254 :10,
M1), 221 :5), 170 :4), 98 :100%).
7. Hoffmann, R.; Hartke, K. Chem. Ber. 1980, 113, 919±933.
8. Yoshikawa, M.; Okaichi, Y.; Cha, B. C. Tetrahedron 1990, 46
:21), 7459±7470.
9. Kitagawa, I.; Cha, B. C.; Nakae, T.; Okaichi, Y.; Takinami,
Y.; Yoshikawa, M. Chem. Pharm. Bull. 1989, 37, 542±544.
10. Wu, J.-C.; Pathak, T.; Tong, W.; Vial, J.-M.; Remaud, G.;
Chattopadhyaya, J. Tetrahedron 1988, 44 :21), 6705±6722.
11. Wu, J.-C.; Chattopadhyaya, J. Tetrahedron 1989, 45 :3), 855±
862.
1.44 :2H, m, CH2-7), 1.46±1.60:4H, m, 2CH ), 1.62±1.82
2
 Â
12. Sosnicki, J. G.; Jagodzinski, T. S.; Liebscher, J. J. Heterocycl.
Chem. 1997, 34, 643±648.
13. Bauer, W.; Kuhlein, K. Methoden der Organischen Chemie; T.
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Â
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37, 605±607.
15. CS Chem3Dw version 5.0, 1996±1999, CambridgeSoft
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