Michael addition of nitroalkanes to nonactivated α,β-unsaturated δ-thiolactams: reactivity, diastereoselectivity, and comparison to α,β-unsaturated δ-lactams

Article abstract of DOI:10.1016/j.tet.2008.12.037

Aliphatic nitrocompounds add to nonactivated α,β-unsaturated δ-thiolactams leading to 4-nitroalkyl functionalized δ-thiolactams in good yields. The addition is a stereocontrolled process with respect to substituents at C-6, and takes place producing trans

Full text of DOI:10.1016/j.tet.2008.12.037

Tetrahedron 65 (2009) 1336–1348
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Michael addition of nitroalkanes to nonactivated
a
,b
-unsaturated -thiolactams:
d
reactivity, diastereoselectivity, and comparison to
a
,b
-unsaturated d-lactams
*
ꢀ
Jacek G. Sosnicki
Szczecin University of Technology, Institute of Chemistry and Environmental Protection, Al. Piasto´w 42, PL-71065 Szczecin, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 12 October 2008
Received in revised form 18 November 2008
Accepted 11 December 2008
Available online 24 December 2008
Aliphatic nitrocompounds add to nonactivated
a,b-unsaturated d-thiolactams leading to 4-nitroalkyl
functionalized
substituents at C-6, and takes place producing trans 4,6-disubstituted adducts in most cases. Ease of the
addition has been studied in relation to the structure of the -thiolactam acceptors, within the
FMO-theory. Comparative study with analogous -lactams has shown the advantages of -unsaturated
-thiolactams in Michael addition and indicated high prospects of these compounds in the synthesis of
4-functionalized piperidine derivatives.
d-thiolactams in good yields. The addition is a stereocontrolled process with respect to
d
d
a,b
d
Keywords:
Michael addition
Nitroalkanes
Reactivity
Ó 2008 Elsevier Ltd. All rights reserved.
Diastereoselectivity
a,b-Unsaturated d-(thio)lactams
5,6-Dihydro-1H-pyridine-2-(thi)one
4-Nitroalkylpiperidine-2-(thi)ones
FMO-theory
1. Introduction
S-nucleophiles.13 Michael addition of neutral N-nucleophiles is not
limited to -unsaturated thiolactams because the products of the
a,b
The Michael addition is one of the most important synthetic
strategies available to the organic chemists.1 Among the many
addition of amines to the open chain secondary and tertiary
a,b-
unsaturated thioamides were also successfully obtained.14
applications, conjugate addition to
a
,
b
-unsaturated
d
-lactams was
Among a broad range of nucleophiles applied to the C–C bond
formation, the addition of aliphatic nitrocompounds play a signifi-
cant role.15 In the presence of a base catalyst, the introduction of
a nitroalkyl group into a molecule allows a modification of the
carbon skeleton and further transformation of the nitroalkyl group
into many other functionalities.16
used in the synthesis of functionalized piperidines, which, due to
a wide range of biological activities,2 are still an attractive synthetic
goal.3 Although the 1,4-addition of nucleophiles to nonactivated
a,
b
-unsaturated lactams is difficult because of the electron-donat-
ing character of the nitrogen atom,4,6 the addition of organometallic
compounds is common.5 Generally, the activation of
-un-
a
,b
There are few fully described procedures in the literature, which
saturated lactams toward conjugated addition by N-acyl,6 N-tosyl,7
N-tert-butoxycarbonyl8 or C3-alkoxycarbonyl9 groups has facili-
tated these reactions. However, the additions of metalloorganic
heteronucleophiles have been reported10 while the reactions with
neutral heteronucleophiles have not.
provided adducts of a,b-unsaturated lactams with nitroalkanes.
Amongst them procedures including lactams activated by N-tert-
butoxycarbonyl (NBoc) group (Fig. 1, 1a, 1b,17a 1c17b) and only one
lactam without a typical electron-withdrawing group (Fig. 1, 1d).18
Recently, the addition of nitroalkanes to nonactivated N-(4-F-ben-
zyl)-5,6-dihydropyridine-2-one (1e) was described, as one of the
steps in the synthesis of naphthyridines, which exhibited an in-
hibition effect on HIV integrase.19 However, no yields of the addi-
tion were given.
Similar to
a,b-unsaturated d-lactams, a,b-unsaturated d-thio-
lactams are promising Michael acceptors affording 4-substituted
piperidine-2-thiones. They also form C–C bonds in the reaction
with organometallics such as alkyllithium, alkylmagnesium,11
and lithium enolates12 and moreover, in contrast to nonactivated
On the basis of our preliminary work, we have communicated that
a,
b
-unsaturated
d-lactams, they easily react with neutral N- and
aliphatic nitrocompounds can be easily added to nonactivated
unsaturated
-thiolactams in the presence of DBU as catalyst,20 yield-
ing 4-nitroalkyl -thiolactams, which due to the high acidity of the
a,b-
d
d
hydrogen atoms at C-3 can be subsequently transformed to 3,4-di-
* Tel.: þ48 91 4494798; fax: þ48 91 4494639.
E-mail address: sosnicki@ps.pl
substituted, subsequently to bicyclic (trans-fused) 2-piperidinones.20b
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.12.037

ꢀ
J.G. Sosnicki / Tetrahedron 65 (2009) 1336–1348
1337
R1, R2=H
O
OMe
R1
O
O
CH NO2
N
Boc
N
N
R
N
Boc
1a,b
O
O
N
O
R2
R1
R2
N
O
NO2
S
H2C
4F-C6H5
2a-d
1e
1c
1d
DBU cat.
+
R4
S
R= (a) COOMe,
(b) CH2OTBDPS
R4
N
H
N
H
H2C
Figure 1.
of nitroalkanes.
a,b-Unsaturated lactams successfully used as acceptors in Michael addition
R4
N
H
S
7 (trans)
N
O
O
3g-m
We have also demonstrated that 4-nitromethyl d-thiolactams are
Scheme 3.
valuable substrates in the synthesis of 4-isothiocyanato-2-
piperidinones21 and chiral pyrrolidin-2-ylidene carboxylate.20a
However, no systematic study on Michael addition of nitro-
compounds to
In continuation of our ongoing program aimed at the synthesis
of 4-nitroalkyl -thiolactams and their application in the synthesis
of polysubstituted piperidines, we now report an extended and
detailed study on the Michael addition of nitroalkanes to -un-
saturated -thiolactams. The donors selected were nitromethane
(2a), 2-nitropropane (2b), nitrocyclohexane (2c) and the thio-
lactam acceptors were NR (R¼Me, Ph; 3a, 3b), 6-allyl NR (R¼Me,
Bn, Ph; 3c–e), 6-(alkyl/aryl) NH (3g–m), and 6,N-diphenyl (3f)
substituted 5,6-dihydro-1H-pyridine-2-thiones. The broad spec-
trum of the acceptors applied allowed identification of the
factors influencing the reactivity, moreover, the application of
a,b-unsaturated d-thiolactams has been undertaken.
entries 2 and 3). However, in a few cases, when a lower tempera-
ture (approx. ꢀ20 ꢁC) was applied, 0.6 equiv of DBU was used. The
optimum conditions of the addition included the excess of the
nitrocompound, which also played the role of solvent (the excess of
reagents 2a, 2b can be recovered on reaction completion). In the
case of nitrocyclohexane, which cannot be easily removed, the
reasonable minimum amount was used together with an additional
small amount of CH3CN. Reactions described in Table 2 (entries 10–
13) as well as in Table 3 (entries 8 and 9) proved that the use of
excess of 2 as neat solution was more effective. The progress of all
reactions was monitored by TLC analysis at frequent time intervals
dependent on total reaction time. The intermediate and final con-
versions of 3 and the ratio of diastereoisomeric products were es-
timated by 1H NMR spectroscopy of the crude reaction mixtures.
Usually, the adducts were obtained in good yields and only
regioselective 1,4-addition was observed. As far as the reactivity
of acceptors is concerned, a significant influence of the type of
N-substituent on the reactivity was observed. A comparison of the
reactivities of thiolactams with the same substituents at position
C-6 and a different one at the nitrogen atom showed that the NPh
d
a,b
d
6-substituted
of the diastereoselectivity of the addition. To compare the reactivity
of -unsaturated -thiolactams with that of the analogous
unsaturated -lactams, a few runs of the additions of nitroalkanes
a,b-unsaturated d-thiolactams enabled examination
a
,b
d
a,b-
d
to the latter were performed. An attempt was made to explain
differences in the reactivity on the basis of the FMO-theory.
2. Result and discussion
group made a,b-unsaturated d-thiolactams more reactive, while the
The titled reactions have been divided into 3 groups, depending
NMe substituted derivatives exhibited the lowest reactivity (see, for
example, Table 1, entry 1 vs 2, 4 vs 6, 7 vs 8 or Table 2, entry 1 vs 2 vs
3). Taking into regard the final reaction times and the conversions of
the substrates, the sequence of NR substituents accelerating the
additions can be proposed as follows: NMe<NBn<NH<NPh. The
substituent at C-6 also influenced the reactivity. Generally,
on the substitution pattern of
a,b-unsaturated d-thiolactam. The
first group comprises NR substituted thiolactams 3a and 3b
(Scheme 1), the second includes 6,N-disubstituted thiolactams 3c–f
(Scheme 2), while 6-substituted NH thiolactams 3g–m belong to
the third group (Scheme 3). The results and conditions of the above
groups of reactions are presented in Tables 1–3, respectively.
the presence of a substituent at C-6 decreased the reactivity of
a,b-
unsaturated -thiolactams in relation to that of their 6-unsub-
d
stituted analogues, but in the case of the allyl substituent the
reduction in activity was more pronounced than that of the de-
rivatives with 6-phenyl group (see for comparison: Table 1, entry 6
vs Table 2, entries 8 and 9). This observation allows us to arrange the
following sequence of C-6 substituents strengthening the reactivity
of thiolactam acceptors: allyl<Ph<H. Both relations indicate that it
R1
R1
NO2
R1
R1
DBU cat.
CH NO2
+
N
S
N
S
R3
R3
4a-4f
2a-2c
3a,3b
is possible to control the reactivity of a,b-unsaturated d-thiolactams
Scheme 1.
by modifying the substituents at the nitrogen atom and at C-6.
With respect to diastereoselectivity, very interesting results
were obtained. Secondary nitroalkanes 2b and 2c gave exclusively
single trans 4,6-disubstituted products in all cases. Such a selectiv-
ity can be explained by the effect of steric interactions between the
bulky donor and 6-substituent (A1,3 strain).22 The same complete
diastereoselectivity was observed in the addition of secondary
nitrocompounds to 6-substituted NBoc lactams 1a, 1b.17a In the
same work, nitromethane as a small donor underwent addition
with 1:1 or 1:3 cis/trans diastereoselectivity. In our investigation
the formation of a cis/trans mixture was also observed for the ad-
dition of nitromethane (2a) to 6,N-disubstituted thiolactams 3c–f
(Table 2, entries 1–5). However, for 6-allyl acceptors the quantity of
trans products 5c–e grew in the sequence NMe<NBn<NPh (Table 2,
entries 1, 2, and 3, respectively). Moreover, NPh derivative 3e with
Generally, the Michael additions of nitroalkanes to
a,b-un-
saturated -thiolactams were carried out at room temperature and
d
were catalyzed with 0.1–0.3 equiv of DBU. A greater amount of the
catalyst accelerated the reaction but simultaneously diminished
the yields (see, for example, Table 1, entries 2 and 3 or Table 3,
R1
R1
R1
R1
NO2
NO2
R1
R1
DBU cat.
+
+
CH NO2
R4
N
S
N
R3
5
S
R4
R4
N
R3
6
S
R3
3c-f
2a-c
Scheme 2.

ꢀ
J.G. Sosnicki / Tetrahedron 65 (2009) 1336–1348
1338
Table 1
Reaction conditions, yields of 4 obtained in the addition reactions of 2 with thiolactams 3a, 3b (according to Scheme 1)
Entry
2a–c
R1
3
R3
Equiv of 2
(equiv of CH3CN)
Temp [ꢁC]
Time [h]
Equiv of DBU
Conversion
4
Isolated yield
4 [%]
of 3a [%]
1
2
3
2a MeNO2
H
a
b
b
Me
Ph
Ph
40 neat
40 neat
40 neat
rt
rt
rt
30
1
0.5
0.2
0.2
0.6
99
>99
99
a
b
b
90
91
50
4
5
6
2b i-PrNO2
CH3
a
a
b
Me
Me
Ph
15 neat
40 neat
15 neat
rt
18
2
0.5
0.2
0.6
0.2
98
97
>99
c
c
d
73
86
82
ꢀ20
rt
7
8
2c c-HexNO2
–(CH2)5–
a
b
Me
Ph
1.5 (6.0)
1.5 (6.0)
rt
rt
4
2
0.2
0.2
>99
>98
e
f
96
72
a
Estimated using 1H NMR spectroscopy.
a
6-allyl substituent produced
a
more trans adduct (trans/
To complete the above part of the study it should be noted that
selective trans addition with respect to the 6-butyl group (in 3h)
was also noted to occur with nitroethane 2d because trans 4,6-di-
substituted product 7p was obtained (Table 3, entry 20). However,
because of the presence in 2d of a stereogenic carbon atom as
a neighbor to NO2, a mixture of diastereomers was formed in this
cis¼86:14; Table 2, entry 3) than NPh thiolactam 3f with a larger 6-
Ph substituent (trans/cis¼67:33; Table 2, entry 4). A decrease in the
temperature of the latter reaction did not change significantly the
trans/cis product distribution (Table 2, entry 5). These results in-
dicated that apart from steric effects, electronic effects also influ-
enced the stereoselectivity of the addition. The latter is especially
pronounced in the conjugation of the N-phenyl ring with the thio-
amide group: a large substituent at C-6 (Ph) disturbed the con-
case. Besides, for practical reasons,
easily obtainable and isomerizable upon treatment with DBU,25 and
the precursors of -unsaturated -thiolactams 3a–e can be di-
b,g-unsaturated thiolactams as
a,
b
d
jugation and changed the
p-electron distribution in the PhNCS
rectly used in the studied addition of nitroalkanes instead of 3a–e
moiety. In this context, it could be assumed that the highest dia-
stereoselectivity in the case of the 6-allyl and NPh substituted
thiolactam is the effect of the best compromise between steric and
electronic effects.
without significant changes in the results.
For the sake of comparison, we examined the reactivity of
a,b-
unsaturated -lactams as analogues of the -thiolactams studied.
d
d
Thus, a few runs of additions of nitroalkanes to the selected lactams
were performed (Scheme 4, Table 4). The reactions were carried out
Interesting and surprising was the fact that 6-substituted NH
thiolactams 3g–m gave exclusively the trans product with nitro-
methane, irrespective of the size of the substituent at C-6, in-
dicating NH as the group responsible for stereocontrolled addition.
The high acidity of NH protons in secondary thioamides23 and the
synthetically proved interaction between chiral thioureas and
nitrocompounds,24 prompted us to assume that during the reaction
course the hydrogen bond between the NH of the thiolactam and
O2NR (or their anionic form) is responsible for complete diaster-
eoselectivity of the addition (Scheme 3).
applying
zation of
states of the mixtures of
d
a
b,g
,
b
-unsaturated
-isomers with DBU in CH3CN. After the equilibrium
-(1(a)) and -unsaturated (1(b))
-lactams were reached in 4 days (Table 4, Scheme 4, Path A), the
d-lactams obtained by previous isomeri-
b,
g
a,b
solvent was removed and to the residue appropriate nitroalkanes
were added (Scheme 4, Path B). The results supported low re-
activity of lactams relative to that of their activated derivatives
(Fig. 1) or their thio analogues (Schemes 1–3). Two of the four re-
actions performed gave no positive result at all. The addition of
Table 2
Reaction conditions, yields, and ratio of 5:6 obtained in the addition reactions of 2 with thiolactams 3c–f (according to Scheme 2)
Entry
1
2
R1
3
c
R3
R4
Equiv of 2
(equiv of CH3CN)
Temp [ꢁC] Time Equiv of DBU Conversion. of 3 [%]; 5:6 (R1) 5:6 Ratioa Isolated
(ratio of 3:5þ6)a
yield 5, 6 [%]
2a MeNO2
H
Me Allyl 180 neat
rt
rt
3 d
6 d
10 d
16 d
18 d
1 d
2 d
3 d
24 h
18 h
29 h
0.2
0.2
(50:50)
(35:65)
(28:72)
(21:79)
80 (21:79)
(18:82)
(4:96)
99 (0:100)
99
a
w50:50
w50:50
w50:50
w50:50
w50:50
w60:40
w60:40
w60:40
86:14
57
2
d
Bn
Allyl 180 neat
Allyl 180 neat
Ph
Ph
b
95
72
79
80
3
4
5
e
f
f
Ph
Ph
Ph
rt
rt
ꢀ20
0.2
0.2
0.6
c
d
d
180 neat
60 neat
>99
96
67:33
68:32
6
7
8
9
2b i-PrNO2
CH3
c
d
e
f
Me Allyl 10 neat
rt
rt
rt
rt
20 h
3 h
2.5 h 0.3
0.3
0.3
90
e
f
g
h
>99:1
>99:1
>99:1
>99:1
69
90
88
75
Bn
Ph
Ph
Allyl 10 neat
Allyl 10 neat
>99
>99
>99
Ph
20 neat
1 h
0.3
10
2c c-HexNO2 –(CH2)5–
c
Me Allyl 1.5 (6.0)
rt
42 h
7 d
12 d
4 d
8 d
7 d
3 d
30 h
2.5 h 0.2
0.2
(1:0.34)
(1:0.37)
20 (1:0.37)
(1:1.3)
49 (1:1.3)
57
97
97
98
i
>99:1
ca. 9
11
c
Me Allyl 4.0 neat
rt
0.2
i
j
j
k
l
>99:1
>99:1
>99:1
>99:1
>99:1
38
39
62
65
63
12
13
14
15
d
d
e
f
Bn
Bn
Ph
Ph
Allyl 1.5 (6.0)
Allyl 4.0 neat
Allyl 1.5 (6.0)
rt
rt
rt
rt
0.2
0.2
0.2
Ph
1.5 (6.0)
a
Estimated using 1H NMR spectroscopy.

ꢀ
J.G. Sosnicki / Tetrahedron 65 (2009) 1336–1348
1339
Table 3
Reaction conditions, yields of 7 obtained in the addition reactions of 2 with thiolactams 3k–m (according to Scheme 3)
Entry
2a–d
R1, R2
3
R4
Equiv of 2
Temp [ꢁC]
Time [h]
Equiv of DBU
Conversion of 3a
7
Isolated
(equiv of CH3CN)
yield 7 [%]
1
2
3
4
5
6
7
2a MeNO2
H, H
g
h
h
i
j
k
l
Et
26 neat
30 neat
60 neat
25 neat
30 neat
30 neat
25 neat
rt
rt
rt
rt
rt
rt
rt
4.5
3
1
0.2
0.2
0.5
0.2
0.2
0.2
0.3
>99
99
99
>99
>99
94
a
b
b
c
d
e
f
80
88
80
79
78
40
64
n-Bu
n-Bu
n-Hex
t-Bu
Ph
5
24
48
2.5
Allyl
>99
8
9
2b i-PrNO2
CH3, CH3
g
g
h
h
i
j
k
m
Et
Et
10 neat
3 (10)
10 neat
3 (10)
10 neat
9 neat
10 neat
10 neat
rt
rt
rt
1.5
2.0
5
20
1.5
1.5
1
0.1
0.1
0.1
0.6
0.1
0.3
0.2
0.3
>99
>99
>99
98
>99
>99
95
g
g
h
h
i
j
k
l
90
80
88
77
73
86
44
10
11
12
13
14
15
n-Bu
n-Bu
n-Hex
t-Bu
Ph
ꢀ20
rt
rt
rt
rt
sec-Bu
1
>99
72 (50:50)b
16
17
18
19
2c c-HexNO2
2d EtNO2
–(CH2)5–
H, CH3
g
h
h
i
Et
1.5 (10)
1.6 (6)
2 (6)
rt
rt
2.5
3
17
4
0.1
0.1
0.6
0.1
>99
96
>99
>99
m
n
n
76
76
83
80
n-Bu
n-Bu
n-Hex
ꢀ22
1.5 (10)
rt
o
20
h
n-Bu
60 neat
rt
4.5
0.2
>99
p
86 (53:47)b
Estimated using 1H NMR spectroscopy.
Mixture of diastereomers.
a
b
nitromethane to NH lactam 1f(b) gave selectively the trans adduct
8f (probably via the same NH/O2N hydrogen bond assistance as
for thiolactams 3g–m) in 17% yield together with 60% conversion of
O transformation of 4-nitrothiolactams, e.g., by the treatment with
dimethyl dioxirane26 generated in situ (Scheme 4). To illustrate the
above synthetic possibilities 4-nitroalkyl
7h were converted into the corresponding
(Scheme 4, Path C; Table 4).
d
-thiolactams 4f, 5f, 7b,
the unsaturated
d-lactam 1f(a). The best result was obtained for
d-lactams in good yields
NPh lactam 1i, which produced adduct 8i in 37% yield (50% con-
version of the substrate).
An attempt at rationalization of the experimentally observed
relations between the structures of -(thio)lactams and their
d
reactivity toward addition was made in terms of the frontier
molecular orbital (FMO) theory. Because the LUMO energy of the
acceptor determines its reactivity in the Michael addition, which is
the greater with a decrease in energy,1a the LUMO energies of
compounds 3 and 1 were calculated. The semiempirical method
PM327 was selected for calculation because this method didn’t
require time-consuming calculations and gave reasonable results
i
CH3CN
1f-1i(a)
+
R4
N
O
R4
N
O
Path A
R3
R3
1f-1i(b)
1f-1i(a)
i = DBU (1 equiv.), 4 days
2
neat
Path B
i
in the explanation of the reactivity of linear a,b-unsaturated thio-
R1
R1
R1
R1
amides.14 The calculated energies of LUMOs of the sets of
compounds are presented in graphical form in Figure 2. In or-
der to complete the above data, the LUMO energies of the
compounds not synthesized in this study were also calculated.
For 6-substituted derivatives the average values of LUMO energy
for quasi 6-axial and 6-equatorial structures were given.
NO2
S
O O
NO2
Path C
R4
N
R4
N
O
R3
R3
8f-i
4f, 5f, 7b, 7h
The main conclusion from the above presented results is that
the LUMO energies change in parallel to the experimentally ob-
served reactivity of the acceptors. Generally, the LUMO energies of
thiolactams are much lower than those of lactams, which makes
the former much more reactive. In both sets of compounds some
further structural dependence on the LUMO level parallel to ex-
perimental results should be pointed out. The most striking is that
Scheme 4.
Finally, ending the synthetic part of this study, we want to show
that the above ineffective, direct synthesis of 4-nitroalkyl -lactams
from -unsaturated -lactams can be replaced with a two-step
sequential synthesis including an effective addition of nitro-
d
a
,
b
d
compounds to a,b-unsaturated d-thiolactams and subsequent S to
Table 4
Synthesis of 4-nitroalkylpiperidin-2-ones 8 (according to Scheme 4)
Entry
1(a)
R1
R3
R4
Ratio of 1(b):1(a)
(Path A)
Equiv (2)
8
Yield 8a [%] (Path B)
Conv. of 1(a)þ1(b)
(Paths A and B) [%]
Yield 8 [%]
(Path C)
Substrates
used (Path C)
1
2
3
4
1f(a)
1g(a)
1h(a)
1i(a)
H
Me
Me
–(CH2)5–
H
H
Bn
Ph
Bu
Bu
Allyl
H
7:3
7:3
8:2
9:1
40 (2a)
20 (2b)
20 (2b)
3 (2c)
f
17
60
93b (82)c
96b (84)c
93b (83)c
87b (63)d
7b
7h
5f
g
h
i
Traces
Traces
37
w0
w0
50
4f
a
Yield assigned by 1H NMR spectroscopy and calculated with respect to 1f–1i(a).
Isolated yields.
Overall yields calculated with respect to b,g-unsaturated isomers of 3.
Overall yield calculated with respect to 3.
b
c
d

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J.G. Sosnicki / Tetrahedron 65 (2009) 1336–1348
1340
LUMO
1
2
3
4
5
6
[eV]
-0.03
0.00
-0.07
-0.09
-0.13
-0.08
-0.13
R=Bu, (X=O)
1h(b)
R=Bu, (X=O) 1f(b)
R=Me, X=O
R=H, X=O
N
O
-0.19
R=Ph, (X=O)
R=Ph, (X=O)
-0.27
-0.31
R=Ph, X=O 1i(b)
R=Boc, X=O
-0.37
-0.40
-0.45
(R=Me)
(R=Ph)
N
O
N
N
-0.55
(R=Boc) 1c
-0.85
OMe
O
O
N
R
X
N
R
N
R
X
R
N
H
X
N
O
Ph
N
Ph
X
-1.00
1d
R=Me, X=S 3c
R=Bn, X=S 3d
-1.11
-1.11 R=Bu, (X=S) 3h
-1.13 R=Ph, (X=S) 3k
-1.14
-1.21
R=Me, X=S 3a
-1.13
-1.23
-1.23
R=H, X=S
R=Ph, (X=S) 3f
R=Ph, X=S 3e
-1.39
R=Ph, X=S 3b
Figure 2. PM3 calculated energies of LUMO orbitals of a,b-unsaturated d-thiolactams and lactams.
the presence of a phenyl ring at nitrogen decreases the energy of
LUMO relative to that of NH (
¼0.14–0.18 eV) and by even more
relative to that of NMe derivatives (
¼0.19–0.25 eV) because of the
increased with decreasing contribution of the aromatic rings. This
result implies that the presence of the chinoline ring in lactam 1d
determines the low LUMO energy and is responsible for its in-
creased reactivity.
D
D
phenyl group conjugation. The substituent at C-6 increases the
LUMO energy of acceptors in comparison to that of 6-unsubstituted
ones, which makes the 6-substituted derivatives less reactive. The
energies of LUMOs of NBoc lactams varied from ꢀ0.31 eV to
ꢀ0.55 eV (1c) are lower than that of NH and NR derivatives. Dif-
ferences in the LUMO energies of both lactams explain the activa-
tion role of NBoc group in Michael addition (Fig. 2). FMO’s theory
approach allowed also better understanding of the addition of
nitroalkane to lactam 1d,18 which is not activated by standard
groups. Thus, good reactivity of lactam 1d is reflected by low energy
of LUMO (ꢀ0.85 eV, Fig. 2, Column 6).
The structures of all compounds were elucidated with the aid of
1D NMR (1H,13C, 13C-DEPT-135) and 2D NMR (1H,1H COSY, 13C,1H
COSY spectroscopy). The configurations at C-4 and C-6 were
established by tentative conformational analysis assuming the
chair-like conformation of the piperidine-2-thione ring, where
hydrogen atoms were denoted as equatorial or axial. The configu-
rational and conformational analyses were based on the values of
J-coupling constants found in 1H NMR and the relation between
J and H,H dihedral angles28 and cross couplings peaks found in
1H,1H COSY spectra. The obtained structures were supported with
the through-space distances derived from the 1H,1H NOESY for
compounds 5d, 5e, and 7k. Since the routine 1H NMR spectra did
not allow direct determination of the coupling constants in some
cases, the resolution enhancement by digitalized filtering was ap-
plied to obtain these data.
In order to identify the element of lactam 1d responsible for the
low LUMO energy, the calculations were performed for the two
hypothetical structures obtained as a result of removal of the
benzene and pyridine rings from the parent compound 1d. The
LUMO energy values obtained for these hypothetical structures
(a)
R2
(b)
NO2
Hax
Hax
Heq
S
Heq
R2
Ph
O2N
Heq
S
;
N
Heq
R1
HeqHax
N
N
R1
S
Hax
Heq
H
ax H
Ph
N
H
S
Hax
5d (R1=Ph, R2=CH2NO2)
5e (R1=CH3, R2=C(CH3)2NO2)
NOE
7k
Figure 3. (a) Fragmental 1H NMR spectra of 5h. (b) Diagnostic NOE effects found in 1H,1H NOESY of 5d, 5e, and 7k.

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J.G. Sosnicki / Tetrahedron 65 (2009) 1336–1348
1341
Based on the above analysis, all main products of 4,6-di-
substituted piperidine-2-thiones were established as trans isomers,
where 4- and 6-substituents are equatorially and axially oriented,
respectively. The 1H NMR spectrum of 5h with nonoverlapped
multiplets best illustrates the analysis performed (Fig. 3, upper). In
the 1H NMR spectrum of 5h one of two geminal protons at C-3 gives
a characteristic doublet of doublets (dd) at 3.05 ppm with two large
coupling constants (JHax-3–Heq-3¼18.9 Hz and JHax-4–Hax-3¼11.1 Hz),
indicating its axial position (CHax-3). The second hydrogen atom at
C-3 appears as doublet of multiplets (dm) with one large geminal
and a few small coupling constants and is concluded as CHeq-3.
These two multiplets and dddd at 2.7 ppm (J 12.9, 11.1, 6.2, 3.2 Hz),
which is of CHax-4 origin indicated the equatorial position of
4-nitroalkyl group. It should be noted that the nitromethyl group at
C-4 adopts an equatorial position in all 4-monosubstituted
compounds. The triplet of doublets at 2.22 ppm (JHax-5-Hax-4¼12.9,
TMS was used as internal reference. Two-dimensional spectra were
acquired using standard Bruker software. In the 1H–1H NOESY ex-
periments a mixing time of 0.75 s was used. Enhanced resolution
spectra were obtained by using Bruker software. Yields determined
by 1H NMR spectra were obtained by using 1,3,5-trimethoxy-
benzene as internal reference. Purity and molecular mass de-
terminations were carried out by gas chromatography–mass
spectrometry (GC–MS) on a Hewlett–Packard instrument model HP
6890 equipped with a mass detector HP 5973. The analytical pro-
cedure was developed on 30 m long capillary column, 0.2 mm in
diameter, with methylsiloxane modified with phenyl groups (5%
Ph, Me siloxane) in the 0.25 mm active phase layer. Silica gel (0.04–
0.063 mm, Merck) was used for preparative column chromatogra-
phy. Infrared spectra were taken with a Specord M80 instrument.
Elemental analyses were performed on EuroEA 3000 series, Euro-
Vector CHNS-O Elemental Analyzer. HRMS analyses were per-
formed on Spektrometr AMD Intectra Mass AMD 402. Melting
points were determined on a Boetius hot stage apparatus. Thio-
lactams 3a,b, 3f29 and 3c–e25 were obtained according to the
methods described earlier.
JHax-5-Heq-5¼12.9, J
¼5.4 Hz) assigned to CHax-5 and the
Hax-5-Heq-6
doublet of doublets at 5.2 ppm (dd, J 5.4, 2.2 Hz) assigned to CH-6eq
supported the axial position of the substituent at C-6. The above
pattern of splitting appears in the 1H NMR spectra of all trans iso-
mers with small deviations in the case of 4-nitromethyl derivatives,
even when some signals are overlapped. The cross couplings found
in NOESY spectra of 5c, 5d, and 7k supported the proposed con-
figuration and conformation of 4,6-disubstituted derivatives
(Fig. 3).
For the sake of comparison, the isolated cis 4,6-disubstituted
isomer 6d exhibited the same coupling constants pattern for
CHeq-3 (CHax-3 is overlapped) as for the trans isomers, indicating
the equatorial position of the 4-nitromethyl group. However, the
CHax-5 proton, which gave a doublet of triplets (dt) with three
large coupling constants (JHax-5–Hax-4¼13.9, JHax-5–Heq-5¼13.9, and
JHax-5–Hax-6¼ca. 11.2 Hz) and CHeq-5 proton giving ddd (J 13.9, 5.6,
3.0 Hz) unequivocally indicated the equatorial position of the C-6
substituent in this case.
4.2. Addition of nitroalkanes to
thiolactams. General procedure
a,b-unsaturated d-
a,b-Unsaturated d
-thiolactam 3y (1.0 mmol) was dissolved in
a solution of nitroalkane,z and a catalytic amountof DBU (Tables 1–3)
was added. In some cases, a small amount of acetonitrile was also
added (Tables 1–3). The mixture was stirred at the temperature and
time indicated in Tables 1–3. When the reaction was complete, 5 ml
of concentrated NH4Cl was added and the solution was extracted
twice with ethyl acetate (2ꢂ50 ml). The organic phase was dried
(MgSO4), filtered, and concentrated in vacuo. The crude product was
purified by column chromatography on silica (n-hexane/ethyl
acetate¼8:2 then 7:3)x and crystallized from the appropriate
solvents.
3. Conclusion
4.2.1. 1-Methyl-4-nitromethylpiperidine-2-thione (4a)
In conclusion, the efficient synthesis of 4-nitroalkyl-piperidino-
Pale yellow oil (169 mg, 90%). IR (thin film):
1348, 1268, 1232, 1110, 1072, 796 cmꢀ1 1H NMR (400.1 MHz,
CDCl3):
n
¼2960, 2916, 1548,
2-thiones by Michael addition of nitroalkanes to
a,b-unsaturated
;
d
-thiolactams nonactivated by electron-withdrawing groups was
d
¼1.68–1.81 (1H, m, CHHax-5), 2.14 (1H, dm, J ca. 11.4 Hz,
described. For 6-substituted derivatives, highly diastereoselective
additions were observed, for steric and electronic reasons. Hydro-
gen bond assistance was found to be responsible for complete
diastereoselective addition to NH derivatives irrespective of the
CHHeq-5), 2.65–2.75 (2H, m, CHH-3, CH-4), 3.25–3.36 (1H, m, CHH-
3), 3.48 (3H, s, NCH3), 3.57 (1H, ddd, J ca.14.4,10.4, 4.9 Hz, CHHax-6),
3.62 (1H, ddd, J ca. 14.2, 6.2, 3.3 Hz, CHHeq-6), 4.30 (1H, dd, J 12.7,
7.9 Hz, CHHNO2), 4.40 (1H, dd, J 12.7, 5.5 Hz, CHHNO2); 13C NMR
size of donor and substituent at C-6. The LUMO energy of
a,b-un-
(100.6 MHz, CDCl3):
d
¼26.2 (CH2-5), 31.4 (CH-4), 43.1 (NCH3), 44.0
saturated -thiolactam acceptors, dependent on the type of sub-
d
(CH2-3), 51.8 (CH2-6), 78.6 (CH2NO2), 196.0 (C-2); GC–MS (EI,
stituents at N-1 and C-6 is the factor influencing the reactivity of
the addition. The direction of activation can be used to design new
reactive acceptors. As revealed from a comparative study, the
Michael additions of nitroalkanes to the corresponding lactams are
less effective because of their low reactivity (high energy of LUMO).
However, the successful synthesis of 4-nitroalkylpiperidin-2-ones
ꢃ
70 eV): m/z¼188 (100, Mþ ), 154 (13), 142 (10), 128 (16), 99 (12), 82
(8), 69 (12), 55 (22), 44 (32), 42 (23), 41 (28); HRMS (EI) for
C7H12N2O2S: calculated 188.0620, found 188.0619.
4.2.2. 4-Nitromethyl-1-phenylpiperidine-2-thione (4b)
Colorless solid (228 mg, 91%), mp 116–118 ꢁC from n-hexane/
from analogous d-thiolactams indicated the way to overcome this
ethyl acetate. IR (KBr pellet):
1372, 1348, 1334, 1232, 1196, 1148, 1036, 868, 764, 740, 698 cmꢀ1
1H NMR (400.1 MHz, CDCl3):
n
¼2948, 2924, 1556, 1498, 1440, 1410,
problem. Finally, it should be emphasized that because of combined
presence of both highly convertible nitroalkyl and thiolactam
groups in 4-nitroalkylpiperidine-2-thione, the compounds
obtained stands as valuable precursors in prospective synthesis of
piperidine derivatives.
;
d
¼1.81–1.94 (1H, m, CHHax-5), 2.23
(1H, dm, J ca. 12.5 Hz, CHHeq-5), 2.81–2.91 (2H, m, CH-4, CHHeq-3),
3.45 (1H, ddd, J 12.8, 9.5, 2.0 Hz, CHHax-3), 3.72–3.85 (2H, m, CH2-
6), 4.38 (1H, dd, J 12.6, 7.7 Hz, CHHNO2), 4.46 (1H, dd, J 12.6, 5.5 Hz,
4. Experimental
4.1. General
y
Instead of 3 their
b
,
g
-unsaturated isomers can be used.
z
In the case of 2-nitropropane an argon atmosphere was used in order to pre-
vent amide formation.
All 1H and 13C NMR spectroscopic measurements were per-
formed on a Bruker DPX 400 spectrometer equipped with a 5 mm
1H/BB-inverse probehead, operating at 400.13 and 100.62 MHz.
x
If 4-nitroalkyl d-thiolactams are hardly soluble, a mixture of eluent with a few
ml of DMSO was used for dissolving the crude product and a so prepared solution
was submitted for chromatographic column.

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J.G. Sosnicki / Tetrahedron 65 (2009) 1336–1348
1342
CHHNO2), 7.21 (2H, d, J 7.2 Hz, C6H5), 7.40 (1H, t, J 7.4 Hz, C6H5), 7.48
(2H, d, J 7.4 Hz, C6H5); 13C NMR (100.6 MHz, CDCl3):
31.5 (CH-4), 44.6 (CH2-3), 53.9 (CH2-6), 78.8 (CH2NO2), 126.1, 128.3,
br d, J ca. 13.5 Hz, CHH), 2.91 (1H, dd, J 17.8, 12.0 Hz, CHHax-3), 3.46
(1H, ddd, J 17.8, 4.7, 2.3 Hz, CHHeq-3), 3.67 (1H, ddd, J 13.5, 12.0,
4.5 Hz, CHHax-6), 3.79 (1H, ddd, J 13.5, 5.5, 2.8 Hz, CHHeq-6), 7.18
(2H, dm, J ca. 8.0 Hz, C6H5), 7.37 (1H, tt, J ca. 7.6, ca. 1.2 Hz, C6H5),
d¼26.4 (CH2-5),
129.9, 146.2 (C6H5), 198.8 (C-2); GC–MS (EI, 70 eV): m/z¼250 (63,
ꢃ
M
þ ), 249 (100), 215 (15), 188 (14), 175 (38), 149 (16), 106 (11), 77
7.47 (2H, t, J ca. 8.0 Hz, C6H5); 13C NMR (100.6 MHz, CDCl3):
d¼22.1,
(20). Anal. Calcd for C12H14N2O2S: C, 57.58; H, 5.64; N, 11.19; S,
12.81%. Found: C, 57.54; H, 5.59; N, 11.23; S, 12.88%.
22.3 (2ꢂCH2), 24.2 (CH2-5), 24.7, 30.1, 32.4 (3ꢂCH2), 41.5 (CH-4),
43.0 (CH2-3), 54.8 (CH2-6), 93.5 (CNO2), 126.1, 128.2, 129.9, 146.3
ꢃ
(C6H5), 200.0 (C-2); GC–MS (EI, 70 eV): m/z¼318 (<1, Mþ ), 271
4.2.3. 1-Methyl-4-(1-methyl-1-nitroethyl)piperidine-2-thione (4c)
Colorless solid (158 mg, 73%), mp 112–114 ꢁC from n-hexane/
(84), 270 (100), 268 (29), 256 (34), 238 (30), 207 (27), 190 (11), 176
(9), 162 (15), 106 (20), 91 (14), 77 (32). Anal. Calcd for C17H22N2O2S:
C, 64.12; H, 6.96; N, 8.80; S, 10.07%. Found: C, 64.18; H, 7.09; N, 8.82;
S, 10.16%.
ethyl acetate. IR (KBr pellet):
n
¼2944, 1534, 1472, 1404, 1380, 1352,
1324, 1244, 1128, 1116, 1076 cmꢀ1
;
1H NMR (400.1 MHz, CDCl3):
d
¼1.55 (3H, s, CH3), 1.58 (3H, s, CH3), 1.66 (1H, qd, J 11.9, 5.8 Hz,
CHHax-5), 1.85 (1H, dm, J ca. 12.0 Hz, CHHeq-5), 2.51 (1H, tdd, J 12.0,
4.4, 3.1 Hz, CHax-4), 2.68 (1H, dd, J 17.6, 12.1 Hz, CHHax-3), 3.22 (1H,
ddd, J 17.6, 4.1, 3.1 Hz, CHHeq-3), 3.46 (3H, s, NCH3), 3.51 (1H, ddd, J
4.2.7. trans (T) and cis (C) 6-Allyl-1-methyl-4-nitromethyl-
piperidine-2-thione (5a:6a)
Unseparable mixture of diastereoisomers (T/C¼1:1). Pale yellow
13.6, 12.1, 4.6 Hz, CHHax-6), 3.61 (1H, ddd, J 13.6, 5.8, 2.0 Hz, CHHeq
-
oil (130 mg, 57%). IR (thin film):
n
¼3076, 2964, 1546, 1512, 1376 br,
6); 13C NMR (100.6 MHz, CDCl3):
d
¼21.2 (CH3), 24.1 (CH3), 24.3
1112 br, 1076, 924 cmꢀ1
;
1H NMR (400.1 MHz, CDCl3):
d¼1.55 (1H,
(CH2-5), 40.6 (CH-4), 42.4 (CH2-3), 42.9 (NCH3), 52.8 (CH2-6), 90.0
ddd, J 13.5, 12.2, 10.1 Hz, CHHax-5 (C)), 1.70 (1H, tdd, J ca. 13.3, 5.6,
0.7 Hz, CHHax-5 (T)), 2.11 (1H, dq, J 13.4, 2.3 Hz, CHHeq-5 (T)), 2.18
(1H, ddt, J 13.5, 6.7, 3.5 Hz, CHHeq-5 (C)), 2.27–2.38 (1H, m, 6-CHH
(T)), 2.45–2.65 (5H, m, CHax-4 (C), CHHax-3 (C), 6-CH2 (C), 6-CHH
(T)), 2.70 (1H, ddd, J 18.1, 11.0, 0.9 Hz, CHHax-3 (T)), 2.78–2.91 (1H,
m, CHax-4 (T)), 3.28–3.38 (2H, m, 2ꢂCHHeq-3 (C, T)), 3.47 (3H, s,
NCH3 (C)), 3.49 (3H, s, NCH3 (T)), 3.65–3.72 (1H, m, CHeq-6 (T)),
3.72–3.79 (1H, m, CHax-6 (C)), 4.21–4.28 (2H, m, 2ꢂCHHNO2 (T, C)),
4.36 (1H, d, J 12.6 Hz, CHHNO2 (T)), 4.37 (1H, d, J 12.8 Hz, CHHNO2
(C)), 5.16–5.25 (4H, m, 2ꢂ]CH2 (T, C)), 5.54–5.65 (1H, m, ]CH (C)),
ꢃ
(CNO2), 196.7 (C-2); GC–MS (EI, 70 eV): m/z¼216 (92, Mþ ), 188 (15),
170 (100), 128 (22), 102 (8), 55 (61). Anal. Calcd for C9H16N2O2S: C,
49.97; H, 7.46; N, 12.95; S, 14.82%. Found: C, 50.03; H, 7.49; N, 13.02;
S, 14.89%.
4.2.4. 4-(1-Methyl-1-nitroethyl)-1-phenylpiperidine-2-thione (4d)
Colorless solid (228 mg, 82%), mp 195–197 ꢁC from n-hexane/
ethyl acetate. IR (KBr pellet):
n
¼1534, 1504, 1492, 1344, 1148, 772,
700 cmꢀ1 1H NMR (400.1 MHz, CDCl3):
;
d
¼1.62 (3H, s, CH3), 1.65
(3H, s, CH3),1.85 (1H, dtd, J 13.2,11.4, 5.7 Hz, CHHax-5),1.96 (1H, dm,
J ca. 13.2 Hz, CHHeq-5), 2.72 (1H, tdd, J ca. 11.6, 4.6, 3.7 Hz, CHax-4),
2.87 (1H, dd, J 17.6, 11.9 Hz, CHHax-3), 3.41 (1H, ddd, J 17.6, 4.6,
2.5 Hz, CHHeq-3), 3.73 (1H, ddd, J 13.6, 11.3, 4.6 Hz, CHHax-6), 3.81
(1H, ddd, J 13.6, 5.7, 3.8 Hz, CHHeq-6), 7.20 (2H, dm, J ca. 8.3 Hz,
C6H5), 7.38 (1H, tt, J ca. 7.4, ca.1.3 Hz, C6H5), 7.45–7.51 (2H, m, C6H5);
5.64–5.74 (1H, m, ]CH (T)); 13C NMR (100.6 MHz, CDCl3):
d¼27.5
(CH-4 (T)), 28.8 (CH2-5 (T)), 30.3 (CH-4 (C)), 32.0 (CH2-5 (C)), 36.9
(6-CH2 (T)), 38.6 (6-CH2 (C)), 41.0 (NCH3 (C)), 43.0 (NCH3 (T)), 43.7
(CH2-3 (T)), 45.0 (CH2-3 (C)), 60.9 (CH-6 (C)), 61.3 (CH-6 (T)), 78.8
(CH2NO2 (T, C)), 119.9 (]CH2 (T)), 120.6 (]CH2 (C)), 130.9 (]CH
(C)), 132.4 (]CH (T)), 196.0 (C-2 (T)), 198.0 (C-2 (C)); GC–MS (EI,
ꢃ
13C NMR (100.6 MHz, CDCl3):
5), 39.9 (CH-4), 42.2 (CH2-3), 53.7 (CH2-6), 89.2 (CNO2), 125.1, 127.2,
d
¼20.2 (CH3), 23.5 (CH3), 23.6 (CH2-
70 eV): (C) m/z¼228 (27, Mþ ), 198 (7), 187 (15), 140 (12), 126 (100),
ꢃ
84 (22), 67 (11), 55 (12), 41 (19); (T) m/z¼228 (30, Mþ ), 198 (6), 187
128.9, 145.2 (C6H5), 198.7 (C-2); GC–MS (EI, 70 eV): m/z¼278 (78,
(13), 140 (15), 126 (100), 84 (25), 67 (11), 55 (12), 41 (21); HRMS (EI)
for C10H16N2O2S: calculated 228.0932, found 228.0929.
ꢃ
M
þ ), 277 (100), 248 (8), 232 (63), 230 (35), 217 (9), 188 (41), 175
(11), 150 (9), 119 (12), 106 (35), 104 (18), 77 (39), 55 (53), 41 (19).
Anal. Calcd for C14H18N2O2S: C, 60.40; H, 6.52; N, 10.06; S, 11.52%.
Found: C, 60.33; H, 6.59; N, 10.02; S, 11.56%.
4.2.8. trans (T) and cis (C) 6-Allyl-1-benzyl-4-nitromethyl-
piperidine-2-thione (5b:6b)
Unseparable mixture of diastereoisomers (T/C¼6:4). Pale yellow
4.2.5. 1-Methyl-4-(1-nitrocyclohexyl)piperidine-2-thione (4e)
Colorless solid (246 mg, 96%), mp 125–127 ꢁC from n-hexane/
oil (289 mg, 95%). IR (thin film):
n
¼2944, 1548, 1496, 1452, 1340,
1176,1108, 924, 728, 696 cmꢀ1; 1H NMR (400.1 MHz, CDCl3):
d¼1.50
ethyl acetate. IR (KBr pellet):
n
¼2932, 2860, 1536, 1448, 1428, 1352,
(1H, td, J ca. 12.5, 4.6 Hz, CHHax-5 (T)), 1.58 (1H, ddd, J 13.5, 11.1,
8.7 Hz, CHHax-5 (C)), 2.02–2.13 (2H, m, 2ꢂCHHeq-5 (T, C)), 2.29–2.51
(3H, m, 6-CHH, 2ꢂ6-CHH (T, C)), 2.55–2.65 (2H, m, 6-CHH (T)), 2.67
(1H, dd, J 16.4, 12.2 Hz, CHHax-3 (C)), 2.86 (1H, dd, J 17.9, 10.3 Hz,
CHHax-3 (T)), 2.87–2.98 (1H, m, CH-4 (T)), 3.40–3.50 (2H, m,
2ꢂCHHeq-3 (T, C)), 3.60–3.69 (2H, m, 2ꢂCH-6), 4.23 (1H, dd, J 12.3,
10.6 Hz, CHHNO2 (C)), 4.25 (1H, dd, J 12.5, 10.4 Hz, CHHNO2 (T)),
4.30–4.39 (2H, m, 2ꢂCHHNO2 (T, C)), 4.40 (1H, d, J 14.9 Hz, NCHH
(T)), 4.49 (1H, d, J 15.0 Hz, NCHH (C)), 5.11–5.22 (4H, m, 2ꢂ]CH2 (T,
C)), 5.53–5.68 (2H, m, 2ꢂ]CH (T, C)), 6.46 (1H, d, J 14.9 Hz, NCHH
(T)), 6.47 (1H, d, J 15.0 Hz, NCHH (C)), 7.21–7.40 (10H, m, 2ꢂC6H5 (T,
1224, 1092, 1076, 848 cmꢀ1
;
1H NMR (400.1 MHz, CDCl3):
d
¼1.15–
1.43 (3H, m, 3ꢂCHH), 1.47–1.87 (6H, m, 3ꢂCHH, 2ꢂCCHHax, CHHax
-
5), 1.93 (1H, dm, J ca. 13.3 Hz, CHHeq-5), 2.17 (1H, tdd, J 12.1, 4.7,
3.1 Hz, CHax-4), 2.45 (1H, dm, J 13.7 Hz, CCHHeq), 2.49 (1H, dm, J
13.8 Hz, CCHHeq), 2.73 (1H, dd, J 17.9, 12.1 Hz, CHHax-3), 3.30 (1H,
ddd, J 17.9, 4.4, 2.8 Hz, CHHeq-3), 3.40–3.50 (4H, m, CHHax-6, NCH3),
3.58 (1H, ddd, J 13.7, 5.7, 2.1 Hz, CHHeq-6); 13C NMR (100.6 MHz,
CDCl3):
d
¼22.0, 22.2 (2ꢂCH2), 24.0 (CH2-5), 24.6 (CH2), 29.9, 32.3
(2ꢂCCH2), 41.3 (CH-4), 42.4 (CH2-3), 43.0 (NCH3), 53.0 (CH2-6), 93.4
ꢃ
(CNO2), 197.1 (C-2); GC–MS (EI, 70 eV): m/z¼256 (50, Mþ ), 226 (19),
210 (100),128 (24),102 (38), 44 (15). Anal. Calcd for C12H20N2O2S: C,
56.22; H, 7.86; N, 10.93; S, 12.51%. Found: C, 56.18; H, 7.89; N, 11.02;
S, 12.56%.
C)); 13C NMR (100.6 MHz, CDCl3):
d
¼27.4 (CH-4 (T)), 29.1 (CH2-5
(T)), 30.4 (CH-4 (C)), 31.5 (CH2-5 (C)), 36.5 (6-CH2 (T)), 38.3 (6-CH2
(C)), 43.8 (CH2-3 (T)), 45.3 (CH2-3 (C)), 54.0 (NCH2 (C)), 55.2 (NCH2
(T)), 57.1 (CH-6 (T)), 57.2 (CH-6 (C)), 79.0 (CH2NO2 (T, C)), 119.8
(]CH2 (T)), 120.4 (]CH2 (C)), 127.6, 127.7, 127.9, 128.0, 128.9, 128.9,
135.1, 135.2 (C6H5 (T, C)), 131.4 (]CH (C)), 132.5 (]CH (T)), 197.0 (C-
4.2.6. 4-(1-Nitrocyclohexyl)-1-phenylpiperidine-2-thione (4f)
Colorless solid (229 mg, 72%), mp 165–167 ꢁC from n-hexane/
ꢃ
ethyl acetate. IR (KBr pellet):
n
¼2928, 2860, 1528, 1500, 1450, 1348,
2 (T)), 200.0 (C-2 (C)); GC–MS (EI, 70 eV): (C) m/z¼304 (4, Mþ ), 303
1252, 1148, 846, 756, 694 cmꢀ1
;
1H NMR (400.1 MHz, CDCl3):
(6), 213 (10), 148 (5), 131 (6), 106 (7), 91 (100), 65 (11), 41 (11); (T)
ꢃ
d
¼1.17–1.47 (3H, m, 3ꢂCHH), 1.55–1.87 (6H, m, 3ꢂCHH, 2ꢂCHH,
m/z¼304 (4, Mþ ), 303 (3), 213 (5), 148 (5), 131 (6), 106 (6), 91 (100),
CHHax-5), 2.04 (1H, dm, J ca. 13.4 Hz, CHHeq-5), 2.37 (1H, tdd, J ca.
11.7, 4.6, 3.8 Hz, CHax-4), 2.52 (1H, br d, J ca. 13.4 Hz, CHH), 2.55 (1H,
65 (11), 41 (13); HRMS (EI) for C16H20N2O2S: calculated 304.1245,
found 304.1248.

ꢀ
J.G. Sosnicki / Tetrahedron 65 (2009) 1336–1348
1343
4.2.9. trans 6-Allyl-4-nitromethyl-1-phenylpiperidine-2-thione (5c)
Pale yellow oil (180 mg). IR (thin film):
¼3060, 2932, 1554,
1492, 1466, 1448, 1412, 1376, 1332, 1150, 1132, 922, 764, 698 cmꢀ1
1H NMR (400.1 MHz, CDCl3):
¼1.88 (1H, ddd, J ca. 13.3, 11.8, 5.6 Hz,
Anal. Calcd for C12H20N2O2S: C, 56.22; H, 7.86; N, 10.93; S, 12.51%.
Found: C, 56.30; H, 7.95; N, 10.90; S, 12.39%.
n
;
d
4.2.13. trans 6-Allyl-1-benzyl-4-(1-methyl-1-nitroethyl)piperidine-
2-thione (5f)
CHHax-5), 2.25 (1H, dq, J 13.3, 2.6 Hz, CHHeq-5), 2.28–2.38 (1H, m, 6-
CHH), 2.58 (1H, dm, J ca. 14.0 Hz, 6-CHH), 2.89 (1H, dd, J 18.0,
10.5 Hz, CHHax-3), 2.92–3.04 (1H, m, CHax-4), 3.50 (1H, ddd, J 18.0,
4.9, 1.9 Hz, CHHeq-3), 3.97 (1H, dm, J 10.4 Hz, CHeq-6), 4.32 (1H, dd, J
12.6, 8.2 Hz, CHHNO2), 4.44 (1H, dd, J 12.6, 5.7 Hz, CHHNO2), 5.08–
5.16 (2H, m, ]CH2), 5.47–5.59 (1H, m, ]CH), 7.19 (2H, dm, J ca.
8.0 Hz, C6H5), 7.40 (1H, tt, J ca. 7.5, ca. 1.3 Hz, C6H5), 7.46–7.52 (2H,
Colorless solid (299 mg, 90%), mp 124–126 ꢁC from n-hexane/
ethyl acetate. IR (KBr pellet):
n
¼2976, 1534, 1508, 1348, 1178, 920,
740 cmꢀ1; 1H NMR (400.1 MHz, toluene-d8):
d
¼0.75 (1H, td, J 12.8,
5.2 Hz, CHHax-5), 0.87 (3H, s, CH3), 0.91 (3H, s, CH3), 1.16 (1H, dm, J
ca. 12.9 Hz, CHHeq-5), 1.71 (1H, dt, J 14.0, ca. 9.4 Hz, 6-CHH), 2.02
(1H, dm, J ca. 14.0, 6-CHH), 2.33 (1H, dddd, J 12.8, 11.0, 6.0, 3.2 Hz,
CHax-4), 2.52 (1H, dd, J 18.3, 11.0 Hz, CHHax-3), 3.02–3.09 (1H, m,
CHeq-6), 3.10 (1H, ddd, J 18.3, 6.0, 1.3 Hz, CHHeq-3), 3.94 (1H, d, J
14.6 Hz, NCHH), 4.84–4.92 (2H, m, ]CH2), 5.07–5.20 (1H, m, ]CH),
6.47 (1H, d, J 14.6 Hz, NCHH), 6.95–7.14 (4H, m, C6H5), 7.20 (1H, d, J
m, C6H5); 13C NMR (100.6 MHz, CDCl3):
5), 36.7 (6-CH2), 44.4 (CH2-3), 62.1 (CH-6), 78.8 (CH2NO2), 119.8
d
¼27.7 (CH-4), 28.8 (CH2-
(]CH2), 127.5, 128.4, 129.7, 144.9 (C6H5), 132.3 (]CH), 199.2 (C-2);
ꢃ
GC–MS (EI, 70 eV): m/z¼290 (94, Mþ ), 289 (96), 249 (29), 202 (11),
188 (100), 149 (15), 118 (16), 104 (16), 93 (15), 84 (20), 77 (45), 67
(12), 51 (10), 41 (17). HRMS (EI) for C15H18N2O2S: calculated
290.1089, found 290.1087.
7.3 Hz, C6H5); 13C NMR (100.6 MHz, toluene-d8):
d
¼19.9 (CH3), 24.0
(CH3), 26.9 (CH2-5), 35.9 (6-CH2), 36.3 (CH-4), 42.8 (CH2-3), 54.7
(NCH2), 57.3 (CH-6), 90.0 (CNO2), 118.9 (]CH2), 128.0, 128.42, 128.9,
136.6 (C6H5), 133.4 (]CH),198.4 (C-2); GC–MS (EI, 70 eV): m/z¼332
ꢃ
4.2.10. trans 4-Nitromethyl-1,6-diphenylpiperidine-2-thione (5d)
(6, Mþ ), 302 (6), 286 (9), 244 (12), 91 (100), 41 (16). Anal. Calcd for
Yellow semisolid (173 mg). IR (KBr pellet):
1464, 1446, 1410, 1348, 1146, 1116, 762, 696 cmꢀ1
(300.1 MHz, CDCl3):
n
¼2928, 1554, 1492,
C18H24N2O2S: C, 65.03; H, 7.28; N, 8.43; S, 9.65%. Found: C, 64.92; H,
7.22; N, 8.49; S, 9.77%.
;
1H NMR
d
¼2.11 (1H, dm, J ca. 13.2 Hz, CHHeq-5), 2.23
(1H, ddd, J 13.2, 12.0, 5.6 Hz, CHHax-5), 2.71–2.90 (1H, m, CH-4),
2.99 (1H, dd, J 18.8, 10.3 Hz, CHHax-3), 3.59 (1H, ddd, J 18.8, 6.0,
1.5 Hz, CHHeq-3), 4.18–4.33 (2H, m, CH2NO2), 5.09 (1H, dd, J 5.6,
2.6 Hz, CHeq-6), 7.01 (2H, dd, J 6.8, 1.5 Hz, C6H5), 7.10–7.35 (8H, m,
4.2.14. trans 6-Allyl-4-(1-methyl-1-nitroethyl)-1-phenyl-
piperidine-2-thione (5g)
White solid (280 mg, 88%), mp 179–181 ꢁC from n-hexane/ethyl
acetate. IR (KBr pellet):
1346, 1260, 1248, 1152, 1060, 928, 852, 768, 700 cmꢀ1
(400.1 MHz, CDCl3):
td, J 13.1, 5.6 Hz, CHHax-5), 2.00 (1H, dq, J 13.1, ca. 2.4 Hz, CHHeq-5),
2.33 (1H, ddd, J 13.9, 10.9, 9.0 Hz, 6-CHH), 2.58 (1H, dm, J ca. 13.9 Hz,
6-CHH), 2.80–2.94 (2H, m, CHH-3, CHax-4), 3.39–3.47 (1H, m, CHH-
3), 3.94 (1H, dddd, J 11.0, 5.6, 4.0, 1.8 Hz, CHeq-6), 5.06–5.14 (2H, m,
]CH2), 5.41–5.52 (1H, m, ]CH), 7.18 (2H, dd, J 8.5, 1.3 Hz, C6H5),
7.40 (1H, tt, J 7.5, 1.1 Hz, C6H5), 7.49 (2H, t, J 7.9 Hz, C6H5); 13C NMR
n
¼2988, 1538, 1494, 1470, 1450, 1400, 1376,
1H NMR
¼1.59 (3H, s, CH3), 1.63 (3H, s, CH3), 1.81 (1H,
2ꢂC6H5); 13C NMR (75.4 MHz, CDCl3):
d
¼27.3 (CH-4), 34.3 (CH2-5),
;
44.4 (CH2-3), 67.8 (CH-6), 79.0 (CH2NO2), 126.8, 126.9, 128.1, 128.4,
d
129.0, 129.5, 138.8, 146.0 (2ꢂC6H5), 200.1 (C-2); GC–MS (EI, 70 eV):
ꢃ
m/z¼326 (56, Mþ ), 325 (100), 167 (11), 149 (16), 129 (22), 91 (16),
77 (20); HRMS (EI) for C18H18N2O2S: calculated 326.1089, found
326.1091.
4.2.11. cis 4-Nitromethyl-1,6-diphenylpiperidine-2-thione (6d)
White solid (85 mg), mp 222–226 ꢁC from n-hexane/ethyl ace-
(100.6 MHz, CDCl3):
(CH-4), 36.3 (6-CH2), 43.1 (CH2-3), 62.7 (CH-6), 90.1 (CNO2), 119.8
d
¼21.1 (CH3), 24.4 (CH3), 26.4 (CH2-5), 36.2
tate. IR (KBr pellet):
n
¼3036, 2924, 1554, 1492, 1464, 1444, 1410,
1312, 1224, 1148, 1114, 764, 696 cmꢀ1; 1H NMR (300.1 MHz, CDCl3):
(]CH2), 127.5 (br),128.3, 129.7,144.9 (C6H5),132.4 (]CH), 200.1 (C-
ꢃ
d
¼2.03 (1H, dt, J 13.9, ca. 11.2 Hz, CHHax-5), 2.46 (1H, ddd, J 13.9, 5.6,
2); GC–MS (EI, 70 eV): m/z¼318 (27, Mþ ), 317 (23), 272 (18), 230
3.0 Hz, CHHeq-5), 2.84–3.04 (2H, m, CH-4, CHHax-3), 3.57 (1H, dd, J
13.2, 3.0 Hz, CHHeq-3), 4.26 (1H, dd, J 12.3, 7.9 Hz, CHHNO2), 4.39
(1H, dd, J 12.3, 5.6 Hz, CHHNO2), 4.85 (1H, dd, J 10.7, 5.6 Hz, CHax-6),
6.83 (2H, dd, J 7.1, 1.5 Hz, C6H5), 7.00–7.20 (8H, m, 2C6H5); 13C NMR
(37), 216 (20), 188 (49),186 (18), 172 (16),105 (34), 97 (54), 77 (100),
69 (51), 55 (30), 51 (28), 41 (75). Anal. Calcd for C17H22N2O2S: C,
64.12; H, 6.96; N, 8.80; S,10.07%. Found: C, 64.05; H, 6.99; N, 8.90; S,
9.99%.
(75.4 MHz, CDCl3):
d
¼31.6 (CH-4), 36.4 (CH2-5), 45.8 (CH2-3), 68.8
(CH-6), 127.7, 127.7, 127.8, 128.5, 128.9, 129.1, 139.1, 144.4 (2ꢂC6H5),
4.2.15. trans 4-(1-Methyl-1-nitroethyl)-1,6-diphenyl-piperidine-
2-thione (5h)
ꢃ
200.5 (C-2); GC–MS (EI, 70 eV): m/z¼326 (56, Mþ ), 325 (100), 167
(11), 149 (16), 129 (22), 91 (16), 77 (20); HRMS (EI) for C18H18N2O2S:
calculated 326.1089, found 326.1090.
White solid (266 mg, 75%), mp 205–207 ꢁC from n-hexane/ethyl
acetate. IR (KBr pellet):
n
¼3064, 2940, 1594, 1534, 1492, 1468, 1444,
1346, 1148, 852, 764, 696, 592 cmꢀ1
;
1H NMR (400.1 MHz, CDCl3):
4.2.12. trans 6-Allyl-1-methyl-4-(1-methyl-1-nitroethyl)piperidine-
2-thione (5e)
d
¼1.53 (3H, s, CH3), 1.54 (3H, s, CH3), 1.99 (1H, dm, J 12.9 Hz, CHHeq
-
5), 2.24 (1H, td, J 12.9, 5.4 Hz, CHHax-5), 2.70 (1H, dddd, J 12.9, 11.1,
6.2, 3.2 Hz, CHax-4), 3.06 (1H, dd, J 18.9, 11.1 Hz, CHHax-3), 3.53 (1H,
ddd, J 18.9, 6.2, 1.9 Hz, CHHeq-3), 5.19 (1H, dd, J 5.4, 2.2 Hz, CHeq-6),
7.10–7.15 (2H, m, C6H5), 7.19–7.23 (2H, m, C6H5), 7.24–7.42 (6H, m,
Colorless solid (177 mg, 69%), mp 92–94 ꢁC from n-hexane/
ethyl acetate. IR (KBr pellet):
1528, 1402, 1358, 1244, 1220, 1124, 1106, 1068, 1052, 996, 930,
852 cmꢀ1 1H NMR (400.1 MHz, CDCl3):
n
¼3076, 2992, 2972, 2948, 2872,
;
d
¼1.53 (3H, s, CH3), 1.58
C6H5); 13C NMR (100.6 MHz, CDCl3):
d
¼21.9 (CH3), 23.9 (CH3), 32.5
(3H, s, CH3), 1.58–1.69 (1H, m, CHHax-5), 1.89 (1H, dm, J ca.
13.4 Hz, CHHeq-5), 2.24–2.34 (1H, m, 6-CHH), 2.61 (1H, dm, J ca.
14.0 Hz, 6-CHH), 2.66–2.77 (2H, m, CHH-3, CHax-4), 3.20–3.32 (1H,
m, CHH-3), 3.47 (3H, s, NCH3), 3.65 (1H, dddd, J 10.5, ca. 5.6, 4.1,
1.6 Hz, CHeq-6), 5.15–5.23 (2H, m, ]CH2), 5.59–5.71 (1H, m,
(CH2-5), 36.1 (CH-4), 42.7 (CH2-3), 67.6 (CH-6), 89.9 (CNO2), 126.6,
126.8, 128.1, 128.3, 128.9, 129.5, 138.6, 146.1 (2ꢂC6H5), 201.1 (C-2);
ꢃ
GC–MS (EI, 70 eV): m/z¼354 (62, Mþ ), 353 (100), 308 (22), 264
(32), 180 (11), 168 (13), 157 (19), 129 (16), 117 (14), 91 (27), 77 (24).
Anal. Calcd for C20H22N2O2S: C, 67.77; H, 6.26; N, 7.90; S, 9.05%.
Found: C, 67.81; H, 6.33; N, 7.96; S, 9.12%.
]CH); 13C NMR (100.6 MHz, CDCl3):
26.5 (CH2-5), 36.1 (CH-4), 36.6 (6-CH2), 42.3 (CH2-3), 43.0 (NCH3),
d
¼20.9 (CH3), 24.1 (CH3),
61.9 (CH-6), 90.1 (CNO2), 119.9 (]CH2), 132.6 (]CH), 196.8 (C-2);
4.2.16. trans 6-Allyl-1-methyl-4-(1-nitrocyclohexyl)piperidine-
2-thione (5i)
ꢃ
GC–MS (EI, 70 eV): m/z¼256 (14, Mþ ), 226 (6), 210 (13), 168 (57),
154 (29), 126 (49), 111 (26), 97 (44), 95 (26), 81 (23), 79 (24), 77
(22), 69 (34), 67 (37), 55 (42), 53 (25), 42 (73), 41 (100), 39 (34).
White solid (112 mg, 38%), mp 135–137 ꢁC from n-hexane/ethyl
acetate. IR (KBr pellet):
n¼2944, 1528, 1448, 1352, 1072, 1048,

ꢀ
J.G. Sosnicki / Tetrahedron 65 (2009) 1336–1348
1344
932 cmꢀ1
;
1H NMR (400.1 MHz, CDCl3):
d
¼1.15–1.43 (3H, m,
CHHax), 2.09 (1H, dm, J ca. 13.1 Hz, CHHeq-5), 2.16 (1H, td, J 13.1,
3ꢂCHH), 1.49–1.62 (3H, m, 2ꢂCHHax, CHHax-5), 1.62–1.75 (3H, m,
3ꢂCHH),1.94 (1H, dq, J 13.5, ca. 2.3 Hz, CHHeq-5), 2.20 (1H, dt, J 14.0,
9.6 Hz, 6-CHH), 2.33 (1H, tdd, J ca. 13.0, 5.5, ca. 2.4 Hz, CHax-4), 2.42
(1H, dm, J ca. 14.0 Hz, CHHeq), 2.47 (1H, dm, J ca. 14.0 Hz, CHHeq),
2.59 (1H, dm, J 14.0 Hz, 6-CHH), 2.80 (1H, ddd, J 18.4, 11.8, ca. 0.8 Hz,
CHHax-3), 3.29 (1H, ddd, J 18.4, 5.4, 2.4 Hz, CHHeq-3), 3.45 (3H, s,
NCH3), 3.65 (1H, dm, J ca. 10.3 Hz, CHeq-6), 5.14 (1H, dq, J 17.0, ca.
1.2 Hz, ]CHH), 5.19 (1H, dm, J 10.2 Hz, ]CHH), 5.57–5.69 (1H, m,
5.1 Hz, CHHax-5), 2.31–2.48 (3H, m, 2ꢂCHHeq, CHax-4), 3.14 (1H, dd,
J 19.0, 11.2 Hz, CHHax-3), 3.57 (1H, ddd, J 19.0, 5.9, 1.7 Hz, CHHeq-3),
5.17 (1H, dd, J ca. 4.9, ca. 2.4 Hz, CHeq-6), 7.10 (2H, dm, J ca. 7.2 Hz,
C6H5), 7.20 (2H, dm, J ca. 7.0 Hz, C6H5), 7.23–7.41 (6H, m, 2ꢂC6H5);
13C NMR (100.6 MHz, CDCl3):
32.2 (CH2-5), 36.0 (CH-4), 42.2 (CH2-3), 67.6 (CH-6), 92.8 (CNO2),
d
¼22.0, 22.1, 24.5, 30.6, 32.1 (5ꢂCH2),
126.6, 126.8, 128.1, 128.2, 128.9, 129.4, 138.9, 146.2 (2ꢂC6H5), 201.4
ꢃ
(C-2); GC–MS (EI, 70 eV): m/z¼394 (<1, Mþ ), 347 (100), 346 (65),
]CH); 13C NMR (100.6 MHz, CDCl3):
d
¼22.0, 22.2, 24.6 (3ꢂCH2),
332 (12), 314 (50), 252 (58), 238 (13), 197 (27),180 (15), 117 (15),103
(20), 91 (49), 79 (25), 77 (42). Anal. Calcd for C23H26N2O2S: C, 70.02;
H, 6.64; N, 7.10; S, 8.13%. Found: C, 70.09; H, 6.60; N, 7.19; S, 8.04%.
26.1 (CH2-5), 29.8, 32.2 (2ꢂCH2), 36.7 (CH-4, 6-CH2), 42.1 (CH2-3),
42.9 (NCH3), 61.8 (CH-6), 93.3 (CNO2), 119.7 (]CH2), 132.6 (]CH),
ꢃ
197.1 (C-2); GC–MS (EI, 70 eV): m/z¼296 (60, Mþ ), 266 (50), 250
(98), 208 (100), 168 (50), 150 (15), 126 (64), 91 (27), 79 (28), 67 (37),
55 (23), 41 (31). Anal. Calcd for C15H24N2O2S: C, 60.78; H, 8.16; N,
9.45; S, 10.82%. Found: C, 60.84; H, 8.03; N, 9.53; S, 10.90%.
4.2.20. trans 6-Ethyl-4-nitromethylpiperidine-2-thione (7a)
White solid (162 mg, 80%), mp 106–108 ꢁC from n-hexane/ethyl
acetate. IR (KBr pellet):
n
¼3176 br, 3060, 2956, 1550, 1352, 1340,
1200, 1136, 1074 cmꢀ1; 1H NMR (400.1 MHz, CDCl3):
d
¼1.01 (3H, t, J
4.2.17. trans 6-Allyl-1-benzyl-4-(1-nitrocyclohexyl)piperidine-
2-thione (5j)
7.4 Hz, CH2CH3),1.60 (1H, dquartet, J 14.0, 7.4 Hz, CHHCH3),1.71 (1H,
dquartet, J 14.0, 7.4 Hz, CHHCH3),1.78–1.84 (2H, m, CH2-5), 2.68 (1H,
dd, J 18.1, 8.1 Hz, CHHax-3), 2.75–2.86 (1H, m, CH-4), 3.13 (1H, dd, J
18.1, 5.0 Hz, CHHeq-3), 3.49 (1H, dquintet, J ca. 6.3, ca. 2.5 Hz, CH-6),
4.34 (1H, dd J 12.5, 8.4 Hz, CHHNO2), 4.41 (1H, dd, J 12.5, 6.4 Hz,
White solid (231 mg, 62%), mp 106–108 ꢁC from n-hexane/ethyl
acetate. IR (KBr pellet):
n¼2936, 1528, 1504, 1452, 1346, 1170, 932,
704 cmꢀ1 1H NMR (400.1 MHz, CDCl3):
;
d
¼1.17–1.43 (4H, m,
3ꢂCHH, CHHax-5), 1.48–1.61 (2H, m, 2ꢂCHH), 1.62–1.76 (3H, m,
3ꢂCHH), 1.89 (1H, dq, J 13.3, 2.4 Hz, CHHeq-5), 2.16–2.32 (1H, m, 6-
CHH), 2.36–2.52 (3H, m, 2ꢂCHH, CH-4), 2.59 (1H, dm, J ca. 14.1 Hz,
6-CHH), 2.96 (1H, dd, J 18.7, 11.1 Hz, CHHax-3), 3.38 (1H, ddm, J 18.7,
ca. 6.0 Hz, CHHeq-3), 3.57–3.65 (1H, m, CHeq-6), 4.37 (1H, d, J
14.9 Hz, NCHH), 5.08–5.18 (2H, m, ]CH2), 5.50–5.61 (1H, m, ]CH),
6.42 (1H, d, J 14.9 Hz, NCHH), 7.23–7.37 (5H, m, C6H5); 13C NMR
CHHNO2), 8.42 (1H, br s, NH); 13C NMR (100.6 MHz, CDCl3):
d¼10.0
(CH3), 28.2 (CH2-5), 28.5 (CH-4), 28.5 (CH2CH3), 41.9 (CH2-3), 54.4
(CH-6), 78.3 (CH2NO2), 199.4 (C-2); GC–MS (EI, 70 eV): m/z¼202
ꢃ
(100, Mþ ), 173 (8), 140 (15), 126 (11), 112 (80), 96 (11), 84 (13), 58
(20), 55 (25), 41 (19). Anal. Calcd for C8H14N2O2S: C, 47.50; H, 6.98;
N, 13.85; S, 15.85%. Found: C, 47.55; H, 7.03; N, 13.92; S, 15.83%.
(100.6 MHz, CDCl3):
d
¼22.0, 22.2, 24.6 (3ꢂCH2), 26.5 (CH2-5), 29.9,
4.2.21. trans 6-Butyl-4-nitromethylpiperidine-2-thione (7b)
White solid (202 mg, 88%), mp 110–112 ꢁC from n-hexane/ethyl
32.1 (2ꢂCH2), 36.3 (6-CH2), 36.7 (CH-4), 42.2 (CH2-3), 55.1 (NCH2),
57.4 (CH-6), 93.4 (CNO2), 119.5 (]CH2), 127.6, 127.9, 128.9, 135.1
acetate. IR (KBr pellet):
1132 cmꢀ1; 1H NMR (400.1 MHz, CDCl3):
1.27–1.40 (4H, m, 2ꢂCH2), 1.50–1.58 (1H, m, CHH), 1.59–1.73 (1H, m,
CHH), 1.75–1.83 (2H, m, CH2-5), 2.66 (1H, dd, J 18.1, 8.4 Hz, CHHax
n
¼3172 br, 3064, 2952, 2860, 1548, 1338,
(C6H5), 132.7 (]CH), 198.6 (C-2); GC–MS (EI, 70 eV): m/z¼372 (<1,
d
¼0.87–0.98 (3H, m, CH3),
ꢃ
M
þ ), 325 (59), 310 (10), 292 (40), 282 (15), 234 (22), 151 (14), 117
(18), 91 (100), 79 (16), 65 (11), 41 (10). Anal. Calcd for C21H28N2O2S:
C, 67.71; H, 7.58; N, 7.52; S, 8.61%. Found: C, 67.80; H, 7.56; N, 7.59; S,
8.55%.
-
3), 2.75–2.87 (1H, m, CHax-4), 3.12 (1H, dd, J 18.1, 4.9 Hz, CHHeq-3),
3.50–3.64 (1H, m, CHeq-6), 4.35 (1H, dd, J 12.5, 8.1 Hz, CHHNO2),
4.41 (1H, dd, J 12.5, 6.4 Hz, CHHNO2), 9.03 (1H, br s, NH); 13C NMR
4.2.18. trans 6-Allyl-4-(1-nitrocyclohexyl)-1-phenylpiperidine-
2-thione (5k)
(100.6 MHz, CDCl3):
d
¼13.9 (CH3), 22.4 (CH2), 28.5 (CH-4), 28.7
(CH2-5), 35.3 (CH2), 41.9 (CH2-3), 53.1 (CH-6), 78.4 (CH2NO2), 199.1
ꢃ
White solid (233 mg, 65%), mp 179–181 ꢁC from n-hexane/ethyl
(C-1); GC–MS (EI, 70 eV): m/z¼230 (58, Mþ ), 184 (14), 140 (12), 126
acetate. IR (KBr pellet):
1150, 1136, 932, 844, 764, 696 cmꢀ1
¼1.17–1.46 (3H, m, 3ꢂCHH), 1.53–1.65 (2H, m, 2ꢂCHH), 1.65–1.81
n
¼2936, 2868, 1530, 1494, 1472, 1450, 1338,
(16), 112 (100), 100 (13), 84 (22), 69 (41). Anal. Calcd for
C10H18N2O2S: C, 52.15; H, 7.88; N, 12.16; S, 13.92%. Found: C, 52.05;
H, 7.93; N, 12.22; S, 13.83%.
;
1H NMR (400.1 MHz, CDCl3):
d
(4H, m, 3ꢂCHH, CHHax-5), 2.11 (1H, ddd, J 13.4, 2.3, 2.0 Hz, CHHeq
-
5), 2.25 (1H, ddd, J 13.9, ca. 11.0, ca. 10.0 Hz, 6-CHH), 2.42–2.61 (4H,
m, 6-CHH, 2ꢂCHH, CHax-4), 2.98 (1H, dd, J 18.7, 11.7 Hz, CHHax-3),
3.45 (1H, ddd, J 18.7, 5.4, 2.4 Hz, CHHeq-3), 3.93 (1H, dm, J ca.
10.8 Hz, CHeq-6), 5.07 (1H, br d, J 17.1 Hz, ]CHH), 5.12 (1H, br d, J ca.
10.1 Hz, ]CHH), 5.40–5.52 (1H, m, ]CH), 7.15 (2H, dm, J ca. 7.3 Hz,
C6H5), 7.39 (1H, tt, J ca. 7.3, 1.3 Hz, C6H5), 7.48 (2H, t, J 8.0 Hz, C6H5);
4.2.22. trans 6-Hexyl-4-nitromethylpiperidine-2-thione (7c)
White solid (204 mg, 79%), mp 68–70 ꢁC from n-hexane/ethyl
acetate. IR (KBr pellet):
n
¼3156, 3056, 2952, 2928, 2860, 1552, 1338,
1136 cmꢀ1 1H NMR (400.1 MHz, CDCl3):
;
d
¼0.89 (3H, t, J 7.1 Hz,
CH3), 1.22–1.43 (8H, m, 4ꢂCH2), 1.48–1.60 (1H, m, CHH-5), 1.61–1.74
(1H, m, CHH-5), 1.77–1.86 (2H, m, CH2), 2.66 (1H, dd, J 18.1, 8.2 Hz,
CHHax-3), 2.75–2.86 (1H, m, CH-4), 3.13 (1H, dd, J 18.1, 5.0 Hz,
CHHeq-3), 3.51–3.60 (1H, dquintet, J ca. 2.6, ca. 6.4 Hz, CH-6), 4.34
(1H, dd, J 12.5, 8.3 Hz, CHHNO2), 4.40 (1H, dd, J 12.5, 6.3 Hz,
CHHNO2), 8.70 (1H, br s, NH); 13C NMR (100.6 MHz, CDCl3):
13C NMR (100.6 MHz, CDCl3):
d
¼22.1, 22.3, 24.7 (3ꢂCH2), 26.2 (CH2-
5), 30.1, 32.2 (2ꢂCH2), 36.4 (6-CH2), 36.7 (CH-4), 42.8 (CH2-3), 62.5
(CH-6), 93.4 (CNO2), 119.6 (]CH2), 127.5 br, 128.3, 129.7, 144.9
(C6H5), 132.6 (]CH), 200.4 (C-2); GC–MS (EI, 70 eV): m/z¼358 (<1,
ꢃ
M
þ ), 311 (100), 310 (54), 278 (27), 270 (33), 268 (43), 216 (13), 204
d
¼14.03 (CH3), 22.5 (CH2), 25.6 (CH2), 28.6 (CH-4), 28.8 (CH2), 28.9
(18), 190 (9), 151 (34), 135 (11), 117 (33), 104 (15), 91 (27), 77 (50), 41
(15). Anal. Calcd for C20H26N2O2S: C, 67.01; H, 7.31; N, 7.81; S, 8.94%.
Found: C, 67.00; H, 7.40; N, 7.69; S, 9.04%.
(CH2), 31.6 (CH2), 35.7 (CH2-5), 41.9 (CH2-3), 53.1 (CH-6), 78.3
ꢃ
(CH2NO2), 199.4 (C-2); GC–MS (EI, 70 eV): m/z¼258 (18, Mþ ), 228
(21), 212 (15), 196 (10), 183 (8), 164 (9), 153 (18), 140 (14), 125 (18),
112 (100), 100 (69), 84 (30), 69 (22), 55 (23), 41 (29). Anal. Calcd for
C12H22N2O2S: C, 55.78; H, 8.58; N, 10.84; S, 12.41%. Found: C, 55.66;
H, 8.64; N, 10.82; S, 12.33%.
4.2.19. trans 4-(1-Nitrocyclohexyl)-1,6-diphenylpiperidine-
2-thione (5l)
White solid (248 mg, 63%), mp 239–242 ꢁC from n-hexane/ethyl
acetate. IR (KBr pellet):
1344, 1238, 844, 766, 700 cmꢀ1
¼1.10–1.43 (4H, m, CH2, CHH, CHHax), 1.46–1.70 (4H, m, CH2, CHH,
n
¼3028, 2936, 2868, 1534, 1492, 1472, 1448,
4.2.23. trans 6-tert-Butyl-4-nitromethylpiperidine-2-thione (7d)
White solid (179 mg, 78%), mp 112–114 ꢁC from n-hexane/ethyl
;
1H NMR (400.1 MHz, CDCl3):
d
acetate. IR (KBr pellet):
n
¼3200, 2968, 1552, 1376, 1324, 1130,

ꢀ
J.G. Sosnicki / Tetrahedron 65 (2009) 1336–1348
1345
1044 cmꢀ1
;
1H NMR (400.1 MHz, CDCl3):
d
¼1.00 (9H, s, C(CH3)3),
(3H, s, CH3), 1.59 (3H, s, CH3), 2.55 (1H, dd, J 16.5, 12.1 Hz, CHHax-3),
2.55–2.65 (1H, m, CHax-4), 3.09 (1H, dd, J 16.1, ca. 3.1 Hz, CHHeq-3),
1.80–1.86 (2H, m, CH2-5), 2.80–2.87 (1H, m, CHHax-3), 2.86–2.93
(1H, m, CHax-4), 3.01 (1H, dd, J 17.3, 4.7 Hz, CHHeq-3), 3.25 (1H, ddd,
J 8.7, 6.8, 1.5 Hz, CHeq-6), 4.38 (1H, dd, J 12.3, 8.9 Hz, CHHNO2), 4.44
(1H, dd, J 12.3, 6.2 Hz, CHHNO2), 8.07 (1H, NH, br s); 13C NMR
3.55 (1H, dquintet, J ca. 7.4, ca. 3.4 Hz, CHeq-6), 9.13 (1H, s, NH); 13
C
NMR (100.6 MHz, CDCl3):
d
¼13.9 (CH3), 21.3 (CH3), 22.4 (CH2), 24.5
(CH3), 26.8 (CH2), 28.1 (CH2-5), 34.8 (CH-4), 40.9 (CH2-3), 54.3 (CH-
ꢃ
(100.6 MHz, CDCl3):
d¼24.3 (CH2-5), 25.7 (C(CH3)3), 29.7 (CH-4),
6), 90.2 (CNO2), 200.0 (C-2); GC–MS (EI, 70 eV): m/z¼258 (Mþ ,79),
34.4 (C(CH3)3), 41.5 (CH2-3), 60.7 (CH-6), 77.4 (CH2NO2), 201.0 (C-
228 (22), 212 (100),170 (32),168 (22),154 (36),128 (18),112 (33), 97
(27), 86 (21), 83 (28), 69 (50), 55 (33), 41 (24). Anal. Calcd for
C12H22N2O2S: C, 55.78; H, 8.58; N, 10.84; S, 12.41%. Found: C, 55.75;
H, 8.39; N, 10.81; S, 12.40%.
ꢃ
2); GC–MS (EI, 70 eV): m/z¼230 (83, Mþ ),173 (18),154 (9),126 (13),
112 (100), 100 (31), 84 (21), 69 (18), 57 (15), 41 (23). Anal. Calcd for
C10H18N2O2S: C, 52.15; H, 7.88; N, 12.16; S, 13.92%. Found: C, 52.06;
H, 7.93; N, 12.22; S, 13.83%.
4.2.28. trans 6-Hexyl-4-(1-methyl-1-nitroethyl)piperidine-
2-thione (7i)
4.2.24. trans 4-Nitromethyl-6-phenylpiperidine-2-thione (7e)
White solid (100 mg, 40%), mp 97–99 ꢁC from n-hexane/ethyl
White solid (209 mg, 73%), mp 112–114 ꢁC from n-hexane. IR
acetate. IR (KBr pellet):
n
¼3450 br, 3180 br, 3052, 1552, 1448, 1340,
(KBr pellet):
n
¼3176 br, 3088, 2928, 2860, 1556, 1536, 1400, 1376,
1120, 760, 704 cmꢀ1 1H NMR (400.1 MHz, CDCl3):
;
d
¼2.03–2.09
1348, 1118 cmꢀ1
;
1H NMR (400.1 MHz, CDCl3):
d¼0.89 (3H, t, J
(2H, m, CH2-5), 2.63–2.73 (1H, m, CH-4), 2.75 (1H, dd, J 18.2, 9.0 Hz,
CHHax-3), 3.26 (1H, dd, J 18.2, 4.6 Hz, CHHeq-3), 4.34 (2H, d, J 6.8 Hz,
CH2NO2), 4.82 (1H, td, J 5.3, 3.1 Hz, CHeq-6), 7.22 (2H, br d, J 7.2 Hz,
C6H5), 7.35 (1H, tt, J 7.1, ca. 1.4 Hz, C6H5), 7.38–7.44 (2H, m, C6H5),
7.1 Hz, CH2CH3), 1.24–1.39 (8H, m, 4ꢂCH2), 1.45–1.73 (4H, m, CH2-5,
CH2), 1.55 (3H, s, CH3), 1.59 (3H, s, CH3), 2.54 (1H, dd, J 16.5, 12.0 Hz,
CHHax-3), 2.58–2.66 (1H, m, CHax-4), 3.08 (1H, br d, J 16.5 Hz,
CHHeq-3), 3.44–3.55 (1H, dquintet, J ca. 3.9, ca. 7.1 Hz, CHeq-6), 9.31
8.69 (1H, br s, NH); 13C NMR (100.6 MHz, CDCl3):
d¼27.7 (CH-4),
(1H, s, NH); 13C NMR (100.6 MHz, CDCl3):
d
¼14.0 (CH3), 21.3 (CH3),
32.4 (CH2-3), 42.1 (CH2-3), 57.0 (CH-6), 78.4 (CH2NO2), 126.3, 128.6,
22.5 (CH3), 24.5, 25.9, 26.8, 28.9, 31.5, 35.1 (6ꢂCH2), 36.7 (CH-4),
129.3, 139.8 (C6H5), 200.6 (C-2); GC–MS (EI, 70 eV): m/z¼250 (100,
40.5 (CH2-3), 54.5 (CH-6), 90.1 (CNO2), 199.4 (C-2); GC–MS (EI,
ꢃ
ꢃ
M
þ ), 216 (12), 203 (41), 202 (40), 188 (20), 175 (13), 156 (28), 131
70 eV): m/z¼286 (28, Mþ ), 256 (47), 240 (100), 206 (15), 198 (51),
(19), 129 (32), 117 (14), 115 (18), 106 (35), 104 (31), 91 (44), 77 (22).
Anal. Calcd for C12H14N2O2S: C, 57.58; H, 5.64; N, 11.19; S, 12.81%.
Found: C, 57.56; H, 5.63; N, 11.27; S, 12.83%.
181 (46), 168 (21), 156 (18), 154 (38), 144 (10), 128 (51), 114 (26), 113
(36), 113 (136), 112 (41), 97 (26), 95 (22), 83 (24), 69 (58), 55 (42), 43
(28), 41 (41). Anal. Calcd for C14H26N2O2S: C, 58.70; H, 9.15; N, 9.78;
S, 11.19%. Found: C, 58.66; H, 8.99; N, 9.77; S, 11.14%.
4.2.25. trans 6-Allyl-4-nitromethylpiperidine-2-thione (7f)
White solid (137 mg, 64%), mp 83–85 ꢁC from n-hexane/ethyl
4.2.29. trans 6-tert-Butyl-4-(1-methyl-1-nitroethyl)piperidine-
2-thione (7j)
acetate. IR (KBr pellet):
1408, 1376, 1348, 1264, 1144, 1042, 996, 924, 876 cmꢀ1
(400.1 MHz, CDCl3):
n
¼3156, 3072, 2964, 1576, 1548, 1444, 1430,
;
1H NMR
Colorless solid (222 mg, 86%), mp 157–159 ꢁC from n-hexane/
d
¼1.77–1.90 (2H, m, CH2-5), 2.28–2.42 (2H, m,
ethyl acetate. IR (KBr pellet):
1380, 1352, 1336, 1312, 1248, 1142, 1058, 1028, 852, 708 cmꢀ1
NMR (400.1 MHz, CDCl3):
n
¼3248 br, 2964, 1526, 1478, 1400,
1H
¼1.00 (9H, s, C(CH3)3), 1.55 (3H, s, CH3),
6-CH2), 2.70 (1H, dd, J 18.1, 7.7 Hz, CHHax-3), 2.83 (1H, m, CH-4),
3.14 (1H, dd, J 18.1, 5.0 Hz, CHHeq-3), 3.62 (1H, m, CHeq-6), 4.35 (1H,
dd, J 12.5, 8.5 Hz, CHHNO2), 4.41 (1H, dd, J 12.5, 6.2 Hz, CHHNO2),
5.20–5.31 (2H, m, ]CH2), 5.68–5.81 (1H, m, ]CH), 8.31 (1H, br s,
;
d
1.57–1.66 (4H, m, CH3, CHHax-5), 1.75 (1H, dtd, J 14.0, ca. 5.9, 1.8 Hz,
CHHeq-5), 2.48 (1H, dd, J 16.2, 11.8 Hz, CHHax-3), 2.60 (1H, dddd, J
13.9, 11.8, 6.0, 4.1 Hz, CHax-4), 3.13 (1H, ddd, J 16.2, 4.1, 1.7 Hz,
CHHeq-3), 3.20 (1H, ddd, J 8.4, 5.8, 2.6 Hz, CHeq-6), 8.18 (1H, s, NH);
NH); 13C NMR (100.6 MHz, CDCl3):
39.9 (6-CH2), 41.9 (CH2-3), 52.0 (CH-6), 78.1 (CH2NO2), 120.5
d
¼28.4 (CH2-5), 28.5 (CH-4),
(]CH2), 132.0 (]CH), 199.6 (C-2); GC–MS (EI, 70 eV): m/z¼214 (46,
13C NMR (100.6 MHz, CDCl3):
26.3 (C(CH3)3), 34.6 (C(CH3)3), 38.3 (CH-4), 40.7 (CH2-3), 62.2 (CH-
d
¼21.1 (CH3), 23.6 (CH2-5), 25.3 (CH3),
ꢃ
M
þ ) 173 (21), 126 (8), 112 (100), 84 (21), 67 (9), 41 (14); HRMS (EI)
for C9H14N2O2S: calculated 214.0776, found 214.0774.
6), 90.4 (CNO2), 202.4 (C-2); GC–MS (EI, 70 eV): m/z¼258 (100,
ꢃ
M
þ ), 212 (55), 201 (11),172 (10),154 (88),128 (27),112 (68), 97 (33),
4.2.26. trans 6-Ethyl-4-(1-methyl-1-nitroethyl)piperidine-
2-thione (7g)
95 (18), 86 (16), 83 (22), 69 (26), 57 (24), 55 (17), 41 (34). Anal. Calcd
for C12H22N2O2S: C, 55.78; H, 8.58; N, 10.84; S, 12.41%. Found: C,
55.69; H, 8.69; N, 10.77; S, 12.44%.
White solid (207 mg, 90%), mp 184–186 ꢁC from n-hexane. IR
(KBr pellet):
1396, 1372, 1352, 1146, 1116, 1052, 1040, 874, 838 cmꢀ1
(400.1 MHz, CDCl3):
CH3), 1.59 (3H, s, CH3), 1.49–1.77 (4H, m, CH2CH3, CH2-5), 2.56 (1H,
dd, J 16.1, 12.2 Hz, CHHax-3), 2.54–2.65 (1H, m, CHax-4), 3.11 (1H, br
n
¼3180 br, 3068, 2988, 2964, 2944, 2876, 1564, 1542,
;
1H NMR
4.2.30. trans 4-(1-Methyl-1-nitroethyl)-6-phenylpiperidine-
2-thione (7k)
d¼0.97 (3H, t, J 7.3 Hz, CH2CH3), 1.55 (3H, s,
White solid (122 mg, 44%), mp 194–197 ꢁC from n-hexane/
ethyl acetate. IR (KBr pellet):
1536, 1452, 1400, 1348, 1116, 848, 760, 704 cmꢀ1
(400.1 MHz, CDCl3):
CHHeq-5), 1.98 (1H, ddd, J 13.3, 11.6, 5.6 Hz, CHHax-5), 2.38 (1H,
ddt, J 12.1, ca. 11.6, ca. 4.6 Hz, CHax-4), 2.67 (1H, dd, J 18.1, 12.0 Hz,
CHHax-3), 3.19 (1H, ddd, J 18.1, 4.7, 2.1 Hz, CHHeq-3), 4.86 (1H, dt, J
5.6, 3.4 Hz, CHeq-6), 7.18 (2H, dm, J 7.3 Hz, C6H5), 7.34 (1H, tt, J ca.
7.2, ca. 1.3 Hz, C6H5), 7.39–7.43 (2H, m, C6H5), 8.74 (1H, s, NH); 13C
n
¼3456 br, 3148, 3052, 2988, 2936,
1H NMR
¼1.49 (6H, s, 2ꢂCH3), 1.91 (1H, dm, J 13.3 Hz,
d, J 16.1 Hz, CHHeq-3), 3.55 (1H, dquintet, J ca. 7.0, ca. 3.4 Hz, CHeq
-
;
6), 8.91 (1H, s, NH); 13C NMR (100.6 MHz, CDCl3):
21.2 (CH3), 24.6 (CH3), 26.3 (CH2CH3), 28.1 (CH2-5), 36.8 (CH-4), 41.1
d
¼10.5 (CH2CH3),
d
br (CH2-3), 55.7 (CH-6), 90.2 (CNO2), 200.1 (C-2); GC–MS (EI,
ꢃ
70 eV): m/z¼230 (100, Mþ ), 207 (6), 184 (62), 168 (16), 154 (15), 142
(12), 112 (22), 100 (17), 83 (20), 69 (48), 58 (19), 55 (25), 41 (28).
Anal. Calcd for C10H18N2O2S: C, 52.15; H, 7.88; N, 12.16; S, 13.92%.
Found: C, 52.06; H, 7.93; N, 12.22; S, 13.83%.
NMR (100.6 MHz, CDCl3):
d
¼22.1, 23.9 (2ꢂCH3), 30.6 (CH2-5), 35.8
(CH-4), 40.8 (CH2-3), 57.6 (CH-6), 89.7 (CNO2), 125.9, 128.4, 129.1,
ꢃ
4.2.27. trans 6-Butyl-4-(1-methyl-1-nitroethyl)piperidine-
2-thione (7h)
139.7 (C6H5), 201.8 (C-2); GC–MS (EI, 70 eV): m/z¼278 (100, Mþ ),
232 (44), 198 (29), 189 (16), 188 (16), 175 (57), 157 (50), 131 (13),
129 (30), 117 (39), 115 (21), 106 (50), 104 (34), 91 (70), 79 (17), 77
(27), 69 (49), 41 (26). Anal. Calcd for C14H18N2O2S: C, 60.40; H,
6.52; N, 10.06; S, 11.52%. Found: C, 60.46; H, 6.55; N, 10.09; S,
11.44%.
White solid (227 mg, 88%), mp 120–121 ꢁC from n-hexane. IR
(KBr pellet):
1112 cmꢀ1 1H NMR (400.1 MHz, CDCl3):
CH3), 1.24–1.39 (4H, m 2ꢂCH2), 1.42–1.72 (4H, m, CH2, CH2-5), 1.55
n
¼3172 br, 3064, 2932, 2860, 1568, 1568, 1538, 1344,
;
d
¼0.92 (3H, t, J 7.1 Hz,

ꢀ
J.G. Sosnicki / Tetrahedron 65 (2009) 1336–1348
1346
4.2.31. trans 6-sec-Butyl-4-(1-methyl-1-nitroethyl)piperidine-
2-thione (7l)
(CH-6), 93.3 (CNO2), 200.2 v br
*
(C-2); GC–MS (EI, 70 eV): m/z¼326
ꢃ
(<1, Mþ ), 279 (69), 264 (19), 246 (100), 208 (32), 194 (21), 184 (13),
151 (11), 128 (12), 117 (14), 91 (17), 79 (17), 67 (13), 55 (15), 41 (18).
Anal. Calcd for C17H30N2O2S: C, 62.54; H, 9.26; N, 8.58; S, 9.82%.
Found: C, 62.55; H, 9.33; N, 8.55; S, 9.93%. *Signal visible at 230 K.
Mixture of diastereomers. White solid (186 mg, 72%), mp 98–
100 ꢁC from n-hexane/ethyl acetate. IR (KBr pellet):
n
¼3172, 3064,
2964, 1568, 1536, 1464, 1400, 1376, 1344, 1112, 852 cmꢀ1 1H NMR
(400.1 MHz, CDCl3): J 6.8 Hz,
;
d¼0.88 and 0.89 (6H, two d,
2ꢂCH3CH), 0.91 and 0.94 (6H, two t, J 7.3 Hz, 2ꢂCH2CH3), 1.06–1.30
(2H, m, 2ꢂCHH), 1.39–1.80 (20H, 2ꢂCHH, 2ꢂCHCH3, 4ꢂCH3,
2ꢂCH2-5), 2.48–2.66 (4H, m, 2ꢂCHH-3, CH-4), 3.12 (2H, dm, J ca.
14.6 Hz, 2ꢂCHH-3), 3.29–3.37 (2H, m, 2ꢂCH-6), 8.77 and 8.67 (2H,
4.2.35. trans 6-Butyl-4-(1-nitroethyl)piperidine-2-thione
(7p major)
Configuration at CaNO2 was not established. White solid,
mp113–115 ꢁC from n-hexane/ethyl acetate. IR (KBr pellet):
n
¼3180
two br s, 2ꢂNH); 13C NMR (100.6 MHz, CDCl3):
d
¼11.0 and 11.1
br, 3060, 2956, 1554, 1458, 1392, 1340, 1104, 812 cmꢀ1
(400.1 MHz, CDCl3):
;
1H NMR
(2ꢂCH2CH3), 14.9 and 15.4 (2ꢂCHCH3), 21.0 and 21.1 (2ꢂCCH3), 24.3
and 24.9 (2ꢂCH2), 25.4 and 25.7 (2ꢂCH2), 37.4 and 37.5 (2ꢂCH-4),
38.6 and 38.8 (2ꢂCHCH3), 40.8 and 40.8 (2ꢂCH2-3), 58.1 and 58.3
(2ꢂCH-6), 90.3 and 90.4 (2ꢂCNO2), 200.9 and 201.0 (2ꢂC-2); GC–
d
¼0.92 (3H, t, J 6.8 Hz, CH2CH3), 1.25–1.39 (4H,
m, 2ꢂCH2), 1.44–1.55 (1H, m, CHH), 1.59 (3H, d, J 6.7 Hz, CHCH3),
1.56–1.74 (3H, m, CH2-5, CHH), 2.38–2.51 (1H, m, CHax-4), 2.62 (1H,
dd, J 18.2, 9.3 Hz, CHHax-3), 3.11 (1H, dd, J 18.2, 4.8 Hz, CHHeq-3),
3.52–3.61 (1H, m, CHeq-6), 4.45 (1H, dquintet, J 9.4, 6.7 Hz, CHNO2),
ꢃ
MS (EI, 70 eV): m/z¼258 (100, Mþ ), 212 (58), 201 (11), 182 (10), 154
(78), 128 (10), 112 (58), 97 (19), 83 (21), 69 (23), 41 (22). Anal. Calcd
for C12H22N2O2S: C, 55.78; H, 8.58; N, 10.84; S, 12.41%. Found: C,
55.72; H, 8.70; N, 10.86; S, 12.45%.
8.76 (1H, br s, NH); 13C NMR (100.6 MHz, CDCl3):
d¼13.9 (CH2CH3),
17.2 (CH3CH), 22.4, 27.7, 28.6 (3ꢂCH2), 33.8 (CH-4), 35.3 (CH2-5),
41.1 (CH2-3), 53.4 (CH-6), 86.0 (CHNO2), 199.3 (C-2); GC–MS (EI,
ꢃ
70 eV): m/z¼244 (57, Mþ ), 214 (11), 198 (30), 170 (20), 154 (22), 140
4.2.32. trans 6-Ethyl-4-(1-nitrocyclohexyl)piperidine-
2-thione (7m)
(19), 128 (11), 114 (21), 112 (100), 97 (23), 83 (22), 69 (30), 55 (39),
41 (29). Anal. Calcd for C11H20N2O2S: C, 54.07; H, 8.25; N, 11.46; S,
13.12%. Found: C, 54.15; H, 8.22; N, 11.50; S, 13.19%.
White solid (205 mg, 76%), mp 144–146 ꢁC from n-hexane/ethyl
acetate. IR (KBr pellet):
n
¼3172, 3064, 2936, 2868, 1564, 1530, 1452,
1352, 1124, 1106, 848, 828 cmꢀ1
;
1H NMR (400.1 MHz, CDCl3):
4.2.36. trans 6-Butyl-4-(1-nitroethyl)piperidine-2-thione
(7p minor)
d
¼0.96 (3H, t, J 7.3 Hz, CH3), 1.15–1.43 (3H, m, 3ꢂCHH), 1.46–1.80
(9H, m, 2ꢂCHH, 3ꢂCHH, 2ꢂCH2), 2.22 (1H, tt, J ca. 11.7, ca. 4.4 Hz,
CHax-4), 2.45 (1H, br d, J ca. 13.5 Hz, CHH), 2.49 (1H, br d, J ca.
13.8 Hz, CHH), 2.63 (1H, dd, J 17.5, 12.2 Hz, CHHax-3), 3.18 (1H, br d, J
17.4 Hz, CHHeq-3), 3.48 (1H, br s, CHeq-6), 8.81 (1H, br s, NH); 13C
Configuration at CaNO2 was not established. White solid,
mp117–119 ꢁC from n-hexane/ethyl acetate. IR (KBr pellet):
n
¼3172,
3068, 2956, 2932, 1572, 1542, 1460, 1416, 1394, 1360, 1344, 1296,
1152, 1108 cmꢀ1 1H NMR (400.1 MHz, CDCl3):
;
d
¼0.93 (3H, t, J
NMR (100.6 MHz, CDCl3):
d¼10.5 (CH3), 22.1, 22.3, 24.6, 26.1
7.0 Hz, CH2CH3), 1.30–1.40 (4H, m, 2ꢂCH2), 1.45–1.60 (1H, m, CHH),
1.57 (3H, d, J 6.8 Hz, CHCH3), 1.60–1.77 (2H, m, CHH, CHHax-5), 1.80
(1H, dm, J ca. 13.5, CHHeq-5), 2.43–2.54 (1H, m, CHax-4), 2.64 (1H,
(4ꢂCH2), 28.3 br (CH2-5), 30.6, 32.4 (2ꢂCH2), 37.9 br (CH-4), 40.2*
(CH2-3), 55.5 (CH-6), 93.4 (CNO2), 198.8* (C-2); GC–MS (EI, 70 eV):
ꢃ
m/z¼270 (75, Mþ ), 224 (100), 190 (12), 142 (24), 116 (39), 81 (15),
dd, J 18.1, 10.2 Hz, CHHax-3), 3.08 (1H, ddd, J 18.1, 4.8, 1.5 Hz, CHHeq
3), 3.48–3.57 (1H, m, CHeq-6), 4.50 (1H, quintet, J 6.8 Hz, CHNO2),
8.82 (1H, br s, NH); 13C NMR (100.6 MHz, CDCl3):
-
67 (18), 58 (20), 55 (19), 41 (22). Anal. Calcd for C13H22N2O2S re-
quires: C, 57.75; H, 8.20; N,10.36; S, 11.86%. Found: C, 57.72; H, 8.30;
N, 10.36; S, 11.85%. *Signal visible at 230 K.
d
¼13.9 (CH2CH3),
16.0 (CH3CH), 22.4, 27.5, 27.9 (3ꢂCH2), 33.1 (CH-4), 35.2 (CH2-5),
41.6 (CH2-3), 53.6 (CH-6), 85.7 (CHNO2), 199.8 (C-2); GC–MS (EI,
ꢃ
4.2.33. trans 6-Butyl-4-(1-nitrocyclohexyl)piperidine-2-thione (7n)
White solid (227 mg 76%), mp 119–121 ꢁC from n-hexane/ethyl
acetate. IR (KBr pellet):
1534, 1450, 1352, 1148, 1100, 844 cmꢀ1
CDCl3):
70 eV): m/z¼244 (74, Mþ ), 214 (12), 198 (43), 170 (27), 154 (23), 140
(27), 128 (15), 112 (100), 97 (29), 83 (30), 69 (40), 55 (48), 41 (35);
HRMS (EI) for C11H20N2O2S: calculated 244.1245, found 244.1242.
n
¼3176, 3068, 2940, 2860, 1658, 1646, 1564,
;
1H NMR (400.1 MHz,
d¼0.91 (3H, t, J 7.0 Hz, CH3), 1.16–1.49 (7H, m, 5ꢂCHH, CH2),
4.3. Synthesis of 4-nitroalkylpiperidine-2-ones (8)
1.49–1.77 (9H, m, 2ꢂCHH, 5ꢂCHH, CH2), 2.17–2.30 (1H, m, CHax-4),
2.46 (1H, br d, J ca. 14.3 Hz, CHH), 2.49 (1H, br d, J ca. 14.3 Hz, CHH),
2.60 (1H, dd, J 17.8, 11.8 Hz, CHHax-3), 3.15 (1H, ddd, J 17.8, 4.5,
Transformations of 4-nitroalkyl
sponding -lactams 8 were carried out according to the procedure
described by Nowaczyk et al.26 with some modification. To a solu-
tion of 4-nitroalkyl -thiolactam (4f or 5f or 7b or 7h) (0.7 mmol) in
d-thiolactams to the corre-
d
1.9 Hz, CHHeq-3), 3.45–3.56 (1H, m, CHeq-6), 8.8 (1H, br s, NH); 13
C
NMR (100.6 MHz, CDCl3):
d¼13.9 (CH3), 22.1, 22.2, 22.4, 24.6, 26.6,
d
28.0, 30.5, 32.4, 34.9 (9ꢂCH2), 37.5 (CH-4), 40.6 (CH2-3), 54.2 (CH-
acetone (10 ml) and water (1 ml), sodium bicarbonate (2.8 mmol)
was added at 0–2 ꢁC. To a stirred suspension oxone (0.35 mmol)
was added. After 15 min of stirring the next 5 portions of oxone
(0.175 mmol) were added at 15 min intervals. After addition of the
last portion of oxone the solution was stirred for additional 30 min
and water (10 ml) was added. (In the case of NH products 8f and 8g
5 ml of concentrated solution of NH4Cl was also added.) The solu-
tion was extracted twice (2ꢂ50 ml) with ethyl acetate. The organic
phase separated was dried (MgSO4), filtered, and concentrated in
vacuo. The crude product was purified by column chromatography
on silica and crystallized from the appropriate solvents.
ꢃ
6), 93.3 (CNO2), 200.7 (C-2); GC–MS (EI, 70 eV): m/z¼298 (39, Mþ ),
252 (100), 218 (20), 194 (13), 170 (30), 144 (19), 112 (17), 69 (16), 67
(18), 55 (17), 41 (22). Anal. Calcd for C15H26N2O2S: C, 60.37; H, 8.78;
N, 9.39; S, 10.74%. Found: C, 60.35; H, 8.83; N, 9.36; S, 10.85%.
4.2.34. trans 6-Hexyl-4-(1-nitrocyclohexyl)piperidine-
2-thione (7o)
White solid (261 mg, 80%), mp 75–76 ꢁC from n-hexane/ethyl
acetate. IR (KBr pellet):
n
¼3164, 3060, 2944, 2864, 1572, 1540, 1450,
1344, 1102, 844 cmꢀ1; 1H NMR (400.1 MHz, CDCl3):
d
¼0.89 (3H, t, J
7.0 Hz, CH3), 1.18–1.48 (12H, m, 4ꢂCHH, 4ꢂCH2), 1.48–1.80 (8H, m,
2ꢂCHH, 4ꢂCHH, CH2), 2.23 (1H, tt, J ca. 11.5, ca. 4.4 Hz, CHax-4), 2.45
(1H, br d, J ca. 14.5 Hz, CHH), 2.49 (1H, br d, J ca. 14.5 Hz, CHH), 2.61
(1H, dd, J 17.8, 11.7 Hz, CHHax-3), 3.16 (1H, dm, J 17.8 Hz, CHHeq-3),
3.52 (1H, br s, CHeq-6), 8.82 (1H, br s, NH); 13C NMR (100.6 MHz,
4.3.1. trans 6-Butyl-4-nitromethylpiperidin-2-one (8f)
White solid (139 mg, 93%), mp 69–72 ꢁC from n-hexane/ethyl
acetate. IR (KBr pellet):
1456, 1432, 1410, 1372, 1356, 1340 cmꢀ1
CDCl3):
¼0.91 (3H, t, J 7.0 Hz, CH3), 1.25–1.40 (4H, m, 2ꢂCH2), 1.44–
1.62 (2H, m, CH2), 1.73–1.80 (2H, m, CH2-5), 2.16 (1H, dd, J 17.3,
n
¼3196 br, 2960, 2936, 1656, 1648, 1554,
;
1H NMR (400.1 MHz,
CDCl3):
d
¼14.05 (CH3), 22.1, 22.2, 22.5, 24.6, 25.9, 26.6, 28.9, 30.5,
d
31.6, 32.4, 35.3 (11ꢂCH2), 37.7 br (CH-4), 41.3 v br
*
(CH2-3), 54.3

ꢀ
J.G. Sosnicki / Tetrahedron 65 (2009) 1336–1348
1347
7.8 Hz, CHHax-3), 2.55 (1H, dd, J 17.3, 5.7 Hz, CHHeq-3), 2.83–2.95
References and notes
(1H, m, CH-4), 3.50 (1H, quintet, J ca. 6.0 Hz, CH-6), 4.37–4.41 (2H,
m, CH2NO2), 6.56 (1H, br s, NH); 13C NMR (100.6 MHz, CDCl3):
1. (a) Perlmutter, P. Conjugate Addition Reactions in Organic Synthesis; Pergamon:
Oxford, 1992; (b) Rossiter, B. E.; Swingle, N. M. Chem. Rev. 1992, 92, 771–806; (c)
Drauz, K.; Scha¨fer, M.; Schwarm, M. Formation of C–N Bonds by Conjugate
Addition of N-Nucleophiles. In Stereoselective Synthesis; Helmchen, G., Hoff-
mann, R. W., Mulzer, J., Schaumann, E., Eds.; Houben-Weyl; Georg Thieme:
Stuttgart, 1995; Vol. E21e, pp 5588–5642; (d) Sibi, M. P.; Manyem, S. Tetrahe-
dron 2000, 56, 8033–8061; (e) Jha, S. C.; Joshi, N. N. ARKIVOC 2002, vii, 167–196;
(f) Davies, S. G.; Smith, A. D.; Price, P. D. Tetrahedron: Asymmetry 2005, 16, 2833–
2891; (g) Guo, H.-C.; Ma, J.-A. Angew. Chem., Int. Ed. 2006, 45, 354–366; (h)
Almas¸i, D.; Alonso, D. A.; Na´jera, C. Tetrahedron: Asymmetry 2007, 18, 299–365;
(i) Tsogoeva, S. B. Eur. J. Org. Chem. 2007, 11, 1701–1716; (j) Lopez, F.; Minnaard,
A. J.; Feringa, B. L. Acc. Chem. Res. 2007, 40, 179–188; (k) Christoffers, J.; Kor-
ipelly, G.; Rosiak, A.; Ro¨ssle, M. Synthesis 2007, 9, 1279–1300.
2. For selected examples see: (a) Leung, D.; Abbenante, G.; Fairlie, D. P. J. Med.
Chem. 2000, 43, 305–341; (b) Vacher, B.; Bonnaud, B.; Funes, P.; Jubault, N.;
Koek, W.; Assie, M. B.; Cosi, C.; Kleven, M. J. Med. Chem. 1999, 42, 1648–1660; (c)
Webber, R. K.; Metz, S.; Moore, W. M.; Connor, J. R.; Currie, M. G.; Fok, K. F.;
Hagen, T. J.; Hansen, D. W., Jr.; Jerome, G. M.; Manning, P. T.; Pitzele, B. S.; Toth,
M. V.; Trivedi, M.; Zupec, M. E.; Tjoeng, F. S. J. Med. Chem. 1998, 41, 96–101; (d)
Babine, R. E.; Bender, S. L. Chem. Rev. 1997, 97, 1359–1472.
3. (a) Rubiralta, M.; Giralt, E.; Diez, A. Piperidines. Structure, Preparation, Reactivity
and Synthetic Application of Piperidines and its Derivatives; Elsevier: Amsterdam,
1991; For selected reviews on piperidines see: (b) Sardina, F. J.; Rapoport, H.
Chem. Rev. 1996, 96, 1825–1849; (c) Laschat, S.; Dickner, T. Synthesis 2000, 1781–
1813; (d) Nadin, A. J. Chem. Soc., Perkin Trans. 1 2000, 2862–2892; (e) Wein-
traub, P. M.; Sabol, J. S.; Kane, J. M.; Borcherding, D. R. Tetrahedron 2003, 59,
2953–2989; (f) Buffat, M. G. P. Tetrahedron 2004, 60, 1701–1729; (g) Huang,
P.-Q. Synlett 2006, 1133–1149; (h) Stead, D.; Brien, P. O. Tetrahedron 2007, 63,
1885–1897.
d
¼13.9 (CH3), 22.4, 27.8 (2ꢂCH3), 28.9 (CH-4), 29.9 (CH2-5), 34.4 br
(CH2-3), 36.4 (6-CH2), 49.7 (CH-6), 78.7 (CH2NO2), 169.6 (C-2); GC–
ꢃ
MS (EI, 70 eV): m/z¼214 (<1, Mþ ), 184 (9), 157 (53), 125 (11), 110
(25), 96 (100), 68 (18), 55 (10), 41 (14). Anal. Calcd for C10H18N2O3:
C, 56.06; H, 8.47; N, 13.07%. Found: C, 56.01; H, 8.42; N, 12.99%.
4.3.2. trans 6-Butyl-4-(1-methyl-1-nitroethyl)piperidin-2-one (8g)
White needles (163 mg, 96%), mp 116–118 ꢁC from n-hexane/
ethyl acetate. IR (KBr pellet):
1536, 1480, 1400, 1378, 1348, 1144, 808 cmꢀ1; 1H NMR (400.1 MHz,
CDCl3):
n
¼3276 br, 2960, 2872, 1666, 1620 br,
d
¼0.91 (3H, t, J 7.0 Hz, CH3), 1.20–1.38 (4H, m, 2ꢂCH2), 1.40–
1.65 (4H, m, 6-CH2, CH2-5), 1.56 (3H, s, CH3), 1.57 (3H, s, CH3), 2.10
(1H, dd, J 17.0, 12.4 Hz, CHHax-3), 2.40 (1H, ddd, J 17.0, ca. 4.7, 1.7 Hz,
CHHeq-3), 2.63–2.73 (1H, m, CH-4), 3.43–3.51 (1H, m, CH-6), 6.73
(1H, br s, NH); 13C NMR (100.6 MHz, CDCl3):
d¼13.9, 21.4 (2ꢂCH3),
22.4 (CH2), 24.2 (CH3), 27.8 (CH2-5), 28.2 (CH2), 33.2 (CH2-3), 35.8
(6-CH2), 36.9 (CH-4), 50.4 (CH-6), 90.3 (CNO2), 170.6 (C-2); GC–MS
ꢃ
(EI, 70 eV): m/z¼242 (<1, Mþ ), 212 (5), 196 (22), 194 (17), 185 (32),
152 (9), 138 (100), 110 (11), 96 (52), 86 (18), 69 (21), 55 (16), 41 (24).
Anal. Calcd for C12H22N2O3: C, 59.48; H, 9.15; N, 11.56%. Found: C,
59.55; H, 9.12; N, 12.00%.
4. Davies, S. G.; Garner, A. C.; Goddard, E. C.; Kruchinin, D.; Roberts, P. M.; Smith,
A. D.; Rodriguez-Solla, H.; Thomson, J. E.; Toms, S. M. Org. Biomol. Chem. 2007, 5,
1961–19691.
5. See for example: (a) Takano, S.; Sato, M.; Ogasawara, K. Heterocycles 1981, 16,
799–801; (b) Deiters, A.; Martin, S. F. Org. Lett. 2002, 19, 3243–3246; (c) Garcia,
E.; Lete, E.; Sotomayor, N. J. Org. Chem. 2006, 71, 6776–6784; (d) Amat, M.; Llor,
4.3.3. trans 6-Allyl-1-benzyl-4-(1-methyl-1-nitroethyl)piperidin-2-
one (8h)
Colorless oil (206 mg, 93%). IR (thin film):
n
¼2936, 1640, 1536,
1452, 1346, 1110, 924, 732, 704 cmꢀ1; 1H NMR (400.1 MHz, CDCl3):
´
N.; Checa, B.; Perez, M.; Bosch, J. Tetrahedron Lett. 2007, 48, 6722–6725; (e)
d
¼1.39 (1H, td, J 13.2, 5.3 Hz, CHHax-5), 1.53 (3H, s, CH3), 1.56 (3H, s,
Oueslati, F.; Perrio, C.; Dupas, G.; Barre´, L. Org. Lett. 2007, 9, 153–156.
6. Pineschi, M.; Moro, F. D.; Gini, F.; Minnaard, A. J.; Feringa, B. L. Chem. Commun.
2004, 1244–1246.
7. Nagashima, H.; Ozaki, N.; Washiyama, M.; Itoh, K. Tetrahedron Lett. 1985, 26,
657–660.
8. (a) Hagen, T. J. Synlett 1990, 3–66; Muller, M.; Schoenfelder, A.; Didier, B.; Mann,
A.; Wermuth, C.-G. Chem. Commun. 1999, 683–684; (b) Herdeis, C.; Kaschinski,
C.; Karla, R.; Lotter, H. Tetrahedron: Asymmetry 1996, 7, 867–884; (c) Coe, D.;
Drysdale, M.; Philps, Ol.; West, R.; Young, D. W. J. Chem. Soc., Perkin Trans. 1
2002, 22, 2459–2472; (d) Lerchner, A.; Carreira, E. M. J. Am. Chem. Soc. 2002,
124, 14826–14827; (e) Lerchner, A.; Carreira, E. M. Chem.dEur. J. 2006, 12,
8208–8219.
9. See for example: (a) Amat, M.; Llor, N.; Bosch, J.; Solans, X. Tetrahedron 1997, 53,
719–730; (b) Amat, M.; Bosch, J.; Hidalgo, J.; Canto´ , M.; Pe´rezLlor, N.; Molins, E,;
Miravitlles, C.; Orozco, M.; Luque, J. J. Org. Chem. 2000, 65, 3074–3084; (c) Ecija,
M.; Diez, A.; Rubiralta, M.; Casamitjana, N.; Kogan, M. J.; Giralt, E. J. Org. Chem.
CH3), 1.75 (1H, dquartet, J 13.2, 2.0 Hz, CHHeq-5), 2.17–2.27 (1H, m,
6-CHH), 2.26 (1H, dd, J 17.4, 12.2 Hz, CHHax-3), 2.52–2.59 (1H, m, 6-
CHH), 2.58 (1H, ddd, J 17.2, 5.9, 2.1 Hz, CHHeq-3), 2.80 (1H, tdd, J ca.
12.5, ca. 5.9, 2.0 Hz, CHax-4), 3.35–3.43 (1H, m, CHeq-6), 3.98 (1H, d,
J 15.0 Hz, NCHH), 5.08–5.15 (2H, m, ]CH2), 5.36 (1H, d, J 15.0 Hz,
NCHH), 5.52–5.64 (1H, m, ]CH), 7.21 (2H, d, J 7.2 Hz, C6H5), 7.25–
7.37 (3H, m, C6H5); 13C NMR (100.6 MHz, CDCl3):
d
¼21.5, 23.8
(2ꢂCH3), 26.9 (CH2-5), 33.4 (CH2-3), 36.4 (6-CH2), 36.5 (CH-4), 47.8
(NCH2), 53.8 (CH-6), 90.2 (CNO2), 119.1 (]CH2), 127.5, 127.8, 128.7,
137.0 (C6H5), 133.5 (]CH), 168.1 (C-2); GC–MS (EI, 70 eV): m/z¼316
ꢃ
(<1, Mþ ), 315 (2), 275 (41), 228 (31), 186 (15), 91 (100); HRMS (EI)
for C18H24N2O3: calculated 316.1787, found 316.1788.
´
2003, 68, 9541–9553; (d) Amat, M.; Perez, M.; Minaglia, A. T.; Peretto, B.; Bosch,
J. Tetrahedron 2007, 63, 5839–5848; (e) Camerero, C.; Gonza´lez-Temprano, I.;
´
Lete, E.; Sotomayor, N. Synlett 2007, 1101–1105; (f) Amat, M.; Perez, M.; Min-
4.3.4. trans 4-(1-Nitrocyclohexyl)-1-phenylpiperidin-2-one (8i)
White solid (184 mg, 87%), mp 183–185 ꢁC from n-hexane/ethyl
aglia, A. T.; Bosch, J. J. Org. Chem. 2008, 73, 6920–6923.
10. Tinarelli, A.; Paolucci, C. J. Org. Chem. 2006, 71, 6630–6633; (c) Herdeis, C.;
Waibel, D. Arch. Pharm. (Weinheim, Ger.) 1991, 324, 269–274.
11. (a) Tamaru, Y.; Harada, T.; Iwamoto, H.; Yoshida, Z.-i. J. Am. Chem. Soc. 1978, 100,
5221–5223; (b) Tamaru, Y.; Kagotani, M.; Yoshida, Z.-i. Tetrahedron Lett. 1981, 22,
3409–3412.
acetate. IR (KBr pellet):
1476, 1432, 1416, 1348, 1308, 768, 696 cmꢀ1
CDCl3):
3ꢂCHH, CHHax-5), 2.01 (1H, dm, J ca. 12.6 Hz, CHHeq-5), 2.36 (1H,
tdd, J ca. 12.2, 4.3, 2.9 Hz, CHax-4), 2.43 (1H, dd, J 16.3, 12.3 Hz,
CHHax-3), 2.52 (1H, dm, J ca. 16.5 Hz, CHHeq), 2.57 (1H, dm, J ca.
16.4 Hz, CHHeq), 2.69 (1H, dm, J ca. 16.3 Hz, CHHeq-3), 3.62–3.68
(2H, m, CH2-6), 7.21 (2H, dm, J ca. 7.4 Hz, C6H5), 7.27 (1H, tt, J 7.6,
1.2 Hz, C6H5), 7.39 (2H, t, J 7.7 Hz, C6H5); 13C NMR (100.6 MHz,
n
¼3072, 2940, 1650, 1592, 1526, 1496,
1H NMR (400.1 MHz,
¼1.15–1.45 (3H, m, 3ꢂCHH), 1.54–1.80 (6H, m, 2ꢂCHHax
;
d
,
12. Tamaru, Y.; Harada, T.; Yoshida, Z.-i. J. Am. Chem. Soc. 1979, 101, 1316–1318.
13. Sosnicki, J. G.; Jagodzin´ ski, T. S.; Liebscher, J. J. Heterocycl. Chem. 1997, 34,
ꢀ
643–648.
ꢀ
´
14. Sosnicki, J. G.; Jagodzinski, T. S.; Hansen, P. E. Tetrahedron 2001, 57, 8705–8718.
15. (a) Ballini, R.; Bosica, G.; Fiorini, D.; Palmieri, A.; Petrini, M. Chem. Rev. 2005,
105, 933–971; (b) Ballini, R.; Barboni, L.; Bosica, G.; Fiorini, D.; Palmieri, A. Pure
Appl. Chem. 2006, 78, 1857–1866; (c) Ballini, R.; Palmieri, A.; Righi, P. Tetrahe-
dron 2007, 63, 12099–12121.
16. Ono, N. The Nitro Group in Organic Synthesis; Wiley-VCH: New York, NY,
2001.
17. (a) Hanessian, S.; Seid, M.; Nilsson, I. Tetrahedron Lett. 2002, 43, 1991–1994; (b)
Gheorghe, A.; Schulte, M.; Reiser, O. J. Org. Chem. 2006, 71, 2173–2176.
18. Chavan, A. P.; Venkatraman, M. S.; Kale, R. R. Tetrahedron Lett. 2004, 45, 6879–
6882.
CDCl3):
d
¼22.1, 22.2, 24.6 (3ꢂCH2), 24.7 (CH2-5), 30.4, 32.2
(2ꢂCH2), 34.0 (CH2-3), 42.2 (CH-4), 50.3 (CH2-6), 93.5 (CNO2),
126.0, 127.1, 129.3, 142.4 (C6H5), 168.2 (C-2); GC–MS (EI, 70 eV):
ꢃ
m/z¼302 (Mþ , 73), 256 (86), 174 (14), 146 (18), 119 (23), 106 (100),
81 (19), 77 (26), 67 (18), 55 (22), 41 (16); HRMS (EI) for
C17H22N2O3: calculated 302.1630, found 302.1632.
19. Morrissette, M. M.; Williams, P. D.; Wai, J. S.; Fisher, T.; Lyle, T. A. PCT Int. Appl
WO 2005086700 A2, 2005.
ꢀ
ꢀ
20. (a) Sosnicki, J. G.; Liebscher, J. Synlett 1996, 1117–1118; (b) Sosnicki, J. G. Synlett
2003, 1673–1677.
ꢀ
21. Sosnicki, J. G.; Westerlich, S. Tetrahedron Lett. 2002, 43, 1325–1328.
Acknowledgements
22. Hoffmann, R. W. Chem. Rev. 1989, 89, 1841–1860.
ꢀ
ꢀ
23. (a) Sosnicki, J. G.; Hansen, P. E. J. Mol. Struct. 2004, 700, 91–103; (b) Sosnicki,
J. G.; Langaard, M.; Hansen, P. E. J. Org. Chem. 2007, 72, 4108–4116 and refer-
ences cited therein.
Financial support by the National Committee for Scientific Re-
search (KBN, Grant No. 3 T09A 106 28) is gratefully acknowledged.

ꢀ
J.G. Sosnicki / Tetrahedron 65 (2009) 1336–1348
1348
24. For example: Okino, T.; Nakamura, S.; Furukawa, T.; Takemoto, Y. Org. Lett.
2004, 6, 625–627.
25. Sosnicki, J. G. Tetrahedron 2007, 63, 11862–11877.
27. PM3 calculations were performed using the HyperChem program (7.52
release).
ꢀ
28. Haasnoot, C. A. G.; DeLeeuw, F. A. A. M.; Altona, A. Tetrahedron 1980, 36, 2783–
26. Nowaczyk, S.; Alayrac, C.; Reboul, V.; Metzner, P.; Averbuch-Pouchot, M.-T.
2792.
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J. Org. Chem. 2001, 66, 7841–7848.
29. Sosnicki, J. G. Tetrahedron Lett. 2009, 50, 178–181.