Thioamidoalkylation of 1,3-dicarbonyl compounds, enol silyl ethers, and enamines

Article abstract of DOI:10.1055/s-2007-966064

Novel syntheses of β-thioamido ketones via thioamido-alkylations of malonates, β-keto esters, β-diketones, enol silyl ethers, and enamines with N-(α-thioamidoalkyl)benzotriazoles are described. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-966064

PAPER
1655
Thioamidoalkylation of 1,3-Dicarbonyl Compounds, Enol Silyl Ethers, and
Enamines
T
hioamidoalkylati
l
on of
1
a
,3-Dicarbonyl Compounds R. Katritzky,*a Ilhami Celik,a,b Ashraf A. A. Abdel-Fattaha,c
a
Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville, FL 32611-7200, USA
Fax +1(352)3929199; E-mail: katritzky@chem.ufl.edu.
b
c
Department of Chemistry, Faculty of Science, Anadolu University, 26470 Eskisehir, Turkey
Department of Chemistry, Faculty of Science, Benha University, Benha, Egypt
Received 16 November 2006; revised 16 February 2007
though this is limited by the availability of the starting
amide); (ii) formation of bond b by using isothiocyanate
as an electrophile to react with aromatic and hetero(aro-
matic) compounds under Lewis acid conditions19 (limited
by the availability of isothiocyanates); (iii) formation of
bond c by treating dithioacids with azides in the presence
of a base promoter20 (limited by the availability of dithio-
acids); (iv) formation of bond d by the N-alkylation of a
thioamide RCSNH2 achieved in two steps by N-benzotri-
azolylalkylation of the thioamide to produce adducts of
type 2 followed by reductive elimination of the benzotri-
azolyl group with sodium borohydride;21 (v) formation of
bond e achieved by treating 2 with 2.1 equivalents of
Grignard reagents;22 and (vi) formation of both bonds a
and c by three-component Kindler reactions23 (used main-
ly for tertiary thioamides).
Abstract: Novel syntheses of b-thioamido ketones via thioamido-
alkylations of malonates, b-keto esters, b-diketones, enol silyl
ethers, and enamines with N-(a-thioamidoalkyl)benzotriazoles are
described.
Key words: thioamides, N-(a-thioamidoalkyl)benzotriazoles, thio-
amidoalkylation, 1,3-dicarbonyl compounds, enol silyl ethers,
enamines
The utility of thioamides as synthetic intermediates is in-
creasingly recognized.1 In the preparation of heterocycles
containing both nitrogen and sulfur two heteroatoms can
be introduced in a single step, to provide, for example,
oxathiazines,2 thiadiazines,3 dithiazines,4 thiazines,5
thiazolines1a and thiazoles.1a Thioamides are precursors
for other substrates.6 Some thioamides possess inhibitory
activity against moulds,7 yeasts,8 dermatophytes,9 and
phytopathogenic fungi in vitro,10 while others are used as
flotation and vulcanization agents, as additives to lubricat-
ing oils and greases, and as interesting ligands in coordi-
nation chemistry.1a
R1
S
a
N
H
R
R2
c
e
d
b
1
The thioamide linkage in thiopeptides is isosteric to the
parent (oxo)amide bond.11 Although the larger size of the
sulfur atom and the longer carbon–sulfur bond length re-
strict the allowed f and Y angles of the amino acids flank-
ing the thioamide group, conformations compatible with
the three major types of regular secondary structure (a-he-
lix, b-sheet, and b-turn) are accessible in thiopeptides.12
The conformational restrictions introduced by the thio-
amides, together with their ability to confer increased en-
zymatic stability13 and increased potency and
selectivity,14 affords thiopeptides potential in drug design.
The thioamide moiety also introduces distinctive spectro-
scopic properties into a peptide, making it a potential
probe of local conformations.15
Figure 1 Classification of available routes to thioamides of type 1
We now report an efficient extension of method v to pre-
pare novel thioamide derivatives of type 4 by the thio-
amidoalkylation of malonic esters, b-keto esters, and b-
diketones with N-(a-thioamidoalkyl)benzotriazoles 2
(Scheme 1 and Table 1). We also describe the reactions of
2 with enol silyl ethers 5, and enamines 6 which produce
novel b-thioamido ketones 7 (Scheme 2 and Table 2).
Thioamidoalkylation of 1,3-Dicarbonyl Compounds
The N-(a-thioamidoalkyl)benzotriazoles 2 were prepared
by known one-pot reactions from benzotriazole, the ap-
propriate aldehyde and thiobenzamide in refluxing tolu-
ene with azeotropic removal of the water.21 Adducts 2
reacted efficiently with the appropriate malonates 3 in the
presence of 1.2 equivalents t-BuOK in DMSO at room
temperature to afford thioamidoalkylated products 4a–f
(80–93%) yields (Scheme 1 and Table 1). The structures
of 4a–f were confirmed by their spectral data together
with elemental analyses. Because the malonic ester func-
tion is attached to a chiral center, in most cases the two
Available routes to thioamides of type 1 can be classified
according to which of the alternative bonds a–e is con-
structed (Figure 1): (i) formation of bond a by the thion-
ation of the corresponding amides with the aid of
phosphorus pentasulfide,16 Lawesson’s reagents, 17 or sul-
fur dihydride catalyzed by triflic anhydride (Tf2O)18 (al-
SYNTHESIS 2007, No. 11, pp 1655–1662
x
x.
x
x
.
2
0
0
7
Advanced online publication: 11.05.2007
DOI: 10.1055/s-2007-966064; Art ID: M07006SS
© Georg Thieme Verlag Stuttgart · New York

1656
A. R. Katritzky et al.
PAPER
methoxy- or ethoxy-carbonyl groups are pro-chiral and We examined similar reactions with b-keto esters: ethyl
1
show different chemical shifts in both the H and 13C benzoylacetate (3f) and methyl (3g), and benzyl acetoace-
NMR spectra. Typical downfield doublets were observed tate (3h) each reacted with N-(a-thioamidoalkyl benzo-
for the thioamide NH group coupled with the adjacent triazoles 2 under similar conditions (t-BuOK/DMSO) to
CH.
give the thioamidoalkylated products 4g–m in 57–90%
yields. Two diastereoisomers formed for 4g–j, but a single
form was seen for 4k–m, as indicated in their NMR spec-
tra. The diastereoisomeric ratios were determined from
their relative integral values in the 1H spectra.
S
Bt
BtH, R1CHO
PhCSNH2
Ph
N
R1
H
2
2a: R1 = i-Pr
We extended the scope of the reaction to include symmet-
rical and unsymmetrical diketones 3i–l. Compounds 2a–c
reacted with acetylacetone (3i), a-benzoylacetophenone
(3j), 2,2,6,6-tetramethylheptane-3,5-dione (3k), and 1-
phenylbutane-1,3-dione (3l), under similar conditions to
provide the expected thioamidoalkylation products 4n–s
(53–90%) (see Table 1).
2b: R1 = i-Bu
2c: R1 = C7H15
2d: R1 = CH2Bn
2e: R1 = C4H9CH(Et)
2f: R1 = c-C6H11
O
O
R3
S
i) t-BuOK, r.t.
ii) 2
O
O
R2
R4
R1
R3
R2
Ph
N
R4
Thioamidoalkylation of Enol Silyl Ethers and
Enamines
H
4
3
For designation of R1, R2, R3 and R4 in 4 see Table 1
N-Substituted benzotriazoles of type BtCNC=O(R) when
treated with Lewis acids form the benzotriazole anion and
Scheme 1
Table 1 Thioamidoalkylation of 1,3-Dicarbonyl Compounds 3
Product
4a
4b
4c
R1
R2
R3
R4
H
H
H
H
Me
Et
H
H
H
H
H
H
H
H
H
H
H
H
H
dra
Yield (%)
92
i-Bu
i-Pr
MeO
EtO
MeO
EtO
t-BuO
MeO
EtO
EtO
EtO
EtO
MeO
MeO
EtO
BnO
BnO
Me
–
–
93
c-C6H11
t-BuO
–
84
4d
4e
Me(CH2)3CH(Et) MeO
–
90
n-C7H15
BnCH2
i-Bu
EtO
EtO
Ph
–
86
4f
–
80
4g
4h
4i
67:33
52:48
67:33
67:33
56:44
60:40
63:37
–
66
i-Pr
Ph
70
i-Pr
Me
Me
Me
Me
81
4j
i-Bu
90
4k
4l
i-Bu
79
n-C7H15
57
4m
4n
4o
4p
4q
4r
Me(CH2)3CH(Et) Me
80
i-Pr
Me
Ph
71
i-Pr
Ph
–
60
i-Bu
i-Bu
n-C7H15
i-Bu
CH3
Ph
Me
–
90
Ph
–
53
t-Bu
Ph
t-Bu
Me
–
70
4s
67:33
70
a Diastereomeric ratio was evaluated by 1H NMR analysis.
Synthesis 2007, No. 11, 1655–1662 © Thieme Stuttgart · New York

PAPER
Thioamidoalkylation of 1,3-Dicarbonyl Compounds
1657
the corresponding acylimmonium cation which then re- Treating 1-piperidinocyclohexene (6) with 2a,b,d,f in the
acts with nucleophiles.24 Compounds of type 2 react sim- presence of zinc bromide in CH2Cl2 at room temperature
ilarly with enol silyl ether 5 in refluxing CH2Cl2 in the afforded b-thioamido ketones 7h–k in 55–73% yields
presence of 2.0 equivalents of zinc bromide. Enol silyl (Scheme 2 and Table 2). The formation of 7h–k is as-
ethers 5 from aryl 5a–d, heteroaryl 5e, cyclic 5f, and acy- cribed to the hydrolysis of the thioamidoalkylation prod-
clic ketones 5g were all used as nucleophiles affording b- uct 8 during the workup.
thioamido ketones 7a–g (33–80%) (Scheme 2 and
Table 2). However, reaction of cyclohexanone-derived
silyl enol ether 5h with 2a under the same reaction con-
ditions failed.
1
Structures of 7a–k were confirmed by their H and 13C
1
NMR spectra and by elemental analyses. Their H NMR
spectra no longer showed distinctive signals of the benzo-
triazolyl group. The doublets at 8.31–9.53 ppm and at
8.68–8.8.86 ppm in the H NMR spectra of 7a–g and
7h–k, respectively, were assigned to the NH proton. The
multiplets at 4.96–5.31 ppm in the H NMR spectra of
7a–g were assigned to the methine proton next to NH. For
7h–k, the new set signals that appeared in their 1H NMR
spectra in the ranges 1.59–1.75 ppm, 2.03–2.45 ppm, and
2.99–3.08 ppm were assigned to the aliphatic protons of
the cyclohexanone ring. The 13C NMR spectra of 7a–k
showed new signals at 192.8–199.1 ppm as well as at
198.4–216.9 ppm, corresponding to carbonyl carbon and
thiocarbonyl carbon, respectively.
1
R1
O
S
OTMS
R2
2a–d,f
1
Ph
N
R2
R3
5a–g
5a: R2 = Ph, R3 = H
ZnBr2, CH2Cl2
H
R3
7a–k
5b: R2 = 4-MeOC6H4, R3 = H
5c: R2 = 4-BrC6H4, R3 = H
5d: R2 = Ph, R3 = Me
5e: R3 = 2-thienyl, R3 = H
5f: R2 + R3 = 2-CH2CH2C6H3(5-OMe)
5g: R2 = t-Bu, R3 = H
hydrolysis
5h: R2 + R3 = -(CH2)4-
Efforts to extend the methodology to the thioamidoalkyla-
tion of nitroalkanes (e.g., nitromethane, nitroethane) ace-
tonitriles (e.g., propionitrile, phenylacetonitrile), esters
(e.g., methyl phenylacetate, ethyl naphthylacetate), acety-
lenes (e.g., hexylacetylene, phenylacetylene), and reac-
tive heterocycles (e.g., thiophene, benzofuran) failed.
2a,b,d,f
R1
N
S
N
ZnBr2, CH2Cl2
Ph
R2
N
R2
H
R3
R3
6
8
R2 + R3 = -(CH2)4-
In summary, N-(a-thioamidoalkyl)benzotriazoles react
efficiently with diverse malonates, b-keto esters, b-dike-
tones, enol silyl ethers, and enamines to afford thioamides
possessing a carbonyl group at the b position. Our stable
and easily prepared starting materials are available from a
wide range of aldehydes and react under mild conditions.
The high yields in most cases of the previously unknown
analogues of thioamide recalls the potential of N-(a-thio-
amidoalkyl)benzotriazoles as advantageous thioami-
doalkylating agents. The byproduct benzotriazole formed
during the reaction was easily removed by washing the re-
action mixture with dilute alkali, making the whole proce-
dure very simple.
For designation of R1, R2, R3 and R4 in 7 see Table 2
Scheme 2
Table 2 Thioamide Ketones 7 Prepared
Product
7a
R1
R2
R3
H
Yield (%)
73
BnCH2
c-C6H11
i-Bu
Ph
7b
7c
4-MeOC6H4
4-BrC6H4
Ph
H
80
H
64
7d
7e
i-Pr
Me
H
77
All mps are uncorrected. 1H and 13C NMR spectra were recorded on
a Varian Gemini (300 MHz) spectrometer in CDCl3 with TMS as
the internal standard. Microanalyses were performed on a Carlo
Erba 1106 elemental analyzer. Column chromatography was per-
formed on silica gel 200–425 mesh. CH2Cl2 was distilled and
DMSO was dried over molecular sieves prior to use. N-(a-Thio-
amidoalkyl)benzotriazoles 2 were prepared according to literature
procedures.21
c-C6H11
n-C7H15
BnCH2
i-Pr
2-thienyl
51
7f
2-CH2CH2C6H3(5-OMe)
60a
33
7g
t-Bu
H
7h
7i
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
55
i-Bu
66b
69c
73
Thioamides 4; General Procedure
7j
BnCH2
c-C6H11
A mixture of 1,3-dicarbonyl compounds 3 (2 mmol) and t-BuOK
(0.45 g, 4 mmol) in DMSO (10 mL) was stirred at r.t. for 40 min.
To the resulting mixture, was added dropwise a solution of appro-
priate N-(a-thioamidoalkyl)benzotriazole 2 (2 mmol) in DMSO (10
mL) and the mixture was stirred at r.t. for 10 h. After quenching
with H2O (20 mL) and extraction with EtOAc (4 × 25 mL), the com-
bined organic layers were washed with H2O, dried (MgSO4) and the
solvent was removed under reduced pressure. The resulting oil was
7k
a Total yield of two isolated diastereoisomers.
b Isolated as diastereoisomeric mixture in a ratio of 86:14.
c Isolated as diastereoisomeric mixture in a ratio of 55:45.
Synthesis 2007, No. 11, 1655–1662 © Thieme Stuttgart · New York

1658
A. R. Katritzky et al.
PAPER
subjected to column chromatography (eluent: hexanes–EtOAc, 3:1)
to give the pure thioamides 4.
13C NMR: d = 199.3, 171.6, 171.2, 142.2, 131.0, 128.5, 126.7, 62.3,
61.9, 59.4, 58.3, 31.8, 31.2, 29.7, 29.1, 26.2, 22.6, 19.6, 14.1, 14.0,
13.9.
2-(3-Methyl-1-thiobenzoylaminobutyl)malonic Acid Dimethyl
Ester (4a)
Yield: 0.621 g (92%); colorless microcrystals; mp 85–86 °C.
Anal. Calcd for C23H35NO4S : C, 65.52; H, 8.37; N, 3.32. Found: C,
65.19; H, 8.67; N, 3.72.
1H NMR: d = 8.65 (d, J = 9.2 Hz, 1 H), 7.75 (d, J = 6.9 Hz, 2 H),
7.48–7.36 (m, 3 H), 5.62–5.56 (m, 1 H), 3.86 (d, J = 3.2 Hz, 1 H),
3.83 (s, 3 H), 3.72 (s, 3 H), 1.88–1.66 (m, 2 H), 1.53–1.44 (m, 1 H),
1.02 (d, J = 6.5 Hz, 3 H), 0.90 (d, J = 6.7 Hz, 3 H).
13C NMR: d = 199.2, 169.2, 168.1, 142.0, 131.1, 128.6, 126.8, 53.4,
53.2, 53.1, 52.8, 41.6, 25.4, 22.7, 22.6.
2-Ethyl-2-(3-phenyl-1-thiobenzoylaminopropyl)malonic Acid
Diethyl Ester (4f)
Yield: 0.706 g (80%); yellow microcrystals (80%), mp 55–57 °C
1H NMR: d = 9.00 (d, J = 9.8 Hz, 1 H), 7.77–7.74 (m, 2 H), 7.47–
7.37 (m, 3 H), 7.28–7.14 (m, 5 H), 5.61 (dt, J = 8.0, 2.4 Hz, 1 H),
4.35–4.23 (m, 2 H), 4.20–4.11 (m, 2 H), 2.90–2.77 (m, 2 H), 2.18–
2.10 (m, 2 H), 1.92–1.75 (m, 2 H), 1.32 (t, J = 7.1 Hz, 3 H), 1.23 (t,
J = 7.1, Hz, 3 H), 1.07 (t, J = 7.4 Hz, 3 H).
13C NMR: d = 199.4, 171.2, 170.4, 142.1, 141.6, 131.1, 128.6,
128.4, 128.3, 126.8, 126.0, 62.9, 62.0, 61.0, 58.9, 34.2, 32.8, 27.2,
14.1, 14.1, 10.0.
Anal. Calcd for C17H23NO4S: C, 60.51; H, 6.87; N, 4.15. Found: C,
60.23; H, 6.86; N, 4.17.
2-(2-Methyl-1-thiobenzoylaminopropyl)malonic Acid Diethyl
Ester (4b)
Yield: 0.654 g (93%); colorless microcrystals; mp 101–103 °C.
Anal. Calcd for C25H31NO4S: C, 68.00; H, 7.08; N, 3.17. Found:
67.73; H, 7.15; N, 3.18.
1H NMR: d = 9.10 (d, J = 9.2 Hz, 1 H), 7.80 (d, J = 6.7 Hz, 2 H),
7.44–7.36 (m, 3 H), 5.34 (dt, J = 9.5, 2.9 Hz, 1 H), 4.30 (q, J = 7.1
Hz, 2 H), 4.13 (J = 7.1 Hz, 2 H), 3.90 (d, J = 3.0 Hz, 1 H), 2.10–2.03
(m, 1 H), 1.33 (t, J = 7.1 Hz, 3 H), 1.23 (t, J = 7.1 Hz, 3 H), 1.07 (t,
J = 7.2 Hz, 6 H).
13C NMR: d = 199.7, 169.4, 167.8, 142.1, 131.0, 128.5, 126.7, 62.4,
62.0, 60.4, 52.2, 32.2, 19.8, 19.6, 14.0.
2-Benzoyl-5-methyl-3-thiobenzoylaminohexanoic Acid Ethyl
Ester (4g)
This compound was obtained as a 67:33 mixture of two diastereo-
isomers. Yield: 0.525 g (66%); colorless microcrystals; mp 98–
101 °C.
1H NMR: d = 8.80–8.73 (m, 1 H), 8.10 (d, J = 7.4 Hz, 0.67 H), 7.90
(d, J = 7.2 Hz, 1 H), 7.80 (d, J = 7.1 Hz, 0.33 H), 7.72 (d, J = 7.0
Hz, 1 H), 7.65–7.34 (m, 7 H), 5.62–5.57 (m, 1 H), 5.00 (d, J = 3.4
Hz, 0.33 H), 4.90 (d, J = 3.1 Hz, 0.67 H), 4.28 (q, J = 7.1 Hz, 1.32
H), 4.17–4.13 (m, 0.66 H), 2.01–1.91 (m, 1 H), 1.80–1.73 (m, 1 H),
1.65–1.56 (m, 1 H), 1.28 (t, J = 7.1 Hz, 2 H), 1.20 (t, J = 7.1 Hz, 1
H), 1.05–1.00 (m, 4 H), 0.94 (d, J = 6.6 Hz, 1 H), 0.90 (d, J = 6.5
Hz, 1 H).
13C NMR: d = 198.9, 198.8, 195.7, 194.4, 169.6, 168.6, 141.9,
136.0, 135.8, 134.3, 133.9, 131.2, 131.0, 129.1, 129.0, 128.6, 128.6
128.5, 126.8, 62.2, 61.9, 55.6, 55.1, 54.1, 53.4, 42.1, 40.8, 25.5,
22.9, 22.8, 22.8, 22.3, 14.1, 13.9.
Anal. Calcd for C18H25NO4S : C, 60.51; H, 7.17; N, 3.99. Found: C,
60.26; H, 7.27; N, 3.97.
2-(Cyclohexylthiobenzoylaminomethyl)malonic Acid Di-tert-
butyl Ester (4c)
Yield: 0.752 g (84%); colorless microcrystals; mp 94–96 °C.
1H NMR: d = 9.23 (d, J = 9.3 Hz, 1 H), 7.78 (d, J = 6.73 Hz, 2 H),
7.47–7.40 (m, 3 H), 5.32 (dt, J = 6.0, 3.3 Hz, 1 H), 7.34 (d, J = 3.4
Hz, 1 H), 1.85–1.58 (m, 6 H), 1.53 (s, 9 H), 1.40 (s, 9 H), 1.33–1.19
(m, 5 H).
13C NMR: d = 199.3, 169.1, 167.2, 142.1, 130.8, 128.4, 126.8, 83.2,
82.9, 59.7, 56.0, 42.2, 30.0, 28.0, 27.7, 26.1, 26.0.
Anal. Calcd for C23H27NO3S: C, 69.49; H, 6.85; N, 3.52. Found: C,
69.40; H, 6.88; N, 3.47.
Anal. Calcd for C25H37NO4S: C, 67.08; H, 8.33; N, 3.13. Found: C,
67.30; H, 8.53; N, 3.13.
2-Benzoyl-4-methyl-3-thiobenzoylaminopentanoic Acid Ethyl
Ester (4h)
This compound was obtained as a 52:48 mixture of two diastereo-
isomers. Yield: 0.537 g (70%); colorless microcrystals; mp 114–
116 °C.
1H NMR: d = 9.49 (d, J = 9.5 Hz, 0.48 H), 9.24 (d, J = 9.2 Hz, 0.52
H), 8.00 (d, J = 7.6 Hz, 1 H), 7.90–7.77 (m, 3 H), 7.68–7.36 (m, 6
H), 5.47 (dt, J = 10, 2.8 Hz, 0.48 H), 5.36 (dt, J = 10.0, 2.6 Hz, 0.52
H), 4.94 (d, J = 2.6 Hz, 0.52 H), 4.86 (d, J = 2.9 Hz, 0.48 H), 4.27
(q, J = 7.1 Hz, 1 H), 4.10 (q, J = 7.1 Hz, 1 H), 2.25–2.12 (m, 1 H),
1.33–0.97 (m, 9 H).
13C NMR: d = 199.7, 199.5, 196.3, 194.1, 170.1, 168.1, 142.2,
142.1, 136.0, 135.3, 134.4, 133.8, 130.9, 130.9, 129.1, 128.9, 128.6,
128.5, 128.3, 126.8, 126.8, 62.6, 61.9, 61.7, 60.2, 53.9, 52.7, 32.6,
32.0, 20.1, 19.8, 14.0, 13.9.
2-(2-Ethyl-1-thiobenzoylaminohexyl)malonic Acid Dimethyl
Ester (4d)
Yield: 0.683 g (90%); yellow oil.
1H NMR: d = 8.98 (d, J = 9.6 Hz, 1 H), 7.78 (d, J = 8.1 Hz, 2 H),
7.48–7.37 (m, 3 H), 5.55–5.49 (m, 1 H), 3.88 (t, J = 2.5 Hz, 1 H),
3.82 (s, 3 H), 3.69 (s, 3 H), 1.83–1.69 (m, 1 H), 1.54–1.42 (m, 3 H),
1.34–1.22 (m, 5 H), 0.98–0.84 (m, 6 H).
13C NMR: d = 199.6, 199.5, 169.7, 168.2, 142.2, 142.1, 131.0,
130.9, 128.5, 126.7, 126.6, 57.3, 57.2, 53.0, 52.8, 51.4, 51.3, 41.8,
41.7, 28.9, 28.7, 28.4, 27.4, 23.0, 22.9, 22.2, 22.0, 14.0, 13.9, 11.0,
9.7.
Anal. Calcd for C20H29NO4S: C, 63.30; H, 7.70; N, 3.69. Found: C,
63.11; H, 7.90; N, 3.63.
2-Methyl-2-(1-thiobenzoylaminooctyl)malonic Acid Diethyl
Ester (4e)
Yield: 0.725 g (86%); yellow oil.
Anal. Calcd for C22H25NO3S: C, 68.90; H, 6.57; N, 3.65. Found: C,
69.01; H, 6.71; N, 3.68.
1H NMR: d = 8.90 (d, J = 9.9 Hz, 1 H), 7.80 (d, J = 6.9 Hz, 2 H),
7.52–7.40 (m, 3 H), 5.43 (dt, J = 7.3, 2.9 Hz, 1 H), 4.34 (q, J = 7.1
Hz, 2 H), 4.16 (q, J = 7.1 Hz, 2 H), 1.85–1.82 (m, 1 H), 1.64 (s, 3
H), 1.61–1.40 (m, 2 H), 1.38–1.23 (m, 15 H), 0.91 (t, J = 6.6 Hz, 3
H).
2-Acetyl-4-methyl-3-thiobenzoylaminopentanoic Acid Methyl
Ester (4i)
This compound was obtained as a 67:33 mixture of two diastereo-
isomers. Yield: 0.498 g (81%); colorless microcrystals; mp 116–
118 °C.
Synthesis 2007, No. 11, 1655–1662 © Thieme Stuttgart · New York

PAPER
Thioamidoalkylation of 1,3-Dicarbonyl Compounds
1659
1H NMR: d = 9.20 (d, J = 8.2 Hz, 0.67 H), 8.86 (d, J = 8.7 Hz, 0.33
H), 7.81–7.76 (m, 2 H), 7.75–7.41 (m, 3 H), 5.51 (dt, J = 9.6, 2.9
Hz, 0.67 H), 5.33 (dt, J = 9.6, 3.1 Hz, 0.33 H), 4.11–4.07 (m, 0.33
H), 4.08 (d, J = 2.8 Hz, 0.67 H), 3.90 (s, 2 H), 3.76 (s, 1 H), 2.49 (s,
2 H), 2.38 (s, 1 H), 2.19–2.04 (m, 1 H), 1.16–1.05 (m, 6 H).
13C NMR: d = 205.0, 202.3, 200.0, 199.9, 170.6, 168.6, 142.2,
141.7, 131.2, 131.0, 128.6, 128.6, 126.8, 126.7, 61.2, 59.7, 59.5,
57.6, 53.1, 52.7, 32.8, 31.7, 31.0, 29.6, 20.1, 20.1, 19.9, 19.8.
2-Acetyl-4-ethyl-3-thiobenzoylaminooctanoic Acid Benzyl
Ester (4m)
This compound was obtained as a 63:37 mixture of two diastereo-
isomers. Yield: 0.703 g (80%); yellow oil.
1H NMR: d = 9.12 (d, J = 8.4 Hz, 0.63 H), 8.86 (d, J = 6.3 Hz, 0.37
H), 7.74–7.71 (m, 2 H), 7.68–7.21 (m, 8 H), 5.69–5.53 (m, 1 H),
5.39–5.03 (m, 2 H), 4.02–4.05 (m, 1 H), 2.40 (s, 2 H), 2.29 (s, 1 H),
1.77–1.65 (m, 1 H), 1.51–1.24 (m, 8 H), 0.94–0.83 (m, 6 H).
Anal. Calcd for C16H21NO3S: C, 62.51; H, 6.89; N, 4.56. Found: C,
62.40; H, 6.81; N, 4.68.
13C NMR: d = 204.7, 204.6, 199.5, 199.4, 169.8, 168.0, 141.9,
141.6, 134.7, 134.6, 131.1, 131.0, 128.9, 128.7, 128.6, 128.5, 128.4,
128.3, 126.7, 126.6, 126.4, 126.3, 66.7, 66.6, 59.6, 59.5, 57.9, 57.8,
57.7, 57.6, 42.3, 42.2, 41.6, 41.5, 29.6, 29.5, 28.5, 28.4, 22.8, 22.7,
21.9, 21.8, 13.9, 13.8.
2-Acetyl-5-methyl-3-thiobenzoylaminohexanoic Acid Methyl
Ester (4j)
This compound was obtained as a 67:33 mixture of two diastereo-
isomers. Yield: 0.578 g (90%); colorless microcrystals; mp 105–
108 °C.
Anal. Calcd for C26H33NO3S: C, 71.04; H, 7.57; N, 3.19. Found: C,
70.73; H, 7.80; N, 3.15.
1H NMR: d = 8.88 (d, J = 9.2 Hz, 0.67 H), 8.45 (d, J = 8.9 Hz, 0.33
H), 7.74–7.73 (m, 2 H), 7.48–7.36 (m, 3 H), 5.77–5.68 (m, 0.67 H),
5.70–5.47 (m, 0.33 H), 4.10 (d, J = 3.3 Hz, 0.33 H), 3.95 (d, J = 3.2
Hz, 0.67 H), 3.82 (s, 2 H), 3.73 (s, 1 H), 2.40 (s, 2 H), 2.33 (s, 1 H),
1.93–1.71 (m, 2 H), 1.69–1.41 (m, 1 H), 1.10–0.95 (m, 6 H).
13C NMR: d = 203.7, 202.2, 199.0, 198.9, 170.2, 168.6, 141.8,
141.5, 131.2, 128.5, 126.8, 126.8, 61.1, 59.6, 53.4, 52.9, 52.6, 52.5,
42.0, 41.0, 30.8, 29.7, 25.5, 25.3, 23.0, 22.9, 22.4, 22.3.
N-(2-Acetyl-1-isopropyl-3-oxobutyl)thiobenzamide (4n)
Yield: 0.414 g (71%); colorless microcrystals; mp 111–112 °C.
1H NMR: d = 9.09 (d, J = 8.0 Hz, 1 H), 7.72–7.69 (m, 2 H), 7.55–
7.40 (m, 3 H), 5.42 (dt, J = 9.5, 3.0 Hz, 1 H), 4.25 (d, J = 3.0 Hz, 1
H), 2.50 (s, 3 H), 2.25 (s, 3 H), 2.10–2.02 (m, 1 H), 1.08–1.04 (m, 6
H).
13C NMR: d = 206.9, 204.1, 200.0, 141.7, 131.2, 128.5, 126.8, 65.2,
60.5, 32.4, 31.8, 30.3, 20.3, 20.0.
Anal. Calcd for C17H23NO3S: C, 63.52; H, 7.21; N, 4.36. Found: C,
63.79; H, 7.41; N, 4.35.
Anal. Calcd for C16H21NO2S: C, 65.94; H, 7.26; N, 4.81. Found: C,
66.18; H, 7.37; N, 4.99.
2-Acetyl-5-methyl-3-thiobenzoylaminohexanoic Acid Ethyl
Ester (4k)
N-(2-Benzoyl-1-isopropyl-3-oxo-3-phenylpropyl)thiobenz-
amide (4o)
Yield: 0.499 g (60%); colorless microcrystals; mp 61–62 °C.
This compound was obtained as a 56:44 mixture of two diastereo-
isomers. Yield: 0.530 g (79%); colorless microcrystals; mp 86–
88 °C.
1H NMR: d = 8.92 (d, J = 8.7 Hz, 0.56 H), 8.51 (d, J = 8.7, 0.44 H),
7.23 (d, J = 7.1 Hz, 2 H), 7.48–7.35 (m, 3 H), 5.76–5.67 (m, 0.56
H), 5.54–5.45 (m, 0.44 H), 4.28 (q, J = 7.1 Hz, 1 H), 4.18 (q, J = 7.1
Hz, 1 H), 4.01 (d, J = 3.3 Hz, 0.44 H), 3.93 (d, J = 3.3 Hz, 0.56 H),
2.39 (s, 2 H), 2.33 (s, 1 H), 1.91–1.71 (m, 1 H), 1.70–1.63 (m, 1 H),
1.45–1.41 (m, 1 H), 1.32 (t, J = 7.1 Hz, 1.6 H), 1.25 (t, J = 7.1 Hz,
1.4 H), 1.05–0.96 (m, 6 H).
13C NMR: d = 204.0, 202.3, 199.0, 198.9, 169.7, 168.2, 141.8,
141.5, 131.2, 131.1, 128.5, 128.5, 126.8, 126.7, 62.2, 61.8, 61.1,
59.8, 53.4, 52.6, 42.0, 41.1, 30.9, 29.6, 25.5, 25.3, 23.0, 22.8, 22.4,
22.4, 14.1, 14.0.
1H NMR: d = 9.54 (d, J = 9.2 Hz, 1 H), 8.08 (d, J = 8.0 Hz, 2 H),
7.97 (d, J = 8.0 Hz, 2 H), 7.87 (d, J = 8.0 Hz, 2 H), 7.74–7.45 (m, 9
H), 6.04 (s, 1 H), 5.58 (t, J = 8.1 Hz, 1 H), 2.40–2.33 (m, 1 H), 1.20
(t, J = 7.8 Hz, 6 H).
13C NMR: d = 199.7, 197.3, 194.2, 142.2, 136.0, 135.1, 134.1,
134.1, 130.9, 129.2, 129.1, 128.7, 128.4, 128.2, 126.9, 61.7, 54.9,
32.5, 20.4, 20.2.
Anal. Calcd for C26H25NO2S: C, 75.15; H, 6.06; N, 3.37. Found: C,
74.90; H, 6.12; N, 3.76.
N-(2-Acetyl-1-isobutyl-3-oxobutyl)thiobenzamide (4p)
Yield: 0.550 g (90%); colorless microcrystals; mp 91–93 °C.
1H NMR: d = 8.73 (d, J = 8.2 Hz, 1 H), 7.70 (d, J = 7.4 Hz, 2 H),
7.48–7.35 (m, 3 H), 5.65–5.60 (m, 1 H), 4.25 (d, J = 3.0 Hz, 1 H),
2.38 (s, 3 H), 2.30 (s, 3 H), 1.94–1.84 (m, 1 H), 1.71–1.61 (m, 1 H),
1.43–1.34 (m, 1 H), 1.00 (t, J = 7.0 Hz, 6 H).
13C NMR: d = 206.2, 204.1, 198.9, 141.4, 131.2, 128.5, 126.7, 66.9,
53.2, 41.3, 31.5, 30.4, 25.5, 22.6.
Anal. Calcd for C18H25NO3S: C, 64.45; H, 7.51; N, 4.18. Found: C,
64.70; H, 7.69; N, 4.19.
2-Acetyl-3-thiobenzoylaminodecanoic Acid Benzyl Ester (4l)
This compound was obtained as a 60:40 mixture of two diastereo-
isomers. Yield: 0.501 g (57%); yellow oil.
1H NMR: d = 8.94 (d, J = 9.1 Hz, 0.6 H), 8.50 (d, J = 9.2 Hz, 0.4 H),
7.72–7.65 (m, 2 H), 7.47–7.33 (m, 8 H), 5.66–5.63 (m, 0.6 H), 5.44–
5.39 (m, 0.4 H), 5.26 (AB system, JAB = 28.2, 12.0 Hz, 1H), 5.13 (s,
1 H), 4.11 (d, J = 3.0 Hz, 0.4 H), 3.99 (d, J = 3.3 Hz, 0.6 H), 2.35
(s, 1.8 H), 2.31 (s, 1.2 H), 1.92–1.81 (m, 1 H), 1.64–1.54 (m, 1 H),
1.39–1.26 (m, 10 H), 0.87 (t, J = 5.2 Hz, 3 H).
Anal. Calcd for C17H23NO2S: C, 66.85; H, 7.59; N, 4.59. Found: C,
66.08; H, 7.66; N, 4.98.
N-[1-(1-Benzoyl-2-oxo-2-phenylethyl)-3-methylbutyl]thio-
benzamide (4q)
Yield: 0.455 g (53%); colorless microcrystals; mp 62–64 °C.
13C NMR: d = 203.8, 202.1, 199.0, 198.9, 169.6, 168.0, 141.7,
141.3, 134.8, 134.7, 131.2, 131.0, 129.0, 128.8, 128.7, 128.6, 128.5,
128.4, 128.3, 126.8, 126.7, 126.4, 67.9, 67.6, 61.1, 59.3, 55.1, 54.2,
33.1, 32.1, 31.7, 30.9, 29.4, 29.2, 29.0, 26.5, 26.2, 22.6, 14.0.
1H NMR: d = 8.66 (d, J = 8.4 Hz, 1 H), 8.20 (d, J = 7.42 Hz, 2 H),
7.90 (d, J = 7.4 Hz, 2 H), 7.74 (d, J = 7.0 Hz, 2 H), 7.68–7.35 (m, 9
H), 6.13 (d, J = 3.8 Hz, 1 H), 5.63–5.57 (m, 1 H), 2.28–2.19 (m, 1
H), 1.71–1.68 (m, 1 H), 1.57–1.46 (m, 1 H), 0.95 (d, J = 6.6 Hz, 3
H), 0.82 (d, J = 6.5 Hz, 3 H).
13C NMR: d = 198.6, 196.5, 195.3, 141.3, 135.9, 135.5, 134.3,
133.8, 131.2, 129.2, 129.0, 128.8, 128.5, 128.4, 126.8, 56.9, 54.4,
40.5, 25.7, 23.0, 21.9.
Anal. Calcd for C26H33NO3S: C, 71.04; H, 7.57; N, 3.19. Found: C,
71.86; H, 7.82; N, 3.24.
Synthesis 2007, No. 11, 1655–1662 © Thieme Stuttgart · New York

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A. R. Katritzky et al.
PAPER
Anal. Calcd for C27H27NO2S: C, 75.49; H, 6.33; N, 3.26. Found: C,
75.28; H, 6.24; N, 3.59.
13C NMR: d = 198.6, 197.7, 164.0, 141.9, 131.0, 130.4, 129.6,
128.4, 127.8, 126.7, 55.5, 39.7, 36.7, 30.3, 30.1, 25.9, 25.8.
Anal. Calcd for C23H27NO2S: C, 72.40; H, 7.13. Found: C, 72.76; H,
7.14.
N-{1-[1-(2,2-Dimethylpropionyl)-3,3-dimethyl-2-oxobutyl]oc-
tyl}thiobenzamide (4r)
Yield: 0.604 g (70%); yellow oil.
N-{1-[2-(3-Bromophenyl)-2-oxoethyl]-3-methylbutyl}thiobenz-
amide (7c)
Yield: 0.518 g (64%); white microcrystals; mp 72–74 °C.
1H NMR: d = 8.40 (d, J = 8.2 Hz, 1 H), 8.11–8.10 (m, 1 H), 7.90 (d,
J = 7.8 Hz, 1 H), 7.88–7.70 (m, 3 H), 7.49–7.34 (m, 4 H), 5.31–5.24
(m, 1 H), 3.50 (AB system, JAB = 17.9 Hz, 5.4 Hz, 2 H), 2.02–1.92
(m, 1 H), 1.76–1.66 (m, 1 H), 1.59–1.50 (m, 1 H), 0.98 (d, J = 1.4
Hz, 6 H).
1H NMR: d = 9.65 (d, J = 8.4 Hz, 1 H), 7.83 (d, J = 8.2 Hz, 2 H),
7.51–7.40 (m, 3 H), 5.32–5.29 (m, 1 H), 5.06 (d, J = 3.0 Hz, 1 H),
1.54–1.41 (m, 3 H), 1.33–1.22 (m, 18 H), 1.21 (s, 9 H), 0.92 (t,
J = 6.4 Hz, 3 H).
13C NMR: d = 213.1, 209.8, 197.8, 141.6, 131.0, 128.4, 126.8, 55.7,
54.8, 45.3, 45.2, 33.4, 31.7, 29.3, 29.1, 28.2, 26.6, 26.3, 22.5, 14.0.
Anal. Calcd for C26H41NO2S: C, 72.34; H, 9.57; N, 3.24. Found: C,
72.05; H, 9.65; N, 3.64.
13C NMR: d = 198.4, 197.4, 141.8, 138.4, 136.5, 131.2, 130.4,
128.5, 126.7, 126.6, 123.2, 51.3, 42.0, 40.4, 25.7, 22.9, 22.4.
N-(2-Benzoyl-1-isobutyl-3-oxobutyl)thiobenzamide (4s)
This compound was obtained as a 67:33 mixture of two diastereo-
isomers. Yield: 0.514 g (70%); colorless microcrystals; mp 136–
138 °C.
1H NMR: d = 8.82 (d, J = 8.3 Hz, 1 H), 8.14–8.11 (m, 2 H), 7.92–
7.89 (m, 1 H), 7.78–7.75 (m, 2 H), 7.68–7.40 (m, 5 H), 5.64–5.60
(m, 1 H), 5.18–515 (m, 1 H), 2.36 (s, 3 H), 2.07–1.88 (m, 1 H),
1.75–1.49 (m, 1 H), 1.02 (d, J = 6.5 Hz, 1 H), 0.98 (J = 6.6 Hz, 1
H), 0.93 (d, J = 6.6 Hz, 2 H), 0.82 (d, J = 6.4 Hz, 2 H).
13C NMR: d = 204.8, 204.2, 199.0, 198.6, 197.5, 195.5, 141.8,
141.4, 136.1, 136.0, 134.4, 134.0, 131.2, 131.1, 129.1, 129.0, 128.6,
128.5, 128.5, 128.4, 126.8, 126.7, 62.6, 61.9, 54.0, 53.8, 41.8, 40.5,
30.4, 30.3, 25.6, 25.5, 23.0, 22.7, 22.4, 22.1.
Anal. Calcd for C20H22BrNOS: C, 59.41; H, 5.48; N, 3.64. Found:
C, 59.41; H, 5.52; N, 3.42.
N-(1-Isopropyl-2-methyl-3-oxo-3-phenylpropyl)thiobenzamide
(7d)
Yield: 0.501 g (77%); yellow microcrystals; mp 125–126 °C.
1H NMR: d = 9.53 (d, J = 8.9 Hz, 1 H), 8.00 (d, J = 7.6 Hz, 2 H),
7.91 (d, J = 6.7 Hz, 2 H), 7.65 (t, J = 7.3 Hz, 1 H), 7.53–7.41 (m, 5
H), 5.08–5.00 (m, 1 H), 4.11 (q, J = 2.9 Hz, 1 H), 2.07–2.00 (m, 1
H), 1.39 (d, J = 7.3 Hz, 3 H), 1.10 (d, J = 6.7 Hz, 3 H), 0.96 (d,
J = 6.7 Hz, 3 H).
13C NMR: d = 206.0, 199.4, 141.9, 135.6, 134.0, 130.1, 129.1,
128.5, 128.3, 126.8, 64.8, 40.5, 32.1, 20.2, 20.1, 17.1.
Anal. Calcd for C22H25NO2S: C, 71.90; H, 6.86; N, 3.81. Found: C,
71.66; H, 6.86; N, 3.79.
Anal. Calcd for C20H23NOS: C, 73.80; H, 7.12; N, 4.30. Found: C,
73.78; H, 7.37; N, 4.29.
b-Thioamido Ketones 7; General Procedure
N-(1-Cyclohexyl-3-oxo-3-thiophen-2-ylpropyl)thiobenzamide
(7e)
Yield: 0.365 g (51%); yellow microcrystals; mp 120–121 °C.
1H NMR: d = 8.69 (d, J = 9.1 Hz, 1 H), 7.79–7.77 (m, 2 H), 7.70 (d,
J = 7.7 Hz, 1 H), 7.48–7.37 (m, 3 H), 7.26 (s, 1 H), 7.16 (t, J = 4.5
Hz, 1 H), 5.30–4.97 (m, 1 H), 3.56 (dd, J = 17.7, 3.6 Hz, 1 H), 3.37
(dd, J = 17.4, 4.8 Hz, 1 H), 2.03–1.91 (m, 1 H), 1.75–1.67 (m, 4 H),
1.25–1.08 (m, 6 H).
ZnBr2 (1.1 g, 5 mmol) was added to a mixture of respective silyl
enol ether 5 or enamine 6 (2.5 mmol) and appropriate N-(a-thio-
amidoalkyl)benzotriazole 2 (2.0 mmol) in CH2Cl2 (20 mL), and the
mixture was refluxed with stirring under argon for 12 h (in the case
of 5) or stirred at r.t. for 3 h (in the case of 6). The mixture was
cooled and subsequently washed with aq 10% NaOH (15 mL). The
organic phase was dried (Na2SO4), and after removal of the solvent,
the residue was subjected to column chromatography over silica gel
eluting with hexanes–EtOAc (5:1) to give the pure product 7.
13C NMR: d = 197.9, 192.8, 143.8, 141.8, 134.6, 132.7, 131.0,
128.5, 126.5, 39.7, 37.8, 30.3, 30.1, 25.8, 25.7.
N-(3-Oxo-1-phenethyl-3-phenylpropyl)thiobenzamide (7a)
Yield: 0.583 g (78%); yellow microcrystals; mp 115–117 °C.
Anal. Calcd for C20H23NOS2: C, 67.19; H, 6.48; N, 3.92. Found: C,
66.82; H, 6.65; N, 3.88.
1H NMR: d = 8.62 (d, J = 8.5 Hz, 1 H), 7.94–7.92 (m, 2 H), 7.71–
7.69 (m, 2 H), 7.59 (t, J = 7.4 Hz, 1 H), 7.49–7.42 (m, 3 H), 7.36 (t,
J = 7.4 Hz, 2 H), 7.27–7.13 (m, 5 H), 5.30–5.25 (m, 1 H), 3.50 (d,
J = 4.3 Hz, 2 H), 2.78 (t, J = 7.7 Hz, 2 H), 2.43–2.36 (m, 1 H),
2.16–2.04 (m, 1 H).
N-[1-(7-Methoxy-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)oc-
tyl]thiobenzamide (7f)
This compound was obtained as a 73:27 mixture of two diastereo-
isomers.
13C NMR: d = 199.8, 197.9, 141.6, 140.9, 136.6, 133.7, 131.0,
128.7, 128.5, 128.4, 128.3, 128.0, 126.7, 126.1, 53.1, 39.8, 34.5,
33.0.
1st Diastereoisomer: Yield: 0.373 g (44%); yellow oil.
1H NMR: d = 9.17 (d, J = 9.1 Hz, 1 H), 7.98 (d, J = 8.8 Hz, 1 H),
7.83 (d, J = 6.7 Hz, 2 H), 7.49–7.36 (m, 3 H), 6.83 (dd, J = 6.5, 2.3
Hz, 1 H), 6.70 (d, J = 2.1 Hz, 1 H) 5.06–4.97 (m, 1 H), 3.86 (s, 3 H),
3.14–2.95 (m, 3 H), 2.24–2.06 (m, 2 H), 1.89–1.81 (m, 1 H), 1.73–
1.62 (m, 1 H), 1.45–1.39 (m, 2 H), 1.34–1.24 (m, 8 H), 0.85 (t,
J = 6.5 Hz, 3 H).
13C NMR: d = 199.2, 197.1, 164.1, 146.8, 141.9, 131.0, 129.7,
128.5, 126.8, 126.4, 113.5, 112.5, 58.6, 55.5, 50.1, 32.0, 30.0, 29.6,
29.2, 29.1, 27.9, 26.7, 22.6, 14.1.
Anal. Calcd for C24H23NOS: C, 77.17; H, 6.21; N, 3.75. Found: C,
77.03; H, 6.26; N, 3.93.
N-[1-Cyclohexyl-3-(4-methoxyphenyl)-3-oxopropyl]thiobenz-
amide (7b)
Yield: 0.557 g (73%); yellow oil.
1H NMR: d = 8.82 (d, J = 8.9 Hz, 1 H), 8.01–7.79 (m, 4 H), 7.47–
7.35 (m, 3 H), 7.13– 6.93 (m, 2 H), 5.02–4.96 (m, 1 H), 3.88 (s, 3
H), 3.59 (dd, J = 18.0, 3.6 Hz, 1 H), 3.34 (dd, J = 18.0, 4.8 Hz, 1 H),
2.05–1.92 (m, 2 H), 1.74–1.63 (m, 4 H), 1.26–1.12 (m, 5 H).
Anal. Calcd for C26H33NO2S: C, 73.72; H, 7.85; N, 3.31. Found: C,
73.61; H, 7.85; N, 3.29.
2nd Diastereoisomer: Yield: 0.136 g (16%); yellow oil.
Synthesis 2007, No. 11, 1655–1662 © Thieme Stuttgart · New York

PAPER
Thioamidoalkylation of 1,3-Dicarbonyl Compounds
1661
1H NMR: d = 8.31 (d, J = 9.3 Hz, 1 H), 7.95 (d, J = 8.8 Hz, 1 H),
7.70 (d, J = 7.1 Hz, 2 H), 7.45–7.33 (m, 3 H), 6.84 (dd, J = 6.5, 2.3
Hz, 1 H), 6.67 (d, J = 2.0 Hz, 1 H), 5.29–5.21 (m, 1 H), 3.85 (s, 3
H), 3.09–2.93 (m, 3 H), 2.38–2.31 (m, 1 H), 2.23–2.01 (m, 2 H),
1.91–1.84 (m, 1 H), 1.48–1.38 (m, 2 H), 1.36–1.26 (m, 8 H), 0.87 (t,
J = 6.5 Hz, 3 H).
13C NMR: d = 198.8, 196.7, 163.7, 146.2, 14.9, 130.8, 129.5, 128.3,
126.5, 113.3, 112.3, 57.6, 55.4, 51.3, 34.1, 31.7, 29.7, 29.6, 29.4,
29.1, 28.5, 26.5, 22.5, 14.0.
Anal. Calcd for C22H25NOS: C, 75.17; H, 7.17; N, 3.98. Found: C,
75.33; H, 7.33; N, 3.95.
N-[Cyclohexyl-(2-oxocyclohexyl)methyl]thiobenzamide (7k)
Yield: 0.481 g (73%); yellow microcrystals; mp 123–124 °C.
1H NMR: d = 8.82 (d, J = 8.7 Hz, 1 H), 7.76 (d, J = 6.9 Hz, 2 H),
7.48–7.36 (m, 3 H), 4.80 (dt, J = 7.7, 2.0 Hz, 1 H), 3.03–3.01 (m, 1
H), 2.45–2.29 (m, 3 H), 2.17–2.11 (m, 1 H), 1.88–1.60 (m, 10 H),
1.20–1.06 (m, 5 H).
Anal. Calcd for C26H33NO2S: C, 73.72; H, 7.85; N, 3.31. Found: C,
73.48; H, 8.03; N, 3.50.
13C NMR: d = 215.5, 199.1, 141.8, 131.1, 128.4, 126.6, 62.3, 51.8,
43.4, 40.8, 34.1, 30.7, 30.1, 28.8, 26.1, 26.0, 25.8, 25.3.
Anal. Calcd for C20H27NOS: C, 72.90; H, 8.26; N, 4.25. Found: C,
73.05; H, 8.57; N, 4.22.
N-(4,4-Dimethyl-3-oxo-1-phenethylpentyl)thiobenzamide (7g)
Yield: 0.280 g (33%); yellow microcrystals; mp 109–111 °C.
1H NMR: d = 8.68 (d, J = 8.0 Hz, 1 H), 7.71 (d, J = 7.1 Hz, 2 H),
7.48–7.30 (m, 3 H), 7.25–7.20 (m, 2 H), 7.17–7.15 (m, 3 H), 5.17–
5.10 (m, 1 H), 3.02 (t, J = 4.0 Hz, 2 H), 2.75 (t, J = 7.0 Hz, 2 H),
2.29–2.18 (m, 1 H), 1.98–1.86 (m, 1 H), 1.14 (s, 9 H).
13C NMR: d = 216.9, 197.7, 141.6, 141.0, 131.1, 128.5, 128.4,
128.3, 126.7, 126.1, 53.0, 44.7, 38.1, 34.6, 33.1, 26.2.
Acknowledgment
The authors would like to thank Dr. C. Dennis Hall for his generous
help. Mr. I. Celik gratefully acknowledges the financial support by
Anadolu University.
Anal. Calcd for C22H27NOS: C, 74.74; H, 7.70; N, 3.96. Found: C,
74.95; H, 7.88; N, 3.96.
References
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Synthesis 1979, 801.
N-[2-Methyl-1-(2-oxocyclohexyl)propyl]thiobenzamide (7h)
Yield: 0.318 g (55%); yellow microcrystals; mp 84–85 °C.
1H NMR: d = 8.83 (br s, 1 H), 7.76 (d, J = 7.1 Hz, 2 H), 7.46–7.37
(m, 3 H), 4.74 (t, J = 10.0 Hz, 1 H), 3.08–2.99 (m, 1 H), 2.45–2.14
(m, 5 H), 1.75–1.62 (m, 4 H), 1.00 (t, J = 5.8 Hz, 6 H).
13C NMR: d = 215.4, 199.2, 141.9, 131.0, 128.5, 126.6, 63.3, 52.3,
43.4, 34.1, 31.6, 28.8, 25.3, 20.4, 20.0.
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(b) Giordano, C.; Belli, A. Synthesis 1977, 476.
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Chem. Soc., Perkin Trans. 1 1973, 771.
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M. A. J. Org. Chem. 1992, 57, 2531. (b) Magnus, P.;
Mendoza, J. S.; Stamford, A.; Ladlow, M.; Willis, P. J. Am.
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1993, 115, 30.
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Anal. Calcd for C17H23NOS: C, 70.55; H, 8.01; N, 4.84. Found: C,
70.62; H, 8.42; N, 4.79.
N-[3-Methyl-1-(2-oxocyclohexyl)butyl]thiobenzamide (7i)
This compound was obtained as a 86:14 mixture of two diastereo-
isomers. Yield: 0.400 g (66%); yellow microcrystals; mp 82–83 °C.
1H NMR: d = 8.68 (d, J = 8.8 Hz, 0.86 H), 8.36 (d, J = 8.1 Hz, 0.14
H), 7.74 (d, J = 6.9 Hz, 2 H), 7.48–7.35 (m, 3 H), 5.18–5.10 (m,
0.86 H), 4.86–4.79 (m, 0.14 H), 3.05–3.01 (m, 0.14 H), 2.82–2.78
(m, 0.86 H), 2.42–2.31 (m, 3 H), 2.19–2.03 (m, 1 H), 2.00–1.85 (m,
2 H), 1.79–1.59 (m, 4 H), 1.48–1.39 (m, 1 H), 1.00 (d, J = 6.5 Hz, 3
H), 0.94 (d, J = 6.6 Hz, 3 H).
13C NMR: d = 214.9, 213.3, 198.6, 196.9, 141.9, 141.6, 131.0,
130.9, 128.4, 126.6, 55.7, 55.5, 55.4, 52.3, 43.4, 43.0, 42.4, 38.2,
33.6, 30.5, 28.5, 26.6, 25.7, 25.4, 25.2, 24.7, 23.6, 23.0, 22.7, 21.7.
Anal. Calcd for C18H25NOS: C, 71.24; H, 8.30; N, 4.62. Found: C,
71.42; H, 8.61; N, 4.60.
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N-[1-(2-Oxocyclohexyl)-3-phenylpropyl]thiobenzamide (7j)
This compound was obtained as a 55:45 mixture of two diastereo-
isomers. Yield: 0.485 g (69%); yellow microcrystals; mp 98–
100 °C.
1H NMR: d = 8.76 (d, J = 9.1 Hz, 0.55 H), 8.47 (d, J = 9.1 Hz, 0.45
H), 7.74–7.66 (m, 2 H), 7.44–7.28 (m, 3 H), 7.27–7.13 (m, 5 H),
5.18–5.11 (m, 0.55 H), 4.90–4.83 (m, 0.45 H), 3.03–2.98 (m, 0.45
H), 2.82–2.63 (m, 2.55 H), 2.37–2.22 (m, 3 H), 2.20–1.71 (m, 4 H),
1.67–1.65 (m, 3 H).
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141.3, 131.1, 131.0, 128.5, 128.4, 128.3, 128.3, 126.7, 126.7, 126.0,
1226.0, 57.4, 57.3, 54.4, 52.3, 43.3, 42.4, 35.7, 33.5, 33.3, 32.9,
31.1, 30.6, 28.6, 26.7, 25.1, 24.8.
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