Synthesis and reactions of the thioamide derivatives of methyl vinvl ketone

Article abstract of DOI:10.1002/jhet.5570440126

(Chemical Equation Presented) The reaction of isothiocyanates with in situ generated carbanions of α,β-unsaturated ketones yielded α,β-unsaturated keto thioamides which in the reaction with acids or bases cyclized to give 2,6-disubstituted thiopyran-4-one

Full text of DOI:10.1002/jhet.5570440126

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167
Synthesis and Reactions of the Thioamide Derivatives of Methyl
Vinyl Ketone
ꢀukasz Groꢁ, Aneta Wesoꢂowska, Sꢂawomir Westerlich, Tadeusz Jagodziꢃski*
Institute of Chemistry and Environmental Protection, University of Technology, Aleja Piastów 42,
71064 Szczecin, Poland
e-mail: jagszcz@ps.pl
Received May 5, 2006
The reaction of isothiocyanates with in situ generated carbanions of ꢀ,ꢁ-unsaturated ketones yielded
ꢀ,ꢁ-unsaturated keto thioamides which in the reaction with acids or bases cyclized to give 2,6-disubstituted
thiopyran-4-ones and in the reaction with ꢀ-bromoesters gave thiazolidin-4-one derivatives. The thiopyran-
4-ones reacted with ꢀ,ꢁ-unsaturated aldehydes to yield tetrahydrothiopyran[2,3-b]pyridin-4-ones, while
thioanilides were formed in the reaction with phenyl isothiocyanate.
J. Heterocyclic Chem., 44, 167 (2007).
presence of sodium tert-pentanolate [3], but a completely
different thioamide was obtained when duplication of the
reaction was attempted in this laboratory.
INTRODUCTION
Although thioamides are known almost since the very
dawn of organic chemistry, their synthetic applicability
has been recognized in full only a few decades ago. High
reactivity of the thioamide group towards both electro-
and nucleophilic agents, often in conjunction with that of
other reactive centers in the molecule, made thioamides
handy building blocks of particular importance in the
synthesis of heterocyclic systems by inter- and intramol-
ecular cyclization [1].
RESULTS AND DISCUSSION
At first, our investigations were aimed at the
preparation of the thioamide derivatives of arylidene-
acetones with benzylideneacetone being selected as the
most readily available model substrate. In order to prevent
addition of benzylideneacetone to its anion, the reaction
was carried out by a simultaneous dropwise addition of
both reactants to the sodium hydride suspension in
monoglyme at 0ºC (Scheme 1). With aromatic isothio-
cyanates the reaction yields were rather high. Aliphatic
and alicyclic isothiocyanates also reacted under these
conditions but we encountered serious difficulties in
isolation and purification of the products.
In many organic compounds, including natural products
foremost, one may find a built in fragment of methyl vinyl
ketone. The synthesis of acyclic thioamides derived from
this ketone is a rather difficult problem because of their
instability and ease of spontaneous cyclization. If a
reasonably simple and efficient synthetic method is
developed, it will certainly come into use as the first step
in the synthesis of heterocyclic compounds hardly
available using other methods. The development of such
method and its application in the synthesis of heterocyclic
systems are the main objects of the present research.
Thus far, in the reaction of isothiocyanates with
derivatives of methyl vinyl ketone substituted at the
methyl with electron acceptor groups 2,3-dihydro-4(H)-
thiopyran-4-ones were formed, while isolation of the
intermediate linear thioamides failed [2]. Moreover, these
thiopyranones were substituted at C-5 and therefore,
unlike enaminones, could not be used in further
transformations. In fact, there is an earlier report on the
synthesis of benzylideneacetone thioanilide in the reaction
of phenyl isothiocyanate with benzylideneacetone in the
In an attempt to define the scope of the reaction we
have found that under similar conditions ꢀ- and ꢁ-ionones
reacted with both aliphatic and aromatic isothiocyanates,
the yields ranging from satisfactory to good. However, in
the case of methyl vinyl ketone the reaction gave a
multicomponent mixture whose purification failed; since
isolation of a reasonably pure thioamide product proved
hardly practicable, no attempts were made to use the
mixture in further cyclization reactions.
The linear thioamides 1a-1m are rather unstable
compounds since they cyclize in part on heating. Column
chromatography was applied therefore to obtain analytical
samples. As shown by 1D nmr (1H, 13C, 13C-DEPT), 2D
1
nmr (13C, H COSY) analysis, the enol structure B is
predominant in solutions.

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ꢀ. Groꢁ, A. Wesoꢂowska, S. Westerlich, T. Jagodziꢃski
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Scheme 1
NaH / R2NCS
Scheme 2
O
monoglyme
R1
OH
O
S
0o C - r. t.
H
r.t.
OH
S
O
S
R1 SH
NHR2
R2
R1
NHR2
R2
R1
N
R1
N
H
H
1a - 1m
B
A
1a - 1m
Et3N/ C2H5OH
reflux
OH
1a
1b
1c
1d
1e
R1
R2
C6H5
C6H4
86
C6H5
4-ClC6H4
C6H5
4-FC6H4
91
C6H5
1-naphtyl
83
ꢀ-ionone
C6H5
61
O
S
R1
SH
NHR2
yield (%)
88
1g
1f
1h
1i
1j
R1
NHR2
6-exo-trig
R1
R2
ꢀ-ionone ꢀ-ionone
ꢀ-ionone ꢁ-ionone ꢁ-ionone
6-endo-trig
CH3
50
C2H5
76
cyclo-C6H11
50
C6H5
80
CH3
59
yield (%)
1k
1m
R1
R2
ꢁ-ionone ꢁ-ionone
C2H5
cyclo-
C6H11
41
O
O
H
yield (%)
59
R1
S
NHR2
R1
S
NHR2
When heated in refluxing ethanol in the presence of
triethylamine, the thioamides 1a-m were slowly converted
into 2,6-disubstituted-2,3-dihydrothiopyran-4-ones (2a-
m). Two days were required to make the conversion
complete. It was noted that with magnesium or sodium
methoxides only a small part of the thioamide underwent
cyclization; this was presumably due to the formation of a
chelate structure.
2a - 2m (30-98%)
was the main product but the thioanilides of ꢀ- and ꢁ-
ionones were also formed in appreciable quantities
(3:2e:2i as 34:2:64).
In accord with the Baldwin rules for trigonal systems,
the exocyclizations leading to three- and seven-membered
rings are favored, whereas the endocyclizations leading to
six- and seven-membered rings are only permitted [4]. In
our case, the cyclization occurring in an alkaline medium
is an intramolecular Michael addition following the 6-
endo-trigonal mechanism. However, if one changes the
alkaline catalyst to an acidic one, the cyclization process
takes the more favored 6-exo-trigonal reaction path
(Scheme 2).
Scheme 3
This hypothesis was confirmed experimentally since
cyclization in refluxing benzene in the presence of p-
toluenesulfonic acid occurred swiftly (1 hour) although
hardly removable by-products were formed. There was no
such problem when the cyclization catalyst was boron
trifluoride in acetic acid; the cyclization was then
practically quantitative within approximately five
minutes.
As it has been proven while investigating the synthesis
of carotenoids, the cyclization of similar polyene
substrates is a proton addition-elimination process. It is
initiated by addition of a proton to C-2 at the terminal
double bond with the formation of a “carbocation” [5] and
a following elimination of the Ha, Hb, or Hc protons. This
The developed method was also tested in the synthesis
of polyene keto thioamides. Pseudoionone reacted with
phenyl isothiocyanate in the presence of sodium hydride
in monoglyme to yield a mixture of linear and cyclic
products. As found by nmr, pseudoionone thioanilide 3

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Synthesis and Reactions of the Thioamide Derivatives of Methyl Vinyl Ketone
169
reaction sequence leads to the formation of the
appropriate rings.
Figure 1
The reactions of thioamides 1a, 1e, 1i, and 3 with ethyl
bromoacetate may serve as another example of
cyclizations following the Baldwin rules. Theoretically,
two products might have been expected: the derivatives of
tetrahydropyridin-2-one (5) generated in a Michael
addition process, and the derivatives of thiazolidin-4-one
(4a-c) formed in the condensation reaction. Only the latter
were obtained in our experiments, this reaction course
being in agreement with the preference of the 5-exo-
trigonal cyclization. Similar reactions of bromoacetic esters
with ꢀ-keto thioamides have been investigated by us earlier
[5]. In the reaction with ethyl bromoacetate, the chroma-
tographically purified linear thioamide 3 yielded a pseudo-
ionone derivative of thiazolidin-4-one 4d. By analogy to
carotenoids [5], a concomitant cyclization of the polyene
fragment of pseudoionone might be expected to occur and
result in the formation of the ꢀ- and ꢁ-ionone structures.
However, this cyclization was not observed in our case.
The thiopyran-4-ones 2a may be also used in further
transformations. As in the case of enaminones [8], 2a has
to be at first deprotonated with the aid of sodium hydride,
but isothiocyanates attack the ring C-5, not the nitrogen
atom (6, Scheme 5). No reaction takes place in the
absence of sodium hydride. With ꢁ,ꢀ-unsaturated
aldehydes, 2a react in the same manner as the linear ꢀ-
keto thioamides; bicyclic structures are formed (e.g., 7a,
b) [9]. However, contrary to earlier findings [9], the
addition-cyclization process of 2a with cinnamic aldehyde
is irreversible owing to the concomitant dehydration
(Scheme 5). A mixture of isomeric tetrahydrothiopyrano-
[2,3-b]pyridin-4-ones 7a, b (3:2 ratio) results.
Scheme 4
The present investigation reveals that both thioamides
1a-m and cyclic thiopyranones 2a-m can be prepared
with great ease. Moreover, their reactivity is high enough
to make them interesting substrates for further synthetic
transformations. The examples presented here serve only
as an indication of this synthetic potential.
Scheme 5
1
1
The H, H NOESY nmr technique has been recently
found as a useful tool for determining the configuration
and conformation [6,7,9]. The same technique is applied
now to make the stereochemical assignments in the 2-
oxodimethylidene moiety of 4a. The correlation observed
1
1
in the H, H NOESY spectra of 4a made it possible to
estimate the through-space interactions between the
following protons or proton groups: =CH vs. C6H5N, =CH
vs. C6H5 (Figure 1). There is every reason to assume that
the ꢀ- and ꢁ-ionone derivatives 4b,c have an analogous
configuration.
EXPERIMENTAL
Melting points were determined on a digital apparatus
Electrotermal model IA9300 and are uncorrected. The H- and
1

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Vol 44
13C-nmr spectroscopic measurements and 1D-13C-nmr and 2D-
Hz), 7.30-7.54 (m, 4H, 2Ph), 7.55-7.73 (m, 5H, 2Ph), 7.91 (d,
1H, PhCH=CH, J=8.83 Hz), 11.87 (s, 1H, NH). Anal. Calcd. for
C17H14ClNOS (315.82): C, 64.65; H, 4.47; N, 4.43; S, 10.15.
Found: C, 64.42; H, 4.46; N, 4.30; S, 10.03.
1
1H, H (COSY, NOESY) were performed in deuteriochloroform
and deuteriodimethylsulfoxide on a Bruker DPX apparatus (400
MHz) spectrometer with tetramethysilane as the internal
standard. The IR spectra were taken with Specord M80
instruments in potassium bromide pellets. Purity and molecular
mass determinations 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 procedure was developed for a 30m-long capillary
column, 0.2 mm in diameter, with methylsiloxane modified with
phenyl groups (5% Ph, Me siloxane) in the 0.25 Xm thick active
phase layer. Elemental analyses were performed on EuroEA
3000 series, Euro Vector CHNS-O Elemental Analyser. All
compounds gave satisfactory elemental analysis (C, H, N, S).
Commercial samples of ꢀ-ionone (90%, Aldrich), ꢁ-ionone
(96%, Aldrich), and pseudoionone (90%, mixture of isomers,
Fluka) were used in the experiments.
General Procedure for Preparation of Thioamides (1a-m).
A solution of the appropriate benzylidene- or alkylideneacetone
(10 mmol) and isothiocyanate (12 mmol) in 10 mL of
monoglyme was added dropwise under nitrogen to a stirred and
cooled (0 °C) suspension of sodium hydride (25 mmol; 80% in
mineral oil) in 25 mL of monoglyme. The reaction mixture was
then stirred for 2.5 h at room temperature or left standing
overnight. The yellow-brown mixture was poured into a dilute
(10%) solution of hydrochloric acid with crushed ice and the
organic product was extracted with ethyl acetate. After a routine
work-up, the crude products were chromatographed in a silica
gel-packed column using the n-hexane/ethyl acetate (1:1)
mixture as the eluent. Recrystallization from an appropriate
solvent gave the final products.
3-Hydroxy-5-phenylpenta-2,4-dienethioic acid (4-fluoro-
phenyl)amide (1c). This compound was obtained in 91% yield
as yellow crystals; mp 153-156ºC (methanol); ir: 3200 (NH),
1632 (C=C, C-H), 1518 (NH, C-N), 1388 (OH, C-O), 1316 (C-
N), 1208 (NCS) cm-1. 1H nmr (deuteriodimethylsulfoxide): –
enol form, ꢀ 6.07 (s, 1H, CH=COH), 6.88 (d, 1H, PhCH=CH,
J=15.41 Hz), 7.34 (d, 1H, PhCH=CH, J=6.52 Hz), 7.36-7.60 (m,
4H, 2Ph), 7.61-7.86 (m, 5H, 2Ph), 11.49 (s, 1H, NH), 14.29 (s,
1H, OH). 13C nmr (deuteriodimethylsulfoxide):
ꢀ 103.65
(CHCOH), 125.04 128.25, 129.33, 129.85, 135.03, 138.96 (Ph),
129.91 (PhCH=CH), 135.68 (PhCH=CH), 167.09 (C-OH),
190.00 (C=S). 1H nmr (deuteriodimethylsulfoxide): – ketone
form, ꢀ 4.30 (s, 2H, CH2CS), 6.87 (d, 1H, PhCH=CH, J=16.02
Hz), 7.31-7.51 (m, 4H, 2Ph), 7.54-7.75 (m, 5H, 2Ph), 7.88 (d,
1H, PhCH=CH, J=8.74 Hz), 11.84 (s, 1H, NH). Anal. Calcd. for
C17H14FNOS (299.37): C, 68.21; H, 4.71; N, 4.68; S, 10.71.
Found: C, 68.03; H, 4.62; N, 4.55; S, 11.52.
3-Hydroxy-5-phenylpenta-2,4-dienethioic acid naphthalen-
2-ylamide (1d). This compound was obtained in 83% yield as
yellow crystals; mp 129-132ºC (cyclohexane); ir: 3232 (NH),
1626 (C=C, C-H), 1500 (NH, C-N), 1394 (OH, C-O), 1326 (C-
1
N), 1208 (NCS) cm-1; H nmr (deuteriodimethylsulfoxide): –
enol form, ꢀ 5.89 (s, 1H, CH=CHOH), 6.14-6.52 (m, 1H,
PhCH=CH), 7.16 (d, 1H, PhCH=CH, J=6.31 Hz), 7.18-7.56 (m,
8H, Ph, naphth.), 7.57-7.71 (m, 5H, Ph, naphth.), 14.26 (s, 1H,
OH); 13C nmr (deuteriochloroform): ꢀ 98.68 (CH=COH),
123.49, 124.61, 125.32, 128.42, 128.58, 128.66, 128.92, 129.00,
135.69, 137.87 (Ph, naphth.), 130.97 (PhCH=CH), 144.81
1
3-Hydroxy-5-phenylpenta-2,4-dienethioic acid phenyl-
amide (1a). This compound was obtained in 86% yield as
yellow crystals; mp 140-143ºC (methanol); ir: 3292 (NH), 1630
(C=C, C-H), 1522 (NH, C-N), 1400 (O-H, C-O), 1318 (C-N),
(PhCH=CH), 162.07 (COH), 190.38 (C=S). H nmr (deuterio-
chloroform): – ketone form, ꢀ 4.33 (s, 2H, CH2C=S), 6.91 (d,
1H, PhCH=CH, J=16.77 Hz), 7.14-7.56 (m, 8H, Ph, naphth.),
7.58-7.71 (m, 5H, Ph, naphth.), 7.82 (d, 1H, PhCH=CH), J=7.20
Hz), 10.45 (s, 1H, NH). Anal. Calcd. for C21H17NOS (333.44):
C, 76.10; H, 5.17; N, 4.23; S, 9.67. Found: C, 76.03; H, 5.02; N,
4.15; S, 9.52.
1
1208 (NCS) cm-1; H nmr (deuteriodimethylsulfoxide): – enol
form, ꢀ 6.00 (s, 1H, CH=COH), 6.75 (d, 1Hd, PhCH=CH,
J=15.8 Hz), 7.32-7.77 (m, 10H, 2Ph), 7.61 (d, 1H, PhCH=CH,
J=7.62 Hz), 11.40 (s, 1H, NH), 14.26 (s, 1H, OH). 13C nmr
(deuteriodimethylsulfoxide): ꢀ 103.90 (CHCOH), 124.68,
128.26, 129.10, 129.35, 135.71, 138.82 (Ph), 129.83
(PhCH=CH), 135.88 (PhCH=CH), 167.04 (C-OH), 189.72
3-Hydroxy-5-(2,6,6-trimethylcyclohex-2-enyl)-penta-2,4-
dienethioic acid phenylamide (1e). This compound was
obtained in 61% yield as yellow crystals; mp 125-127ºC
(hexane/benzene); ir: 3304 (NH), 2970-2880 (OHꢃꢃꢃS=C, C-H),
1642 (C=C, C-H), 1586 (C=C), 1526 (NH, C-N), 1400 (OH, C-
1
(C=S). H nmr (deuteriodimethylsulfoxide): – ketone form, ꢀ
1
O), 1322 (C-N), 1208 (NCS) cm-1. H nmr (deuteriodimethyl-
4.30 (s, 2H, COCH2CS), 6.99 (d, 1H, PhCH=CH, J=16.22 Hz),
7.32-7.77 (m, 10H, 2Ph), 7.86 (d, 1H, PhCH=CH, J=7.73 Hz),
11.80 (s, 1H, NH). Anal. Calcd. for C17H15NOS (281.38): C,
72.57; H, 5.37; N, 4.98; S, 11.40. Found: C, 72.11, H, 5.23; N,
4.95; S, 11.72.
sulfoxide): – enol form, ꢀ 0.80 (s, 3H, CH3), 0.88 (s, 3H, CH3),
1.10-1.23 (m, 1H, =CHCH2CHH), 1.30-1.43 (m, 1H,
=CHCH2CHH), 1.52 (s, 3H, CH3), 1.94-2.03 (m, 2H,
=CHCH2CHH), 2.34 (d, 1H, CHCH=CH, J=9.62 Hz), 5.46 (s,
1H, C=CHCH2), 5.81 (s, 1H, CH=COH), 5.90 (d, 1H,
C=CHCOH, J=15.21 Hz), 6.37 (dd, 1H, CHCH=CH, J=15.21,
9.94 Hz), 7.30-7.52 (m, 3H, Ph), 7.58 (d, 2H, Ph, J=7.78 Hz),
11.25 (s, 1H, NH), 14.11 (s, 1H, OH). 13C nmr (deuterio-
dimethylsulfoxide): ꢀ 22.87 (CH3), 23.00 (=CCH2), 26.95 (CH3),
27.04 (CH3), 31.33 (CHCH2CH2), 32.58 (CH2CH2C), 53.98
(CHCH=CH), 102.29 (CH=COH), 122.11 (CH=CHCH2),
128.36 (CH=CHCOH), 131.17 (CH=CHCOH), 132.93
(CH3C=CH), 124.54, 126.55, 129.01, 138.79 (Ph), 166.73
3-Hydroxy-5-phenylpenta-2,4-dienethioic acid (4-chloro-
phenyl)amide (1b). This compound was obtained in 88% yield
as yellow crystals; mp 160-163ºC (methanol); ir: 3252 (NH),
1632 (C=C, C-H), 1540 (NH, C-N), 1390 (OH, C-O), 1334 (C-
N), 1210 (NCS) cm-1.1H nmr (deuteriodimethylsulfoxide): – enol
form, ꢀ 5.98 (s, 1H, CH=COH), 6.76 (d, 1H, PhCH=CH,
J=15.47 Hz), 7.29 (d, 1H, PhCH=CH, J=6.24 Hz), 7.30-7.54 (m,
4H, 2Ph), 7.55-7.73 (m, 5H, 2Ph), 11.44 (s, 1H, NH), 14.18 (s,
1H, OH). 13C nmr (deuteriodimethylsulfoxide):
ꢀ 103.93
1
(COH), 189.97 (C=S). H nmr (deuteriodimethylsulfoxide): –
(CHCOH), 124.86, 128.30, 129.07, 129.35, 135.66, 137.33 (Ph),
129.91 (PhCH=CH), 136.16 (PhCH=CH), 167.38 (C-OH),
189.92 (C=S). 1H nmr (deuteriodimethylsulfoxide): – ketone
form, ꢀ 4.29 (s, 2H, CH2CS), 6.82 (d, 1H, PhCH=CH, J=15.87
ketone form, ꢀ 0.84 (s, 3H, CH3), 0.87 (s, 3H, CH3), 1.10-1.23
(m, 1H, =CHCH2CHH), 1.30-1.43 (m, 1H, =CHCH2CHH), 1.49
(s, 3H, CH3), 1.94-2.03 (m, 2H, =CHCH2CHH), 2.34 (d, 1H,