vilsmeier-haack reactions of a-hydroxyketene dithioacetals...
TRANSCRIPT
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Chapter 5
Vilsmeier-Haack Reactions of a-Hydroxyketene Dithioacetals:
Synthesis of Substituted Pentadienethioates
5.1 Introduction
The chloromethyleneirninium salts derived from acid chlorides like POCL
and N,N-disubstituted tbrmamides such as DMF are potential intermediates
involved in the Vilsmeier-Ilaack-Arnold reaction^.'^ They have been extensively used for thc formylation of activated aromatic, heteroaromatic and fully
conjugated ~ ~ s t e m s . ~ ~ ' The broad synthetic utility of these iminium salts is not
only restricted to formylation of electron rich compounds, but also has been
widely exploited for electrophilic substitutions followed by intramolecular
cyclizations, producing a variety of heterocyclic compounds. The reactions of
Vilsmeier-Haack reagents with a-oxoketene dithioacetals have led to some facile
carbonyl transposition strategies which could be employed in the synthesis of
polyene natural products like ~arotenoids. '~,~ Our research group has recently
investigated the reactions of tr-oxoketene dithioacetals derived from benzyl
methyl ketones with Vilsmeier reagents leading to the formation of
chlorosubstituted 2,4-pentadienthioates involving a 1,5 alkylthio shift of the
iminoalkylated intermediate.": In continuation of this study, we have investigated
the reactions of a-hydroxyketene dithioacetals with chloromethyleneiminium
-
salts which proceeded with a 1,s methylthio shift and afforded functionalized
pentadienethioates, thereby effecting a 1,3 carbonyl group transposition.
5.1.1 Carbonyl Group Transpositions: Applications in Organic Synthesis
Despite the abundance of carbonyl group in organic compounds, its
transposition within the molecular frameworks for the realization of synthetic
objectives has not been fully exploited. Junjappa and Dieter have extensively
studied reductive and alkylative 1,3-carbonyl group transpositions involving
12-addition of organometallic reagents either on vinylogous thiolesters or on
a-oxoketene dithioacetals to form the intermediate carbinol acetals and their
subsequent acid induced transformations to a$-unsaturated thiolester~.~. '~
Simple and alkylative carbonyl group transpositions are of considerable synthetic
importance for introducing new C-C bonds in a regiospecific manner. Among the
numerous variants, 1,2- ;and 1,3-carbonyl group transpositions are by far the most
intensively investigated reactions. There are also a limited number of examples
involving l,4-transfer of carbonyl group, while those involving 1,5- and
1,6-transpositions are generally confined to intramolecular hydride shifts only."
Reports from the research group of Junjappa have shown that the sequential 1,2-
addition of NaBF-l., or Grignard reagents to polyenyl ketene dithioacetals followed
by boron triflouride etherate assisted methanolysis could lead even to 1,11-
transposed polyene e s t c r ~ . ~ " . ~
5.1.2 1,3-Carbonyl Group Transpositions: General Strategies
Wharton KI ui. have reported an elegant route for 1,3-carhonyl group
transposition which involves a rapid reaction between the epoxy ketone derived
from (+)-a-ionone 1 and hydrazine. The geometric isomers of 4 formed in the
ratio ca. 1: 1 and were oxidized to give E-a-damascone 5 and its Z counterpart
(Scheme 1 ).I2
-
Scheme 1
In another approach. Trost er al. have achieved the 1,3-transposition via a
[2,3] sigmatropic rearrangement (Scheme 2).13
Me OH SPh
Me
10 11 12 Scheme 2
Buchi rf ul have synthesized p-damascone 17 from the oxime 13 of
p-ionone viu an intramolecular migration of the oxygen atom of the oxime to the
remote carbon of a conjugated double bond (Scheme 3).14
16 17
Scheme 3
-
The carbonyl group present in cyclooct-1-en-3-one 18 was alkylatively
transposed by Dauben et ul. by the sequential Grignard reaction and pyridinium
chlorochromate mediated oxidation (Scheme 4) '
19
Scheme 4
Exan~ples of 1,3-carbonyl group transposition reactions involving
hnctionalized ketene dithioacetals would be discussed later.
5.1.3 Chloromethylenein~inium Salts: Preparation and Synthetic Applications
Chloromethyleneiminium salts, popularly known as Vilsmeier reagents,
are employed for a wide range of synthetic objectives including formylation of
electron rich substrates. The Vilsmeier-Haack reaction generally proceeds via the
attack of the carbonyl oxygen of the amide 21 to POCb to form an adduct 22,
which reacts further to give the chloromethyleneimium salt 23 (Scheme 5).la
I'OCI, R3Na40POCI~ - R, CI - , - ,ky
R7 H R2 Rz H CI 0
OPOCI,
2 1 22 23
Scheme 5
The cl1loromethyleneirninium salt generally reacts with an electron rich
substrate at its electron rich centre, leading to the formation of an intermediate
irninium salt which on basic hydrolysis affords the corresponding aldeheyde. For
example, Mekonnen el al. have reported the formylation at the 5-position of the
imidazo[2,1-hjoxazole 24 employing Vilsmeier Haack reagent (Scheme 6) . l 6
-
24 25
Scheme 6
In the case of carbonyl compounds like simple enolizable ketones,
chloroformylated products are obtained and the reaction involves iminoalkylation
of the en01 form of the substrate followed by hydrolysis of the iminium salt
formed.'" When multiple irninoalkylations occur on enolizable ketones like
dibenzyl ketone 26, cyclizations of the pentadienaldehyde 27 formed during
hydrolysis occurs, resulting in the formation of pyrilium salt which reacts with
water to afford substituted pyrones 28 (Scheme 7).17
26 27 Scheme 7
In continuation with the studies on reactivity of dithioketals with
Vilsmeier-Haack reagent we have observed that the iminoalkylated intermediate
derived from the dithioketal 29 also cyclizes in a similar fashion to afford 3,5
diphenyl-4H-pyran-4-one 31 (Scheme 8).8C
EMF/ POC13
16h. r t .
30 31 Scheme 8
-
Multiple iminoalkylated intermediates can be cyclized in the presence of
NH4CI or NH40Ac to afford substituted pyridines and napthyridines. Isobutene
32 on treatment with chloromethyleneiminium salts 33 afforded 2,7-
napthyridines 34 in good yields (Scheme 9).18
- .p CHO
Scheme 9
Studies from this laboratory have resulted in an expedient synthesis of
aryl pyridine carbaldehydes 37 from carbinols 36 derived from acetophenones 35,
by treatment with chloromethyleneiminium salts followed by quenching with
ammonium acetate (Scheme I O ) . ' ~
0 H,C OH
CH, CHJMgl -- - A']
X Ft,O 4 2 8 0 ~ ~ 1 2 h * , 3 NH40Ac
35 36 37 Scheme 10
When the same protocol was extended to aliphatic alcohols like r-butanol
38, functionalized napthyridines 39 were formed (Scheme 11).
H3C OH K 1 . POCId DMF( 6 equiv.) -.
n3c' YH:, 2. r t . , 15h 3. NH,OAG CHO
38 39 Scheme 11
Benzofused 1,4-diazepinones 40 on treatment with Vilsmeier reagent
followed by quenching with NH4CI afforded pyrido-fused benzodiazepine-2-ones
41(Scheme 12)."'
-
40 41
Scheme 12
4-N-(methy1formamido)pyridine underwent reaction with (COC1)x to
afford the intermediate 43, which underwent aerial oxidation to form a carbene
which then cyclized and subsequently gave 5-substituted-N-methyl isatin 47.
(Scheme 13)."
Scheme 13
Acetylation reactions under Vilsmeier-Haack reaction conditions are
usually less efficient compared to formylation reactions. However the Vilsmeier
reaction using dimethyl acetamide and POCI, was used in acylation reaction of
hexahydropyroloindolizine 48 to afford an inseparable mixture of the two
regioisomers 49a and 49b in good yields (Scheme 14).*~
a
- . ,. A,/ , I
N~ I -. I '3 q" POCl3 \ ~ ~ - \ 1
* q0 YC + CH3 48 49a 49b
Scheme 14
-
Triflouron~ethanesulfbnic anhydride has been used to activate DMF to
generate the iminium salt 51. which on treatment with nucleophiles like primary
and secondary alcohols. thiols etc., afforded new iminium salts 52 which were
later converted to esters 51 and 0-alkyl thiolesters 53 by hydrolysis and thiolysis 7 3 respectively (Scheme
Scheme 15
Nagarajan et 01 have observed that a ring opening of dibenzodiazepinone
ring occurs on treatment with chloromethyleneiminum salts followed by
cyclization to afford benzimidazole 56 derivatives (Scheme 16).24
POCI, IDMF -- h 0
55 56 Scheme 16
5.1.4 a-Hydroxyketene Dithioacetals: Synthetic Uses
a-Hydroxyketene dithioacetals are potent intermediates in many synthetic
transformations." T'hey are usually prepared from anxoketene dithioacetals by
reduction using NaBK, or by a 12 addition of organolithium or organomagnesium
reagents. 'The carbinol acetals 58 derived from a-oxoketene dithioacetals 57 of a
variety of cyclic and acylic active methylene ketones by 1,2-addition of Grignard
-
reagents. on boron triflouride etherate assisted methanolysis afforded the
a$-unsaturated S-methyl esters 59. The hydrolysis of these carhinols using
boron triflouride etherate in the presence of water gave the corresponding
a,B-unsaturated esters 60 (Scheme 1 7).yd
58
Scheme 17
5,s-Bis(methylthio)substituted pentadienaldehydes 63 were synthesized from
the a-oxoketene dithioacetals 61 employing a sequential 1,2 reduction using NaBH4
and chloromethyleneim~nium salt mediated formylation reaction (Scheme 1 8).8ab
0 SCW, NaBH, H3c ,"qH3 POCt3, L I M L HIG:cw, H329 SCH, ---' SCHl
R R R
Scheme 18
o,o)-Bis(methylthit,)substituted polyenaldehydes were prepared by a
combination of sequential aldol condensation, reduction and Vilsmeier Haack reaction.
This is exemplified by the synthesis of 9,9-bis(methy1thio) nonapentenaldehyde 67
(Scheme 19).'"'
-
0 SCH,
I NaOMeI MeOH MeOH R R
66 67
Scheme 19
Recent studies from our research group have developed a facile method
for the synthesis of methylthio substituted 4-aryl pyridines 70 from aryl substituted
a-hydroxyketene dithioacetals 69 via the sequential Grignard-Vilsmeier reactions,
followed by quenching with ammonium acetate (Scheme 2 0 ) . ~ ~ ~
69
Scheme 20
We envisioned that the modification of this protocol involving
1,2-addition of organomagnesium reagents followed by dehydration of the
resulting carbinol and subsequent iminoalkylation could lead to variously
functionalized polyenes and heterocycles.
5.2 Results and Discussion
The Vilsmeier-Haack reaction of the carbinols derived from tr-oxoketene
dithioacetals leads to iminoalkylated intermediates which on aqueous work up
could in principle, afford conjugated pentadienaldehydes, which could be further
used for carbonyl group transposition reactions and other synthetic
transformations. Contraty to our expectations, the iminoalkylated intermediate
-
underwent a 1.5-shift of one of the methylthio groups, to afford the
corresponding pentadienethioates in good yields.
5.2.1 Reactions of 4,4-Bis(methylsulfanyl)-2-phenyl-3-buten-2-o1 with Chloromethyleneiminium Salts: Synthesis of Substituted 3-Aryl-5- methylsulfanyl-2,4-pentadienethioates
The 2-(4-chlorophenyl)-4,4-bis(methylsulfanyl)-3-buten-2-ol 69a was
prepared by the Grignard reaction of the corresponding a-oxoketene dithioacetals
68a by the 1 &ddition of methyl Grignard reagent. The crude carbinol was then
treated with the chloromethyleneiminium salt derived from POC13 and DMF at
room temperature for 12 hours. Subsequent work up using aqueous K2CO3
solution, extraction with diethyl ether and column chromatography over silica gel
using hexane:cthyl acetate (9:l) as eluent afforded a yellow crystalline solid in
55% yield (Scheme 21). This compound was identified as S-methyl (2E,4E)-3-(4-
chlorophenyl)-5-(methylsulfanyl)-2,4-penatdienethioate 71a on the basis of
spectral data (Scheme 2 I).
OH SCH,
SCH, 2equiv.. 12 h, r t .
X X X
Yield (%)
60
60
60
50
45
Scheme 21
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The 'H NMR spectrum (300 MHz, CDCl-,) of 71a shows two singlets for
three protons each, at 6 2.30 and 2.33 ppm, which are due to the two methylthio
groups. The singlet at 6 5.73 is due to the styryl proton. The protons of the
olefinic bond connected to one of the methylthio group appears as two doublets at
6 6.54 and 7.5 respectively, showing [runs coupling (J = 15.3 Hz). The doublets
at 6 7.15 (J = 9 Hz) and 6 7.26(5 = 9 Hz) integrating for two protons each are due
to the para substituted aromatic ring. The "C NMR (100.4 MHz, CDC13) shows
signals at 6 11.9 and 14.4 ppm due to the two methylthio groups. The aromatic
and olefinic protons appear at 119.9, 121.4, 128.6, 130.3, 134.7, 137.8, 142.1 and
149.7 ppm respectively. The carbonyl group shows peak at 6189.2 ppm. IR
spectrum (KBr) showed bands at v 1640, 1565, 1540, 1020 cm-'. EIMS of 71a
showed the molecular ion peak at m/z 284 (5 %).
The structure was further confirmed based on HMBC and C, H-COSY
experiments (Fig 1 and 2).
-
1 I
up-
s-
1
Fig 1. HMBC correlation spectrum of 71a
Fig 2. C,H-COSY spectrum of 71a
The HMHC spectrum shows a long range connectivity between the
protons of one of the methylthio group (-SCH3) at 2.30 ppm and the carbonyl
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l . " l . b ~ , l l . l " l l . . . , l ' . l !'a4
Fig. I 'H NMR(300 MHz, CDCb) Spectrum of Compound 71a
Fig. I1 I" C NMK(75 MHz, CI)C13) Spectrum of Compound 71a
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Fig. 111 IR Spectrum of Compound 71a
Fig. IV Mass Spectrum(GCMS) of Compound 71a
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carbon at 190 ppm, thereby confirming the presence of the thiolester moiety in
the molecule. The protons of the second methylthio group at 2.34 ppm shows
connectivity with an sp2 carbon at 138 ppm, indicating that the second methylthio
group is attached to the alkene double bond. The alkene proton Ha at 7.6 pprn
shows connectivity to two sp2 carbons- the one a to the carbonyl group at 120 ppm
(assigned by C,H-COSY) and the one at 138 ppm could be the ring carbon. The
alkene proton Hb at 6 6.5 ppm shows connectivity to a sp3 carbon at 11.9 pprn
(-SCH3), further establishing this connectivity. This proton also shows long range
connectivity to a carbon at 6 150 ppm. The styryl proton at 6 5.7 pprn shows
connectivity to the thiolester carbonyl, indicating that it is present on the carbon
atom a to the carbonyl group. It also shows connectivity to the sp2 ring carbon at
6 138 ppm and with the olefinic carbon at 6 121 pprn.
Other a-hydroxyketene dithioacetals 69b-e under similar reaction
conditions gave the corresponding pentadienethioates 71b-e in 45-67% yields and
were characterized with the help of analytical and spectral data, which will be
discussed in the experimental section of this chapter.
The a-oxoketene dithioacetal 72 derived from a-tetralone also underwent
1,2 addition of methyl Grignard reagent to afford the corresponding carbinol 73
which on iminoalkylation afforded the pentadienethioate 74 in 60% yields
(Scheme 22).
Scheme 22
The structure of the product was confirmed by HMBC experiment (Fig. 3).
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Fig 3. HMBC Spectrum of 74
One of the S-methyl carbons (6 14.84) shows connectivity with a proton
at 6 6.5 ppm indicating that this methylthio group is attached to the double bond.
The carbonyl carbon (6 194) shows connectivity with the second methylthio group
indicating the presence of the thiolester functionality in the molecule. Thus the
structure of 74 was confirmed on the basis of further assignments as shown in fig 3.
However, our efforts to extend this reaction to the a-hydroxyketene
dithioacetals derived from propiophenone afforded complex reaction mixtures.
The proposed mechanistic pathway for the formation of the pentadienethioate
involves a 1 J-shift of the methylthio group of the iminium salt intermediate 77 as well
as a 1,3-carbonyl group transposition. The chloromethyleneiminium salt mediated
dehydration of the a-hydroxyketene dithioacetal 69 would afford the corresponding
l,l-bis(methylthi0)-3-aryl-1,3-butadiene 75. The reaction of the diene 75 with
chloromethyleneiminium salt would lead to an iminoalkylated intermediate 77,
which would cyclize to form the intermediate 78. Addition of a molecule of water
triggers an intramolecular 1,s-shiA of an S-methyl group to form the thiolester
-
intermediate 80. Subsequent elimination of a molecule of N,N-dimethyl amine
from 80 affords the pentadienethioate 71 (Scheme 23).
OH SCH,
SCH, w -+ X
69 75
Scheme 23
Base induced intramolecular 1.3- and 1,5-shifts of alkylthio groups of
ketene dithioacetals are reported in literature. Junjappa et a1 have observed an
intermolecular thioallylic rearrangement involving a 1,3-shift of the alkylthio
group while studying a-methyl deprotonation of the a-oxoketene dithioacetals 81
using NaH as base (Scheme 24).26
-
r- X -
aH, SMe
SMe SMe SMe
X-
d
SMe SMe SMe SMe SMe
84 85
Scheme 24
a-Allyl ketene dithioacetals 87, under identical reaction conditions
underwent an intramolecular migration of the alkylthio group involving
1,6-conjugate addition to the mobile oxopentadienyl intermediate 88, to afford
the corresponding dienes 91 in good yields (Scheme 25).17
90 Scheme 25
A recenl report from this laboratory describes an interesting intramolecular
1,5-shift of the methylthio group of the a-oxoketene dithioacetal 92 derived from
benzyl methyl ketone, by reaction with Vilsrneier reagents leading to the formation
of the corresponding chloro substituted pentadienethiolesters 96 (Scheme 26)''
-
95 96
Scheme 26
5.2.2 Reactions of 1-(1,3-Dithiolan-2-yliden)-2-phenyl-2-propanos with Chloromethyleneiminium Salts
Our studies on bis(cinnamoy1) ketene dithioacetals had established that
the methylthio groups present in these substrates are more vulnerable to
hydrolysis than their cyclic analogues.28 We next attempted to examine the
reactivity patterns of the a-hydroxyketene dithioacetal 98, derived from the
addition of methyl Grignard to cyclic ketene dithioacetal 97, towards Vilsmeier-
Haack reagents. Unlike in the case of S-methyl ketene dithioacetals, the carbinol
acetal on dehydration and subsequent iminoalkylation afforded the expected
forrnyl derivative 99 in good yields (Scheme 27).
98
Scheme 27
The ' I NMK spectrum (300 MHz, CDCI,) shows a singlet for four
protons at 6 2 3 0 and 3.26 ppm due to the dithiolan moiety. The doublet at 6 6.2
-
(J = 9 Hz) pprn is due to the styryl proton. The proton a to the dithiolan moiety
appears as a singlet at 6 6.2 ppm. The aromatic protons appear as a multiplet for five
protons at 6 7.3 pprn and the aldeheyde proton appear as a doublet at F 9.2 pprn
(J = 9 Hz). l'he ' 3 ~ NMR (100.4 MHz, CDC13) shows signals at 6 36.2 and 41
pprn due to the two methylthio groups. The aromatic and olefinic protons appear
at 6 110.5. 115.9, 125. 127.2, 128.6, 128.9, 129, 130.2, 136.2, 154, and 159 pprn
respectively. The carbonyl group shows peak at 6 193 ppm.
As in the case of S-methyl ketene dithioacetals, the first step in the
proposed mechanism involves dehydration of the a-hydroxyketene dithioacetal 98
triggered by chloromethyleneirninium salt to afford the corresponding 2-[2-aryl-2-
propenylidenel-l,3-dithiolanes 100, which undergoes subsequent iminoalkylation
with chloromethyleneirninium salt leading to the formation of an iminoalkylated
ketene dithioacetal intermediate 101. Hydrolysis of 101 would afford the
corresponding 4-(1,3-dithiolan 2-yliden) 3 phenyl-2-butenal 99 (Scheme 2 ~ ) . ~ ' ~
102 99 Scheme 28
5.3 Experimental
Melting points are uncorrected and were obtained on a Buchi-530 melting
point apparatus. lnfra red spectra were recorded on Shimadzu IR-470
spectrometer and the f'requencies are reported in cm-'. Proton NMR spectra were
-
recorded on a Bruker DRX-300 (300 MHz), Bruker WM 250 (250 MHz) or on a
Bruker WM 400 (400 MHz) spectrometer in CDC13. Chemical shifts are
expressed in parts per million downfield from internal tetramethyl silane.
Coupling constants .l are given in Hz. Electron impact Mass spectra were
obtained on a Finnigen --Mat 3 12 instrument.
5.3.1 General Procedure for the Synthesis of 3-Aryl pentadienethioates 71a-e
The methyl Grignard reagent was prepared from 1.41 g (10 mmol) methyl
iodide, 0.3 g (10.7 mmol) magnesium and a pinch of iodine crystals (0.10 g) in
ether. The methyl magnesium iodide was cooled to 0-5 "C and the ketene
dithioacetals (7.2 mmol) in ether was added slowly over 15 min. The mixture was
stirred at this temperature for half an hour and was poured over cold saturated
ammonium chloride solution. It was then extracted with ether (3 x 50 mL). The
combined organic layer was washed with water and dried over anhydrous sodium
sulphate. Ether was removed and the a-hydroxyketene dithioacetals formed were
used for the next step without further purification.
The Vilsmeier reagent was prepared by mixing ice cold dry DMF (50 mL)
and POCl, (1.24 mL, 10 mmol). The mixture was then stirred for 15 min. at room
temperature. The crude tx-hydroxyketene dithioacetals obtained from the
Grignard reaction were dissolved in dry DMF and added in about 15 min at
0-5 "C. The reaction mixture was the stirred for 12h at room temperature, added to
cold saturated K2C-03 solution (300 mL) and extracted with diethyl ether (3 x 50 mL).
The organic laycr was washed with water, dried over anhydrous Na2S04 and
evaporated to give the crude product which was chromatographed using hexane:
ethyl acetate (98:2) as eluent to give the aryl pentadienethioates 71a-e.
-
C,,H,,CIOS, Ma1 Wt. 284 83
i;,3H,iBr0S2
Mol Wt 32'3 28
~'-~efhyl(2~,4E)-3-(4-chloropheny-5-
(methylsulfany1)-2.4-pentadienethioufe 71a was
obtained by the Vilsmeier reaction of 4,4-
bis(methylsulfany1)-2-phenyl-3-buten-2-01 69a (2
g, 7.2 mmol) as yellow crystalline solid. Yield 1.2
g (60%), mp 43-45 "C. IR v,,dcm ' 1640, 1565, 1540, 1020. 'H NMR (300 MHz, CDCI,) 6 2.30
(s, 3H, SMe), 2.33 (s, 3H, SMe), 5.73 (s, IH,
olefinic, HL), 6.52 (d, IH, 5 = 15.3 HZ, olefinic,
H ~ ) , 7.15 (d, 2H, J = 1 1 Hz, aromatic), 7.59
(d, l H, J = 15.3 Hz, olefinic, H" pppm. "C NMR
(75MHz , CDC13) 6 11.9, 14.4, 119.9, 121.4,
128.6, 130.3, 134.7, 137.8, 142.1, 149.7, 189.2
ppm. EIMS m/z (%) 284 (M', 5), 252 (25), 237
(96), 205 (72), 189 (30), 149 (loo), 139 (32), 113
(25), 101 (28), 75 (70).
~'-~eth~l(2E,4E)-3-(4-bromophenyI,-5-
(methylsulfanyl)-2.4-penladienethioare 71b was
obtained by the Vilsmeier reaction of
2-(4-bromopheny1)-4,4-bis(methylsu1fanyl)-3-
buten-2-01 69b (2 g, 7.2 mmol) as yellow
crystalline solid. Yield 1.2 g (60%) ; mp 60 "C. 'H
NMR (300 M H c CDCI3) 6 2.29 (s, 3H, SMe),
2.32 (s. 3H, SMe), 5.72 (s, IH, olefinic He), 6.51
(d, l H, J = 15.3 Hz, olefinic, H ~ ) , 7.08 (d, 2H, J =
8.1 Hz, aromatic), 7.41 (d, I , J = 8.1 Hz,
aromatic), 7.58 (d, IH, J = 15.3 Hz, olefinic, Ha)
ppm . liC NMR(75.47 M H z CDC13) 6 10.9, 13.4,
118.8, 120.3, 121.8, 129.8, 130.3, 130.5, 137.2,
141.1, 144.0, 148.0, 188.0ppm.
-
C,,HI~O~S? Mol W 280 41
C,rH,,OS,
Mol Wt 264 41
(methylsulfay~-2.4-pen/adienethioate 71c was
obtained by the Vilsmeier reaction of 2-(4-
ol 69c ( 2 g, 7.4 mmol) as yellow crystalline solid.
Yield 1.2 g (60%). IR v,,/cm-' 1595, 1470, 1420,
1240, 1165,785. 'H NMR (90 MHz, CDCI,) G 2.10
(s, :iH, SMe), 2.41 (s, 3H, SMe), 3.80 (s, 3H, OMe),
5.91 (s, IH, olefinic, Hc), 6.75 (d, IH, J = 18 Hz,
oletinic, H ~ ) , 7.15 (m, 4H, aromatic), 7.65 (d, IH, J
= 18Hz, olefinic, Ha) ppm. "C NMR (22.5 MHq
CK1l) 6 10.9, 13.4, 118.8, 120.3, 121.8, 129.8, 130.3,
130.5, 137.2, 141.1, 144.0, 148.0, 188.0 ppm. GCMS
mlz (%) 281 (S), 267 (7), 202 (8), 191 (7), 159 (lo),
145 (9), 135 (loo), 121 (25), 107 (22), 92 (25),
77 (48).
(methylsulfany1)-2,4-pentadienelhioale 71d was
obtained by the Vilsmeier reaction of 2-(4-
methylphenyl)-4.4-bis(methylsulfanyl)-3-buten-2-ol
69d ( 2g, 7.9 mmol) as deep brown oil. Yield 1 g
NMR (300 MHz, CDCI,) G 2.29 (s, 3H, SMe), 2.32
(s, 3H, SMe), 2.45 (s, 3H, Me), 5.84 (s, IH, olefinic,
H'), 6.67 (d, IH, J = 15.3 Hz, olefinic, H ~ ) , 7.18
(m, J H , aromatic), 7.76 (d, IH, J = 18 Hz, olefinic,
Ha)ppm. ''c NMR (75 MHq CDC13) 15 10.9, 13.4, 118.8, 120.3, 121.8, 129.8, 130.3, 130.5, 137.2,
141.1, 144, 148, 188 ppm. ElMS mlz (%) 264 (7),
23 1 ( 9 x 2 16 (1 00), 184 (40), 173 (3 I), 168 (77), 140
(39), 128 (52), 114 (59), 75 (32).
-
SCH.
'SCH:,
C,JH,,OS,
Mol Wt 250 38
2 4-pentadienethioate 71e was obtained by the
Vilsmeier reaction of 2-phenyl-4,4-
b1s(methylsulfanyl)-3-buten-2-ol 69e (2 g, 8.4
mmol) as a brown oil. Yield 1.14 g (55 %). IR
v,,/cm~' 1655, 1545, 1430, 1140, 760. ' H NMR
(90 MHz, CDCI,) F 2.31 (s, 3H, SMe), 2.40
(s. 3H, Sme), 5.90 (s, IH, oletinic, HC), 6.65 (d,
IH, J = 18 Hz, oletinic, H'), 7.45 (m, 4H,
aromatic), 7.60 (d, IH, J = 18Hz, olefinic, Ha)
ppm. GCMS m/z (%) 250 (2), 203 (loo), 160
(231, 155 (47), 130 (25), 115 (27), 102 (lo),
77 (12).
S)-~ethyl I-(( E )- (methylsulfanyl) ethenyll-3,4-
dihydro-2-napthalenecarbothioate 74 was
obtained by the Vilsmeier reaction of 2-
[bis(methylsulfanyl)methy lenel-l -methyl-l,2,3,4-
tetrahydro-I-napthalenol 73 (2 g, 7.5 mmol) as a
yellow clystalline solid. Yield 1.2 g (60%).mp
102-104 'C.'H NMR (200 MHz, CDCI3) 6 2.37
(s, 3H, SMe), 2.41 (s, 3H, SMe), 2.62 (m, 2H,
methylene), 2.74 (m, 2H, methylene), 6.52 (d, IH,
J = 16 Hz, olefinic, H'), 6.56 (d, IH, J = 16 Hz,
olefinic, Ha), 6.87 (d, IH, J = 16Hz, olefinic, H~)
7.21 (m, 3H, aromatic), 7.51 (d, IH, J = 8 Hz,
aromatic) ppm. I3C NMR (75 MHz, CDCI,) 6
12.6, 14.9, 26.1, 28.8, 30.1, 30.6, 121.3, 126.2,
126.7, 127.9, 128.8, 129.2, 130.8, 134.5, 134.6,
138.9, 140.1, 194.2 ppm.
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5.3.2 General Procedure for the Synthesis of 4-(1,3-Dithiolan-2-y1iden)-3- aryl-2-butenal 99
The methyl Cirignard reagent was prepared from 1.41 g (10 mmol) methyl
iodide, 0.3 g (10.7 mmol) magnesium and a pinch of iodine crystals (0.10 g) in
ether. The methyl magnesium iodide was cooled to 0-5 O C and the cyclic ketene
dithioacetals (8.4 mmol) in ether was added slowly over 15 rnin. The mixture was
stirred at this temperature fbr half an hour and was poured over cold saturated
ammonium chloride solution. It was then extracted with ether (3 x 50 mL). The
combined organic layer was washed with water and dried over anhydrous sodium
sulfate. Ether was removed and the a-hydroxyketene dithioacetal fbrmed were
used for the next step without further purification.
The Vilsmeier reagent was prepared by mixing ice cold dry DMF (50 mL)
and POC1, (1.24 mL, 10 mmol). The mixture was then stirred for 15 min. at room
temperature. The crude a-hydroxyketene dithioacetal obtained from the Grignard
reaction were dissolved in dry DMI' and added in about 15 min at 0-5°C. The
reaction mixture was stirred for 12h at room temperature, added to cold saturated
K2C03 solution (300mli) and extracted with diethyl ether (3 x 50 mL). The
organic laycr was washed with water, dried over anhydrous Na2S04 and
evaporated to give the crude product which was chromatographed using hexane:
ethyl acetate (98:2) as eluent to give 99.
-
99 was obtained by the Vilsmeier reaction of
1-(1,3-dithiolan-2-yliden)-2-phenyl-2-propanol 98
(2 g, 8.4 mmol) as a white crystalline solid. Yield o H c , i-) (." , .. -L .~ s 1.14 g (55%). mp 110 "C. ' H NMR (300 MHz, .-I
CDCl,) 8 3.27 (m, 4H, -SCH,-), 6.1 1 (d, l H, J =
C I ~ H I ~ O S ~ 9Hz, olefinic), 6.42 (s,lH,olefinic), 7.54 (m, 5H, Mo Wl 248 37 aromatic), 9.28 (d, IH, J = 9Hz, CHO) ppm. "C
NMR (75 MHz, CDCI,) 6 36.2, 41.0, 110.5,
115.9, 125.7, 127.2, 128.6, 128.9, 129.0, 130.2,
136.2, 154.0, 159.0, 193.0 ppm ElMS mlz (%)
248 M',(6), 222 (23), 191 (20), 172 (42), 149
(IOO), 143 (45), 115 (90), 105 (25), 85 (30).