chapter four reactions of acyl ketene dithioacetals...
TRANSCRIPT
Chapter Four
Reactions of Acyl Ketene Dithioacetals with
Chloromethylenic Iminium Salts
4.1 lntroduction i<eactions of chloromethylenic iminium salts, with electron' rich ardirlatic
substrates. con~monly referred to as the Vilsmeier-Haack reaciiun, provide one of the
most popular methods for the introduction of formyl group under electrophilic
conditions.'.' The reagent is usually prepared by treating phosphorous oxychloride with an
excess of N.N-dimethyl f ~ r m a m i d e . ~ ~ ~ ' However a combination of other N,N-disubstituted
formamides and acid chlorides are also u ~ e d . ~ - l ' Besides formylation, Vilsmeier-Haack and
related reactions have found application in the synthesis of heterocycles. The reaction of
carbonyl compounds with chloromethylene iminium salts have attracted a lot of attention
in recent years. While simple, enolizable ketones lead to the formation of chlorovinyl
aldehydes carbonyl compounds possessing other fknctionalities lead to a variety of
transformations. Reaction of aliphatic substrates with chloromethylene iminium salts lead
to the tbrmation of a variety of multihnctionalized intermediates of potential applications
in organic synthesis
4.1.1 Reactions of functionalized ketene dithioacetals with chloro-
methylene iminium salts
Ketene dithioacetals undergo a i clriety of electrophilic substitution reactions at the
a-posit~on Aroyl ketene dithioacetals, for example, undergo bromination and nitrosation
reactions at the a-position to afford the correspo~ding a-bromo or a-nitroso compounds
in good yields.'2 Similarly it has been found that benzoyl ketene dithioacetal undergo
reaction with chloromethylene iminium salt prepared from POCI3 and DMF to afford the
corresponding a-formyl ketene dithioacetal (Scheme 1).
DMF
Scheme 1
However with acyl ketene dithioacetal 3 the a-formylated product was not
obtained. Instead the acyl group was transformed into the chlorovinyl functionality 13
(Scheme 2).
ucH3 - m 3 DMF H2C H3C
Scheme 2
Usually the acyl group is converted to a chlorovinyl aldehyde group on treatment
with the Vilsmeier reagent. A few instances where the acyl group is transformed into the
chlorovinyl group is also found in the ~iterature.'~." It has been shown that the chlorovinyl
cornpound is not an intermediate in the formation of chloroethylenic aldehyde.I6 Once the
chlorovinyl intermediate has been formed, it would not be sufficiently electron rich for
hrther iminoalkylation to take place.
The reaction of acyl ketene dithioacetals with sodium borohydride undergo
regioselectively at the carbonyl group to afford allylic alcohols substituted with alkylthio
groups. These carbinols are not stable and are known to undergo rearrangements. When
they were treated with chloromethylene iminium salt prepared from DMF and POCI,,
sequential elimination of a molecule of water and iminoalkylatio~i followed by alkaline
hydrolysis afford 5.5-bis(methylthi0)-2.4-pentadienaldehydes 7 (Scheme 3).
a DMF 0 H C v S C H 3
7
R=H, Alkyl
Scheme 3
The reaction affords excellent yields of the aldehyde when R is an alkyl group. i t is
important to note that the ketene dithioacetal functionality provide sufficient activation for
the first iminoalkylation at the terminal carbon to take place effectively. At the same time
products derived from multiple iminoalkylations are not isolated in this reaction.
The 5,s-bis(methy1thio)-2.4-pentadienaldehyd 7 obtained by sequential reduction
and fomylation of acyl ketene dithioacetals are valuable starting materials for the
synthesis of conjugated polyenaldehydes with terminal ketene dithioacetal functionality.
Thus the addition of methyl Grignard to the pentadienaldehyde 7 followed by treatment \ 1 with the chloromethylene iminium salt lead to the formation of 7,7-bis(methy1thio)-246-
heptatrienaldehyde 9 (Scheme 4)
POCh +
DMF R
R=Alkyl
Scheme 4
The 5,5-bis(methy1thio)-2.4-pentadienaldehyde 7 can also be transformed into the
9,9-bis(methy1thio)-2,4,6,8-nonatetraenaldehyde 13 . The reaction involves a sequence of
aldol condensation, sodium borohydride reduction and Vilsmeier-Haack formylation.
Thus when the pentadienaldehyde 7 was allowed to condense with acetone in methanol in
the presence of sodium methoxide as the base, the 8,s-bis (methy1thio)-3,5,7-octatriene-2-
ones 11 was obtained in good yield. Sodium borohydride reduction of this ketone
followed by treatment with Vilsmeier-Haack reagent prepared from POCI? and DMF
:\ afford the nonatetraenaldehyde 13 (Scheme 5).
W +
SCH3
H3C CH3 SCH3
MeOH
DMF
13
Scheme 5
Subsequent aldol type condensation, reduction, formylation, sequence of this
aldehydes afford a general method for the synthesis of polyenaldehydes having terminal
ketene dithioacetal functionality. These ketene dithioacetals, in which, the
bis(methylthio)methylene functionality is seperated from the carbonyl group by conjugated
double bonds are valuable substrates for carbonyl group transpositions. When these ketene
dithioacetals are subjected to regioselective reduction of the carbonyl group by sodium
borohydride in absolute ethanol, the corresponding carbinols are obtained in high yields.
These polyenols undergo a smooth rearrangement in-methanol in the presence of a Lewis-
acid such as boron trifluoride etherate to afford the corresponding polyene esters in
excellent yields."
The reaction of ketene dithioacetals with electrophilic iminium salts remain largely
unexplored. Unlike ketene acetals or aminals, ketene dithioacetals are moderate. and
therefore more selective in their reactivity. Studies on the reactions of hnctionalized
ketene dithioacetals with chloromethylene iminium salts may lead to the discovery of
interesting transformations and valuable end-products.
4.1.2 Vilsmeier-Haack reactions of dithioketals
It has been mentioned that enolizable ketones react with chloromethylene iminium
salts to afford (3-chlorovinyl aldehydes. The chloro substituent at the P-position of the
enaldehydes may be replaced by sulhr nucleophiles which would lead to the formation of
j3-alkylthio or (3-arylthio enaldehydes. However the chloroformylated products are not
always obtained in high yields and the chlorovinyl aldehydes obtained from aliphatic
ketones are rather unstable. An earlier report from this laboratory describes the reaction
of dithioketals with the Vilsmeier-Haack reagent prepared from POCI, and DMF " 0- Alkylthio ethylenic aldehydes are obtained in good yields in this reaction from aliphatic.
cyclic and aryl alkyl ketones.
SBu
, R Tic&
Scheme 6
The ketone was first treated with butanethiol in the presence of TiCI4 to afford the
corresponding dithioketals. The dithioketals were subsequently subjected to the reaction
with chloromethylene iminium salt prepared from POCI, and DMF at 0,5"C. The reaction
mixture was then allowed to stir at room temperature for 12-15 hours. Saturated
potassium carbonate was used for the alkaline hydrolysis. Purification of the crude
Table: Reaction of dithioketals with chloromethylene iminiumsalts
Entry Substrate Products Yield Ref
"4\"" CH, CH, h C Ii,
CH, C H O
enaldehydes was carried out on silica gel using hexane as the eluent. The p-alkylthio
ethylenic aldehydes were obtained as a mixture oft.; and Z isomer E isomer was the
major product in most of the acyclic systems. Selected examples of the enaldehydes
prepared by this method are given in table 1
4.2 Results and Discussion
The reaction of acetyl acetone with chloromethylene iminium salts have been
studied by several groups. Holy and Arnold showed that acetyl acetone on treatment with
the Vilsmeier reagent prepared from POC13 and Dh4F afforded 2,4-dichlorobenzaldehydei9
18 (Scheme 7).
17 18
Scheme 7
The reaction apparently involves multiple iminoalkylations followed by
electrocyclic ring closure and aromatization. When the Vilsmeier reagent was prepared
from POCI, and N-formyl morpholine, further iminoalkylation could occur before
cyclization and the dialdehyde 19 was obtained as the product.20(~cheme 8).
17 19
Scheme 8
Several other 1,3-dicarbonyl compounds also gave chloro substituted aromatic
aldehydes under Vilsmeier-Haack reaction ~ondit ions.~ '
4.2.1 Reactions of acyl ketene dithioacetals with Vilsmeier reagent
We have examined the reaction of the acyl ketene dithioacetals derived from acetyl
acetone with Vilsmeier-Haack reagent. The ketene dithioacetal 20 was allowed to react
with Vilsmeier reagent prepared from POCI, (2.3 mL, 25 mmol) and DMF (19mL, 0.25
mol) at room temperature for six hours. The reaction mixture after treatment with
saturated potassium carbonate solution was extracted with ether. The residue obtained on
the evaporation of the organic layer was subjected to column chromatography and a solid
product was isolated. The product obtained had a mp 42-43°C. Based on the spectral
data the product was identified to be 3-[bis(methylthio)methylene]-2,4-dichloro-1.4-
pentadiene 21 (Scheme 9).
DMF
Scheme 9
The proton NMR spectrum (90 MHz, CDC13, Fig 1) showed a singlet of 6H at 6
2.35 ppm due to the SCH, protons. A combination of two doublets at 6 5.49 (2H, J = l 8
Hz) and 6 5.51 (2H, J=18 Hz) were due to the methylene protons.
The mass spectrum (EIMS Fig 2) showed the molecular ion peak at d z 241
Other prominent peaks were at d z 225 (loo%), 190, 178, 143, 108, 91, 82, 63.
The IR spectrum (KBr, Fig 3) showed the prominent bands at 1600, 1500, 1130,
1190,900, 710 cm-'.
As mentioned earlier, it is rather unusual that the Vilsmeier reaction of the acyl
group ends just at the chlorovinylation stage. 3-Acetyl pyrroles 22 are known to give
Fig.1 'H NMR Spectrum (90 MHz) of compound 21
ix'- H,CS S C H , D 2 ,
i
-
I
lr-- /
\r
- - . .. L - L 2 I 0 P 8 7 6 5 4 3
*- 2 I 0
Fig.2 Mass Spectum (EIMS) of compound 21
Fig.3 IR Spectum (KBr) of compound 21
chlorovinyl substituted pyrroles 23 under Vilsmeier-Haack reaction conditions".'*
(Scheme 10).
Usually when an enolizable ketone is treated with chloromethylene iminium salt, it
is belived that the enol form of the ketone undergo an iminoalkylation first, to afford an
intermediate enaminoketone 25 which on further reaction with the iminium salt give a
dication 26.22 Substitution of CI- to the dication 26 afford the chlorovinyl substituted
iminium ion 27 which on alkaline hydrolysis afford the chloroethylenic aldehyde 28
(Scheme 11). The enolization of the ketone is assisted by the HCl liberated when the
carbonyl oxygen replaces the chlorine of the chloromethylene iminium salt to afford the
iminium salt 30 (Scheme 12).
In acyl ketene dithioacetals or acetyl pyrroles there is a high degree of
delocalization of electron density to the carbonyl group This may result in the assistance
of the ketene dithioacetal functionality in the addition of the carbonyl oxygen to the
chloromethylene iminium salt.
Scheme 10
H20 NaOAc )
N
27 28
Scheme 11
14 29 30
Scheme 12
35
Scheme 13
The addition of CI- to dication 33 and elimination of DMF affords the chloro
substituted diene 35. Once the chloro substituted diene is formed, further substitution is
unlikely (Scheme 13).
Ketene dithioacetals having other alkylthio substituents also underwent similar
reactions. The ketene dithioacetal 36 possessing bis(buty1thio)methylene functionality
gave the chloro substituted triene 37 (Scheme 14).
BUS A SBu
% DMF
A,J SBu
37
Scheme 14
The ketene dithioacetal derived from benzoyl acetone also underwent the
Vilsmeier reaction in a similar fashion (Scheme 15) to give the chloro substituted diene.
The structureof the diene 39 was confirmed with the help of spectral data..
&,fCH3 DMF
u o'ic u
Scheme 15
The results described here shows that the cyclic or acyclic ketene dithioacetals do
not give multiple iminoalkylations or cycloaromatization reactions. Not only that the
electron rich ketene dithioacetal hnctionality do not promote the iminoalkylation reaction
but it apparently prevents it. It seems that the chloroformylation reactions of enolizable
carbonyl compounds are facilitated by electronwithdrawing substituents at the carbonyl
carbon. We have noticed that while 0-chloro acetophenone undergo facile conversion to
the correspondir\g chlorofonnylated product, the I-p-chlorophenyl ethanol do not react
with the Vilsmeier reagent to afford thep-chlorosubstituted cinnamaldehyde (Scheme 16).
Scheme 16
4.2.2 Reduction of acyl ketene dithioacetals followed by reaction with
chloromethylene iminium salts
Though a-0x0 ketene dithioacetals as such do not undergo the imino alkylation
reactions with the Vilsmeier-Haack reagent prepared from POCb and D m , the allylic
carbinols derived from them should undergo iminoalkylation reactions smoothly. 3-
Bis(methy1thio)methylene pentane-2,4-dione was subjected to sodium borohydride
reduction in refluxins absolute ethanol for one hour, the reaction mixture aAer workup
with saturated ammonium chloride solution was extracted with diethyl ether. dried and
evaporated. The TLC of this mixture showed several spots. The mixture was subjected
to reaction with four equivalents of Vilsmeier reagent prepared from POCll and DMF
without further purification. The GCMS (Fig 4) of this mixture showed the presence of
several components. The mass spectra of a major component showed a molecular ion
peak at m/z 172 suggesting that it could be the bis(methy1thio) substituted triene 44 . This
could have resulted from the dehydration of the carbinol 46, apparently in the GC column.
Another component ofthe mixture, corresponding to the molecular ion at m/z 142 may be
due to the thiol ester 45
The Vilsmeier reaction was carried out by stirring at room temperature for eight
hours. Then the mixture was treated with saturated potassium carbonate solution and
extracted with diethyl ether. The organic layer was dried, evaporated and the residue was
column chromatographed. A product was isolated as an yellow crystalline solid in 46%
yield which melted at 108-109°C. Based on the spectral data, this product was identified
to be 4-[bis(methylthio)methylene]-2,5-heptadiene-l,7-dial 47 .(Scheme 17).
The proton NMR spectrum (90 MHz, CDC13, Fig 5) showed a singlet at 625ppm
for six protons due to the methylthio group. The two vinylic protons a to the carbonyl
group appeared as a double doublet (J=15 Hz and 7 Hz) at 6.33 ppm. The other two
vinylic protons showed a doublet at 6 7.82 ppm (J=15 Hz). The aldehydic protons
appeared as a doublet at 6 9.7 ppm (J=7 Hz).
The Carbon-13 NMR spectrum (22.5 MHz, CDC13, Fig 6) of the
compound 47 showcd just six peaks. The methylthio group appeared at 6 18.5 ppm. The
vinylic carbon C-2 and C-6 appeared at 6 13 1.8 ppm.while C-3 and C-5 showed a peak at
6 147.5 ppm. The signal due to the quaternary carbon C-4 was at 6134.5 ppm, while the
sulfur substituted quaternary carbon appeared at 6 156.2 ppm. The peak at 6 193.6 was
due to carbonyl groups
b i n d a n c e - . - H& xH3 xH,
1 ! i
I 2000000 ; 1500000~ i
i I i
'L- l " 1 l , l l , l l . , , , ,
5.00 10.00 15.00 20.00 25.00 ,=uxn-& -- - --
Scan 4 8 4 ( 7 . 1 6 3 rain): - 1
Fig.4 GCMS of compounds 44 & 45
Fig.5 'H NMR Spectrum (90 MHz) of compound 47
,
SC ti, ,,,,*I. m rn
a \
1
/
J J,
//
kk* 10 4 8 7 d 5 I 3 2 / 0
*
Fig.6 "C NMR Spectrum (22.5 MHz) of compound 47
m 3 DMF
Scheme 17
The IR spectrum (KBr, Fig 7) of the compound showed a band at v 1660 cm'l due
to the carbonyl groups. Another band due to the unsaturation appeared at v 1580 cm-'.
Other prominent bands in the IR spectra were at v 1420, 1280. 1100 and 960 cm.'.
Analysis of the spectral data of the compound 47 indicates that the molecule is highly
symmetric. In the proton NMR and 13c NMR spectrum the two halves of the molecule
shows identical peaks. The spin-spin coupling of the vinylic protons has a ./ value of 15
Hz. This clearly indicates that the double bond has got E steirochemist~y.
The mechanism of the reaction might involve initial dehydration of the carbinol 46
to afford the triene 44 . The allylic carbinols derived from the acyl ketene dithioacetals are
known to undergo dehydration leading to the formation of sulfur substituted diene2'
Further iminoalkylation of the electron rich triene should afford the iminium salt 48 which
on alkaline hydrolysis should afford the isolated dialdehyde 47.
Fig.7 IR Spectrum (KBr) of compo~~l~d 47
The high stereoselectivity observed, in the formation of the trat~s enaldehyde could be
because of the steric crowding in the iminium salt intermediate 49 which should have
formed if the cis isomer were the product.
We have next examined the reaction of the cyclic ketene dithioacetal 50 derived
from acetyl acetone. The ketene dithioacetal 50 was first subjected to the sodium
borohydride reduction in absolute ethanol. The mixture was refluxed for one hour, cooled
and treated with saturated ammonium chloride solution. It was then extracted with diethyl
ether dried and evaporated, and the residue was then chromatographed on silicagel using a
mixture of hexane and ethyl acetate as eluent. A liquid product was isolated which was
identified to be the (cyclic borinate) 51 on the basis of its spectral data.
50 51
Scheme 18
The proton NMR spectrum (CDCI,, 90 MHz) of 51 showed multiplets between F 1 . 1 and
1.6 ppm due to the six methyl protons. The four methylene protons of the 1,3-dithiolan
moiety also appeared as multiplet between 6 3.1 and 3.6 ppm. The two protons attached
to the allylic carbons appeared as quartet ( J ~ 6 . 5 Hz) centered at 64.22ppm. The mass
spectrum of 51 showed the molecular ion peak at m/z 216. The base peak was at m/z I44
(100%). Other prominent peaks were at d z 201, 171, and 159. The IR spectrunl
showed prominent bands at v=1570, 1440, 1360, 1270, 1200, 1 100cm~'
It is interesting to note that the borinate ester 51 which is a proposed intermediate
in the borohydride reduction could be isolated as a pure and stable compound even after
an ammonium chloride workup of the reaction mixture.
The crude product mixture obtained by the sodium borohydride reduction of the
cyclic ketene dithioacetal 50 was directly subjected to the reaction with chloromethylene
iminium salt without purification. The mixture of products after the borohydride
reduction would contain the free carbinol, the borinate ester and even the triene given by
dehydration. Therefore it was anticipated that the reaction of the crude mixture would
give an overall better yield of the expected product. The Vilsrneier reaction was carried
out with four equivalents of the reagent prepared from POC1, and DMF(1: 10) by stirring
at room temperature for eight hours. The reaction mixture after usual workup with
saturated potassium carbonate was extracted with diethyl ether, dried and evaporated.
'fhe !residue was column chromatographed on silicagel using hexane:ethylacetae (90: 10) as
the eluent. Two products could be isolated from the mixture. One of the products was a
solid having a melting point 148-149°C. This product was identified to be 4-(1,3-
dithiolan-2-ylidene)-2,5-heptadiene-1,7-dial 53 (Scheme 19) on the basis of spectral data.
The proton NMR spectrum (90 MHz, CDCI3, Fig 8) showed a singlet for four I
hydrogens at 6 3.6 ppm due to methylene protons of the 1,3-dithiolane moiety. The
vinylic protons of C-2 and C-6 appeared as a double doublet (J=15 Hz and 7 Hz) at 66.30
ppm. The vinylic protons of C-3 and C-5 appeared as a doublet (&I5 Hz) centcred at 6
7.38 ppm. The doublet (J=7 Hz) at 6 9.62 is due to the aldehydic proton.
Fig.8 'H NMR Spectrum (90 MHz) of compound 53
a DMF
u
Scheme 19
The mass spectrum of 53 (Fig 9) showed the molecular ion peak at d z 225
(82.7%). The base peak was at m/z 140 (100%). Other prominent peaks were at d z
196, 168, 136 and 96.
The IR spectrum of 53 (KBr, Fig 10) showed a band due to the carbonyl carbon at
v=1680 cm-'. The band at 1580 is due to the unsaturation. Other major bands present in
the 1R spectrum are at v 1460 and 1 130 cm-I. Another product isolated from this reaction
was an yellow oil, which was identified to be 4-(1,3-dithiolan-2-ylidene)-2,5-hexadiena 52
(Scheme 19) based on the spectral data. The proton NMR spectrum of this compound
showed a singlet for four protons at 6 3.45 ppm. A double doublet (J=7Hz and 2 Hz) at 6
5.35 ppm is due to the vinylic proton at C-6 which is cis to the vinyiic proton at C-5. The
other vinylic proton at C-6 and the vinylic protons at C-2 and C-5 appeared as a complex
lnultiplet between 6 6.0 and 6.6 ppm. The vinylic proton at C-3 appeared as a doublet
(J=15 Hz) at 6 7.38 ppm. The doublet (J=7.5 Hz) at 6 9.58 ppm was due to the aldehydic
proton. The EIMS of the compound 52 showed the molecular ion peak at mlz 198
(34.3%). The peak at d z 141 was the base peak. Other prominent peaks in the mass
Fig.9 Mass Spectrum (EIMS) of compound 53
Fig.10 IR Spectrum (KBr) of compound 53
spectrum were at mlz 97, 84 and 49. The IR spectrum (neat) showed a band due to the
carbonyl group at ~ 1 6 6 0 cm". Another band at ~ 1 5 8 5 cm-' was due to the double
bonds. Other bands were at v=1495, 1130 cm-'.
The mechanism and stereochemistry of the reaction of cyclic ketene dithioacetal 50
are similar to that of acyclic ketene dithioacetal 20. The products are obtained by the
dehydration of the intermediate followed by iminoalkylation. The major product 53 has
been obtained by the iminoalkylation at both the terminals of the intermediate triene . The
enaldehydes formed have the traris stereochemistry as indicated by the coupling constants
of the vinylic protons. As in the case of acyclic ketene dithioacetal, this can be attributed
to steric reasons.
The reduction of acyl ketene dithioacetals having methylthio substituents, and
treatment of the resultant allylic carbinols with the Vilsmeier reagent prepared from POCI?
and DMF gave the 5,s-bis(methylthi0)-2,4-pentadienaldehydes. We have examined
similar reactions with acyl ketene dithioacetals, having cyclic ketene dithioacetal moiety.
The 3-(1.3-dithiolan-2-ylidene) butanoae 54 was prepared from ethyl methyl ketone. The
ketone was allowed to react with carbon disulfide in the presence of sodium t-butoxide as
the base in benzene and the resultant dithiolate dianion was alkylated with 1.2-dibromo
ethane. The reaction mixture was washed with water and the organic layer was dried and
evaporated, to give the crude ketene dithioacetal which was purified by chromatography
on silicagel. The ketene dithioacetal was reduced with sodium borohydride in refluxing
ethanol. The mixture was treated with saturated ammonium chloride solution and
extracted with diethyl ether. The organic layer was dried and evaporated to give the crude
allylic alcohol 55. This carbinol was allowed to react with the Vilsmeier reagent prepared
from POC13 and D m . The reaction was carried out by stirring at room temperature for
six hours. After alkaline hydrolysis using cold saturated potassium carbonate solution the
mixture was extracted with diethyl ether. The organic layer was dried and evaporated to
give the crude pentadienaldehyde 56 (Scheme 20).
POC1) * DMF
Scheme 20
An NMR examination of the crude product mixture indicated that i t consists of
more than 95% of the expected pentadienaldehyde 56. The c n ~ d e product was then
purified by chromatography over silcagel using hexane as eluent. The pure product was
isolated in 78% yield as a red liquid which solidifies on cooling in a refrigerator. The
proton NMR spectrum (CDCI3, 200 MHz) of the dienaldehyde 56 showed a singlet at 6
2.00 ppm for three protons, which was due to the CH3 group. The methylene groups of
the 1.3-dithiolan moiety appeared as a singlet integrating for four protons at 6 3.51 ppm.
The double doublet (J= I5 Hz and 8 Hz) centered at 6 5.98 ppm was due to the vinylic
proton a-to the carbonyl group. The vinylic proton at the P-carbon appeared as a doublet
(J=15 Hz) at 6 7.44 ppm. The aldehydic proton appeared as a doublet (J=8Hz) at 6 9.55
ppm. In the Carbon-13 NMR spectrum (CDCI3, 50.3 MHz) the methyl carbon appeared
at 6 18.48 ppm while the methylene carbon of the 1.3-dithiolan moiety appeared at 6
38.14 ppm. The vinylic carbon C-2 and C-3 appeared at 6 124.37 and 153.22 ppm
respectively. The quaternary carbons C-4 and C-2' appered at 6 120.16 and 6 153.35 ppm
respectively. The carbonyl carbon showed up at 6 193.72 ppm. Stereoselectivity of the
transformation was similar to those reactions described earlier. The Oisomer of the
enaldehyde was formed exclusively, apparently due to steric reasons
4.2.3 Addition of Grignard reagent to acyl ketene dithioacetals followed
by reaction with chloromethylene iminium salts
Since the allylic carbinols given by the reduction of acyl ketene dithioacetals
undergo reaction with the Vilsmeier reagent to afford the 2.4-pentadienaldehydes
stereoselectiviely in good yields, we have contemplated on extending this reaction to
similar carbinols obtained by the addition of carbon nucleophiles to the carbonyl group of
acyl ketene dithioacetals. When we have attempted the reaction of alkyl Grignard
reagents with acyl ketene dithioacetals derived from aliphatic ketones, though the resultant
carbinols were obtained in good yields, subsequent reaction with chloromethylene irniniurn
salts gave complex reaction mixtures. However when the Grignard reaction was carried
out on benzoyl ketene dithioacetals the resultant carbinol underwent a smooth reaction
with the Vilsmeier reagent prepared from POCI3 and DMF (Scheme 21).
SCH3 escH CH,MgBr. p i c H 3 \
B20 \
m, , DMF
58
Scheme 21
The reaction mixture was worked up as usual with saturated potassium carbonate
solution, extracted with diethyl ether dried evaporated and the residue was
chromatographed on silicagel using petroleum ether:ethyl acetate (19: I) as the eluent. A
product isolated in 62% yield was identified as 2.2-dimethylthio-211-pyran 58, on the basis
of spectral data.
The proton NMR spectrum (90 MHz. CDCI,) showed a singlet of three protons at
6 2.40 ppm due to the methylthio group. Another singlet at 6 2.45 (3H) pprn was also due
to the methylthio group. A singlet of one hydrogen at 6 5.88 ppnl was due to the vinylic
proton at the C-3 of the pyran ring. The vinylic proton at the C-5 position showed a
doublet at 6 6.65 ppm (.1=8 Hz). Another doublet (IH) at 6 7.75 ppm (J=8Hz) was due
the vinylic proton at the C-6 position of the pyran ring. A singlet (5H) at 6 7.35 ppm was
due to aromatic protons.
The mass spectrum showed the molecular ion peak at m/z 250. Other prominent
peaks were at m/z 203, 155, 115.
The IR spectrum showed prominent peaks at v=1650, 1560, 1440, 1480, 1280,
940 cm-I. it also showed a broad band at v=1020 cm.'
A probable mechanism for the formation of 2H-pyran has been given in scheme 22.
The 1.1-bis(methylthi0)-3-phenyl substituted butadiene 59 for~netl by the dehydration of ! t the alcohol 57 undergo irninoalkylation to give the ilninium salt 60 on treatment with the
Vilsmeier reagent It is interesting to note that in pentamethinium salts analogous to 60
the iminium functionality is usually trans to the ketene dithioacetal moiety, when there is
no substitution at the 3-position. But when the phenyl group was introduced at the 3-
position, the iminium salt where in the phenyl group is trans to the iminiuni functionality is
found to be the more stable isomer. Hydrolysis of the iminium salt 60 afford the
pentadienaldehyde 61 which undergo electrocyclic ring closure to afford the 2H-pyran 58 11
that has been isolated
CH3 SCH3 WscH3 - m3 p i C H 3
\ DMF \
Scheme 22
4.3 Conclusions The Vilsmeier-Haack reaction of acyl ketene dithioa~etals ind~cate that the
chloroformylation reaction, that is frequently found with enolizable carbonyl coml)ounds,
is not feasible for these substrates. The reaction gave only the chloro substituted dienes or
trienes having the bis(methylthi0) hnctionality and corresponding chloroethylenic
aldehydes could not be prepared. A reasonable explanation for this behaviour has been
provided. However the allylic alcohols derived from acyl ketene dithioacetals on the
selective reduction of the carbonyl group by sodium borohydride in absolute ethanol
underwent dehydration and subsequent iminoalkylation selectively and efficiently The
corresponding pentadienaldehydes or polyenaldehydes were formed in reasonably good
yields. The iminoalkylations in these substrates have been found to be stereoselective
The iminium group has been introduced on the opposite side of the ketene dithioacetal
group, and as a result the frutrrs enaldehydes were exclusively formed. But when an aryl
group was present a- to the ketene dithioacetal moiety, the diene obtained after
dehydration had the aryl group at the 3-position. Here the iminoalkylation takes place
trans to the q l group rather than the ketene dithioacetal group. As a result the formyl
group was introduced cis to the ketene dithioacetal moiety. This geometry was suitable
for an electrocyclic ring closure leading to 2H-pyrans. The pentadienaldehydes and the
2H-pyrans synthesized in these studies are important substrates for further sy~~thetic
transformations.
4.4 Experimental
The general experimental details are given in chapter 3 . The experimental procedure for
the preparation of starting materials are also given in chapter 3
4.4.1 Reaction of acyl ketene dithioacetals 20 and 36 with Vilsmeier
reagent
General I'rocedure
To the Vilsmeier reagent prepared from POCI, (2.3 mL. 25 mnol) and DMF (19
mL, 0.25 mol) diacetyl ketene dithioacetal (5 mmol) was added and stirred at room
temperature for 6 hours. The reaction mixture was poured into ice cold saturated solution
of potassium carbonate and extracted with ether. The residue was dried over sodium
sulphate and column chromatographed on silica gel using a mixture of hexane and ethyl
acetate (80:20) as eluent.
3-/bis(merhyl1hio)me1hylenr/-2, -I-dichloro- I . -I-petr/t~t/re~re 2 1
Obtained as a solid. Yield (0.52 g, 43%). mp 42-4j°C IK
v,/cm'l 1600, 1500, 1130, 1190. 'H NMR (90 MHz. CDC13)
6 2.35 (6H, s, SMe), 5.5 (4H, d, J=18 Hz, vinylic) ppm. ElMS
mlz 241 (M*, I%), 225 (100%). 190 (34.196). 178 (29%). I 5 5
(l5.9%), 143 (27.8%), 131 (34'/0), 121 (6 3%), 108 (165%).
91 (20.5%). 82 (27.8%).
3-/bis(bu~lrhio)merhylt.,re/-2,4-dichloro-1. 4-pentad~erre 37
Obtained as an oily liquid. Yield (0.71 g, 44%). 1R ~, , , /crn~~
2580, 1620, 1200, 1120. 'H NMR (90 MHz, <'D('I,) 6 5 5
(4H, d, J=18 Hz,vinylic protons), 2.8 (4H, t , J=13.5 Hz,
SCH2). 0.9 (6H, t, J=6 Hz, CH;), 1.25-1 8 (8H, nl, CHz) ppm.
"C NMR (22.5 MHz, CDCI3) 6 13.87. 22.04, 32.02, 34.36.
119.53. 135.66, 140.58. 141.71 ppm.
4.4.2 Reaction of ketene dithioacetal 38 with Vilsmeier reagent To the Vilsmeier reagent prepared fiom POCi; (0.6 mL, 6 mmol) and DMF (SmL,
0.06 mol) ketene dithioacetal 38 (0.53 g, 2 mmol) dissolved in DMF (10 mL) was added
and stirred at room temperature for 6 hours. The reaction mixture was poured into ice
cold saturated solution of potassium carbonate and extracted with ether. The residue was
dried over sodium sulphate. The solid product obtained was recrystallized from petroleum
ether.
I-~he1r~l)-3-(chloro)-2-(1.3-d1~hrolo,1-2-ylidene)-3-h1r/et1e-I-
otle 39
Obtalned a crystalline solid Yield (0 21 g. 37%), mp '70-72°C U lR v,dcm" 1620, 1440. 1265 'H NMK (90 MHz. CDCI,)
63.4 (4H, s, SCH2), 5 5 (2H, d. J=18 Hz. vinylic proton). 7 3-
8.25 (6H. m, aromatic) ppm EIMS mlz 282 (M' , 8 1%). 254
(3.3%). 226 (35.4%), 105 (56 7%), 77 (100%)
4.4.3 Preparation of 4-[bis(methylthio)methylenel-2,s-heptadine1,7-
dial
To a mixture of absolute ethanol and dry dichloromethane (1: 1) ketene dithioacetal
of acetyl acetone ( 1 0 2 g, 5 mmol) was added followed by sodium borohydride (0.76 g.
20mmol) and refluxed for one hour. The reaction mixture was poured into cold saturated
solution of ammonium chloride and extracted with chloroform. The residue was dried
over sodium sulphate. The residue dissolved in DMF (10 mL) was added to the Vilsmeicr
reagent prepared at O°C from POCI, (I 9mL, 20 mmol) and DMI: (16 mL. 0.2 mol). The
reaction mixture was stirred at room temperature for eight hours. It was then poured into
cold saturated solution of potassium carbonate and extracted with ether. The res~due was
dried over sodium sulphate and column chromatographed on silica gel using a mixture of
hexane and ethyl acetate as eluent.
l-/hrs(mrthylfhio)me1hyl~t1~']-2,5-hrp~adret1r-l, 7-dral47
Obtained as crystalline solid Yield (0 64 y. 48%). tnp 108-
llO0C IR v,~cm.' 1660, 1100, 1580 '1-1 NMR (00 MHz,
CDCI,) 6 2 5 (6H, S. SCH3), 6 33 (211, dd. ./=ISHz. ./=7 I f f ,
vinylic), 7.8 (2H. d, J-15 Hz, vinylic), 9.7 (2H, d. ./=7 lir,
CHO) ppm. ',c NMR (22.5 MHz, CDCI,) 618.5, 13 1.8,
134.5, 147.5, 156.2, 193.6 ppm.
4.4.4 Reduction of 3-(1,3-dithiolan-2-ylidene)-2,4-pentanedione
To a mixture of absolute ethanol and dry dichloromethane ( ] : I ) cyclic ketene
dithioacetal of acetyl acetone (1.01 g, 5 mmol) was added followed by sodium
borohydride (0.75 g, 20 mmol) and refluxed for one hour. The reaction mixture was
poured into ice cold saturated solution of ammonium chloride and extracted with
chloroform. The residue was dried over sodium sulphate and subjected to colurnn
chromatography using a mixture of hexane and ethylacetate (85;15) as eluent.
Obtained an oily liquid. Yield (0.43 g, 40%). IR v,,,icn~"
1570. 1440, 1360. 1270, 1200, 1100 'H NMR (00 MHz. U
CI>CI,) 6 1 . 1 - 1 6 (bH, m, Ct-i3), 3.1-3.6 (4H, m. SC112). 4 2:!
(2H, q, J=65 Hz, CH) ppnl. GCMS m/z 216 (M' , 3 1.94.b),
4.4.5 Preparation of 4-(1,3-dithiolan-2-ylidene)-2,S-hexadiena and 4-
(1,3-dithiolan-2-ylidene)-2,5-heptadiene-1,7-dial
'To a mixture of absolute ethanol and dry dichloromethanc ( 1 I ) cyclic ketene
dithioacetal of acetyl acetone (1.01 g, 5 mmol) was added followed by sodium
borohydride (0.75 g, 20 mmol) and refluxed for one hour. The reaction mixture was
poured into ice cold saturated solution of ammonium chloride and extracted with
chloroform. The residue was dried over sodium sulphate and added to Vilsnieier reagent
prepared at 0°C from POC11(1.9 mL, 20 mmol) and DMF (16 mL. 0.2 mol) The reaction
mixture was stirred at room temperature for eight hours. It was then poured into ice cold
saturated solution of potassium carbonate and extracted with ether. The residue was
subjected to column chromatography using a mixture of hexane and ethyl acetate (YO: 10)
as eluent. Two products were isolated.
- / - ( I . 3-di!hioln1~-2-ylidene)-2,5-hextrdiet1~1/ 52
Obtained a liquid product. Yield (0.23 g, 23%). 1R v,,,,,/cni'
1660, 1585, 1495, 1400, 1130. 'H NMR (90 MHz, CDCI?) 6
3 45 (4H, s. SCHZ), 5.35 ( lH, dd, ./=7 Hz. ./=2 Hz, vinylic),
6 0-6 6 (3H. m, vinylic), 7 38 (IH, d, .I I5 I l l , \ I I I V ~ I C ) . 0 5 8
( l H, d, ./=7 5 Hz, CHO) ppm. EIMS rnlz 198 (M , 34 340).
171 (17.5%). 141 (100%). 97 (40%), 8.1 (42 5 % ) . 49 (63 840).
149°C 1R v,,,,/cm~' 1680. 1580, 1460, 1130. 'H NhlK (90 ' '
MHz. CDCII) 6 3.6 (4R. s. SCHZ), 6.3 (2H. dd, J -I~I~z. 1-7 U
Hz, vinylic), 7.38 (2H, d, ./=I5 Hz, vinylic), 9.62 (2H, (1, .1=7
Hz. CHO) ppm EIMS rn/z 225 (MI, 82 7%). 196 (94 5'10).
4.4.6 Preparation of 4-(1,3-dithiolan-2-ylidene)-2-pentcr1al To a mixture of absolute ethanol and dry dichloromethane (1: l ) cyclic ketene
dithioacetal of ethyl methyl ketone 54 (0.87 g, 5 mrnol) was added followed by sodiuril
borohydride (0.38 g, 10 mrnol) and retluxed for one hour. The reaction mixture was
poured into ice cold saturated solution of ammonium chloride and extracted with
chloroform. The residue was dried over sodium sulphate. The crude carbinol obtained
was added to Vilsmeier reagent prepared at 0°C from POCI, (0.')0 nlL, 10 mrnol) and
DMF (8 mL, 0.1 mol). The reaction mixture was stirred at room temperature for eight
hours It was then poured into ice cold saturated solution of potassium carbonate and
extracted with ether. The residue was subjected to column chromatography using a
mixture of hexane and ethyl acetate (90: 10) as eluent.
&(I. 3-dithiolat~-2-~lidet1e)-2-~1e~1te11~11 56
Ohtained as red liquid. Yield (0.72 g. 7846). IR \maJctn-l
1660. 1580, 1520. 1280. 1 130. 'H NMR (200 Mllz. C'DCI,) IS
2.00 (3H, s, CHI), 3.5 1 (4H, s, SCHz), 5.98 ( I H, dd, J=15 Hz,
J=8 Hz, vinylic), 7.44 (IH. d, ./=I5 Hz, vinylic), 9.5 (IH, d,
J=8 Hz, CHO) ppm. 1 3 ~ NMR (50 MHz. CDCI3) 6 18.48,
3814, 120.16, 124.37, 153.22, 153.35, I9372 ppm.
4.4.7 Preparation of 2,2-dimethylthio-4-phenyl-2H-pyran
To a solution of Grignard reagent (3 mmol) prepared from methyl iodide (0.2 mL.,
3 mmol) and magnesium (0.072 g, 3 mmol) in diethyl ether (30 mL) at 0-5°C the benzoyl
ketene dithioacetai 1 (0.45 g, 2 mrnol) dissolved in diethyl ether (I0 mL.) was introduced.
The mixture was stirred for another one hour at the same temperature and was then added
to saturated ammonium chloride solution (100 mL) The organic layer was seperated "
The aqueous layer was extracted with diethyl ether (2 X 30 mL). 'The combined organic
layer was washed with water,.dried (Na2S04) and evaporated under vaccum The crude
alcohol obtained was directly used for the next step
The Vilsmeier reagent was prepared from DMF (2.5 mL. 30 lnrnol) and POCl,
( 0 3 mL, 3 mmol) by slowly adding POCI, to DMF with cooling and stirring (0-5°C) The
mixture was allowed to stir for 30 min after the addition of POC13. Then the crude alcohol
(0.48 g, 2 mmol) obtained obtained from the first step was diluted with I)MF ( I 0 niL.) and
added slowly to the vilmeier reagent kept stirring at 0-5°C The mixture was then allowed
to stir at room temperature for fifteen hours. It was then added to cold saturated solution
of potassium carbonate and extracted with diethyl ether (100 mL X 3). The combined
organic layer was dried and evaporated under vacuum. The residue obtained was
chromatographed on silicagel using petroleum ether:ethyl acetate (1: 19) as the eluent
2,2-d1merhyl1h1u--l-phenyl-2I-I-1~yrat1 58 sin,
Obtained as an yellow oil. Yield (0.27 g, 54%). 1R v,,,,/cm~'
I H NMR (90 MHz. CDCI1) 6 2 40 (3H. s. SCHI), 2.45 (3tl. s,
SCH3), 5.88 (IH, s, vinylic), 6.65 (IH, d, .J=8 Hz. vinylic).
7.35 (SH, s, aromatic), 7.75 (IH. d. .l=8 Hz, vinylic) ppm
GCMS mli. 250 (M' ) 2011, 155, 105.
4.5 References
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Weissenfels, M.; Pulst, M. Z. Chem. 1976, 16, 337.
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Seshadri, S. J. Sci. [?id. Res. 1973, 32, 128.
Meth-Cohn, 0 . ; Tarnowski, B. A h . Hererocycle. ('hem. 1982. 31. 207
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