- Cha~ter Three

f3-Alkylthioethylenic Aldehydes: Synthesis and Applications

in the Preparation of Substituted Phenols

3.1 Introduction B-Alkylthitrethylenic aldehydes are potential multifinctional intermediates in

organic synthesis ' ' However the synthetic utility of this class of compounds is not widely

explored. This may be attributed to the non-availability of a simple and convenient

method for their preparation. Recently a report from this laboratory6 have described an

expedient protocol for their preparation from enolisable ketones, which involve Vilsmeier-

Haack formylation of the intermediate dithioketals. As a result, the P-alkylthioethylenic

aldehydes can now be prepared in quantities and we have examined some reactions to

explore their synthetic potential. The aldol condensations and sequential aldol-Michael

additions were examined. Methods for the preparation of phenols with a variety of

substitution patterns could be developed as a result of these studies.

3.1.1 Synthesis of Aromatic Compounds from Acyclic Precursors Construction of aromatic rings from acyclic precursors is a valuable method for the

synthesis of highly substituted aromatic compounds.' The aromatic annulation reaction

has the advantage that the substituents can be introduced at the desired position by

cho,,sing the appropriate acyclic precursors during the construction of the ring itself.

Some of the important methods that lead to the convergent synthesis of substituted

benzenes starting from acyclic starting compounds has been summarised in the following

3.1.1. I Synthes~s of Substituted Phenols Ketones flanked by two methylene groups can act as 1,3-binucleophiles in its

reaction with a 1.-bielectrophile to give substituted phenols. Malondialdehydes or its

synthetic equivalents are frequently used as the 1,3-dielectrophilic three carbon fragments.

Malondialdehydes having electron withdrawing substituents such as 2-nitromalonaldehyde

1 have received lot of attention (Scheme I ) . * " ~

H V H + Rl&R2 - NO: R''+R2 NO2

1 3

Scheme 1

Other substituted malonaldehydes were also used in the synthesis of phenols.20-"

However this method for the synthesis of phenols suffer from the disadvantage that

malonaldehydes are rather unstable and expensive. Certain heterocyclic compounds such

as the pyrimidine derivatives 4 and 5 can act as malonaldehyde equivalents in their reaction

towards ketones to afford substituted phenols.2427

a&-Unsaturated aldehydes having a chloro or N,N-dimethylamino substituent at

a-position also knction as a synthetic equivalent of substituted malonaldehyde. They

react with the dianion of ethyl acetoacetate to afford substituted salicylates 8 (Scheme

2).2"

X = Cl, NMe2 R = akyl aryl

Scheme 2

Similarly the reaction of the fluorosubstituted iminium salt 10 with

dimethylacetone dicarboxylate also gave the corresponding substituted phenol 11 (Scheme

Scheme 3

Like malonaldehyde other P-ketoaldehydes also behave as 1.3-bielectrophiles in

their reaction with ketones to afford phenols having an additional substituent at three

position. Though P-ketoaldehydes could be less reactive than malonaldehydes they are

more easily accessible and relatively more stable. p-Ketoaldehydes derived from aryl alkyl

ketones. aliphatic ketones and cyclic ketones react with acetone dicarboxylic acid or its

esters to give respective substituted phenols.30.3' Simple aliphatic ketones also may react

with P-ketoaldehydes if a substituent such as a nitroso group or an aryl diazo group is

present at the a-position.32.33 Though P-diketones also can be used in similar reactions, if

at least one of the component is not symmetric a mixture of regioisomeric products could

be formed." a.P-Unsaturated ketones, having a substituent such as N,N-dialkylamino,

alkoxy or chloro group at P-position can also function as an equivalent of 1,;-

d ike t~ne .~ ' .~ '

Doubly deprotonated P-ketoesters can be silylated to afford the disilylated enol

diene 12 which undergo acid catalysed regio-selective addition to p-oxoacetals or a,P-

unsaturated ketones having leaving groups at the P-position leading to the formation of

substituted salicylates (Scheme 4).3740

T M 4 e + @ OMe - XCb

OTMS

12 13 14

Scheme 4

An interesting sequential addition of Reformatsky reagent to a-

oxoketenedithioacetals followed by electrocyclic ring closure and aromatisation also

afford substituted salicylates 16 (Scheme 5).41

SMe @ OoR

Scheme 5

Diels-Alder cycloaddition reactions involving suitable dienes and dienophiles

prov;de a versatile protocol for the synthesis of substituted phenols. Aromatisation of the

cycloadduct involve elimination of the leaving groups present, dehydrogenation or loss of

small molecules such as carbondioxide or nitrogen. Danishefsky's diene has been found to

be versatile in the synthesis of substituted phenols. The aromatic unit of milbemycin-P-3

has been synthesised by the cycloaddition reaction of an acetylenic ester and Danishefsky's

diene (Scheme 6 ) ''

xylene + -xi?

Me RO

0

20

Scheme 6

The cycloadduct obtained from Danishefsky's diene and substituted oxazol-5(4H)-

ones 22 on subsequent treatment with base afforded aminosubstituted phenols 25 (Scheme

7) 4'

OMe OMe

i) NaOK THF c&- Q, Ar

NHCOPh NH2

Scheme 7

Cycloaddition of vinyl ketenes with acetylenes provide another efficient annulation

route to highly substituted aromatic systems."47 Thus the vinyl ketene 27 generated from

the unsaturated a-diazo ketone 26 via the photochemical Wolff rearrangement combines

with, the substituted acetylene in a regiospecific [2+2] cycloaddition Subsequerrt

phol:ochemical or thermal ring opening followed by electrocyclic ring closure and

tautomerisation krnishes the annulated phenol 30 (Scheme 8).48 The a-diazo-p-

ketoderivatives prepared from a$-unsaturated carbonyl compounds on thermal Wolff

rearrangement also gave dienyl ketenes which underwent benzannulation leading to the

formation of the respective phenolic derivatives."

Scheme 8

The intermediates generated by the addition of allylic Grignard reagents or

organolithium reagents to vinylogous esters on cycloaromatisation hrnish substituted

phenols 34 (Scheme 9 ) .50 This reaction has been hrther extended for the preparation of

catechol mono ether^.^'

33 34

Scheme 9

Kim and GO-workers have shown that phenolic compounds could be readily

prepared vla a sequential Michael addition Claisen condensation reactions of two

appropriate three carbon fragments such as a-bis(methylthi0) substituted aliphatic ketones

and a,P-unsaturated 1,3-Michael-Claisen annulation using I, l-bis-

(methylthi0)-2-propanone and a-methylene lactones provide dihydrobenzohrans and

tetrahydrochromans.s9 Trolox is a well known a n t i o ~ i d a n t ~ ~ used in food industry in place

of a-tocopherol (vitamin E) and also a synthetic precursor of a-tocopherol." Solladie

and co-workers have developed a 1,3-Michael-Claisen annulation method for the synthes~s

of a Trolox analogue 38 from substituted a-methylene 6-valerolactone and 1,l-bis-

(methylthi0)-2-propanone 36 ( ~ c h e m e l o ) . ~ ~ They have also synthesized the insectiside

Precocene I I ~ ~ by elaborating this protocol

SMe

Scheme 10

The carbanion generated from dimethyl-l,3-acetonedicarboxylate reacts with

propynals to give substituted phenols. The reaction apparently involve an initial Michael

addition followed by intramolecular aldol c~ndensa t ion .~~ Similar reactions with alkynyl

ketones have been reported earlier (Scheme 1 1).65.66

Scheme 11

3.1.1.2 Syr~thesis of Other Substituted Aromatic C o m p o u d Aromatic annulation reactions are valuable for the synthesis of other classes of

substituted benzene derivatives as well. Some selected examples shall be illustrated here

to highlight the various approaches.

The treatment of allylic carbinols obtained by the addition of ally1 grignard reagents

to (x-oxoketenedithioacetals with boron trifluoride etherate gave the respective

cycloaromatised compounds. The example shown in Scheme 12 employs the ketene

dithioacetal derived from a-tetra~one.~' Similarly addition of methallyl Grignard followed

by treatment with HBF, also gave benzannulated product^.^' Subsequently the reactions

of a-oxoketenedithioacetals and other similar substrates with benzyl magnesium bromide

and propargyl magnesium bromide also have been shown to afford cycloaromatised

products 44 (Scheme 12).~''~

SMe -

44

Scheme 12

The Diels-Alder cycloaddition route to aromatic compounds also could be

achieved from acyl ketenedithioacetals via the 1,3-butadienes 45 prepared from them by

the addition of methyl magnesium iodide followed by dehydration. Scheme 13 illustrates

the cycloaddition reaction of bis(methylthi0) substituted 1,3-butadiene with dimethyl

acet:ylene d ica rbo~~la te .~ '

45 46 47

Scheme 13

Naturally occurring anticancer antibiotics, such as calicheamycin y, contain a

strained ene-diyne moiety which under appropriate conditions undergo nucleophilically

induced Bergman ~ ~ c l o a r o m a t i s a t i o n . ~ ~ ~ ~ ~ Recently it has been shown that Bergman

cycloaromatisation can also take place under photochemical conditions. Thus the ene-

diyne 47 on irradiat~on in the presence of a hydrogen donor gave a naphthalene derivative

49 (Scheme 14).19

Scheme 14

3.1.1.3 Ar~t~ulatiotr Heactrons on Heterocyclic Precursors

Most of the earlier methods for the synthesis of benzene derivatives from acyclic

precursors has been summarised in the review by Bamfield and Gordon7 The

conventional approach towards synthes~s of benzoheterocycles involve reactions of

substituted benzene derivatives with appropriate reagents followed by cyclisation of the

intermediate formed under suitable conditions. An alternative approach would be to begin

with1 heterocycles and transform them to benzoheterocycles through aromatic annulation.

Katritsky and co-workers have recently described the synthesis of polysubstituted

benzothiophenes from 2-(benzotriaz0le-l-~lmeth~l)thio~henes.~~ The carbanion generated

from 2-(benzotriazole-I-ylmethyl)thiophenes undergo Michael type addition to a#-

unsaturated ketones to afford various substituted benzothiophenes 52 (Scheme 15).

Similarly polysubstituted carbazoles8' and naphthalenes also could be prepared by this

approach.

Scheme 15

Junjappa's group have successhlly extended their cycloaromatisation method for

the synthesis of benzoheterocycles. The reaction of allylic lithium reagents prepared from

heterocycles undergo 1,2-addition or conjugate addition to acyl ketene dithioacetals

Subsequent cyclisation in the presence of Lewis acid such as boron ttifluoride etherate

lead to the formation of substituted b e n z o h e t e r ~ c ~ c l e s . ~ ~ ~ ~ ~ Scheme 16 illustrates the

applil:ation of this method in the synthesis of substituted indazolones The allylic lithiuni

reagent 53 prepared from antipyrine on treatment with LDA undergo conjugate addition

with the a-oxoketene dithioacetal 54 to afford the intermediate enone 55 which on

subsequent cyclisatlon in the presence of boron-trifluoride etherate in refluxing benzene

afford the substituted indazolone 56.84

OMe

59

OMe I

OMe

P k N

I

/N Me SMe

56

Scheme 16

Aromatic compounds having a variety of substitution patterns and functional

groups can be prepared starting from appropriate acyclic precursors. This method is also

valuable for the synthesis of polynuclear aromatic compounds and aromatic rings

amulated to heterocycles

3.2 Results and discussion The method that has been reported for the synthesis of 13-alkylthioethylenic

aldehydes from carbonyl compounds has been generalised. Several aliphatic, cyclic

and aryl-alkyl ketones were transformed to respective P-alkylthioethylenic aldehydes.

Ketones were first transformed to the respective dithioketals by treating with

butanethiol, in the presence of titanium tetrachloride. The dithioketals formed are

subsequently treated with the chloromethyleneiminium salt. Some of the ketones gave

din~erisation products or cyclotrimerisation products in addition to or instead of the

expected enealdehydes. The reaction of [3-alkylthioethylenic aldehydes with different

aliphatic wbony l compounds were examined. The 3-butylthio-2-methyl-2-

pentenaldehydes prepared from diethyl ketone acted as a four carbon synthon in its

reaction with diethyl ketone and benzyl methyl ketone. The reaction proceeded with

inter and intra molecular aldol reactions to afford substituted phenols as products. With

dibenzyl ketone P-alkylthioethylenic aldehydes behaved as three carbon synthons. Here

the: reaction involves an aldol-Michael sequence, leading to the formation of substituted

phenols.

3.2.1 Synthesis of P-Alkylthioethylenic Aldehydes

13-Alhylthioethylenic aldehydes were prepared starting from enolisable carbonyl

compounds in a two step process. First the ketone was allowed to react with butanethiol

in the presence of' TiClj to give the respective dithioketal in nearly quantitative yields.q'

The dithioketal prepared was purified by column chromatography over silica gel and then

subjected to the Vilsmeier-Haack reaction. The Vilsmeier reagent was prepared by

treating POCI3 wlth excess of DMF (10 equivalents) at 0-5'C for half an hour The

dithioketal was added to the Vilsmeier reagent at 0-5'C and the mixture was allowed to

stir at room temperature for 12 to 15 hours. The reaction mixture was treated with

sa1:urated KzCO, solution, extracted with diethyl ether, dried and evaporated. The crude

0-alkylthioethylemc aldehyde obtained were purified by flash column chromatography

over silica gel.

59

Scheme 17

Table I :Synthesis of fidkylthioethylenic aldehvdes <

57.58 Dithioketals Aldehyde ratio Yield

57 58 ,a, .

Table 1 :Synthesis of ~alkylthioethylenic aldehydes (contd)

57,58 Dithioketals Aldehyde U Z ratio Yield

57 58 (%)

Several a,b-unsaturated aldehydes were prepared by this procedure6 and were

characterised. The stereoselectivity of the reaction depends primarily on the structure of

the starting dithioketal The enealdehydes obtained from the aliphatic acyclic dithioketal

have got their aldehyde group [runs to the butylthio group (Scheme 17).

SBu

The stereoselectivity is attributed to the higher stability of the iminium salt 59 in

which the alkylthio group is trutts to the iminium functionality compared to the iminium

salt 63, where the alkylthio group is cis to the iminium functionality. Dithioketals derived

from aryl alkyl ketones also show similar selectivity. The ratio of E isomer is usually

above 90%. However p-methoxy substituted dithioketal gives upto 20% of the Z isomer.

The details of various P-alkylthioethylenic aldehydes prepared are given in Table 1

While attempting the preparation of the P-alkylthioethylenic aldehyde from benzyl

methyl ketone we have isolated a crystalline solid which was subsequently identified as a

substituted naphthalene derivative 62 (Scheme 18) along with the expected 0- alkylthioethylenic aldehyde 58c. The aldehyde was formed in low yield (3 1%) as a

mixture o f E and Z ~somers (30:70).

Scheme 18

The formation of the compound 62 might involve dimerisation of the intermediate

dithioketal 57c On closer examination we have found that this compound is actually

formed at least partially in the first step itself. But on column chromatography it was

difficult to separate it from the dithioketal itself However it is not very clear whether the

cycloaromatisation proceed krther under the Vilsmeier-Haack condition. This possibility

could not be ruled out for two reasons. The expected P-alkylthioethylenic aldehyde 58c

was obtained only in small amounts and the yield of the cycloaromatised product was

higher after the treatment with Vilsmeier reagent. Mechanism might involve the formation

of intermediate vinylsulfide which might undergo addition to the carbocation 64 generated

from the dithioketal. The final product might have resulted from the electrocyclic ring

closure of the intermediate triene 66 followed by the elimination of the butylthio group

(Scheme 19).

Scheme 19

3.2.2 Cyclotrimerisation Reactions of Dithioketals The reaction of some substituted acetophenones with Tic& and butane thiol

followed by treatment with the Vilsmeier reagent gave cyclotrimerised products along

with the expected [3-alkylthioethylenic aldehydes.

The cyclotnmensation reactions of ketones under acid catalysed conditions are not

very general. However convenient preparative methods have been developed using ketals

in the presence of protic acids and Lewis acids." Cyclotrimerisations of ketones in the

presence of alcohols are also efficient which presumably proceeds through the formation

of ketal intermediate.86 Cyclotrimerisation of ketones have been observed directly in the

presence of solid super acid catalyst ~ a f i o n - ~ . ~ ' . ~ ~

In the present reaction it may be the vinyl sulfide that undergo cyclotr~mersation

reacion. Our efforts to cyclotrimerise dithioketals in the presence of Lewis acids such as

boron trifluoride etherate or titanium tetrachloride also did not afford the expected

products in preparatively useful yields.

R

Ti% CHCI, (i)POCI,, DMF

( i i ) K ~ q . H20 +BUSH - -

Scheme 20

68 R Yield (%)

b Me 9

When acetophenone was allowed to react with butanethiol in the presence of

titanium tetrachloride in chloroform and the product formed on subsequent treatment with

Vilsmeier reagent and work up gave 1,3,5-triphenyl benzene 68a in 8% yield (Scheme 20)

in addition to the respective P-alkylthioethylenic aldehyde. Similarly p-methyl

acetophenone also gave the respective cyclotrimerised product under these condition.

3.2.3 The Reactions of 3-Butylthio-2-methylpent-2-enal58b with Ketones

Carbonyl compounds flanked by two methylene groups 2 can act as 1.3-

binucleophilic synthons. They can react with 1,3-bielectrophilic compounds such as a,P-

unsaturated ketones having a leaving group at (3-position 69, 1.3-dicarbonyl compounds

70, or acetylenic ketones 71 to afford cycloaromatisation reactions leading to the

fonr~ation of phenols 72 and 73, where both the components would act as three carbon

fragments

In principle the reaction may give any one of the regioisomeric phenols 72 and 73

selectively or a mixture of them depending on the reactivity of the ketone used as well as

the nature of the 1.3-dicarbonyl compounds or its equivalent. It has been mentioned

earlier that substituted malonaldehydes and P-ketoaldehydes are suitable 1.3-electrophiles

for the synthesis of phenols. However these intermediates are usually unstable and

relatively more stable synthetic equivalents are considered as better synthons. The P- alkylthioethylenic aldehydes 58 is an attractive synthetic equivalent of P-ketoaldehydes 74.

Moreover the P-alkylthioethylenic aldehydes are complementary to the P- alkylthioethylenic ketones 75 in reactivity. The synthesis of the P-alkylthioethylenic

ketone 75 involve the conversion of the enolisable ketone to the j3-ketoaldehyde 74

followed by treatment with butanethiol in the presence of an acid catalyst (Scheme 21)

Scheme 21

There are several examples in the literature which involve a,b-unsaturated esters

or nitr riles such as 77 or 78 having a y-methylene group participating as a four carbon

fragment in cyclisation reaction involving another two carbon fragment with adjacent

donor and acceptor sites

In such reactions the y-methylene group acts as the donor, and the carbonyl group

or the nitrile group behaves as the acceptor. The two carbon fragment that could be used

in such reactions is usually a Michael acceptor 79 and less frequently an active methylene

ketone 80. The reaction of an active methylene ketone will be more facile if the four

carbon fragment has a formyl group instead of ester or nitrile.

When we have initiated the reaction of the 0-alkylthioethylenic aldehyde 58b

derived from diethyl ketone with active methylene ketones we were interested in finding

out ,which would be the most preferred pathway , from among the several possible modes

of reaction. It has been shown that the aldol condensation of active methylene ketones

with P-alkylthioethylenic aldehydes provide good yields of the 2,4-pentadienones 82

(Scheme 22).

81

Scheme 22

Some of these dienones have been hrther used in the synthesis of donor and

acceptor substituted butadienes, which have shown to be NLO active.89 Schemes 23 and

24 shows the reaction sequences leading to the formation of NLO active materials.

Scheme 23

SBu SBU

R H

Scheme 24

R&R1 R4*R'

BUS \ OH HO \ R2

R3 R~ R3

94 94A

Scheme 25

Similar dienes that could be prepared by the aldol type condensation of active

methylene ketones may undergo cyclisation to give the cycloaromatised products or

pyrylium salts. The pyrylium salt can be further converted to the aromatic compounds or

pyridine (Scheme 25) .

The aldol 89 or the dienone 90 may further undergo an intramolecular aldol

condensation to give the substituted benzene 93. Alternatively an intramolecular Michael

type addition of 90 (R~=CHZR') should lead to the formation of the phenol 94. j3-

Alkylthioethylenic aldehydes having a y-methylene group such as those derived from

aliphatic ketones can in principle act as a four carbon component in cycloaromatisation

reactions. The fact that the y-methylene group is cis to the aldehyde functionality further

favours cyclisation after the initial addition reaction. The initial reaction could be a

Michael addition when we use Michael acceptors as the two carbon fragment. We may

also use the enolisable ketones as the two carbon fragment, where the overall reaction

would involve sequential inter and intra aldol condensations (Scheme 27). However in the

latter case the intramolecular cyclisation in the final step would largely depend on the

stereochemistry of the intermediate aldol 100 or the enone 101.

Scheme 26

However the aldol 100 may undergo fkther intramolecular aldol reaction and

subsequent elimination of water molecules would lead to the aromatic product.

Scheme 27

The 3-butylthio-2-methyl pent-2-enal 58b could be prepared from diethyl ketone

dithioketal on treatment with Vilsmeier reagent prepared from POCI3 and DMF (Table I ) .

The aldehyde was obtained exclusively as a single stereoisomer. The stereochemistry of

the aldehyde was assigned on the basis of NMR spectrum. The aldehyde functionality is

frans to the butylthio substituent. We have first attempted the reaction of this aldehyde

with diethyl ketone itself Diethyl ketone is capable of acting either as a two carbon

fragment or as a three carbon fragment in the cyclisation, though the methylene groups are

not much activated. The reaction was carried out in the presence of sodium tertiary

butoxide as the base in a mixture of refluxing tertiary butanol and benzene. The column

chromatography of the product mixture gave a crystalline solid which was identified as 3-

ethyl-2,4,6-trimethyl phenol 104 (Scheme 28).

The NMR spectrum (90 MHz, CDC13, Fig la) shows a singlet for three methyl

groups at F 2.2 ppm. The triplet (3H) and the quartet (2H) due to the ethyl group were

present at 6 1.1 and 6 2.6 ppm respectively. The phenolic OH was present as a singlet at 6

4.5 ppm whereas the single aromatic proton gave a singlet at 6 6.8 ppm. The structure

was further confirmed with the help of I3c NMR (22.64 MHz, CDCI,, Fig lb). The

signals due to the methyl groups were present at 11.46, 13.68, 15.72 and 19.09 ppm. The

signal at 6 121.24. 127.23. 129.58, 139.64 and 150.23 ppm were due to the aromatic

carbons . The IR (KBr. Fig Ic) spectrum of the compound showed a band due to the

hydroxy group at 3400 cm-'. The other prominent bands were at 2990, 1580, 1470 cm-I

etc. The mass spectrum (GCMS, Fig Id) of the compound showed the molecular ion

peak. at mlz 164

Scheme 28

It may appear that the mechanism of the reaction involve the participation of

diethyl ketone as a 1,3-binucleophile and P-alkylthioethylenic aldehyde as 1,3-

bielectrophile. If the aldehyde acted as a four carbon fragment the reaction would result in

the fmnation of a substituted benzene with the butylthio group intact 105 (Scheme 29)

Scheme 29

Fi. la 'H NMR spectrum (90 MHz) of compound 104

160 1 LO 120 110 0 60 10 20 0

Fig. l b "C NMR Spectrum (22.64 MHz) of compound 104

4000 3000 2000 1500 loo0

Fig. lc IR Spectrum (KBrj of compound 184

8001300 1 16L

i

600000

LOO 000 I 200000 135

9 1 105 I

1 115 0 -

50 60 70 80 90 100 110 120 130 160 IS0 160 170 .

Fig. Id Mass Spectrum (GCMS) of compound 104

Another probable mechanism which would explain the formation of 104 can also

be proposed (Scheme 30). The initial step of the reaction could be an aldol type addition

of the enolate derived from diethyl ketone to j3-alkylthioethylenrc aldehyde. The

intermediate aldol might undergo a cyclisation to give an intermediate pyran 108 which

might finally lead to the formation of 1.5-diketone 110. Alternatively this diketone can

also form by the solvolysis of the aldol 107. But it appears that the formation of the

dikctone 110 depends on the geometry of the aldol 107, which favours cyclisation.

Me Q - OH,

Me Me Me

Scheme 30

The intramolecular aldol condensation of the 1,Sdiketone 110 would lead to the

formation of the phenol 104. Subsequent studies on the reaction using unsymmetric

aliphatic ketones such as benzyl methyl ketone indicates that, this mechanism in which the

aldehyde participates as a four carbon synthon is more probable.

3.2.4 Reaction with Substituted Benzyl Methyl Ketones. In the reactlon of diethyl ketone and P-alkylthioethylenic aldehyde 58b leading to

the formation of substituted phenol, the actual mechanism of the reaction could not be

clearly understood We have further examined the reaction of P-alkylthioethylenic

aldehyde 58b with o-methoxybenzyl methyl ketone. o-Methoxybenzyl methyl ketone is an

unsymmetric ketone where one of the methylene group is more activated than the other.

This would provide an opportunity to clearly distinguish whether the aldehyde actually

participate as a four carbon fragment in the reaction. The reaction was conducted in a

mixture of tertiary butanol and benzene in the presence of sodium tertiary butoxide as the

base. The reaction mixture after the usual work up and column chromatography gives a

crystalline product. which was identified as 2,3,6-trimethyl-4-(2-methoxyphenyl) phenol

112a (Scheme 3 1 )

The structure of the 2.3.6-trimethyl-4-(2-methoxyphenyl) phenol was confirmed by

spec:tral data. The NMR spectrum (90 MHz, CDCI3, Fig 2a) shows two singlets for three

methyl groups at 6 2.0 (3H) and 2.15 (6H) ppm respectively. The singlet (3H) due to the

methoxy protons is present at 6 3.75 ppm. The multiplet (4H) at 6 6.7-7.4 ppm is due to

the aromatic protons. The singlet due to the hydroxy group is present at 6 4.55 ppm. The

structure was further confirmed with the help of I3c NMR (22.64 MHz, CDCI,, Fig 2b).

The signals due to the methyl groups were present at 6 12.17, 15.78, and 17.00 ppm

respectively. The signal at 6 55.34 ppm is due to methoxy carbon. The signals at 6

110.51, 119.84, 120.41, 121.87, 128.84, 129.36, 130.82, 131.45, 134.13, 151.23, 156.84

ppm were due to aromatic carbons. The IR (KBr, Fig 2c) spectrum of the compound

showed a band due to the hydroxy group at 3480 cm-'. The other prominent bands were

at 3000. 2920, 1580, 1470 cm.' respectively. The mass spectrum (EIMS. Fig 2d) of the

compound showed the molecular ion peak at m/z 242

b

r klcl J

I !, I P \I<

I

I I I I

I : I I / ' 8 8

I 1 II 11 , I , , ! I I I

I ! ] , /j i , ] , ' 1 /,/I

i ..A ~ - 1- 1

200 180 160 1LO 120 100 80 60 L 0 20 0 - 20

Fig. 2b I3C NMR Spectrum (22.64 MHz) of compound 112a

Fig. 2c IR Spectrum (KBr) of compound 11h

r ;?'+

! !I 2L2 1008 q,- .,/

I 1 / 0 \ l c 1 I \f i

I

I

I I

1 : I

8 8

1 5 2 212 1 227 '

5 0 100 150 LOO 2 50 300

Fig. 2d Mass Spectrum (EIMS) of compound 112a

The substituted phenol 114, which should be expected if both the starting aldehyde

and ketone acted as three carbon synthon was not formed in their reaction. If the

aldehyde acted as a four carbon fragment the substituted phenol 113 where the

buty~thiogroup is intact would have been formed.

~ e * Ra t-BuOWC6H6 - - B u 8 d ? ~ e e '

/ Me

10 h reflux BUS HO ' Me

111

Scheme 31

112 R Yield (%)

a. o-OMe 60

b. p-OMe 65

c. H 65

Hence the th~rd alternative mechanism suggested earlier gains more ground. The

mechanism in the case of substituted benzyl methyl ketone may be depicted as follows

The selectivity in the final cyclisation could be due to the involvement of a

thermodynamically more stable enolate (Scheme 32).

0 OH,

Me

Me

Scheme 32

The reactlon was extended to other similar ketones such as benzyl methyl ketone

and 4-methoxy benzyl methyl ketone to afford the corresponding substituted phenols as

the products (Scheme 3 1). Spectral data of the products are provided in the experimental

section.

Though we have further examined this reaction employing other aliphatic and aryl

alkyl ketones, complex product mixtures were formed under various reaction conditions

We could not opt~mise the conditions, though different combination of solvent, base and

temperature were examined. The reaction involving dibenzyl ketone gave products in

good yields, thoush P-alkylthioethylenic aldehydes acted as three carbon fragment in those

reactions.

3.2.5 Reactions of P-Alkylthioethylenic Aldehyde 58b and Dibenzyl Ketone

We have next examined the reaction of dibenzyl ketone with the P- alkylthioethylenic aldehyde derived from diethyl ketone. The reaction was done as usual

in a mixture of retluxing tertiary butanol and benzene in the presence of sodium tertiary

butoxide. The work up and column chromatographic purification of the product mixture,

gave a crystalline solid in 68% yield. The product was identified as the substituted phenol

3-ethyl, 4-methyl-2.6-diphenyl phenol 121 (Scheme 33), the structure of which was

confirmed by spectral data. The NMR spectrum (90 MHz, CDC13, Fig 3a) shows a singlet

for methyl group at 6 0.85 ppm. The triplet (3H) and the quartet (2H) due to the ethyl

group were present at 6 0.9 and 2.2 ppm respectively. The phenolic hydrogen was present

at 6 4.6 ppm. The multiple1 (1 1H) at 6 6.9-7.7 ppm is due to aromatic protons. The

structure was further confimed by 13C NMR spectrum (22.64 MHz, CDC13, Fig 3b). The

signals at 6 14.32 and 18.93 ppm are due to the methyl carbons. The signal at 6 23.73

ppm is due to the methylene carbon. The signals due to aromatic carbons were present at

6 125.23, 126.97. 127.73, 127.98, 128.35, 128.65, 129.09, 129.25, 129.32, 130.48.

131.50, 136.11, 138.10, 140.91 and 148.78 ppm respectively. The IR (KBr, Fig 3c)

spectrum of the compound showed a band at 3500 cm" due to hydroxy group. The other

prominent bands in the IR spectrum were at 3500, 3000, 1600, 1440 cm.' respectively.

The mass spectrum (GCMS, Fig 3d) of the compound showed the molecular ion peak at

mlz 288.

58 b 120 121

Scheme 33

In this reaction the dibenzyl ketone acted as a 1,3-binucleophilic three carbon

component. This could be because both the methylene groups are activated due to the

presence of phenyl substituents. Also the presence of phenyl substituents should help the

Fig. 3a 'H NMR Spectrum (90 MHz) of compound 121

Y - 160 140 120 100 8 0 6 0 40 20 0

Fig. 3b "C NMR Spectrum (22.64 MHz) of compound 121

Fig. 3c IR Spectrum (KBr) of compound 121

Fig. 3d Mass Spectrum (GCMS) of compound 121

intermediate dienone to be in a suitable stereochemistry for the intramolecular Michael

type cyclisation (Scheme 34).

Scheme 34

3.2.6 Reactions of 3-Aryl-3-butylthiopropenaldehydes 58 f-k with Dibenzyl Ketones

Several P-alkylthioethylenic aldehydes could be prepared from substituted

acetophenones and other aryl alkyl ketones. When the 3-butylthio,3-

phenylpropenaldehyde 58f was allowed to react with dibenzyl ketone in the presence of

sodium tertiarybutoxide in a mixture of tertiary butanol and benzene the 2,3,6-

triphenylphenol 124a was formed in 61% yield (Scheme 35).

The structure of the product was confirmed by spectral data. The NMR spectrum

(90 MHz, CDCI,, F I ~ 4a) shows the singlet due to hydroxy group at 6 5.35 ppm. The

multiplet (17 H) due to aromatic protons was present at 6 6.9-7.8 ppm. The structure was

then confirmed with "C M spectrum (22.64 MHz, CDCI,, Fig 4b). The signals present

at 6 122.32, 12641, 127.33, 127.63, 128.50,'128.76, 129.30, 129.63 and 131.09 ppm

were due to aromatic carbons. The IR (KBr, Fig 4c) of the compound shows a peak at

3400 cm-' which 1s due to hydroxy group. The other prominent bands were present at

3400, 1600, 1400 cm'l respectively. The mass spectrum (GCMS, Fig 4d) shows the

molecular ion peak at m/z 322.

58 f-k

Scheme 35

124 R Yield (%)

Obviously in this reaction the dibenzyl ketone acted as a 1,3-binucleophile. The

reaction might involve electrocyclic ring closure of the intermediate enolate formed from

the pentadienone This reaction has been shown to very general. The D-alkylthioethylenic

P

N U) r. . -

i

-- -

13 1 2 11 10 9 8 7 6 5 I 3

.rC, 2 1 0

d

Fig. 4n 'H KMR Spectrum (90 MHz) of compound 124a

Fig. 4b "C NMR Sgedrum (22.64 MHz) of compound 124a

4000 3000 2000 1500 1000

Fig. 4c IR Spectrum (KBr) of compound 124a

Fig. 4d Mass Spectrum (GCMS) of compound 124a

aldehydes 58 g-k prepared from other substituted acetophenones also gave the

corresponding phenols 124 b-f on reaction with dibenzyl ketone, under similar conditions.

3.2.7 Reaction of 0-Butylthio-3-naphthylpropenaldehyde 581 with Dibenzyl Ketone When 3-butylthio-3-naphthylpropenaldehyde 581 was allowed to react with

dibenzyl ketone the expected phenol 125 was formed in 56% yield (Scheme 36). Here

also the reaction was canied out in a refluxing mixture of tertiary butanol and benzene in

the presence of sodium tertiary butoxide as base.

Scheme 36

The reaction involves electrocyclic ring closure of the intermediate enolate formed

from the pentadienone, obtained by the initial aldol condensation. The structure of the

product was confirmed by spectral data. The NMR spectrum (200 MHz, CDCI?, Fig 5a)

shows the presence of hydroxy proton at 6 5.4 ppm as singlet. The multiplet between 6

6.9-7.9 ppm was assigned to 19 aromatic protons. The structure was further confirmed by

13c NMR spectrum ( 5 0 . 3 MHz, CDCI,, Fig 5b). It shows only the signals due to aromatic

carbons. The signals were present at 6 122.64, 125.71, 125.85, 126.87, 127.36, 127.46,

127 54, 127.66, 127.91. 128.41, 128.50, 128.87, 129.31, 129.80, 131.10, 131.92, 133.10,

135.28, 137.80, 138.60, 141.42 and 149.46 ppm respectively. IR (KBr, Fig 5c) spectrum

shows a band due to hydroxy group at 3500 cm". The other prominent bands were

present at 3020. 1600, 1480 cm-I. The mass spectrum (EIMS, Fig 5d) shows the presence

of the molecular ion peak at m/z 372.

3.3 Conclusions The reaction of 13-alkylthioethylenic aldehydes with aliphatic ketones having two

adjacent enolisable methylene groups were examined in the presence of a base such as

sodium t-butoxide in refluxing benzene, t-butanol mixture. The reaction leads to the

formation of substituted phenols in moderate to good yields. The E-isomer of P-butylthio-

P-ethyl-a-methyl propenaldehyde acts as a four carbon component in its reactions with

aliphatic ketones. The reaction sequence involve an initial aldol addition followed by

rearrangement and an intramolecular aldol condensation. In the reaction involving P- alkylthioethylenic aldehydes and dibenzyl ketone both of the reactants act as three carbon

components. The reaction involves an aldol Michael sequence and leads to the formation

of substituted phenols. In the present studies only reactions leading to the substituted

phenols were persuade. However P-alkylthioethylenic aldehydes are valuable

multifunctional synthons. Stereoselective addition of enolates to these intermediates

would lead to the formation of highly functionalised aldols which can be transformed into

important target molecules

3.4 Experimental 2

DMF was dried by azeotropic distillation using sodium dried benzene, distilled

under reduced pressure and kept over type 4A molecular sieves. o-Methoxy phenyl

acetone and p-methoxy phenyl aceone were purchased from Lancaster. TLC analysis

were performed on silicagel coated glass plates and visualised in an iodine chamber or

developed using KMnOd spray. Proton NMR spectra were recorded on a Varian 390 (90

MHz) or Joel EX YO (90 MHz) or Bruker WM 300 (300 MHz) or Bruker WM 200 (200 13 MHz) spectrometer in CDCI?.. C NMR spectra were recorded either on a Bruker WM

300 (76.49 MHz) or Jeol GSX 400 (100.6 M H z ) or on a Bruker WM 250 (62.9 M H z ) or

Fig. SP 'H NMR Spectrum (200 MHz) of compound 125

fig. 5b I3C NMR Spectrum (50.3 MHz) of compound 125

Fig. 5d Mass Sped- (EIMS) of compou;ld 125

wen in on a Bruker Wh.1 200 (50.3 MHz) spectrometer in CDCI,. Chemical shifts are b'

pprn ( 6 ) relative to ~ntemal tetramethylsilane. Coupling constants (J) are given in Hz. IR-

spectra were recorded on a Shimadzu IR-470 spectrophotometer and are given as cm-I.

Electron impact mass spectra were obtained on a Finnigen-Mat 3 12 instrument. GCMS

wet-e obtained on a Hewlert Packard 5890 Series 11 G€ connected to a 5890 mass

selective detector Melting points were determined on a 'Scientific' capillary melting point

apparatus and are uncorrected

3.4.1 General Procedure for the Synthesis of Dithioketals from Carbonyl ~ o m ~ o u n d s ~

A solution of ketone (40 mmol) and butanethiol (80 mmol) in chloroform (50 mL)

uncler nitrogen was cooled to 0-5°C and titanium tetrachloride (2.8 mL) was slowly added

into the flask with stirring The reaction was allowed to attain room temperature during

the next few minutes. stirred at room temperature for 12 hours and poured into crushed

ice The organic part was extracted with chloroform (3 X 50 mL). The chloroform

extract was dried and evaporated to give the crude dithioketals. They were further purified

by column chromatography over silica gel using hexane as eluent.

3.4.2 General Procedure for the Preparation of j3-Alkylthioethylenic Aldehyde.

The Vilsmeier reagent was prepared by mixing dry DMF (50 nlL) and

phcrsphorous oxychloride ( I I mL, 120 mmol) at 0°C slowly in 15 minutes. The reagent

was stirred under this condition for an hour and the dithioketal was added slowly. The

temperature was raised gradually to 30°C, stirred for 12 hours and poured into crushed

ice. A cold saturated solution of potassium carbonate (200 mL) was added to this mixture

until the effervescence ceased. Extracted with diethyl ether dried over anhydrous sodium

sulphate and concentrated The reddish brown oil obtained was purified by column

chr~~rnatography over silica gel using ethyl acetate:hexane (2:98) as eluent.

(I.)-3-B7rt7ilth/o-2-hutenal58a was obtained from the Vilsmeier

reaction of dithioketal prepared from acetone as brown oil,

yield 2.15g (3J%), 'H NMR (90 MHz, CDCI,) 6 0.85 (t,J= 7 3

c LO Ox..., C,,H,,OS

F. W. 234.35

Hz, 3H, CH,), 1 1 - 1 8 (m, 4H, CH2), 2.3 (s , 3H, CH,), 2.7 (t,J=

7.3 Hz, 2H, SCH2), 5.85 (d. J=, IH, vinylic), 9.85 (d, J=, IH,

CHO) ppm; ''c NMR 13.39, 21.72, 29.41, 3117, 120.50,

1'64.48. 186.79 (C=O) ppm; IR (KBr. v,,) 2950. 1650 ( G O ) .

15'75, 1375, 1450, 1555 cm-' ; GCMS (m/z)56 (66%). 59

( l2%), 68 (12%), 87 (4.9%), 101 (loo%), 158 (13.1%, M.).

IE)-3-ButyJl)tlio-2-methyl-2-penlenaI 58b was obtained from the

Vilsmeier reaction of dithioketal prepared from diethyl ketone as

dark brown oil, yield: 5g, (67%); 'H NMR (60 MHz, CDCI,) 6

I 0 (m, 6H. CH3). 1.20-1.50 (m, 4H, CH2), 1.75 (s, 3H, CHI),

2.70-3.21 9 (m, 4H. SCHZ and vinyl protons), 9.60 (s, 1H.

CHO). 1R (neat) v,,, 1658 (C=O), 1569 (C=C).

3-Ntrtyl1hio-2-pheriy/-2-butenal 58c was obtained from the

Vilsmeier reaction of dithioketal prepared from benzyl methyl

ketone as dark brown oil, E : Z ratio 30:70, yield: 2 9 g (31%); 1 H hMR (60 MHz, CDCI,) E isomer 6 080-1.15 (m, 3H, CH,),

2.55 (s, 3H, CH3), 2.40-3.00 (m, 2H, SCHZ), 6.80-7.3 (m, 5H,

aromatic), 9.90 (s, IH. CHO) ppm.;; IR (neat) v,, 1667 (C=O),

1556 (C=C) cm-'.

Z isomer 6 0.80-1.15 (m, 3H, CH3). 2.08 (s, 3H. CH,).

2.40-3 00 (m, 2H, SCH,), 6.80-7.30 (m, SH, aromatic), 10.35

(s, IH, CHO) ppm..

I-Het~zyl-4-methylriaph~ha/er~e 62 was obtained from the

Vilsrneier-Haack reaction of the dithioketal derived from benzyl

methyl ketone as colourless crystalline solid, yield: 1.586

(34?/0), mp 55-57°C; 'H NMR (90 MHz, CDCI,) 6 2.45 (s, 3H.

CH;). 4.4 (s. 2H, CHI), 7-8.05 (rn. 1 lH, aromatic) ppm.; "C

NMR (22.64 MHz, CDCI,) 6 21.57 (CH3). 38.87 (CH2).

12408. 12503, 125.54. 125.96. 126.05. 127.96, 128.38. ,+,

12864. 12963. 130.43, 134.25. 134.94, 136.37, 140.67 C , H : .

(aromatic) ppnl . 1R (KBr. v ,,,,) 3050, 3020, 2900, 1590, 1485, F W 232 i?

1445. 1070. 1030. 970. 945 cm-'; GCMS ( d z ) 51 (2.2%), 63

( 2 ;'?/0), 77 ( 2 2%). 91 (4 4%), 108 ( 10 9%). 1 15 (14.2%). 128

(6.6%), 139 (6 0%). 155 (12.6%), 165 (2.7%), 189 (46%).

202 (23.8%), 217 (73.5%), 23 1 (224%). 232 (lOOO/o,M').

3-H1tplthio-3-pher,yl-2-propenal 581 was obtained from the

Vilsmeier reaction of acetophenone dithioketal as dark brown

oil. F; Z 955 . yield: 3g (38%); 'H NMR (300 MHz, CDC13) I.:

isorner 6 0.95 (t. J-7.3 Hz, 3H), 1.46 (sxt, J=73 Hz, 2H), 1.72

(qui. J=73 Hz. 2H), 2.87 (t, J-7.3 Hz, 2H), 6.07 (d, J=78 Hz.

C,,H,,OS IH). 7.44 (s. 5H. aromatic), 9.45 (d. J=78 Hz, IH, CHO) F. W . 220.32 ppm.; "C NMR (75.45 MHz, CDCI3) 6 13.55 (CH3). 22.06

(C:Hz), 29.61 (CHz), 32.33 (CH2S), 122.33, 128.39, 129.3 1,

130.03, 135.43(aromatic), 167.89 (vinylic). 189.36 (C=O)

ppln.; IR (neat) v,,, 2950, 2910. 2850, 1655. 1555 cm-I.;

EIMS ( d z ) 77. 91, 102, 112, 163,220 (M').

Z isomer 'H NMR (300 MHz, CDC13) 6 0.85 (t, J=7.5

Hz. 3H), 1.46 (sxt, J=73 Hz, 21-I), 1.72 (qui, J=73 Hz. 2H).

2.60 (t, J=7 3 Hz, 2H), 6.35 (d, IH, J=78 Hz), 7.44 (s, 5H),

10.05 (d, J=78 Hz. IH) ppm.

1.3.5-lriphet1j~l henzetre 68a was obtained by the Vilsmeier

reaction of dithioketal of acetophenone (which was prepared by

treatlng the ketone with butanethiol in presence of TiCQ as

colourless crystalline solid, yield: 0.32g, (8 %), mp 172-173°C;

'H NMR (250 MHz, CDCl3) 6 7.35-7.83 (m,18H, aromatic)

I ppm.; 1 3 ~ NMR (62.9 MHz, CDCb) 6 125.17, 127.35, 127.54,

128.84, 141.12, 142.33 ppm. (aromatic); IR (KBr, v,) 3050,

153 (19.3%). 202 (29.5%). 215 (12.5%), 226 (65.9%), 276

(182%). 306 (100%. M').

3-Hutylthio-3-(4-nrrthy@hei1yI)-2-prop/ 58g was obtained

from the Vilsmeier reaction of dithioketal derived from p-methyl

acetophenone as an yellow oily liquid, E : Z 99:1, y~eld: 3 6 g

(38%); IH NMR (300 MHz, CDCI,) E isomer 6 0.96 (t, J=7.5

Hz, 3H), 1.46 (sxt, J=7.3 Hz, 2H), 1.72 (qui, J=7.3 Hz, 2H),

MI 2.40 (s, 3H), 2.86 (t, J=7.3 Hz, 2H), 7.20-7.33 (m, 4H), 9.29 (d,

CMHISOS 7.8 Hz, 1H) ppm.; 13C NMR (75.45 MHz, CDCI,) 6 13.40, F W 234.35 21.15, 21.93, 29.54, 32.24, 122.05, 128.97, 129.15, 132.43,

140.24, 168.18, 189.56 ppm.; IR (neat) v, 2950, 2910, 2850,

1650, 1550 cm-I; GCMS (mlz) 115, 135, 177,219,234 (M').

Z isomer 'H NMR (300 MHz, CDCI,) 6 0.85 (t, J=7.5

Hz, 1H), 1.46 (sxt, Jz7.3 Hz, 2H), 1.72 (qui, J=7.3 Hz, 2H),

2.40 (s, 3H), 2.60 (t, 3=7.3 Hz, 2H), 6.35 (d, J=78 Hz, IH),

7.20-.7.33 (m, 4H), 10.25 (d, J=7.8 Hz, 1H) ppm.

1,3,5-lri(4-methy@henyI)bezene 68b was isolated as white

c crystalline solid from the reaction of p-methyl acetophenone,

yield: 0.40g (9 %). mp 179-180 "C; 'H NMR (90 MHz) 6 2.5 (s.

9H), 7.3 (d. J=9 Hz. 6H). 7.8 (d, J=9 Hz, 6H), 8.3 (s, 3H) ppm.;

"C NMR S 21.63, 129.27, 130.26. 133.57, 133.84, 138.40. Ur

144.13 ppm.. IR (KBr, v,) 3000, 2900, 2850, 1580, 1500, C2,H2,

FW 348.48 1420 cm"; GCMS d z 91, 348 (M+).

3-H11~~lthro-3-~4-rnethox):pher1yl)-2-propenu 58h was obtained

from the Vilsmeier reaction of dithiokeral of [I-rnethoxy

acetophenone as yellow oil, E : Z 82:18, yield: 7g (70%); 'H

NMR (90 MHz, CDCI,) f: isomer 6 0.95 (t, J=73 Hz, 3H),

r i m 1 30-1.90 (m, 4H), 2.95 (t, J=73 Hz, 2H), 3.90 (s, 3H), 6.10 (d,

J='7.8 Hz, IH), 6.90 (d. J=8 Hz, 2H), 7.4 (d, J=8 Hz, 2H), 9.30 -M. (d, J=7.8 Hz. IH) ppm.; "C NMR (22.5 MHz, CDCI;) G 13.59

C,,H,,OIS (CH;), 22.15 (CHz), 29.76 (CH2), 32.53 (CHzS), 55.42 (OCH,), F W 250.35

113.89. 122.14. 130.49, 161.39 (aromatic), 168.20 (vinylic),

189.93 (C=O) ppm.; IR (neat) v, 2950, 2910, 2820, 1645,

1590 cm'l; ElMS d z 89, 94, 135, 193, 207, 250 (W).

Z isomer 'H NMR (90 MHz, CDC13) 6 0.90 (t, J=73

Hz. 3H), 1 30-1 9 0 (m, 4H), 2.55 (t, J=73 Hz, 2H), 3.90 (s,

3H), 6.35 (d, J=78 Hz, IH), 6.90 (d, J=8 Hz. 2H), 10.25 (d,

J==7.8 Hz, IH) ppm.

3-Bt1tylthio-3-l4-chlorophenyl)-2-propenul 58i was obtained

from the Vilsmeier reaction of dithioketal of p-chioro

acetophenone as yellow oil, E : Z 88:12, yield: 7.43g (73%); 'H

NMR (90 MHz, CDCI3) (E isomer) 6 0.95 (t, J=73 Hz, 3H,

CHs), 1.25-1 9 0 (m, 4H, CHZ), 2.85 (t, J=73 Hz, 2H, SCH2),

C,,H,,OCIS 6.05 (d, Jx7.8 Hz, IH, vinylic), 7.2-7.6 (m, 4H, aromatic), 9.20 FW 254.77 (d, J=7.8 Hz, lH, CHO) ppm.; NMR (22.5 MHz, CDCI,) 6

13.42 (CH,), 21.98 (CH2), 29.56 (CH2), 32.43 (CHzS), 122.68

(vinylic), 128.67, 130.55, 133.84, 136.22 (aromatic), 166.36

(vinylic), 188.98 (C=O) ppm.; IR (neat) v, 2950, 2910, 2850,

1655, 1550 cm"; GCMS (mlz) 57, 75, 101, 136, 155, 197, 254

(M'), 256 (M'+ 2).

Z isomer 'H NMR (90 MHz, CDCI,) 6 0.90 (t, J=7.3 HZ,

3H, CH,), 1.25-1.90 (m, 4H, CHZ), 2.85 (t, J=7.3 HZ, 2H,

SCHZ), 6.20 (d, J=7.8 Hz, 1H, vinylic), 7.20-7.60 (m, 4H,

aromatic), 10.20 (d, J=7.8 Hz, IH, CHO) ppm.

3-Butylthio-3-(2-thienyl)-2-propen-Ial58m was obtained from

the Vilsmeier reaction of dithioketal of acetylthiophene as yellow

oil, E : Z ratio 8020, yield: 6.5g (72%); 'H NMR (60 MHz,

CDCI,) E isomer 6 0.60-1.10 (m, 3H, CH,), 1.10-1.80(m, 4H,

CH2), 2.40-2.90 (m, 2H, SCHZ), 5.82 (d, J=8 Hz, lH, vinylic),

6.80-7.40 (m, 3H, aromatic), 9.35 (d, J=8 Hz, IH, CHO) ppm.;

C,,H,,OS, IR (neat) v, 2900, 2850, 1660, 1585, 1415 cm-I, EIMS m/z F W 226.35

97, 109, 137, 169, 226 (M')

Z isomer 'H NMR (60 MHz, CDC13) 6 0.60- 1.10 (m, 3H,

CH,), 1.11-1.80 (m, 4H, CHI), 2.40-2 90 (m, 2H, SCH2), 6.22

(d, J=8 Hz, lH, vinylic), 6.80-7.40 (m, 3H), 9 87 (d. J=8 Hz,

IH, CHO) ppm

2-Butylthiocyclohex-I-ene curbaldehyde 58d was obtained from

the Vilsmeier reaction of dithioketal derived from cyclohaxanone

as yellow oil, yield: 5.2g (65%); 'H NMR (90 MHz, CDCI,) 6

C,,H,sOS 0.90 (t, J=6 Hz, 3H, CH3), 1.4-1.9 (m, 8H, CH2), 2.2-2.6 (m,

FW 198.32 4H, CH2), 2.8 (t. J= ~ H z , 2H, SCH?), 10.3 (s, IH, CHO) ppm;

'" NMR (22.5 MHz, CDCI,) 6 13.48 (CH3), 21.30, 21.75,

22.97, 23.98, 30.67, 31.41, 31.86 (CH2), 137.00, 155.88

(vinylic), 193.12 (C=O) ppm.; IR (neat) v, 2910, 2850, 1660,

1570, 1450, 1250 crn-'; GCMS m/z 79, 141, 198 (M').

2-Formyl-I-propylthio-3,4-dihydro~phfhalene 58e was

obtained from the Vilsmeier reaction of dithioketal of a-

tetralone as yellow oil, yield: 6g (65%); 'H NMR (60 MHz,

C,,H,@S CDCI3) 6 0.98-1.10 (m, 3H, CH3), 1.50-1.65 (m, 4H, CH2), 2.72

FW 232.34 (m, 4H, SCH2, allylic CH*), 7.30-8.13 (m, 4H, aromatic), 9.42

(s. lH, CHO) ppm.; IR (neat) v, 1667 (C=O), 1549 cm.'

3.4..3 Reaction of (E)-3-Butylthio-2-methylpent-2-enal with Diethyl Ketone: Formation of 3-Ethyl 2,4,6-trimethyl phenol 104

To a solution of sodium t-butoxide prepared by refluxing sodium (920 rng, 40

mm'ol) and t-butanol (50 mL), a mixture of 3-butylthio-2-methylpent-2-enal (1.9g, 10

mmol) diethyl ketone (1.8g, 20 mmol) and benzene (50 mL) were added and refluxed for

10 hours. The reaction mixture was poured over crushed ice (200g) and then acidified

with 50% acetic acid. Extracted with chloroform (3 x 75 mL) The chloroform layer was

washed with water (3 x 100 mL). It was dried with anhydrous sodium sulphate and

evaporated to get the crude product and column chromatographed over silica gel (60g)

using hexane: ethyl acetate (9: 1 ) as eluent to give 104.

3-Ethyl 2,4,6-trimethyl phenol 104 was obtained as colourless

crystalline solid, yield: 1.13g (69%), mp 95-96°C; 'H NMR (90

MHz, CDCI,) 6 I . 1 (t, 3H, CH,), 2.2 (s, 9H, CHI), 2.6 (quartet,

2H, CH2), 4.5 (s, IH, OH), 6.8 (s, IH, aromatic) ppm.; 13c

"VMt NMR (22.64 MHz, CDCI,) G 11.46 (CH3). 13.68 (CH3), 15.72

"0

I& (CH3), 19.09 (CH3), 22.88 (CHZ), 119.68, 121.24, 127.23,

129 58, 139.64, 150.23 (aromatic) ppm.; IR (KBr,v-) 3400, CllH160

FW 164.24 2990, 1580, 1470, 1440, 1380, 1330, 1300, 1260, 1230, 1210,

1100 cm-I; GCMS (mlz) 77 (4.4%), 91 (8.2%), 105 (7.4%), 115

(3%), 128 ( l . l%) , 135 (12.1%), 149 (100%),164 (48.9%. M').

3.4.4 Reaction of (E)-3-Butylthio-2-methylpent-2-enal with Substituted Benzyl Methyl Ketone: General Procedure

To a solution of sodium t-butoxide prepared by refluxing sodium (920 mg, 40

mmol) and t-butanol (50 mL). a mixture of P-alkylthioethylenic aldehyde (1.9g, 10 mmol),

ketone (20 mmol) and benzene (50 mL) were added and refluxed for 10 hours. The

reaction mixture was poured over crushed ice (200g) and then added 50% acetic acid till it

is acidic. Extracted with chloroform ( 3 X 75 mL) The chloroform layer was washed

with water (3 x 100 rnL) It was then dried with anhydrous sodium sulphate and

evaporated to get the crude product, which was column chromatographed over silica gel

usin,g hexane: ethyl acetate (9: 1) as eluent.

2,3,6-trimethyl-4-(3-metho*yphenyl) phenol 112b was obtained

from the reaction between 3-butylthio-2-methyl pent-2-enal

(19g, 10 mmol) and 4 -methoxy phenylacetone (25g. 15 mmol)

as colourless crystalline solid, yield: 157g (65%), mp 118-

120°C; 'H NMR (90 MHz, CDCb) G 2.1 (s, 3H, CH,), 2.2 (s,

~ I O hfefloMc 6H, CH,), 3.8 (s, 3H, OCH3), 4.7 (s, IH, OH), 6.8-7.3(m, 5H, HI

aromatic) ppm.; I3c NMR (22.64 MHz, CDCI3) G 12.26, 15.72, C16Ht80

F. W. 242.31 17.33, 55.22, 113.37, 119.78, 122.20, 129.42, 130.54, 132.97,

134.28, 135.12, 150.99, 158.15 ppm.; IR (KBr, v,,) 3450,

3000, 2950. 2900. 2825, 1605, 1575, 1505, 1470, 1380, 1335,

1300, 1280, 1240, 1215, 1175, 1080, 1025 cm-I.; EIMS (mlz)

130 (11.8%). 184 (14.1%), 218 (16.6%), 226 (29.1%), 241

2,3,6-Trimethyl-4-(2-methoxyphenyl) phenol 112a was obtained

from the reaction between 3-butylthio-2-methyl pent-2-enal

( 1.9g, 10 mmol) and 2-methoxy phenylacetone (2.5g, 15 mmol)

as colourless crystalline solid, yield: 1.45g, (60%), mp 124-

125°C ; 'H NMR (90 MHz, CDCI3) 6 2.0 (s, 3H, CH,), 2.15 (s,

HO 6H, CH3), 3.75 (s, 3H, OCH,), 4.55 (bs, lH, OH), 6.7-7.4 (m, Me

5% aromatic) ppm.; I3c NMR (22.5 MHz, CDCI,) 6 12.17, C I ~ I P O

FW 242.31 15.78, 17.00, 55.34, 110.51, 119.84, 120.41, 121.87, 128.14,

129.36, 130.82, 131.45, 134.13, 151.23, 156.84 ppm.; IR (KBr,

v,) 3480, 3000, 2920, 1580, 1470, 1295, 1250, 1210, 1110,

1010 cm-I.; 121 (4.8%), 139 (5.2%), 152 (10.7%), 165 (10.6%),

181 (6.7%), 199 (9.6%), 212 (21.3%), 227 (17.1%), 242

(loo%, M').

2,3,6-Trimethyl.4-phenyl phenol 112c was obtained from the

reaction between 3.butylthio-2-methyl pent-2-enal (1.9g, 10

mmol) and benzyl methyl ketone (2g, 15 mmol) as colourless

crystalline solid, yield: 1.38g (65%), mp 103-104°C; 'H NMR

(60 MHz, CDCb) 6 2.1 (s, 3H, CH3), 2.25 (s, 6H, CH,), 4.65 (s,

lH, OH), 6.9 (s, lH, aromatic), 7.15-7.6 (m, 5H, aromatic)

ppm.; 13c NMR (22.64 MHz, CDCI,) 6 12.23, 15.70, 17.30,

119.75, 122.19, 126.24, 127.88, 129.30, 129.61, 132.82,

134.73, 142.65, 151.14, 157.35 ppm.; IR (KBr, v,) 3400,

1580, 1470, 1300, 1240, 1220, 1080 cm".

3.4.5 Reaction of 3-Butylthio-2-methylpent-2-enal with Dibenzyl ketone: Formation of 3-Ethyl-4-methyl 2.6-diphenyl phenol 121

To a solution of sodium t-butoxide prepared by refluxing sodium (920 mg, 40

mmo:l) and t-butanol (50 mL), a mixture of P-alkylthioethylenic aldehyde (1.9g, 10 mmol),

dibenzyl ketone (32g, 15 mmol) and benzene (50 mL) were added and refluxed for 10

hours;. The reaction mixture was poured over crushed ice (200g) and then added 50%

acetic acid till it is acidic. Extracted with chloroform (3 x 75 mL). The chloroform layer

was washed with water (3 x 100 mL) It was dried with anhydrous sodium sulphate and

evaporated to get the crude product and column chromatographed over silica gel (60g)

using hexane: ethyl acetate (9:l) as eluent to give 121

3-Ethyl Cmethyl 2,6diphenyl phenol 12lwas obtained as

colourless solid, yield: 1.96g (68%), mp 78-79°C; 'H NMR (90

hCk,CDCb) S 0.85 (s, 3H, CH,), 0.9 (s, 3H, CH,), 2.2 (s, 2H,

CHZ), 4.6 (s, lH, OH), 6.9-7.7 (m, 1 IH, aromatic) ppm.; 13C

+ NMR (22.64 MHz, CDCI,) 6 14.32, 18.93, 23.73, 125.23,

126.97, 127.73, 127.98, 128.35, 128.65, 139.09, 129.25,

129.32, 130.48, 131.50, 136.11, 138.10, 140.91, 147.78 ppm.;

C 2 ~ H 2 ~ 0 IR (KBr, v,) 3500, 3000, 1600, 1440, 1430, 1400, 1310,

FW 288.38 1240. 1150, 1060, 1020 cm-'; GCMS (mlz) 51 (5.5%), 77

(11%). 101 (6.6%), 115 (9.9%), 128 (10.4%), 152 (8.2%), 165

(8.8%), 181 (4.4%), 202 (5.5%), 215 (8.9%), 239 (18.7%), 258

(15.4%), 273 (27.5%), 288 (loo%, M).

3.4.6 Reaction of B-Alkylthioethylenic Aldehydes with Dibenzyl ketone: General Proct-dure

To the base sodium t-butoxide prepared by refluxing sodium (920 mg, 40 mmol)

and t-.butan01 (50 mL), a mixture of P-alkylthioethylenic aldehyde (10 mmol) and dibenzyl

ketone (4.2g, 20 mmol) were added and refluxed for 10 hours The reaction mixture was

poured over crushed ice (200g) and then added 50% acetic acid till it is acidic. Extracted

with chloroform (3 x 75 mL) The chloroform layer was washed with water (3 x 100 mL)

It was dried with anhydrous sodium sulphate and evaporated to get the c ~ d e product and

column chromatographed over silica gel (60g) using hexane: ethyl acetate (9: 1) as eluent.

2,3.6-Triphenyl phenol 124a was obtained by the reaction

between 3-butylthio-3-phenylprop-2-enal (2.2g, 10 mrnol) and

dibenzyl ketone (3.2g, 15 mmol) as colourless crystalline solid,

yield: 1.84g (61%). mp 150-15 1°C; 'H NMR (90 MHz, CDCI,)

6 5.35 (s, lH, OH), 6.9-7.8 (m, 17H, aromatic) ppm.; "C NMR

(22.64 MHz, CDC13) 6 122.32, 126.41, 127.33, 127.63, 128.50, C24H180

128.76, 129.30, 129.63, 13 1.09 (aromatic) ppm.; IR (KBr, v,,) FW 322.40

3400, 1600, 1400, 1180, 1110 cm-'; GCMS ( d z ) 215 (8.5%).

252 (2.5%), 265 (1.4%), 289 (6.6%), 302 (11%). 322 (loo%,

M').

3-(4-Methy1phenyl)-2,6-diphenyl phenol 124b was obtained

from the reaction between 3-butylthio-3-(4-methylpheny1)-prop-

2-end (2.3g, 10 mmol) and dibenzyl ketone (3.2g, 15 mmol) as

colourless crystalline solid, yield: 2.39g (71%). mp 186-187°C;

'H NMR (90 MHz, CDCI3) 6 2.25 (s, 3H, methyl), 5.3 (s, lH,

OH), 6.7-7.9 (m, 16H, aromatic) ppm.; 13c NhCR (22.4 MHz,

C~SHZOO CDCI3) 6 21.03 (CH,), 122.38, 127.30, 127.57, 128.41, 128.50,

FW 336.43 128.82, 129.33, 129.51, 129.72, 131.12, 135.57, 136.04,

138.04, 111.56, 149.74 (aromatic) ppm.; IR (KBr, v,,,) 3400,

1600. 1410, 1180 cm"; GCMS (m/z) 302 (14%), 303 (8.5%).

321 (7%), 336 (loo%, M').

3-(4-Mefhoryphenyl)-2,6d;phenyl phenol 124c was isolated

from the reaction between 3-butylthio-3-(4-rnethoxypheny1)-

prop-2-enal (25g, 10 mmol) and dibenzyl ketone (3.2g, 15

mmol) as colourless crystalline solid, yield: 2.57g (73%), mp

167-168°C; 'H NMR (200 MFh, CDCI,) 6 3.7 (s, 3H, OCH,),

5.25 (s,lH, OH), 6.6-7.65 (m, 16H, aromatic) pprn.; ',c NMR

,)Me (50.3 MHz, CDCI,) 6 55.06 (OCH,), 113.16, 122.31, 127.05,

Ca2002 127.25, 127.29, 127.57, 128.49, 128.87, 129.33, 129.72,

FW 352.43 130.70, 131.11, 133.38, 135.58, 137.93, 141.21, 149.74, 158.22

(aromatic) ppm.; IR (KBr, v,) 3500, 3010, 1600, 1520, 1460,

1290, 1250, 1210, 1170, 1080, 1020 ern.'; EIMS ( d z ) 77 (4%),

91 (3%), 151 (4%), 202 (7%), 252 (3%), 289 (13%), 303 (5%),

352 (100%. M*).

3-(4-Ni~rophet1yl)-2,6d;phenyl phenol 124f was obtained from

the reaction between 3-butylthio-3-(4-nitropheny1)-prop-2-enal

(2.7g, 10 mmol) and dibenzyl ketone (3.2g, 15 mmol) as very

pale yellow crystalline solid, yield: 1.87g (5 I%), mp 1 15-1 17°C; I H NMR (200 MHz, CDCI,) 6 5.3 (s, lH, OH), 7-8.1 (m, 16H,

, aromatic) ppm.; I3c NMR (50.3 MHz, CDCI,) 6 122.10,

C24HnN01 123.08, 127.46, 127.84, 128.26, 128.77, 128.92, 129.21, FW 367.40 129.35, 13013, 130.49, 131.06, 134.71, 137.37, 139.35,

146.49. 148.05, 150.10 (aromatic) ppm.; IR (KBr, v,,,) 3400,

1680, 1510, 1420, 1380 cm-l; EIMS (mh) 5 1 (2%), 115 (3%),

189 (5%), 215 (13%), 289 (12%). 302 (24%), 367 (loo%, M').

3-(4-Bromophenyl)-2,6d~phenylphenol 124e was isolated from

the reaction between 3-butylthio-3-(bromopheny1)-prop-2-enal

C24HI-OBr

FWJOL 30

(3%. 10 mmol) and dibenzyl ketone (3.2g, 15 mnol) as

colourless crystalline solid, yield: 2.65g (66%), mp 197-198°C;

'H NMR (200 MHz, CDCI,) G 5.4 (s, IH, OH), 6.6-8 (m, 16H.

aromatic) ppm.; 13c NMR (50.3 MHz, CDCI,) 6 120.58,

121.91, 127.04. 127.30, 127.65, 128.37, 128.81, 129.10,

129.67. 130.66, 130.84, 131.05, 134.88, 137.46, 139.75,

140.1 1 , 149.66 (aromatic) ppm.; IR (KBr, v,,) 3500, 3000,

1600, 1450, 1400, 1280, 1230, 1180, 11 10, 1170, 1010 cm-l;

ElMS (mlz) 51 ( 5 % ) , 91 (lo%), 138 (14%), 161 (25%), 215

(36%). 252 (9%). 302 (39%). 359 (7%). 400 (89%). 401(28%.

M')402 (100 %), 403 (34%).

3-N-C'hlorophery()-2,641pherylphenol 124d was isolated from

the reaction between 3-butylthio-3-(4-chloropheny1)-prop-2-enal

(2 6g. 10 mmol) and dibenzyl ketone (3 2g. 15 mmol) as

colourless crystalline solid, yield 2 lg (59%), mp 165"C, 'H

NMK (90 MHz. CDC13) 6 5 35 (s, IH, OH), 6 9-7 8 (m, 16H.

aromatic) ppm.; "C NMR (22.64 MHz, CDCI,) 6 122.20,

127.33, 127.51, 127.93, 128.59, 129.00, 129.33, 129.87,

130.94, 13 1.09, 132.58, 137.71, 149.89 (aromatic) ppm.; IR

(KBr, v,,) 3500, 3050, 3020, 2950, 2850, 1700, 1485, 1410,

1390. 1300, 1280, 1235, 1175, 1110, 1090, 1010, 900, 835, 815

, EIMS (rnlz) 57 (79.1%), 71 (77.6%), 85 (62.7%), 97

(30.6%). 105 (25.4%). 113 (10.4%). 127 (18.2%). 139 (7.4%).

1 5 1 (13.2%), 182 (12.6%). 215 (13.3%), 252 (4.2%), 276

(9.8%), 291 (13 5%). 302 (19.0%). 320 (20.6%), 356 (100%.

M*), 358 (M'+ 2).

3.4.7 Reaction of 3-Butylthio 3-naphthyl prop-2-enal with Dibenzylketone: Formation of 2.6-Diphenyl-3-(2-naphthyl) phenol 125

To a solution of sodium t-butoxide prepared by refluxing sodium (920 mg, 40

mmol) and t-butanol (50 mL), a mixture of 3-butylthio 3-naphthyl prop-2-enal (2.7g, 10

mmol) ketone (3.2g, 15 mmol) and benzene (50 mL) were added and refluxed for 10

hours. The reaction mixture was poured over crushed ice (200g) and then added 50%

acetic acid till it is acidic. Extracted with chloroform (3 x 75 mL). The chloroform layer

was washed with water (3 x 100 mL). It was dried with anhydrous sodium sulphate and

evaporated to get the crude product and column chromatographed over silica gel (60g)

using hexane: ethyl acetate (9: 1) as eluent to give 125.

2,6-Diphenyl-3-(2-naphthyl) phenol 125 was obtained as a

colourless crystalline solid, yield: 2. lg (56%), mp 205-206°C; 'H

NMR (200 MHz, CDCI3) 5.4 (s, IH, OH), 6.9-7.9 (m, 19H,

aromatic) ppm.; 13c NMR (50.3 MHz, CDCI,) 122.64, 125.71,

125.85, 126.87, 127.36, 127.46, 127.54, 127.66, 127.91,

128.41. 128.50, 128.87, 129.31, 129.80, 131.10, 131.92,

133.10, 135.28, 137.80, 138.60, 141.42, 149.76 (aromatic)

CzsHzoO ppm.; IR (KBr. v,) 3500, 3020, 1600, 1480, 1400, 1270,

FW 372.46 1170, 1010 cm.'; EMS (mlz) 77 (1 I%), 1 15 (8%), 170 (1%).

176 (6%), 215 (13%). 265 (19%), 302 (9%), 355 (20%), 372

(loo%, M').

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