Research Collection

Doctoral Thesis

Studies on intramolecular S-N-reactions at saturated carbon

Author(s): Farooq, Saleem

Publication Date: 1972

Permanent Link: https://doi.org/10.3929/ethz-a-000089154

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Diss. Nr. 4755

Studies on Intramolecular Sn- Reactions

at Saturated Carbon

THESIS

submitted to the

SWISS FEDERAL INSTITUTE OF TECHNOLOGY

ZURICH

for the degree of Doctor of Technical Sciences

presented by

SALEEM FAROOQ

dipl. Chem. ETH

born 22 January, 1944

Citizen of India

Accepted on the recommendation of

Prof. Dr. A. Eschenmoser

Prof. Dr. J. D. Dunitz

Juris Druck+Verlag Zurich

1972

i

ISBN 3 260 03180 4

Dedicated to my dear mother

and

my wife

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I welcome this opportunity to express my gratitude and profound

indebtedness to Prof. Dr. A.Eschenmoser for his valuable advice

and the constant interest which he took in my work.

I am grateful to the Volkart Foundation, Winterthur for granting

me a scholarship from September 1967 to September 1970.

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Contents

Bimolecular nucleophilic substitution reactions atsaturated carbon 9

1. Introduction 9

2. Endocyclic Sjj-reaction with benzyl-(o-fluoro-methoxysulfonyl)-p-tolylsulfone ? 18

3. Is the deprotonated form of benzyl-(o-methoxy-sulfonyl)-p-tolylsulfone capable of acquiringa precyclic 1,6-arrangement of the reaction centres ? 25

4. Is the exocyclic Sjj-process in benzyl-(o-iodo-methoxysulfonyl)-p-tolylsulfone kinetically farsuperior to its intermolecular counterpart ? 32

5. Reaction of benzyl-(o-methoxysulfonyl)-p-tolyl-sulfone in sulfolane 40

Experimental Section 43

1. Preparation and reactions of benzyl-(o-fluoro-methoxysulfonyl)-p-tolylsulfone, bis (benzyl-(o-sulfonyloxy)-p-tolylsulfone)-methane, benzyl-(o-iodo-methoxysulfonyl)-p-tolylsulfone and benzyl-(o-methoxy-sulfonyl)-p-tolylsulfone 44

2. Deuterated compounds 58

3. Crossing experiments 66

3.1. With benzyl-(o-fluoromethoxysulfonyl)-p-tolylsulfone and benzyl-(o-dideuterofluoro-methoxysulfonyl)-p-trideuterotolylsulfone 66

3.2. With bis (benzyl-(o-sulfonyloxy)-p-tolylsulfone)-methane and bis (benzyl-(o-sulfonyloxy)-p-tri-deuterotolylsulfone)-methane-d2 78

3.3. With benzyl-(o-iodomethoxysulfonyl)-p-tolyl-sulfone and benzyl-(o-dideuteroiodomethoxy-sulfonyl)-p-trideuterotolylsulfone 85

3.4. With benzyl-(o-methoxysulfonyl)-p-tolylsulfoneand benzyl-(o-trideuteromethoxysulfonyl)-p-trideuterotolylsulfone 104

4. Control experiments 108

Summary 114

References 116

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Bimolecular nucleophilic substitution reactions at

saturated carbon

1. Introduction

Nucleophilic substitution at saturated carbon belongs to the best documented

reactions of organic chemistry. Kinetic data has given evidence for the existence

of two limiting mechanistic types of nucleophilic substitution processes at a satu¬

rated carbon [ 1 ]. The first mechanism, in which the rate of substitution is

dependent only on the substrate concentration and independent of the nucleophile

(N) concentration, is termed S.4 (substitution, nucleophilic, unimolecular). The

second mechanism, where the rate of substitution is dependent on both the sub¬

strate and nucleophile (N) concentrations, is called the S..2 (substitution, nucleo¬

philic, bimolecular) mechanism. Stereochemical data [1] of nucleophilic sub-

SJ. L-C" »-L + C+ -= r—r. »• N-C"" + ""C-NN \ I Racemization \ /

/ N- \! \S„2 L-C"

"•» L-C-N =-^ . »- L + »»C-N

N\ J Inversion y

(I)

stitution reactions at chiral carbon atoms has provided a further distinction of

the two mechanisms. S.J. reactions lead predominantly to racemized products,

whereas S..2 reactions give inverted products. To accomodate both the kinetic

and stereochemical data S^l reactions were postulated as involving carbonium

ions, formed in a rate-determining step, which react with a nucleophile (N) in

a subsequent product-controlling step. The existence of carbonium ions has been

well established [2]. On the other hand, S^Ji reactions, where the rate-con¬

trolling step is also the product-controlling step, have been considered as in¬

volving transition states of the type (I) in which the nucleophile (N) and the

leaving group (L) are colinear and span the apical positions of the trigonal bi-

pyramid from which the leaving group (L) is displaced.

The experimental evidence that S~2 reactions are invariably accompanied

by steric inversion (Walden inversion) [ 3 ], and that S.j2 reactions have not

- 10 -

been observed at bridgehead carbons 14 ], has provided the generally accepted

concept for a rear-side attack of the nucleophile in S-J reactions '.

Whether S„2 reactions involve trigonal bipyramidal transition states or in-2}

termediates of the type (I) has been questioned [ 5 ] '. Although there is no

compelling experimental evidence for S~2 reactions proceeding via trigonal bi¬

pyramidal intermediates, Eschenmoser, Scheinbaum and Navratil [6] recognized,

in 1965, the implications that could be imposed on S.^2 reactions if these were

to proceed via trigonal bipyramidal intermediates. Reasoning that pseudorotation ,

as first postulated by Berry for PF, [ 7 ], could also take place in these inter¬

mediates, they investigated the stereochemical consequences. The following postu¬

lates were made:

(a) The formation of a trigonal bipyramid occurs by an apical attack

(attack on a face of the tetrahedron)' of the nucleophile (N) at a

tetrahedral carbon atom, and consequently the leaving group (L) leaves

via an apical position (principle of microscopic reversibility). An

equatorial attack (attack on an edge of the tetrahedron) is energetically

unfavourable.

1) For recent theoretical interpretations of SN2-stereochemistry see [8] .2) Experimental evidence has been provided for intermediates in nucleophilic

substitution reactions at phosphorus [9] . There is also evidence which

supports the possible formation of intermediates in substitution reactions atsilicon [10] and sulfur ["H] •

3) Pseudorotation was postulated by Berry to be an intramolecular process bywhich the apical ligands (L4,L5) and two of the equatorial ligands (L,, L„, L,,)of a central atom having trigonal bipyramidal geometry are interchanged as

depicted in the above figure. The ligand which remains equatorial is calledthe pivot about which pseudorotation is said to take place. From each trigonalbipyramid three new ones can be formed by pseudorotation about the three

equatorial pivots. Another possible stereomutation process for trigonal by-pyramidal species, called the turnstile rotation, has been proposed byUgi [12].

4) Four possibilities: one is the 'normal' rear-side attack and three frontalattacks.

- 11 -

(b) The angle L-C-N in the trigonal bipyramidal intermediate should be

large.

(c) The electronegative ligands in the trigonal bipyramidal intermediate

should favour apical positions (Bent [13], Muetterties [14]).

All the possible pseudorotations in the four trigonal bipyramidal intermediates

formed by an apical attack of a nucleophile at a chiral carbon atom prior to loss

of the leaving group were examined. It was concluded that an apical attack of a

nucleophile at a chiral carbon atom (with apical departure of the leaving group)

could lead to inversion, retention or racemization at the centre undergoing sub-5)

stitution if trigonal bipyramidal intermediates were invoked.' It was suggested,

therefore, that inversion of configuration in S.J2 reactions does not necessitate

a rear-side attack of the nucleophile. Further, that S.J! reactions at a bridgehead

substitution centre are unknown was explained on the basis that the formation of

a normal unstrained trigonal bipyramid at the bridgehead is rendered impossible

for steric reasons.

The non-compelling requirement of a rear-side attack in S.J2 reactions leads

to the question whether a frontal attack of a nucleophile at a saturated carbon

atom is possible. A method for testing this was visualized in the possible exist¬

ence of endocyclic SN-reactions. Endocyclic SN-reactions at saturated carbon

were defined as intramolecular substitution reactions, that occur by an S-^-ana-logous mechanism and have both the nucleophile and the leaving group as parts

Exocyclic

Fig. 1

5) Pseudorotation has received great interest in current literature and varioustopological representations describing all the possible isomers of a speciesZI4L2L3L4L5 having trigonal bipyramidal geometry and the pseudorotationpathways interconnecting all the isomers have been given [ 15 ]. The aboveconclusion is readily derived using one of these representations.

- 12 -

of one and the same ring. In comparison to this an exocyclic substitution process

was defined as an intramolecular SN-reaction in which the leaving groupis exo¬

cyclic to the ring [ 16 ]. Fig. 1 illustrates a definition of thesetwo types of sub¬

stitution processes. A differentiation of these two typesof reactions is relevant

because in small ring systems endocyclic SN-reactions would require a frontal

attack of the nucleophile on the saturated carbon atom or added strain for the

linearization of the nucleophile and the leaving group. At present, there is no

authentic example of an endocyclic S^-reaction at a saturated carbon in ring

systems containing 4-6 atoms. However, numerous examples arefound in the

literature where endocyclic SN-reactions have been postulatedand the con¬

sequences of such a formulation ignored. Fig. 2 shows a sample of publi¬

cations [17] in which endocyclic S,--reactions have been postulated. In none of

these cases has the reaction mechanism been proved. There are of course an

unlimited number of known exocyclic S^-reactions; here, the nucleophile can

attack from the rear while displacing the leaving group.

In order to test the feasibility of endocyclic SN-reactions, Eschenmoser

and Tenud prepared and investigated the reactions of benzyl-(o-methoxysulfonyl)-

p-tolylsulfone (1) [16]. This model substrate was choosen as the geometry of

oo, cclTs

i(I) Ts

(n)

the molecule renders an intramolecular attack of the nucleophilic sulfonyl carb-

anion, formed by the deprotonation of (1), on the methyl substitution centre from

the rear (colinear with the sulfonyloxy leaving group) impossible. An intramolec-

- 13 -

=5^

_

w* t*r.m the iv

Fig. 2 A sample of publicationsin which endocyclic SN-reactions have been

formulated.

- 14 -

ular attack of the sulfonyl carbanion on the methyl substitution centre (1,6 ar¬

rangement of the reaction centres), as depicted in (n), would necessarily require

a frontal attack.

The reaction of benzyl-(o-methoxysulfonyl)-p-tolylsulfone (1) under the reac¬

tion conditions a), b) and c) gave in high yields (> 90%) the product «-phenyl-

^V*v0>80%

, yy-i''UL co= 0.08 m

^A^/CHj

CH2CH3 °" ^^^CH/^I a) 1.0 equiv NaH/dioxane/75°C/17hr '

(1)b) 1.0 equiv NaH/monoglyme/750C/26hr (2)

'' c) 1.0 equiv KO-t-Bu/monoglyme/ * '

room temp/30 min M+ = Na+, K+

ethyl-(o-sulfonyloxy)-p-tolylsulfone sodium or potassium salt (2). Under all condi¬

tions investigated, the methyl transfer (l)-*-(2) was shown to proceed intermo-

lecularly and not by an endocyclic SN-process. The following proofs were given

[16]:

1) When the reaction, under the reaction conditions a), was quenched after 15 min¬

utes, the product (2) (~23%), the demethylated educt (4) (~38%) and the meth¬

ylated educt (3) (~ 36%) were isolated.

r^YS°3CH3 (3)X=H=Y dQ f^YS°3"M+ksJj\CH^CX3 (3a) X=D/Y=H dg ^XCH Y=H

| (3b) X=H/Y=D d3 |2

(4a) Y=DTs (Y3) (3c) X=D=Y d6

Ts (Y3)M+ = Na+

- 15 -

2) Crossing experiments with equimolar amounts of (1) and the hexadeuterated

analogue (la) under the reaction conditions a), b) and c) gave a deuterium dis-

SO,2\

^CH„

OI

CDg

Ts(d3)

(la)

tribution in the product of d :d-:dg =1:2:1, which was in full accord with an

cSOgM"1"

CH'.CX„

Ts (Y3)

(2) X=Y=H d

(2a) X=D/Y=H dg(2b) X=H/Y=D dg(2c) X=Y=D d„

M+ = Na+, K+

intermolecular process. The results of the crossing experiments are summarized

in Table 1.

- 16 -

Crossing experiments: 0.5 equiv (1) + 0 5 equiv (la)DJ-•(2) +(2a) + (2b) + (2c)

Experi¬ment Nr.

Concen¬ Deuterium distribution in

tration Base/ the methylsulfonesters of(1) + (la) Solvent Temp Time (2)+(2a) + (2b) + (2c)7)

(mol/1) (°C) (hr) Eao+d0

d3+d6

d3

= 100%

d6

1 0.08 NaH/monoglyme 75 16 25.9 49.1 25.02 0.08 NaH/monoglyme 75 16 27.6 48.0 24.43 0.08 KO-t-Bu/monoglyme rt 1 27.2 48.5 24.34 0.005 KO-t-Bu/monoglyme rt 1 26.7 49.5 23.85 0.005 KO-1-Bu/monoglyme rt 15 26.8 48.7 24.56 0.005 KO-t-Bu/monoglyme rt 18 27.7 49.0 23.37 0.08 NaH/dioxane 75 1/4 25.9 49.5 24.68 0.08 KO-t-Bu/monoglyme 0 1/6 26.0 49.1 24.9

Control experiments:

a) Equimolar amounts (t 0.5%) of theseparately prepared methylsulfon-esters of (2) and (2c), mixed andrecrystallized (93%) 50.9 0.0 49.1

b) Equimolar amounts (t 0.5%) of theseparately prepared salts (2) and (2c)mixed and methylated 49.9 0.0 50.1

c) dito 49.2 0.0 50.8

Calculatec1:

Intramolecular d : dQ : d. =o 3 6

1:0:1 54.7 0.0 45.3

Intermolecular d : dQ : d. =o 3 6

1:2:1 27.4 50.0 22.6

Table 1

6) Deuterium distribution in (la): M+: 83.2% d6, 15.3% ds, 1.5% d4;P+ = (Nr+-CD3C6H4S02): 94.0% d3, 5.5% d2, 0.5% di; F+ = (M+-S020CD*):89.5% d3, 9.3% d2, 1.2% dl.

7) Deuterium distribution determined on the fragment P+ = (M+-SO„CH„)

- 17 -

3) The trideuterated educt (5) was heated at 75 C for 26 hours in monoglyme;

the reisolated educt (5) (83%) showed only a loss of ca. 3% of the trideutero-

S02^0 CH3\I ^0-CH2-CH2-0-CH3

V>-CH9 CD3 CD3I

2

Ts (III)

(5)

methyl group. This showed that the oxonium ion (III) was not being involved in

transferring the -CD„ respectively -CH,, groups during the crossing experiments

in monoglyme.

4) The crossing experiment Nr. 8 was quenched after 10 min reaction time with

CFoCOOD. Besides the products the educts (1) and (la) were isolated and showed

(nmr and ms) ca. 30% deuterium in the benzylic methylene group and an un¬

changed deuterium distribution in the methyl groups of the educts. This showed

that there was no equilibration of the -CH, and -CD„ groups in the educts under

the reaction conditions. A 1:1 mixture of the products (2) and (2c) in monoglyme

during 12 hours at room temperature remained unchanged, showing that there

was no equilibration of the C H„ -/CD„-groups in the products.

That the reaction (1)—*(2) was proceeding completely intermolecularly,

even at low concentrations (0.005 molar) where an intermolecular pathway should

become statistically more favourable, and not by an endocyclic S^-process was

interpreted as resulting from the preference of tetrahedral carbon for a rear

side attack by a nucleophile in S.^2 reactions.

8) In a kinetic study, Tenud [16] also showed the reaction (IV)—»(V)

a:% ^^ or38"C

CH3 CH

(IV) (V)

2to be a bimolecular process (-d (IV)/dt = k (IV) with

k =1.02 + 0.10-10"4 l.mol"1^"1).

S^CH3

3

- 18 -

2. Endocyclic S,.-reaction with benzyl-(o-fluoromethoxysulfonyl)-p-tolylsulfone (6) ?

Assuming that S„2 reactions involve the formation of trigonal bipyramidal

intermediates, it may be argued that the failure of (1) to undergo an endocyclic

SN-reaction may rest on the fact that the formation ofthe trigonal bipyramid (VI),

with a hydrogen atom in an apical position, is energetically unfavourable. This

trigonal bipyramid could be stabilized by replacing the apical hydrogen by the

(VII)

much more electronegative fluorine atom (VII) (postulate (c), page 11). Two

possible reaction pathways could be envisaged from the bipyramid (VTI); firstly,

(X)

the trigonal bipyramid could undergo pseudorotation about an equatorial hydrogen

atom as pivot to produce the bipyramid (VIII) from which the apical sulfonyloxy

- 19 -

leaving group can be expelled (postulate (a), page 10)) to give (DC). Secondly, the

fluoride anion can be displaced in an exocychc S-j-reaction to give the sultone9)

(X).' At the outset of the present investigation benzyl-(o-fluoromethoxysulfonyl)-

p-tolylsulfone (6) was prepared and its reactions with strong bases investigated.

SO

CH„

Ts

2^0

A*1) MeOH/reflux2) Ag20/CH3CN/rt

1

3) FCH2J/CH3CN/rt

f*^S02^0

Us* CH2FTs

(1) (6)

The beautifully crystalline benzyl-(o-fluoromethoxysulfonyl)-p-tolylsulfone (6)was obtained in yields of 75% from (1), by treating the corresponding silver saltof (1) with fluoroiodomethane [18] in acetomtrile at room temperature. Thenmr of (6) showed singlets at 2.46 ppm (PI1-CH3) and 4.91 ppm (-CH2-), a doubletat 5.68 ppm (-CH2F) with a large coupling constant of 50.5 cps (coupling with F*9)and a multiplet between 7.25-8.25 ppm (aromatic protons), Fig. 3a) The mass

spectrum showed besides a weak molecular peak at m/e 358 (M+) the character¬istic fragments: m/e 245 (M+^SOCI^F), 203 (M+-Ts) and 91 (C7H7+). The itspectrum was dominated by the strong peaks at 1380 and 1188 cm~l (as- and s-

fluoromethoxysulfonyl-stretching), 1325 and 1160 cm"' (as- und s-sulfone-stretch-wg)-

Reaction of benzyl-(o-fluoromethoxysulfonyl)-p-tolylsulfone (6) m monoglyme

(c0 = 0.08 molar) with 1 mol equivalent potassium t-butoxide at room temperature

gave the potassium salt (7) and approximately 0.5 equivalents of the unchanged

cSO,'2N

o c0= 0.08 m

rTT CH,F1-° e(luiv KD-t-Bu

1 2 mnnno-lume/rt/dn m

Ts

(6)

monoglyme/rt/40mm

^s

(7)

a

SOgM"1"+ c

M+F~

IS02^o

CH„ CRjF1

2

Ts

M+=K+ (6)

Me30+BF4"/,rCH2CV ca. 20 hr

SO3CH3

C^CH2

Ts

(8)

9) The exocychc SN-process does not necessarily require the formation of (VII)as an intermediate.

- 20 -

starting material (6) was recovered. Methylation of the raw salt (7)with excess

trimethyloxonium tetrafluoroborate in methylene chloride during ca.20 hours

gave the easily crystallizable «-phenylethenyl-(o-methoxysulfonyl)-p-tolylsulfone

(8) in yields of ca. 30% (with respect to starting material (6)). Whenthe reaction

was carried out under the same conditions but with 2 mol equivalents of potassium

t-butoxide no starting material was recovered, and (8) was obtained in a yield of

76% after methylation of (7).

«-phenylethenyl-(o-methoxysulfonyl)-p-tolylsulfone (8) showed in its nmr

spectrum two singlets at 2.48 ppm (PI1-CH3) and 3.75 ppm (-O2SOCH3), two

doublets at 6.18 and 6.71 ppm with a small coupling constant of 1 cps (=iJJ )and a multiplet between 7.25 and 8.25 ppm (aromatic protons), Fig. 3c). (The

coupling of the vinylic protons was not observed on the HA 100 spectrometer at

a sweep width of 1000 cps). The mass spectrum showed besides a very weak

molecular peak at m/e 352 the following fragments: m/e 257 (M^-C^SCHs), 197

(M+-TS), 91, 77, 65, 51, and 39 (characteristic fragments of phenyl). The ir

spectrum showed very strong absorptions at 1364 and 1185 cm"* (methoxysulfonyl-

stretching), 1317 and 1150 (sulfonyl-stretching) and 990 cm-1 (C-O-stretching).

For the formation of (7), three possible reaction pathways had to be

considered: (i) an exocyclic S-j-reaction to give the sultone (X), which in a

S02--0«+

SO3 M+

MB I~„

+HB*CH„

CH-'CH2"

^^"^c^"2

I ITs Ts

(X) (7)

subsequent fast elimination step (faster than the formation of (X)) gives (7);

(ii) an endocyclic SN~process to give (IX) followed by the fast loss of HF; (iii)

rrso3~M+ MV (*^SOZM+ hb

***^CH^CH2F"

l^Ac^CH2+ MV

Ts Ts

(K) (7)

an intermolecular S^ reaction to give (DC) with subsequent elimination of HF.

1 i T . : T. .: T

- 21 -

,:T:,,,;;;,',','J,,

I' '

i'

V

I

WH^ftJL^ kf^WWI/rtUIHti^n1 Wf«i^»***K*W

- 22 -

Crossing experiments with the pentadeuterated analogue (6a) of (6) were carried

out to distinguish between the inter- and the two intramolecular pathways.

Benzyl-(o-dideuterofluoromethoxysulfonyl)-p-trideuterotolylsulfone (6a) was

prepared from (9)10) by treating the silver salt of (9) with dideuterofluoroiodo-

^

so2\0I

CH2 CH3

Ts(d,)

(9)

1) MeOH/reflux2) Ag20/CH3CN/rt

»

3) FCDgj/CHgCN/rt^

S02vQ

9H2^FTs (d3)

(6a)

methane [19] (98.4% d2, 1.6% dj) in acetonitrile at room temperature. The irspectrum of (6a) was similar to the undeuterated compound (6) apart from the

appearance of a sharp peak at 1018 cm"'. In the nmr spectrum, only a singletat 4.91 ppm (-CH2-) and a multiplet between 7.30 and 8.20 ppm (aromatic protons)was observed. Integration over 2.4 ppm showed 5.2% of 3H and there was no

integration between 5.6 and 6.61 ppm, Fig. 3b). The deuterium distribution in (6a)was obtained from the mass spectrum and is given in Table 2.

Deuterium distribution in (6a)11)

m/e fragment deuterium distribution

363-361 M+ 79.8% d5, 18.4% d4, 1.8% d3

248-246 M+-02SOCD2F 82.1% d3, 16.7% d2, 1.2% dj

Table 2

Equimolar amounts of (6) and (6a), under the influence of strong bases

would produce the salts (7) + (7a) + (7b) + (7c) in the ratio of 1:1:1:1 if the re¬

action were intermolecular; and only the salts (7) + (7c) in a ratio of lj^ if the

reaction were intramolecular. The summarized results of the crossing experi¬

ments are given in Table 3.

10) Benzyl-(o-methoxysulfonyl)-p-trideuterotolylsulfone (9), 80.0% d3, 17.5% d2,1.5% d2, 1,0% d0, was prepared from oc, ot, a-trideuterotoluene asdescribed by Tenud [ 16 ].

11) The deuterium distribution in the FCD20-group was set equal to the deuteriumdistribution in FCDgJ used for the preparation of (6a).

- 23 -

Ts(Y3) M+ = ]

(7) X=Y=H(7a) X=DA=H(7b) X=H/Y=D(7c) X=D=Y

Ts(Y3)

dod2

- 24 -

The results clearly show that under all conditions investigated the reaction

(6)—*-(7) proceeds completely intermolecular ly, even at the very low concentra¬

tion of 0.005 molar. The experimental values of d d2, dg, and dg are in close

agreement with the calculated values for an intermolecular pathway. Fig. 4a)

shows the mass spectrum of the methylsulfonesters (8) + (8a) + (8b) + (8c) from a

crossing experiment (Nr.2). All crossing experiments were carried out with

1 mol equivalent base and hence ca. 0.5 mol equivalents of the starting materials13)

(6) and (6a) were recovered; the mass spectrum' showed that no equilibration of the

deuterated groups was taking place in the educts under the reaction conditions.Control

experiments (Table 3) showed that there was no equilibration in the products to

give the deuterated species d, and d„ during the methylation of a 1:1 mixture of

the salts (7) and (7c); and also that there was no significant exchange of the

deuterated groups during the recording of the mass spectra of the methylsulfon¬

esters.

Therefore, from these results it is assumed that (DC) is primarily formed

by an intermolecular attack of the sulfonyl carbanion (resulting from the depro-

tonation of (6)) on a fluoromethoxy substitution centre with expulsion of the

benzyl-(o-sulfonyloxy)-p-tolylsulfone group. (DC) then loses HF in a subsequent

fast (as compared to the formation of (DC)) elimination step under consumption of14)

an equivalent amount of base to give (7).'

That the endocyclic S..-reaction was not taking place can readily be explained

on the grounds of the unfeasibility of a frontal attack of the sulfonyl carbanion at

the fluoromethoxy substitution centre. This would tend to reflect and strengthen,"

as in the reaction (1)—»-(2), the requirement for a rear side attack by the

13) See experimental section.

14) In an intermolecular process the formation of the species (XI) could have

^yso3cH2F

kJ^c^CH2 (XI)ITs

been expected. As this is not detected, it must be assumed that the relativerate of reaction of (XI) with the deprotonated educt to produce (7) must be .faster then the reaction of (6) with the deprotonated educt.

- 25 -

nucleophile in S.^2 reactions. However, how is the fact that the exocyclic SN~reaction to give (X) was also not taking place to be assessed?

General experience shows that intramolecular pathways are kinetically much

more favourable than their intermolecular counterparts [ 20 ]. It might have been

expected therefore that the exocyclic S^-process could counterbalance the un¬

favourable expulsion of a poor leaving group (fluoride anion) because of its intra-

molecularity. However, as this is not the case it is suggested that the failure of

(6) to undergo an exocyclic SN-reaction may be a consequence of the relative

rates of displacement of the fluoride and the benzyl-(o-sulfonyloxy)-p-tolylsulfone

group; the displacement of the latter being faster than the displacement of the15)

fluoride anion.'Furthermore, the effect of a oe.-fluorine atom, though not well

understood, may lead to a slight enhancement in the displacement rate of the

benzyl-(o-sulfonyloxy)-p-tolylsulfone group. Conversely, the inductive effect of

the sulfonyloxy group may lead to a considerable disactivation in the displacement

rate of the fluoride anion. In other words, substitution reactions at RSO„0-CH„iFV*

involving fluoride as leaving group should be much slower than at R-CH„-F.

3. Is the deprotonated form of benzyl-(o-methoxysulfonyl)-p-tolylsulfone (1)

capable of acquiring a precyclic 1,6-arrangement of the reaction centres ?

The significance of the results that the reaction (1)—»-(2) proceeds inter-

molecularly and not by an endocyclic SN-process rests on the assumption that

there are no factors which limit the intramolecular approach of the sulfonyl

carbanion to the substitution centre. The results of the reaction of the fluoride

15) Sn2 reactions of alkyl fluorides are approximately 10 times slower thanthe corresponding alkyl benzenesulfonates and alkyl iodides [ 5 ].

16) The effect of an oc -fluorine atom seems to be dependent on the reactionconditions. Compare for example the reactivities of FCH9Br and CH,CH0Br

[5]:z 6 z

KJ/acetone CH3ONa/CH3OH

CHgCHgBr 1.0 1.0

FCH2Br 0.79 4.77

- 26 -

(6)—»-(7) were not able to make a favourable contribution towards this assump¬

tion, nor were they able to discredit it. It became imperative therefore to show

that the reaction centres in the deprotonated form of (1) were capable of acquir¬

ing a precyclic 1,6-arrangement. A method of showing this became apparent;

the fluorine atom in (6) must be replaced by an iodine atom (better leaving group)

in order to facilitate the exocyclic S-.-reaction, as depicted in (XII). The plausible

assumption was made that the conformational factors in (XII) would be similar to

those in the deprotonated form of (1).

S(¥o i r^Vso2^o

I ITs Ts

(XII) (X)

Treatment of the silver salt of (1) with methylene iodide in refluxing

acetonitrile did not give the expected iodide (10) but bis (benzyl-(o-sulfonyloxy)-p-

'S02^0rr£-'

-SO^ 1) MeOH/reflux Vj* Ts

| 2) Ag2Q/CH3CN/rt X

l**VUs^CH2 CH3 3) CH2J2/CH3CN/reflux N. (10)

O^OTs Ts

(ID

tolylsulfone)-methane (11) in a yield of 60%. Although (11) was not the substrate

that was originally planned, it brought with it the properties that were

desired in (10), namely a good leaving group (benzyl-(o-sulfonyloxy)-p-tolyl

sulfone) for an exocyclic S.,-process.

- 27 -

The nmr of (11) showed singlets at 2.47 ppm (Ph-CH3), 4. 84 ppm (-CH2-)and 5.70 ppm (-O-CH2-O-), besides a multiplet between 7.18-8.15 ppm (aromaticprotons), Fig. 5a). In the mass spectrum the characteristic fragments:m/e 509 (M+-Ts), 309 (TsCH2PhS02+), 169 (TsCH2+), 139 (CH3PhSO+),91 (C7H7+), 30 (CHgO-1") and 28 (CH2CH2+) were observed.

Reaction of (11) under the reaction conditions a) and b) gave the salt (7),

^S

•S03CH203S

CH„ H2C

Ts Ts

(11)

-^a) 1.0 equiv KO-t-Bu/

^> monoglyme/rt/0.08m/40 min

1

b) 1.0 equiv KO-t-Am/benzene/45°C/0.02 m/45 min

- 28 -

.SO,

*CH,

2^0

ICHo

2d

Ts(d3)

0)

1) MeOH/reflux2) Ag20/CH3CN/rt

3) CD2J2/CHgCN/reflux.aS03CD2°3SN^

CH„•AJ

12 ^Ts(d3) Ts(dg

(11a)

The ir spectrum of (11a) was very similar to that of the undeuterated compound(11). In the nmr one singlet at 4.85 ppm (-CH2-) was observed besides a multipletbetween 7.25-8.20 ppm (aromatic protons), Fig. 5b). From the mass spectrum,the deuterium distribution in (11a) was determined and is given in Table 4.

17)Deuterium distribution in (11a)

m/e fragment deuterium distribution

1. batch 511-514 M+-02SC6H4CD3 76.1%d5, 16.2%d4, 1.9%dg, 5.8%d22. batch 511-514 M+-02SC6H4CD3 83.0%d5, 15.6%d4> 1.4%dg

Table 4

Equimolar amounts of (11) and (11a) were subjected to the reaction condi¬

tions a) and b), and the deuterium distribution in the products (7) + (7a) + (7b)+(7c)

was determined by analyzing the mass spectrum of the corresponding methylsulfon-

S03CH20oS)0

CH2 Kfr^^^Ts Ts

- 29 -

l.'.v.i "T,, ,,-Tr-f- T ; ,V

UwiW>VA. *»rnw*f^innlQA*' «>">' —"fc^V

^"'''•^ ' jl' jl-- i 'j, " i' 'i .' r1 "^4

,S03CH203S

ogp-poi

so2

CH, CH,

Fig. 5a) NMR (A60, CDClg) of (11)

,A

I.. ..' .. .-£- ,T, ;,,, i:,,v,T, ^=fe•"s?

Ip**»v««*vW*V*NU*'

=£ :"''i'.'.'.'.'i ' "i,1" I- ^ ly.'.'.V.'.'i'.1

ocrc©i

S02 S02

Y ^»CD, CO,

Fig. 5b) NMR (A60, CDClg) of (11a)

- 30 -

esters (8) + (8a) + (8b) + (8c). The results of the crossing experiments in monoglyme

are given in Table 5a).

Crossing experiments: 0.5 equiv (ll)+0.5 equiv (11a)— (7) + (7a) + (7b) + (7c)

Experi¬ment Nr.

Concen¬

tration

(ll)+(lla)Base/Solvent Temp Time

Deuterium distribution in

the methylsulfonesters of

(7) + (7a) + (7b) + (7c)

(mol/1) (°C) (min) Zd0+d2+d3+d5 =100%

1 0.08 KO-1-Bu/monoglyme rt 40 28.2 28.6 21.3 21.9

2 0.08 KO-t-Bu/monoglyme rt 3 28.5 29.0 21.8 20.7

Calculated:

Mermolecular d„ :d„ :d„ :dK =1:1:1:1 27.7 32.0 20.4 19.9

Intramolecular d :d2 :d3 :dg = 1:0:0:1 54.4 3.2 1.0 41.4

Table 5a)

The deuterium distribution in the products from the crossing experiments

with (11) and (11a) in monoglyme clearly shows that the reaction (11)—^(7) was

proceeding intermolecularly and not by an exocyclic SN-process. These results

were rather disappointing as they raised a certain doubt about the plausible

assumption that the sulfonyl carbanion was capable of approaching the substitution

centre. These results are not so easily understood. It can be suggested that an

equilibration of the deuterated groups was taking place in the educts (11) and

(11a) under the reaction conditions. In fact, the deuterium distribution in the

educts which were recovered did show an exchange of the deuterated groups,

Table 6, as measured by mass spectroscopy. However, a solid 1:1 mixture of

(11) and (11a) when analyzed by mass spectroscopy also showed an almost total

exchange of the deuterated groups, Table 6. It was not possible therefore to

determine whether the exchange in the educts was taking place during the reaction

or during the recording of the mass spectrum. The results of the crossing

experiments in monoglyme are therefore insignificant and no conclusion can be

drawn from them.

- 31 -

Deuterium distribution in (ll) + (lla):

fragment Zd" 0

d0

+ dg + dg

d2 d3

100%

d5

Educts (ll) + (lla)recovered from

crossing experimentNr. 1 (Table 5a)

M+-02SC6H4CY3 20.1 26.8 27.1 26.0

Weighed 1:1 mixtureof (11) and (11a) M+-02SC6H4CY3 25.2 27.4 22.8 24.6

Calculated:No exchange

Complete exchange

54.4

27.7

3.1

32.0

1.0

20.4

41.5

19.9

Table 6

The results of the crossing experiments with (11) and (11a) in benzene,

Table 5b), show that (11) is capable of undergoing an exocyclic S -reaction and

thus establishing the validity of the assumption that an intramolecular approach

of the reaction centres is possible. The experimental values of d , d„, d„ and

Crossing experiments: 0.5 equiv (11)+0.5 equiv (lla)-*-(7)+(7a)+(7b) + (7c)

Experi¬ment Nr.

Concen¬

tration Base/(ll)+(lla) Solvent Temp Time

Deuterium distribution in

the methylsulfonesters of

(7) + (7a) + (7b) + (7c)

(°C) (min) £dodg+dg^5 = 100%

do d2 d3 d5

1 0.02 KO-t-Am/Benzene 45 40 37.1 16.6 12.7 33.6

2 0.01 KO-t-Am/benzene 45 40 38.5 16.0 12.1 33.4

Calculated18^:

Inter molecular d :d„:d, :d& =Intramolecular d.Jdoidori,- =

1:1:1:1

1:0:0:1

26.1

54.3

30.2

0.0

22.0

0.7

21.7

45.0

Inter :Intra =1:1 40.2 15.1 11.4 33.3

Table 5b)

18) The calculated values are slightly different to those given in Table 5a) asthese crossing experiments were carried out with (11a) which came from asecond batch (see Table 4).

- 32 -

d„ show that the reaction (11)—M7), in benzene, is proceeding to about 50%o

intramolecular ly and 50% intermolecularly (compare the experimental values with

the calculated values for inter :intra = 1:1).

In light of the general experience that intramolecular reactions are far more

favourable than their inter molecular counterparts, the 50% intramolecularity of

the reaction (11)—(7) was unsatisfactory. However, it was not possible to

determine whether the educts (11) and (11a) were being partially equilibrated

during the reaction in benzene, for reasons already mentioned, thus rendering

these results undependable. Therefore, it became desirable to replace the benzyl-

(o-sulfonyloxy)-p-tolylsulfone group in (11) by another good leaving group such

that a 1:1 mixture of the undeuterated and the pentadeuterated analogue did not

exchange the deuterated groups during the recording of the mass spectrum. This

was realized in the originally planned benzyl-(o-iodomethoxysulfonyl)-p-tolyl-

sulfone (10).

4. Is the exocyclic S,.-process in benzyl-(o-iodomethoxysulfonyl)-p-tolylsulfone

(10) kinetically far superior to its intermolecular counterpart ?

- .,+

aSOgCHgOgSv^^NaJ/acetone/rt r^-^\t^s°2NX) (i^^Y'S03 M'

CH2H-cA^ ^kAcB-^V kAc„

|2 -2, ,2 p

Ts Ts Ts Ts

(11) (10) M+ = Na+

(4)

The crystalline benzyl-(o-iodomethoxysulfonyl)-p-tolylsulfone (10) wasobtained in yields of 85% from (11). The ir of (10) was very similar to that ofthe fluoride (6). In the nmr spectrum three singlets were observed at 2.45 ppm(Ph-CH3), 4. 84 ppm (-CH2-) and 5. 84 ppm (-O2SOCH2J) besides a multiplet bet¬ween 7.20 and 8.20 ppm (aromatic protons), Fig. 6a). No molecular peak wasobserved in the mass spectrum, characteristic peaks at 339 (M+-J), 309 (M+-OCH2J), 245 (M*-02S0£h2J), 139 (CH3CgH4SO+) and 91 (C7H7+).

Benzyl- (o-iodomethoxysulfonyl)-p-tolylsulfone (10) under the reaction condi¬

tions a), b), c) and d) provided the sodium, respectively the potassium salt, (7)

- 33 -

-SO.'2^0

I

SCH„

Ts

(10)

CH2Jc =0.08mo

a) l.Oequiv KO-t-Bu/monoglyme/rt/40 min

b) 1.0 equiv KO-t-Am/benzene/45°C/40 min

c) 1.0 equiv KO-t-Am/sulfolane/45°/40 min

d) ca. 1.0 equiv NaH/sulfolane/45°C/2 hr

^s.

SO,"M+d

+

C^CH2ITs + M+J

(7)

M+=Na+, K+

SO3CH3

ITs

S02^0I

CHg CH2J

Ts

(10)

(8)

19)and approximately 0.5 equivalents of the starting material (10) was recovered.

After methylation of (7) with trimethyloxonium tetrafluoroborate the isolated

oc-phenylethenyl-(o-methoxysulfonyl)-p-tolysulfone (8) was in all its properties

identical to (8) isolated from the reaction of (6) with potassium t-butoxide.

As once again crossing experiments would have to decide whether the

reaction (10)—*(7) was proceeding intramolecularly or intermolecularly, the

pentadeuterated analogue (10a) was prepared in an analogous manner to the pre¬

paration of (10).

(^ S03CD203S

CH„ M

Ts(d3) ts(d3)

(11a)

Naj/acetone/rt

^

SO,

'2

Ts(d3)

(10a)

so3 MT

CH0 CD2J ^^Cft,Ts(d3)

M+ = Na+

(4a)

Apart from differences between 900-1000 cm,the ir of (10a) was similar

to the undeuterated analogue (10). The nmr spectrum of (10a) showed one singlet

19) Under the reaction conditions d) it was difficult to control the exact amountof NaH added and hence the starting materials were recovered in varyingyields, consequently also the salt (7) isolated as the methylsulfonester (8).

- 34 -

i,,'.','.i,'.\ i i T... ,: i ' , i i =te

l'

: A

r, t-

L-

I'

, I .777-+-

Of"?SO,

CH,

Fig. 6a) NMR (A60, CDClg) of (10)

jl|__Tr.v.'.i-.v.i.1 I

' " I ' "'

^-^CH2 CD2Jso,

CD,

Fig. 6b) NMR (A60, CDClg) of (10a)

- 35 -

at 4.81 ppm (-CH2-) and a multiplet between 7.17 and 8.13 ppm (aromatic protons),integration over 2.4-2.5 ppm showed 4.7% of 3H and there was no integration at5.8 ppm, Fig. 6b). See Table 7 for deuterium distribution in (10a), as determinedby mass spectroscopy.

Deuterium distribution in (10a)20)

m/e fragment deuterium distribution

342-344 M+-J 81.1% d5, 17.3% d4, 1.6% d3

310-312 M+- OCD2J 83.2% d3, 16.1% d2, 0.7% dt

Table 7

The results of the crossing experiments with equimolar amounts of (10) and

(10a) in monoglyme and benzene are summarized in Table 8a). All crossing

experiments were carried out with one mole equivalent base and hence ca. 0.5

equivalents of the starting materials (10) +(10a) were recovered, the mass spectra

S02N)ICHoJ

CH„l

Ts

(10)

SO,2\)

CH2 CD2J

TS(dg)

(10a)

r^YS03"M+*Okc^x2

Ts (Y3)

r^YS°3CH3WAc^cx2

Ts(Y3)

(7) X=H=Y

(7c) X=D=Y

(8) X=H=Y

(8c) X=D=Y

20) The deuterium distribution in the JCD20-group was set equal to thedeuterium distribution in CD„J„ used for the preparation of (11):98.5% d2, 1.5% dr

- 36 -

Crossing experiments:'' ' 0.5 equiv (10)+ 0. 5 equiv (10a)—*(7)+(7c)

Experi¬ Concen¬ Base/ Deuterium distribution inment Nr. tration

(10)+(10a)

Solvent Temp Time the methylsulfonesters of

(7) + (7c)

(mol/1) (°C) (min) Z)d0+d2+d3+d5 = 100%

do d2 d3 d5

1 0.20 KO-1-Bu/monoglyme rt 40 50.4 3.8 4.1 41.72 0.08 KD-t-Bu/monoglyme rt 40 49.2 5.1 4.8 40.93 0.08 KO-t-Bu/monoglyme rt 40 52.3 2.1 2.6 43.04 0.05 KO-t-Bu/monoglyme rt 40 48.1 6.9 6.2 38.85 0.08 KO-t-Am/benzene 45 40 44.4 11.0 9.4 35.26 0.02 KO-t-Am/benzene 45 40 48.1 6.0 5.7 40.27 0.005 KO-t-Am/benzene 45 40 53.3 1.4 2.3 43.08 0.0025 KO-t-Am/benzene 45 40 50.1 5.5 5.0 39.4

Calculated

Intramolecular d :d2:d,:d- =Intermolecular d :d0:d, :dK =

o I o 5

1:0:0:1 54.6 0.0 0.6 44.8

1:1:1:1 26.3 30.1 22.1 21.5

Table 8a)

of which showed these to be a 1:1 mixture of (10) and (10a). ' Therefore no

significant exchange of the deuterated groups was taking place in the educts

21) Control experiments to show that there was no equilibration of the deuterated

groups in the products (7) +(7c) and that there was no deuterium scramblingin the methylsulfonesters (8) +(8c) during the recording of the mass spectrawere not repeated as this was already established during the crossingexperiments with the fluoride (6) +(6a), see Table 3.

22) See experimental section. An example is given below.

z

d0

do+d2+d3+d5 = 100%

d2 d3 d5

Educts (10) +(10a) recoveredfrom crossing experiment Nr.2

(Table 8a))

48.9 1.1 1.5 48.5

Weighed 1:1 mixture of

(10) +(10a)48.4 0.9 1.5 49.2

Calculated:.. ,

No exchange

complete exchange

54.6

26.3

0.0 0.6

30.1 22.1

44.8

21.5

The slightly low value of d and the slightly high value for d,- are inter¬

preted as arising from a secondary isotopic effect (k /k_=0.80) in themass spectrometer.

- 37 -

J_Ju ..it*, I ,i, Lzi «o «o to no wo wo aoo

Fig. 4a) Mass spectrum of the methylsulfonesters (8)+(8a)+{8b)+(8c) from

crossing experiment with (6)+(6a).

HIKKf

cx?«o

"S

,, 4,1 ill it 1 j, ,iaso

00

1are

Fig. 4b) Mass spectrum of the methylsulfonesters (8)+(8c) from crossingexperiment with (10)+(10a).

D.L100"

"a••

i, mil 4 Hln i i ,ISO

1

w

Fig. 4c) Mass spectrum of a 1:1 mixture of the methylsulfonesters (8) +(8c).

- 38 -

during the reaction. The deuterium distribution in the methylsulfonesters of the

products is in quite close agreement with the calculated values for an intramolec¬

ular pathway. Fig. 4b) shows the mass spectrum of the methylsulfonesters (8)+(8c)

from a crossing experiment (Nr. 3, Table 8a)). It must be assumed therefore that

the sultone (X) formed by an exocyclic SN-reaction, as depicted in (XII), under¬

goes a fast (as compared to the formation of (X)) elimination reaction with an

equivalent amount of base to give (7).

kA^ CH2-J ^^ACH-CH2 V^C^CH2I I ITs Ts Ts

(XII) (X) (7)

Though these results are not to be underestimated, the slightly high values

for d, and d„ for an intramolecular process in the crossing experiments given

in Table 8a) were disturbing. An obvious explanation would have been that a part

of the reaction was proceeding intermolecularly. If this were the case then

through dilution the intramolecular pathway should become statistically more

favourable. However, this is not the case as is readily seen by comparing experi¬

ments, in monoglyme, Nr. 1 (0.2 molar) and experiment Nr. 4 (0.05 molar) in

Table 8a); or experiment Nr. 6 (0.02 molar) and experiment Nr. 8 (0.0025 molar)

in benzene. There is no pronounced concentration effect as would be expected for

competitive inter and intramolecular processes. Carrying out two separate cross¬

ing experiments (Nr. 2 and Nr. 3) under identical conditions also gave varying

values for d, and d, in the separate experiments. It is tempting to attribute this

inconsistent behaviour to solvent effects (formation of clusters ?), which are not

well understood. With this is in mind a different solvent with a high dielectric

constant -sulfolane (D = 44), was chosen in which the crossing experiments with

(10) and (10a) were repeated.

Table 8b) documents the crossing experiments with (10) and (10a) in sulfolane

as solvent.

- 39 -

Crossing experiments:'' '0.5 equiv (10) + 0. 5 equiv (10a)—*(7) + (7c)

Experi¬ Concen¬ Deuterium distribution inment Nr. tration Base/ the methylsulfonesters of

(10)+ (10a) Solvent Temp Time (7) + (7c)

+ d2+d3 + d5 = 100%(mol/1) (°C) (hr)

1 0.08 KO -t-Am/sulfolane 45 2/3 52.7 1.3 1.6 44.42 0.08 KO--t-Am/sulfolane 45 2/3 52.1 1.3 2.1 44.53 0.16 KO-t-Am/sulfolane 45 2/3 50.9 2.9 3.9 42.34 0.08 NaH/sulfolane 45 15 53.5 1.9 2.1 42.55 0.16 NaH/sulfolane 45 2 50.4 2.1 2.7 44.86 0.33 NaH/sulfolane 45 2 51.2 2.8 3.6 42.47 0.64 NaH/sulfolane 45 2 52.7 1.5 3.1 42.7

Calculated:

Intramolecular d :d„ :d„ xl-

Intermolecular AQ :d£ :d3 :d5

= 1:0:0:1 54.6 0.0 0.6 44.8

= 1:1:1:1 26.3 30.1 22.1 21.5

Table 8b)

The experimental values for d , d,, d„ and d,-, given in Table 8b) are in

extremely good agreement with the calculated values for an intramolecular23)

process.' It is to be noted that despite the high concentration of 0.64 molar

(experiment Nr. 7), where an intermolecular pathway should become more favour¬

able, the reaction (10)—»-(7) proceeds practically completely intramolecularly. We

had at last a system in which it was shown that not only was the intramolecular

precyclic 1,6-arrangement of the reaction centres possible but also that it was

kinetically far superior to an intermolecular pathway.

These encouraging results prompted us to reexamine the the methyl transfer

(!)-•• (2) in sulfolane.

23) It must be kept in mind that the experimental values can contain an error ofca. 2%.

- 40 -

5. Reaction of benzyl-(o-methoxysulfonyl)-p-tolylsulfone (1) in sulfolane

^/^•CH0CH3 1.0KD-t-Bu/sulfolane/ ^-^CH^0^ (2)*2

ITs

(1)

45°C/40 minI Ts

aSW"\_/-CH3CH/CH3

Ts (13)

Under the reaction conditions given above, benzyl-(o-methoxysulfonyl)-p-24)

tolylsulfone (1) gave (2) identified as the p-toluidinium salt (13) in yields of

The methyl transfer (1)—*(2) in sulfolane was found to be an intermolecu-

lar reaction, in accord with the results of Tenud [ 16 ] in the solvents dioxane

and monoglyme. Proofs for the intermolecularity of this reaction are:

a) The formation of the intermediates (3) and (4) which is compulsory for an

a80^ + f^V^S03CH3CH3 kACH^CH3

I2

ITs Ts

(1) (3)r^VS°2^0 c = 0.08 m

CH2 CH3 0.5 KO-t-Bu/sulfolane/| 45°C/10 min ^j?\^SO;m+ ^x^SO^M"1"

CY + \Y(1) ^ ^CH^^"3 ^^^CH,

ITs Ts

(2) M+ = K+ (4)

2

24) This was identical to (13) described by Tenud [ 16 ] .

- 41 -

intermolecular reaction was detected. The reaction mixture, of the reaction of

25)(1) with 0.5 equivalents potassium t-butoxide in sulfolane, showed after 10

min reaction time a composition of ~ 29% (1), ~28% (2), ~ 20% (3), ~22% (4)

as determined by nmr.

b) Crossing experiments with equimolar amounts of (1) and the hexadeuterated

analogue (la) were carried out. The results of these crossing experiments27)

are reproduced in a summary form in Table 9), and show that the reaction

SO,

CH„

2s O

I

CH,

^so3 IVf

(1)

Ts

r^V^OkA

kACH/CX3Ts (Y3)

i^Y^^CD,

CH,

I*

Ts(d3)

- 42 -

Crossing experiments: 0. 5 equiv (l) + 0.5equiv (la)—»(2) +(2a) + (2b) + (2c)

Experi¬ment Nr.

Concen¬

tration

(1) + da)Base/Solvent

Temp Time

Deuterium distribution in

the methylsulfonesters of

(2) + (2a) + (2b) + (2c)

(mol/1) (°C) (hr) £do + d3+d6 = 100%

d0 d3 d6

1

2

3

0.08

0.08

0.005

KO-t-Bu/sulfolaneKO-t-Bu/sulfolaneKD-t-Bu/suUolane

45

45

45

2/32/33

26.8

28.2

27.3

50.1

50.0

48.6

23,1

21.8

24.1

Calculated:

Intermolecular d :d, :d» =

Intramolecular dQ :dg :dg =1:2:1

1:0:1

27.6

55.4

50.0

0.0

22.4

44.6

Table 9

The intermolecularity of the reaction (1)—•(2), together with the exocyclic

SN-reaction (10)-»(7), strengthen the concept of a rear side attack by a nucleo-

phile in Sj^2 reactions, and suggest that the general experience according to

which intramolecular pathways are preferred to their intermolecular counterparts

is not to be extended to include endocyclic SN-reactions at a tetrahedral carbon

atom.

However, one question still remains to be answered: is the reaction

(1)—»(2) proceeding intermolecularly because the endocyclic S,,-process is un-

CCTk — OtsTs Ts

(ii) (xm)

favourable owing to the low effectiveness of the sulfonyloxy as a leaving group

in the deprotonated specie (n) (due to the delocalization of the sulfonyl carbanion

in the T-system as shown in (XIII)) and not because of a frontal attack?

In other words is (II) reacting only with the neutral educt (1) ? A question,

perhaps difficult to answer, warrants further study for our results to gain

their full impact.

- 43 -

Experimental Section

I am indebted to the following persons and their co-workers:

PD Dr. J. Seibl

Prof. Dr. W. Simon

Mr. W. Manser

for the recording and interpretation of the mass

spectra, obtained on a Hitachi RMU/6A resp. 6D

spectrometer. D.I. = Direct Intake, M.T. = Micro

Intake, N.I. = Normal Intake. Deuterium distribution

was determined on strongly enlarged peaks.

for the recording of the nmr spectra on the Varian

spectrometers HA 100 (100 Mcs), A60 (60 Mcs) orT60 (60 Mcs) with tetramethyl silane (6 =0) as inter¬nal standard. The chemical shifts are given in ppm,the coupling constants J in cps. s = singlet, d =

doublet, q = quadruplet, m = multiplet.

for the elemental analyses and molecular weightdeterminations.

The infrared spectra were obtained on a Perkin Elmer PE 257 spectrophotometer.The intensities of the bands are given as s (strong), m (medium) and w (weak).

The melting points, determined in open tubes on an apparatus by Dr. Tottoli, and

boiling points are uncorrected.

Care was exercised in carrying out all reactions involving strong bases under

extreme water-free conditions. All glassware was dried overnight at 120°-140°C.

- 44 -

Preparation and reactions of benzyl-(o-fluoromethoxysu]fonyl)-p-tolylsulfone,

bis (benzyHo-sulfonyloxy)-p-tolylsulfone)-methane, benzyl-(o-iodomethoxy-

sulfonyl)-p-tolylsulfone and benzyl-(o-methoxysulfonyl)-p-tolylsulfone

CJH3I

2

Ts

(1) (6)

*2)A solution of 3.40 g (10 mmol) of benzyl-(o-methoxysulfonyl)-p-tolylsulfone (1)in 100 ml anhydrous methanol 3) was refluxed for 15 hr. After the removal ofthe solvent by rotary evaporation at ca. 40°C, the residual oil was dissolved in100 ml anhydrous acetonitrile *4) and 1.30 g (5.6 mmol) of freshly preparedsilver oxide added to the stirred solution. The stirring was continued for 2 hr

at room temperature, after which the solution was filtered through cellite toremove excess silver oxide. Approximately 60 ml of acetonitrile was distilledoff at atmospheric pressure to remove the water formed (azeotrop: 16% H2O/77°C). To the cooled (0°C) solution was added 1.70g (10.6 mmol) of fluoroiodo-methane*5) and the solution stirred for 17 hr at room temperature under exclu¬sion of light and air moisture. The yellow precipitate of silver iodide wasremoved by filtration and the filtrate concentrated by rotary evaporation at ca.40°C. Chromatography (silicagel, *6) chloroform/methylene chloride = 1:1) ofthe residual oil, followed by recrystallization of the resulting solid from benzene/hexane at room temperature afforded 2.60 g (73% with respect to (1)) of benzyl-(o-fluoromethoxysulfonyl)-p-tolylsulfone (6), mp 99.5°C. For analysis a samplefrom a similar experiment was recrystallized twice from benzene/hexane anddried for 15 hr at 23°C and 0.01 mm, mp 99.5°C.

C15H15F°5S2

IR (CHC1,) 3020 m, 2930 w, 1600 m, 1576 w, 1495 w, 1480 w,1448 m, 1415 w, 1380 s, 1325 s, 1305 s, 1293 m,1274 w, 1250 w, 1188 s, 1160 s, 1150 s, 1140 s,1118 w, 1090 s, 1072 s, 1020 m, 995 s, 890 w,835 m cm"1.

calcd C 50.22 H 4.22 F 5.30 S 17.89 %found C 50.35 H 4.42 F 5.18 S 17.90 %

*1) I am indebted to R. Hobi for his help during the preparation of this compound.*2) For preparation of (1) see L. Tenud [16].*3) Methanol, puriss, Fluka AG.*4) Acetonitrile, distilled twice over P2O5 and once over K2CO3.*5) Fluoroiodomethane, prepared using the procedure of A.E. von Arkel and

E. Janetzky [18], bp 48°-51°C.*6) Silicagel (0.05-0.2 mm), Merck AG, used throughout this work for column

chromatography.

- 45 -

NMR (CDClJ

A60J

MS (RMU/6A)

M.T. 120°

6 = 2.46 (s, 3H), 4.91 (s, 2H), 5.68 (d, J =50.5, 2H),7.25-8.25 (m, 8H) ppm.

"~r

360 (1.5/M++2), 359342 (0.5), 340 (1.8),203 (10.8)139 (6.0)111 (3.0)106 (4.0)95 (1.8)88 (1.8)77 (12.8)67 (3.0)62 (5.0)51 (14.0)40 (3.0)

(3.0)27

173 (25.5),138 (1.5),110 (5.5),105 (2.0),92 (9.0),87 (1.0),76 (2.1),66 (5.0),57 (2.0),50 (5.0),39 (22.3),

(2.5/M++l309 (1.6),166 (2.0),137 (4.5),109 (56.0),103 (1.0),91 (100),83 (8.3),75 (2.0),65 (61.5),55 (2.2),44 (2.5),38 (2.5),

), 358 (10.294 (1.8),165 (5.5),120 (2.0),108 (1.5),97 (2.2),90 (20.0),79 (3.0),74 (1.0),64 (11.5),53 (3.0),42 (4.0),33 (6.8),

8/M+),245 (4.0),155 (5.8),118 (2.0),107 (1.5),96 (1.0),89 (41.3),78 (15.0),69 (2.0),63 (25.5),52 (6.0),41 (8.2),29 (4.2),

1.-JL— ^ls fi^S5Xid£^s^2^°2Sl"^i.^Jy2§HM0S^i.!n£,yEILe_(ll)

S03CH203S

CH2 H2C

(11)

A solution of 5.1 g (15 mmol) of benzyl-(o-methoxysulfonyl)-p-tolylsulfone (1) in150 ml anhydrous methanol*!) was refluxed for 7 hr. The oily residue obtained

upon vacuum removal (rotary evaporator) of the solvent at ca. 40°C was dissolvedin 50 ml acetonitrile**) and again the solvent evaporated at reduced pressure. Theresidual oil was finally dissolved in 150 ml acetonitrile, 2.13 g (9.06 mmol) of

freshly prepared silver oxide added, and the reaction mixture stirred for 2.5 hrunder nitrogen at room temperature. After filtration through cellite approximately90 ml of acetontrile was distilled off at atmospheric pressure. The remainingsolution was cooled (0°C) and 4.5 g (16.8 mmol) of methylene iodide *z) addedand the reaction mixture heated under gentle reflux for 38 hr. The yellow preci¬pitate was removed by filtering through cellite, and the filtrate concentrated byrotary evaporation at ca. 40°C to yield a viscous oil, which was chromatographed(silicagel, chloroform/methylene chloride 1:1) to give 4.86 g of a crystallizingoil. Recrystallization from chloroform/hexane at room temperature afforded 4.10gof small white needles, containing chloroform. The chloroform was removed bypulverizing the crystals and drying at 50°C and 0.02 mm for 24 hr. Yield 3.00g(60% with respect to (1)) of (11), mp 173°C.

*1) See footnote on page 44.

*2) Methylene iodide, purum, Fluka AG, distilled, bp 77°-78°C (9.5mm).

- 46 -

C29H28°10S4

Mol wt (CHgClg)

IR (CHClg)

NMR (CDC1,)A60

MS (RMU/6D)D.I. 350°

calcd

found

calcd

found

C 52.39

C 52.32

664. 81

681

H 4.25

H 4.29

S 19.29 %S 19.16 %

3025 m, 2930 w, 1598 s, 1572 w, 1492 w, 1477 m,

1447 m, 1379 s, 1321 s, 1302 s, 1290 s, 1185 s,

1158 s. 1147 s, 1138 s, 1088 s, 1064 m, 1039 m,

1019 w, 941 s, 888 w, 832 s, 659 m cm-1

& = 2.47 (s, 6H), 4.84 (s, 4H), 5.70 (s, 2H),7.28- 8.15 (m, 16H) ppm.

511 (2.5), 510 (4.0), 509 (11.1), 481 (2.4),479 (10.9), 311 (1.0), 310 (1.2), 309 (5.8),246 (5.9), 245 (4.5), 172 (5.0), 171 (10.5),165 (5.8), 156 (5.5), 155 (18.5), 149 (6.0),140 (6.6), 139 (16.0), 137 (5.1), 125 (5.0),123 (12.5), 121 (4.5), 115 (6.2), 109 (9.5),107 (14.5), 98 (6.5), 97 (6.5), 92 (11.7),90 (8.0), 89 (8.3), 85 (6.0), 83 (6.8),81 (6.5), 79 (7.5), 78 (5.5), 77 (12.1),71 (10.0), 70 (7.0), 69 (U.0) 67 (6.0),64 (15.0), 63 (5.8), 60 (10.0) 58 (4.2),56 (7.0), 55 (16.0), 51 (5.2), 48 (4.6),44 (39.5), 43 (83.5), 42 (8.7) 41 (19.0),38 (6.3), 36 (16.1), 32 (26.5) 31 (6.2),29 (80.5), 28 (100), 27 (10.5)

480 (3.8),308 (1.8),169 (14.0),141 (19.5),124 (6.2),108 (5.0),91 (57.0),82 (4.5),73 (8.9),65 (14.5),57 (20.2),45 (20.0),39 (12.0),30(79.1),

1.3_. jtenz^^(o^iodj^e^hoxy_sjM>n^^ (10)

.S03CH203S.

CH2CH2J

A solution of 1.33 g (2 mmol) of bis (benzyl-(o-sulfonyloxy)-p-tolylsulfone-methane (11) and 299.8 mg (2 mmol) of sodium iodide in 100 ml anhydrous ace¬tone*!) was stirred for 47 hr at room temperature, under exclusion of lightand air moisture. The white precipitate of the sodium salt (4), identified bynmr, was filtered off and the filtrate concentrated at reduced pressure and ca.

40°C to give a yellow oil. Chromatography (silicagel, chloroform/methylenechloride = 1:1) of the oil, followed by crystallization from benzene/hexane at

*1) Acetone, pro analysi, Merck.

- 47 -

room temperature yielded 771 mg (81%) of the crystalline iodide (10), mp 104 C.For analysis a sample from a similar experiment was recrystallized twice from

benzene/hexane and dried for 15 hr at 23°C and 0.001 mm, mp 104°C.

C^H-.JO.S, calcd C 38.69 H3.24 J 27.22 S 13.75%10 la D ^

found C 38.84 H 3.41 J 27.16 S 13.79 %

Mol wt (CH„C19) calcd 466.33found 467

IR (CHClJ 3025 w, 2930 w, 1600 m, 1578 w, 1495 w, 1480 m,a

1450 m, 1379 s, 1326 s, 1305 m, 1251 m, 1186 s,1160 s, 1150 s, 1141 s, 1118 m, 1090 s, 1068 m, .

1021 w, 975 s, 890 w, 855 w, 835 m, 658 m cm".

NMR (CDClJ J> = 2.45 (s, 3H), 4.84 (s, 2H), 5.84 (s, 2H),A60

J7.20- 8.20 (m, 8H) ppm.

MS (RMU/6D) 341 (0.4), 340 (1.5), 339 (4.0), 311 (5.5), 310 (8.7),D.I. 80° 309(45.0), 281 (5.3), 268 (4.0), 254 (3.0), 247 (3.0),

246 (6.2), 245(31.5), 217 (8.0), 167 (3.0), 166(10.8),165 (9.0), 156 (2.0), 155 (8.0), 154(13.1), 142 (2.0),141 (15.0), 140(10.5), 139 (100), 138 (4.2), 137(12.2),136(2.0), 127 (3.0), 126 (5.5), 122 (2.3), 111 (5.0),109 (4.1), 106 (5.0), 92(5.5), 91(45.5), 90(57.0),89 (36.7), 79 (3.2), 78(11.4), 67 (6.0), 66 (3.5),65(25.8), 64(8.4), 63(13.1), 62(3.2), 52(3.0),51 (8.0), 50(3.5), 45(5.9), 44(2.8), 43(3.0),41 (5.1), 40(3.7), 39(15.8), 38(2.5), 32(4.0),31 (3.0), 30(5.2), 29(11.1), 28(3.0).

1.4. Reaction of benzyl-(o-fluoromethoxysulfonyl)-p-tolylsulfone (6) with

P^j^sjum_t^butoxide_j^JJ}£f£zine.

S°2\)^

f^YSOlM+ ^f^YSOZC*ZCH CH2F k:J^c^CH2 U^kc^CH2I

2I I

Ts Ts Ts

(6) (7) (8)

1.4.1. With 2.0 mol equiv potassium t-butoxide

To a stirred solution of 370 mg (1.035 mmol) of benzyl-(o-fluoromethoxysulfonyl)-

- 48 -

*1)p-tolylsulfone (6) in 10 ml anhydrous monoglyme was added, at room temper¬ature, 10 ml of a 0.207 molar solution of potassium t-butoxide *2) in monoglyme.A deep yellow solution was formed which gradually became colourless, and thesolution was neutral towards litmus paper within 15 min. After stirring for anadditional 30 min under nitrogen, the solvent was removed by rotary evaporationat ca. 40°C and the remaining solid extracted with chloroform/water (3 x 30 ml

CHCI3, 3 x 10 ml H2O). The combined chloroform extracts were dried (Na2S04)and the solvent removed by rotary evaporation at ca. 40°C to yield 10 mg of asolid which was not further characterized. The water extracts were combined

and evaporated to dryness on a rotary evaporator at ca. 40°C and the remainingsolid further dried for 72 hr at room temperature and 0.01 mm. Potassium

fluoride was removed by dissolving the potassium salt (7) in 55 ml anhydrousmethylene chloride*3) and filtering through a glass-filter. The filtrate containingthe potassium salt (7) was evaporated to dryness by rotary evaporation at ca.40°C : 380 mg of a white solid. To this was added 278 mg (1.96 mmol) of tri-

methyloxonium tetrafluoroborate and 30 ml methylene chloride, and the hetero¬

geneous mixture stirred for 22 hr at room temperature under nitrogen. Thevoluminous precipitate formed was removed by filtration, and the methylenechloride solution washed with ice-water till the water extracts were neutral. The

methylene chloride extract was dried (Na2S04) and the solvent removed by rotaryevaporation at ca. 40°C to yield 360 mg of an oil which was crystallized from

benzene/hexane at room temperature to give small white needles weighing 275 mg(76% with respect to (6)) of oc-phenylethenyl-(o-methoxysulfonyl)-p-tolylsulfone(8). For analysis a sample was crystallized three times from benzene/hexaneand dried at 25°C and 0.03 mm for 48 hr. Melting point 133°-135°C.

C16H16°5S2 Calcd c 54-55 H4.58 S 18.20 %found C 54.62 H 4.65 S 18.11 /O

IR (CHCU) 3022 m, 2960 w, 1598 m, 1568 w, 1493 w, 1472 w,1451 w, 1435 w, 1364 s, 1317 s, 1304 s, 1291 m,1263 w, 1185 s, 1150 s, 1135 m, 1119 w, 1102 m,1081 s, 1055 m, 1018 w, 990 s, 885 w, 826 m,811 m cm-1.

NMR (CDCU & = 2.48 (s, 3H), 3.75 (s, 3H), 6.18 (d, J =1, 1H),A60

°

6.71 (d, J = 1, 1H), 7.25 - 8.25 (m, 8H) ppm.

NMR (CDCU) £ = 2.49 (s, 3H), 3.75 (s, 3H), 6.15 (s, 1H)*4),HA 100 6.66 (s, 1H)*4), 7.28- 8.20 (m, 8H) ppm.

MS (RMU/6D) 352(1.0/M+), 258 (1.0), 257 (3.0), 213 (3.5),D.I. 80° 200 (1.5), 199 (6.0), 198 (11.5), 197 (100),

168 (1.0), 167 (2.0), 166 (1.5), 165 (9.0),153 (1.0), 152 (1.5), 151 (1.0), 150 (1.5),

*1) Monoglyme = 1,2-dimethoxyethane, purum, Fluka AG, distilled twice overlithium aluminium hydride.

*2) Potassium t-butoxide, pract. Fluka AG, sublimed (ca. 200°C/0.01 mm)twice and dissolved in monoglyme.

*3) Methylene chloride, distilled over P2O5.*4) The splitting of these signals was not observed on the HA 100 spectrometer

at a sweep width of 1000 cps.

- 49 -

1.4.2.

149 (1.8) 148 (1.9), 141 (1.0), 140 (1.5), 139 (11.0),138 (2.5) 137 (16.8), 136 (3.5), 134 (0.5), 133 (1.0),124 (0.5) 123 (1.5), 122 (1.0), 121 (2.0), 120 (1.0),119 (1.5) 118 (6.0), HI (1.8), 110 (1.2), 109 (9.2),108 (1.0) 107 (1.0), 105 (2.2), 104 (1.5), 103 (4.9),102 (5.1) 101 (12.8), 97 (1.0), 96 (1.5), 95 (1.0),92 (3.0) 91 (10.2), 90 (6. 8), 89 (5.5), 87 (1.0),86 (1.0) 85 (1.0), 84 (1.1), 83 (1.0), 82 (1.0),81 (1.5) 80 (1.0), 79 (5.9), 78 (12.2), 77 (8.9),76 (5.0) 75 (5.8), 74 (2.1), 73 (1.5), 71 (1.0),70 (0.8) 69 (2.0), 67 (1.5), 66 (1.0), 65 (8.1),64 (2.1) 63 (4.0), 62 (1.2), 61 (5.0), 57 (2-7),56 (1.9) 55 (1.8), 53 (1.5), 52 (4.0), 51 (7.0),50 (4.0) 45 (5.0), 44 (1.2), 43 (3.0), 42 (l.D,41 (3.0) 40 (1.9), 39 (7.0), 38 (1.3), 37 (1.0),32 (l.D 31 (0.8), 30 (1.0), 29 (2.0), 28 (3.5),27 (2.0) 26 (1.0).

With 1 0 mol equiv potassium t-butoxide

To a stirred solution of 345.9 mg (0.965 mmol) of benzyl-(o-fluoromethoxy-sulfonyl)-p-tolylsulfone (6) in 12.1 ml monoglyme was added at room temperature5 ml of a 0.193 molar solution of potassium t-butoxide in monoglyme. The deepyellow colour of the solution, formed upon addition of the base, slowly disappearedand became colourless within 10 min, and the solution was neutral towards litmus

paper. After allowing to stir for a further 30 min at room temperature under

nitrogen the solvent was removed on a rotary evaporator at ca. 40°C. The re¬

maining solid was extracted with chloroform/water (3 x 30 ml CHCI3, 3 x 10 ml

H2O). The chloroform extracts were combined, dried (Na2SC>4) and evaporatedat reduced pressure to give a crystallizing oil which was recrystallized twicefrom benzene/hexane and vacuum - dried for 15 hr at room temperature: 144 mg(41.5%) of the starting material (6), mp 99.5°C.

IR (CHClg)

NMR (CDC1,)

A60d

MS (RMU/6D)D.I. 80°

Identical to the IR of the analysed product.

H-F51, 2H),6 = 2.47 (s, 3H), 4.92 (s, 2H), 5.69 (d, J,

7.25-8.25 (m, 8H) ppm.

358(2.5/M+), 340 (2), 293 (4), 246 (3), 245 (13),244 (2), 227 (3), 205 (5), 204 (6), 203 (58), 185 (4.5),181 (4), 180 (4), 175(5.5), 174 (9.5), 173 (100),166 (3), 165 (5), 157 (2.5), 156 (2.5), 155 (15),154 (4.5), 140 (3), 139 (10), 138 (2), 137 (5), 110(6),109 (71), 107 (3), 106 (10), 105 (10), 92 (5), 91 (53),90 (54), 89 (9.5), 84 (5), 80 (7.5), 79 (7), 67 (2),66 (2), 65 (22), 64 (5), 63 (9), 62 (2.5), 52 (2.5),51 (6), 50 (3), 45 (2.5), 44 (2), 43 (2), 41 (5),40 (2.5), 39 (11), 38 (2), 33 (6), 32 (4), 29 (2),28 (15), 27 (3).

- 50 -

Natural isotopic distribution :

m/e measured average of 3 measurements

358

359

360

100

18.6-19.0

10.8-11.9

100 % M+18.8 % M++l11.4 % M++2

The water extracts were combined and the water removed by rotary evaporationat ca. 40°C. The solid obtained was dried for 15 hr at room temperature(0.005 mm), dissolved in 50 ml methylene chloride, filtered to remove thepotassium fluoride and again evaporated to dryness at reduced pressure. Tri-methyloxonium tetrafluoroborate (145 mg, 1 mmol) and 15 ml of anhydrousmethylene chloride was added to the dried salt and the reaction mixture stirredunder nitrogen for 22 hr. After filtration, to remove the voluminous precipitate,the methylene chloride solution was washed with ice-water till the water extractswere neutral, and the methylene chloride extract dried over Na2S04. Removalof the solvent by rotary evaporation and crystallization of the residual oil frombenzene/hexane yielded 124 mg (36.5% with respect to (6)) of ex-phenylethenyl-(o-methoxysulfonyl)-p-tolylsulfone (8). For analytical data this was crystallizeda second time: 121 mg, mp 133°-134°C.

IR (CHClg)

NMR (CDC1,)

A606

MS (RMU/6D)D.I. 80°

Identical to IR of the analysed product.

6= 2.46 (s, 3H), 3.72 (s, 3H), 6.18 (d, J = l, 1H),6.70 (d, J = l, 1H), 7.24-8.25 (m, 8H) ppm.

352 (1.0/M+), 259 (0.5), 258 (0.8), 257 (2.5), 213 (2.5),199 (6.5), 198 (11), 197(100), 183 (3), 167 (2), 166 (1.2),165 (12), 148 (2), 139 (13), 138 (2.5), 137 (17), 136 (4),121 (2), 118 (6.5), 109 (11.5), 105(2), 103(4.5),102(5), 101(14), 92(4), 91(11.5), 90 (7.5), 89 (5),79 (5), 78 (3.5), 77 (8), 76 (5), 75(7), 74(2), 65(8.5),64(3), 63(4), 61(6), 52(2.5), 51(5.5), 50(3), 45(6),44 (2), 43 (2), 41 (2.5), 39 (5.5), 32 (5), 28 (15), 27 (2.5).

Natural isotopic distribution:

m/e measured average of 3 measurements

257

258

259

100

17.62-17.75

6.40 - 7.26

100 % P+= (M+-17.67 % P + 16.70 % P++2

O3SCH3)

- 51 -

1.5. Reaction of bis (benzyl-(o-sulfonyloxy)-p-tolylsulfone)-methane (11) withbases

S03CH3

+

^Y03M+ ^ (i^Y^°l^-\J-C]h

Ts

(4)

1.5.1. 1.0 mol equiv KO-t-Bu/monoglyme/room temp/40 min/c0 = 0.08 molar

To a stirred solution of 256 mg (0.386 mmol) bis (benzyl-(o-sulfonyloxy)-p-tolyl-sulfone)-methane (11) was added at room temperature 2 ml of a 0.193 molarsolution of potassium t-butoxide in monoglyme. The yellow colour of the reaction

mixture formed upon addition of the base disappeared within a few minutes, andthe clear colourless solution was neutral towards litmus paper within 10 minutes.

After stirring for a further 30 min under nitrogen, the solvent was removed byrotary evaporation at ca. 5°C. The residual oil was extracted with chloroform/water (3 x 30 ml CHCI3, 3 x 10 ml H2O).The chloroform extracts were combined, dried (Na2S04) and concentrated atreduced pressure and 40°C to provide an oily residue. This was crystallizedonce from chloroform/hexane and the crystals dried at 54°C and 0. 001 mm for24 hr : 103 mg (40.2%) of the starting material (11), mp 170°C.

IR (CHCI3) Identical to the IR of the analyzed product.

NMR (CDCL,) S = 2.48 (s, 6H), 4.84 (s, 4H), 5.71 (s, 2H),A60 7.27-8.16 (m, 16H) ppm.

The combined water extracts were evaporated by rotary evaporation at ca. 40 C.

Two 30 ml portions of methylene chloride were added and removed at reduced

pressure, and the residual solid dried at room temperature and 0.001 mm for

20 hr : 133 mg solid, containing the salts (4) and (7). (4) was separated by dissol¬

ving (7) in 10 ml methylene chloride, (4) remained undissolved and was centri-

fuged. The solution of (7) in methylene chloride was evaporated to dryness atreduced pressure on a rotary evaporator : 78 mg. This was methylated with 75 mg

- 52 -

(0. 5 mmol) trimethyloxonium tetrafluoroborate in 7 ml methylene chloride during27 hr at room temperature under nitrogen. After filtration, the methylene chlor¬ide solution was diluted with 20 ml methylene chloride and washed with ice-watertill neutral, dried (Na2SC>4) and concentrated by rotary evaporation to provide68 mg of an oil. Two recrystallizations from benzene/hexane afforded 38 mg(27.7%) of (8), mp 133°C.

IR (CHC1„) Identical to IR of analyzed product.

NMR (CDC1J 6= 2.43 (s, 3H), 3.69 (s, 3H), 6.09 (s, 1H), 6.61 (s, 1H),HA 100 7.16-8.10 (m, 8H) ppm. A slight impurity (< 2%) at

3.76 and 4.88 ppm due to (1).

The methylene chloride insoluble salt (4), 49 mg, was dissolved in 1 ml hot water(acidified with 3 drops of 0.1 n HC1 solution) and a solution of 22 mg p-toluidinehydrochloride*!) m l ml water added and the milky solution allowed to stand atroom temperature. The crystals formed were filtered and dried over phosphorpentoxide at reduced pressure (0.1 mm) for 4 hr : 41 mg (24.6%) of (12),mp 195°-196°C.

NMR (CF,COOH)*2) 6= 2.38 (s, 3H), 2.48 (s, 3H), 5.21 (s, 2H),HA 100 7.25-8. 80 (s+m, 15H) ppm.

1.5.2. 1.0 mol equiv KO-t-Am/benzene/45°C/45 min/c0 =0.02 molar

A solution of 489.3 mg (0.736 mmol) bis (benzyl-(o-sulfonyloxy)-p-tolylsulfone)-methane (11) in 36.8 ml dry benzene*3) was thermostated at 45°C. To this wasadded 2 ml of a 0.368 molar solution of potassium t-amylate in benzene.*4)After allowing the reaction mixture to stir for 45 min at 45°C under nitrogen,the solvent was removed from the neutral reaction mixture by rotary evaporationat room temperature, and the residual oil extracted with chloroform/water.The dried (MgS04) chloroform extracts were concentrated by rotary evaporationat ca. 40°C, and the resulting oil filtered through 5g silicagel (CHCI3/CH2CI2 =1:1) and crystallized from chloroform/hexane. The crystalline product was driedfor 48 hr at 58°C and 0.01 mm to yield 224 mg (46%) of the starting material(11), mp 173°-174°C.

IR (CHC1„) Identical to IR of the analyzed product.

NMR (CDClo) S = 2.42 (s, 6H), 4.73 (s, 4H), 5.58 (s, 2H),HA 100 7.20-8.10 (m, 16H) ppm.

The combined water extracts were evaporated to dryness by rotary evaporation

*1) p-Toluidine hydrochloride, purum, Fluka AG.*2) The nmr was identical to that given by L. Tenud [ 16 ].*3) Benzene, distilled once over NaH and once over LiAlH4.*4) Potassium t-amylate prepared by adding t-amyl alcohol to a suspension of

potassium in refluxing benzene.

- 53 -

at ca. 40 C, and the residual solid dried over phosphor pentoxide at reduced

pressure (0.01 mm) during 12 hr : 262 mg. The salt (4) was separated from (7)by dissolving the latter in 6 ml methylene chloride. Removal of the solvent fromthe methylene chloride solution by rotary evaporation gave 151 mg of (7); to thiswas added 100 mg (0. 76 mmol) trimethyloxonium tetrafluoroborate and 10 mlmethylene chloride and the heterogeneous reaction mixture stirred for 19 hr atroom temperature under nitrogen. Filtration, followed by washing of the diluted

(with ca. 25 ml methylene chloride) reaction mixture with ice-water till the

washings were neutral, and concentration of the dried (MgS04) methylene chlorideextract at reduced pressure provided an oil. This was filtered through 5g sili-

cagel (CHCI3/CH2CI2 =1:1) and crystallized from benzene/hexane: 78 mg (30%)of (8). A second crystallization gave 52 mg, mp 133°-134°C.

IR (CHClg) Identical to IR of the analyzed product.

NMR (CDCI3) 6= 2.41 (s, 3H), 3.67 (s, 3H), 6.08 (s, 1H), 6.60 (s, 1H),HA 100 7.14 - 8.13 (m, 8H) ppm.

The in methylene chloride insoluble salt (4), 118 mg, was dissolved in 2 ml hotwater and 50 mg (0.35 mmol) of p-toluidine hydrochloride in 1 ml water (acidifiedwith 3 drops of 0.1 n HC1 solution) added. The crystals which separated on

standing at room temperature were filtered: 94 mg (30.2%) of (12), this wasrecrystallized from methanol/water and dried over phosphor pentoxide at roomtemperature and 0.01 mm for 19 hr. Melting point 195°-197°C.

NMR (CF3COOH) S= 2.34 (s, 3H), 2.43 (s, 3H), 5.17 (s, 2H),HA 100 7.0 - 8. 80 (s+m, 15H) ppm.

(^VS°2^0 ^yS°3M+ f^Y-S°3CihKX

CH2 CH2J

Ts

(10) (7) (8)

1.6.1. ca. 1.0 mol equiv NaH/sulfolane/45°C/2 hr/c0 =0.08 molar

To a stirred solution of 150 mg (0.322 mmol) of benzyl-(o-iodomethoxysulfonyl)-p-tolylsulfone (10) in 4 ml sulfolane, *1) maintained at 45°C (thermostat), wasadded 14.3 mg of sodium hydride (55-60% suspension in mineral oil).*^) The

*1) Sulfolane, purum, Fluka AG, distilled once over KOH, twice over CaH2,bp 115°C (0.7mm).

*2) Sodium hydride, 55-60% suspension in oil, purum, Fluka AG.

- 54 -

formation of gas bubbles on addition of sodium hydride persisted for roughly0.5 hr, and the yellow reaction mixture became neutral towards litmus paperwithin two hours of reaction time. This was then poured on ice-water andextracted with chloroform (3 x 30 ml CHCI3, 3 x 10 ml H2O). The combinedchloroform extracts were dried (Na2S04) and the solvent removed at reduced

pressure and ca. 40°C. Removal of the sulfolane from the residue by distillation

(130°C/0. 5 mm) yielded 51 mg of an oil which was crystallized from benzene/hexane: 37.5 mg (25%) of the starting material (10), mp 103. 5°C.

IR (CHCI3) Identical to IR of the analyzed product.

NMR (CDClJ £>= 2.45 (s, 3H), 4.85 (s, 2H), 5.85 (s, 2H),A60 7.21 - 8.24 (m, 8H) ppm.

The combined water extracts were concentrated by rotary evaporation at ca.

40°C, and the sulfolane removed by distillation (130°C/0.5 mm) to afford 122 mgof a solid. To this was added 55 mg (0.68 mmol) trimethyloxonium tetrafluoro-borate and 10 ml dry methylene chloride. The heterogeneous reaction mixturewas stirred for 17 hr at room temperature, under nitrogen. The methylenechloride solution was filtered, diluted with ca. 20 ml methylene chloride andwashed with ice water till neutral. The methylene chloride extract was dried

(Na2S04) and concentrated by rotary evaporation to afford an oil which wascrystallized from benzene/hexane to provide 47.0 mg (36.2% with respect to(10)) of oc-phenylethenyl-(o-methoxysulfonyl)-p-tolylsulfone (8), m.p. 133°C.

IR (CHClJ 3020 w, 2958 w, 1598 m, 1568 w, 1492 w, 1472 w, 1450 w,1435 w, 1364 s, 1318 s, 1304 s, 1290 m, 1264 w, 1181 s,1150 s, 1135 m, 1119 w, 1101 m, 1081 s, 1056 m, 1019 w,990 s, 885 w, 825 m, 811 m cm"1.

NMR (CDC1„) 6= 2.46 (s, 3H), 3.72 (s, 3H), 6.14 (d, J = 1, 1H),A 60 6.65 (d, J=l, 1H), 7.20-8.20 (m, 8H) ppm.

(Small impurity < 4% at 3.78 and 4. 88 ppm, which maybedue to (1)).

1.6.2. 1.0 mol equiv KO-t-Am/sulfolane/45°C/40 min/c0 =0.08 molar

A solution of 150 mg (0.322 mmol) of benzyl-(o-iodomethoxysulfonyl)-p-tolyl-sulfone (10) in 4 ml sulfolane was thermostated at 45°C. Under stirring, 0.67 mlof a 0.48 molar solution of potassium t-amylate in benzene was quickly addedand the reaction mixture allowed to stir for 40 min at 45°C, during which itbecame neutral towards litmus paper. This was then poured on ice-water andextracted with chloroform (3 x 30 ml CHCI3, 3 x 10 ml H2O). The chloroformextracts were combined, dried (Na2S04) and concentrated at reduced pressure.The sulfolane was removed from the oily residue by distillation at 125°C and0.01 mm. 79 mg of an oil was obtained which was filtered through 6 g silicagel(CHCI3/CH2CI2 =1:1) and crystallized from benzen/hexane: 67 mg (45%) ofbenzyl-(o-iodomethoxysulfonyl)-p-tolylsulfone (10), mp 104°C.

IR (CHCU) Identical to IR of the analyzed product.

- 55 -

NMR (CDC1,) o= 2.44 (s, 3H), 4.82 (s, 2H), 5.81 (s, 2H), 7.18- 8.17A 60 (m, 8H) ppm.

The water extracts were combined and concentrated by rotary evaporation at

ca. 40°C, sulfolane removed by distillation (125°C/0.01 mm), and the solidresidue (101 mg) methylated with 45 mg (0.31 mmol) of trimethyloxonium tetra-fluoroborate in 5 ml methylene chloride during 21 hr at room temperature. The

reaction mixture was filtered and the methylene chloride solution washed with

ice-wafer till neutral. The solvent was removed from the dried (Na2SC>4)methylene chloride extract to yield 74 mg of an oil, which was filtered through

silicagel (CHCI3/CH2CI2 =1:1) and recrystallized five times from benzene/hexaneto afford 12.0 mg (10.6%) of the methylsulfonester (8), mp 134°-135°C.

IR (CHC1,) Identical to that of the analyzed product.

NMR (CDC1„) 6 = 2.45 (s, 3H), 3.72 (s, 3H), 6.14 (s, 1H), 6.63 (s, 1H),HA 100

J7.20-8.13 (m, 8H) ppm.

1.6.3. 1.0 mol equiv KO-t-Am/benzene/45°C/40 min/c0 = 0.02 molar

1 ml of a 0.368 molar solution of potassium t-amylate in benzene was added to

a stirred solution of 171.6 mg (0.368 mmol of benzyl-(o-iodomethoxysulfonyl)-p-tolylsulfone (10) in 18.4 ml anhydrous benzene*!) maintained at 45°C. After

allowing the reaction mixture to stir for 40 min under nitrogen, the solvent wasremoved by rotary evaporation at room temperature. The residue was extracted

with chloroform/water. The chloroform extracts were dried (Na2SC>4) and

evaporated at reduced pressure to afford 83 mg of an oil, which was crystallizedfrom benzene/hexane: 73 mg (42.5%) of the starting material (10), mp 104°C.

IR (CHCI3) Identical to the IR of the analyzed product.

NMR (CDCL,) 6= 2.43 (s, 3H), 4.79 (s, 2H), 5.80 (s, 2H),A60 7.16-8.12 (m, 8H) ppm.

The water extracts were evaporated to dryness by rotary evaporation at ca.

40°C, and dried for 15 hr at room temperature and 0.001 mm. 20 ml methylenechloride was added to the dried solid (98 mg) and the resulting solution filteredto remove undissolved material (KJ). The filtrate was evaporated to dryness byrotary evaporation to afford 65 mg of a solid. To this was added 50 mg (0.34mmol) trimethyloxonium tetrafluoroborate and 5 ml methylene chloride. After16 hr of stirring under nitrogen, the reaction mixture was filtered, diluted with

methylene chloride and washed with ice-water till neutral. The methylene chlo¬ride extract was dried (Na2SC>4), concentrated at reduced pressure and the oilyproduct crystallized from benzene/hexane to give 28 mg (21.6%) of Of-phenyl-ethenyl-(o-methoxysulfonyl)-p-tolylsulfone (8). A second crystallization provided17 mg, m.p. 133°-134°C.

IR (CHClJ Identical to the IR of the analyzed product.

*1) Benzene, distilled twice over lithium aluminium hydride.

- 56 -

NMR (CDCU) &= 2.41 (s, 3H), 3.68 (s, 3H), 6.09 {s, 1H), 6.61 (s, lH),HA 100 7.18-8.19 (m, 8H) ppm.

1.7. Reaction of benzyl-(o-methoxysulfonyl)-p-tolylsulfone (1) with

^otessJumj^butoxJde_j^ju^Ifolane_

Ts Ts

(1) (2) (13)

To a thermostated (45 C) and stirred solution of 193 mg (0.567 mmol) benzyl-(o-methoxysulfonyl)-p-tolylsulfone (1) in 7.1 ml sulfolane (co=0.08 molar) wasadded 1 ml of a 0.567 molar solution of potassium t-butoxide in monoglyme.The yellow colour of the solution formed upon addition of the base disappearedwithin 10 min and the solution was neutral towards litmus paper. After stirringfor a further 30 min, the reaction mixture was poured on ice-water and extractedwith chloroform.

The chloroform extracts were dried (Na2S(>4) and concentrated by rotary eva¬poration. The residue yielded, on removal of sulfolane (130°C/0.3 mm), 5 mg ofan oil which was not further characterized. On concentration of the water extracts

by rotary evaporation and removal of sulfolane (130°C/0.3 mm) 204 mg of a whitesolid was obtained.

NMR (CF,COOH) 6= 1.85 (d, J=7, 92.5% of 3H, C-CH3), 2.54 (s, 3H, 100%,T60 Ph-CH3), 5.32 (s, 7.1% of 2H, -CH2-, desmethyl compound

(4, M+=K+)), 5.93 (q, J=7, 92.9% of 1H), 7.34 - 8.20 (m,8H) ppm.

59 mg (0.416 mmol) p-toluidine hydrochloride in 2 ml water was added to a hotsolution of 148 mg of the white solid in 1 ml of water (acidified with three dropsof 0.1 n hydrochloric acid). The crystalline derivative (13), which separated oncooling, was filtered and dried for 2 hr at 50°C and 11 mm. 151 mg (86%) of(13), mp 242°-244°C.

NMR (CF3COOH)*1) S= 1.80(d, J=7, 3H), 2.43 (s, 3H), 2.50 (s, 3H),A60

°

5.91 (q, J=7, 1H), 7.27-8.84 (s+m, 12H) ppm.

*1) The nmr was identical to that given by L. Tenud [ 16 ].

- 57 -

1.8. Detection of the intermediates in the reaction of (1) with 0.5

KO-t-Bu in sulfolane

H)mol equiv

so^0 SOgM+

CH2

Ts

(1)

ITs

(3)

SCH-CH3

Ts

(2)

'CH,

Ts

(4)

0.5 ml of a 0.567 molar solution of potassium t-butoxide in monoglyme was

added to a stirred and thermostated (45°C) solution of 193 mg (0.567 mmol)benzyl-(o-methoxysulfonyl)-p-tolylsulfone (1) in 7.1 ml sulfolane. After stirringfor 10 min under nitrogen, the reaction mixture was poured on ice-water and

extracted with chloroform (3 x 30 ml CHC13, 3 x 10 ml H2O).The combined chloroform extracts were dried (Na2S04), concentrated by rotaryevaporation at ca. 40°C and the sulfolane removed from the residual oil bydistillation (125°C/0.1 mm) to yield 80 mg of an oil.

NMR (CDCk)

A60J

1.65 (d,J=7,48.6% 3H)2.43 (s, 98.9% 3H)3.77 (s, 100% 3H)4.91 (s, 50% 2H)5.39 (q,J=7,46.6% 1H)7.28-8.28 (m, 8H)

C-CHL of (3)

PI1-CH3 of (1) and (3)O-CH3 of (1) and (3)-CH2- of (1)-CH- of (3)

aromatic protons of (1) and(3).

The water extracts were combined and evaporated by rotary evaporation at ca.40°C and the sulfolane removed by distillation (125°C/0.1 mm) to yield 126 mgof a white solid.

NMR (CF„COOH)

A606

*2)1.82 (d,J=7, 47.9% 3H)2.43 (s, 100% 3H)3.88 (s, TO% 3H)5.32 (s, 51.4% 2H)5.95 (q,J=7, 46.8% 1H)7.32-8.34 (m, 8H)

C-CH, of (2)Ph-CH3 of (1), (2) and (4)O-CH3 of (1)-CH2- of (1) and (4)-CH- of (2)

aromatic protons of (1),(2) and (4).

Result: After 10 min reaction time, the reaction mixture contained 29.4% (1),22.1% (4), 19.9% (3) and 28.6% (2).

*1) When the reaction was carried out with 1 mol equivalent KO-t-Bu, and thereaction quenched after 1 min with 5 ml 0.1 n HC1 solution, and extracted with

chloroform/ice-water practically no (^ 8 mg) chloroform soluble productswere obtained, showing that the reaction was complete within this time and

rendering the detection of the intermediates under these conditions impossible.*2) The solid contained ca. 20% sulfolane, broad multiplets centred at 3.3 and

2.4 ppm. The singlet at 3. 88 ppm was assigned to the -O-CH3 of (1). Although(1) should have been extracted into the chloroform phase, the presence ofsulfolane could have caused slight amounts of (1) to be present in the waterextract.

- 58 -

2. Deuterated compounds

2.1. Methylene-d2-iodide [19]

*2)

A mixture of 300 g (1.13 mol) of freshly distilled methylene iodide' and 100 ml

of a 10% solution of sodium deuteroxide in deuterium oxide *3) was heated under

reflux, bath temperature 110°C, for 24 hr. The solution was cooled, the organiclayer separated and again heated under reflux with 70 ml of a fresh 10% solution

of sodium deuteroxide for 24 hr. This procedure was repeated with decreasingvolumes of the sodium deuteroxide solution (50, 50, 40, 40 ml). After the final

exchange *4) the organic layer was separated, dried (Na2S04), and distilled

through a Vigreux column (30 cm). 165 g (55%) of the light orange product,

methylene-dg-iodide, was obtained. Boiling point 58°-58.5°C (10 mm).

m (CHClg) 3000 w, 2303 w, 838 s cm"1.

MS(RMU/6D) 271 (1.5/M++1), 270 (100, M+), 269 (1.1), 268 (1.0),N.I. 200° 254 (9.0), 144 (1.7), 143 (73.5), 142 (1.5), 141 (5.0),

139 (5.0), 135 (3.0), 129 (1.8), 128 (2.0), 127(27.0).

Deuterium distribution:

m/e measured average of 3 measurements

269 1.48-1.54 1.5 % dj270 98.52-98.46 98.5 % d2

2.2. Fluoroiodomethane-d2 [18]

To 82 g (305 mmol) of methylene-d2-iodide, heated to 120°C, was added 68 g(155 mmol) of mercurous fluoride*5) in small portions under vigorous stirringover a period of ca. 3 hr. The low-boiling product was trapped in a spiralcondenser (cooled with dry-ice/isopropanol). Distillation of the raw productafforded 3.2 g (6.5%) of fluoroiodomethane-d2, bp 49°C.

MS(RMU/6D) 163 (1.0/M++1), 162 (80.0/M+), 161(1.0), 160(1.0),N.I. 200° 145 (1.9), 144 (3.1), 143 (7.5), 142 (0.8), 141 (0.8),

139 (2.0), 129 (1.5), 128 (1.5), 127 (7.5), 36 (3.0),35 (100), 34(2.0), 32(16.0), 31(2.9), 30(12.0),29 (1.0), 28(19.0), 20(2.1), 19(2.5).

*1) I am indebted to R. Hobi for his help during the preparation of thedeuterated compounds.

*2) Methylene iodide, purum, Fluka AG, distilled, bp 77°-78°C (9.5 mm).*3) 216 g of a 30% solution of NaOD in D20 (purum, Fluka AG, » 98% D)

were diluted with 400 ml of D20 (Eidg. Inst, fiir Reaktorforschung, Wiiren-lingen, > 99. 7% D).

*4) The amount of incorporated deuterium was monitored by IR (CHCI3):CH2J2: 1110 cm"1, CHDJ2: 1080 cm-1, CD2J2: 838 cm"1.

*5) Mercurous fluoride, The British Drug Houses Ltd.

- 59 -

Deuterium distribution:

m/e measured average of 2 measurements

162 98.34, 98.38161 1.62, 1.66

98.4 % d21.6 % dj

2.3. Trideuterotoluene [21]

To a vigorously stirred mixture of 30 g (460 mmol) zjnc dust, 45 ml (780 mmol)o-deuteroacetic acid*!), and 200 ml anhydrous ether *^) maintained at 3°C wasadded 20 g (100 mmol) of benzotrichloride*3) in 80 ml ether over a period of10 hr. The reaction mixture was allowed to stir at 3°C for 14 hr. After theaddition of 200 ml water, the solution was filtered, to remove excess zinc, andthe ethereal solution washed three times with 100 ml portions of water, twotimes with 100 ml portions of a 10% solution of NaHC03 and finally two timeswith 100 ml portions of water. The ether extract was dried (Na2S04), and theether removed by distillation at atmospheric pressure. The crude product was

distilled, at ca. 530 mm. Redistillation over sodium at atmospheric pressuregave 3.28 g (34.5% with respect to benzotrichloride) *4) of trideuterotoluene,bp 109°-111°C, n2°°=1.4944.

IR (CHCU 3085 m, 3060 m, 3005 m, 2210 w, 21