Synthesis and chemistry of enantiomerically pure 10,11-dihydrodibenzo[b,f] thiepines

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www.rsc.org/obc | Organic & Biomolecular Chemistry

Synthesis and chemistry of enantiomerically pure

10,11-dihydrodibenzo[b,f ]thiepines

Paul Wyatt,* Andrew Hudson, Jonathan Charmant, A. Guy Orpen and Hirihattaya Phetmung

Received 23rd November 2005, Accepted 14th March 2006

First published as an Advance Article on the web 3rd May 2006

DOI: 10.1039/b516606c

Several chiral thiepines were efﬁciently constructed using sulfur diimidazole in combination with a

variety of bislithiated carbon fragments. The sulfur atom in these thiepines is found to be unusually

unreactive compared to diphenylsulﬁde.

Synthesis

Introduction

The strategy for the synthesis of thiepines is the same as that used

The dibenzothiepine is an important substructure within many

biologically active compounds. These include isoﬂoxythiepine

which is a potent neuroleptic¹and thiepine 1, which has shown

promising antidepressant activity.²We have communicated the

synthesis of optically pure seven membered sulfur heterocycles –

thiepines.³We now report the synthesis of a variety of thiepines in

full as well as reactions that were attempted with these compounds.

in the synthesis of corresponding phosphepines.⁸The syntheses

of compounds 3 to 8 have been reported before in that context.

In brief, the overall synthesis involves the formation of a stilbene

such as diﬂuorostilbene 2 which is then dihydroxylated, protected

(Scheme 2) and a double lithiation performed before ring closure

on electrophilic sulfur (see Scheme 4). The only carbon–carbon

bond formed in the synthesis is in making the stilbenes.

There are several methods for the formation of thiepines

and many include a carbon–carbon bond formation in the ring

forming step. Hence an intramolecular acylation reaction⁴or

double Knovenagel condensation⁵have been used (Scheme 1) as

has ring expansion⁶and other methods.⁷Our strategy involves

the formation of a carbon–sulfur bond in the ring forming step

with both carbon–sulfur bonds being made in the same reaction

(see Scheme 4).

Scheme 2

We have previously used low-valent titanium made from TiCl₃

for this step⁹and have also used the combination of titanium

powder and trimethylsilyl chloride,¹⁰but a much more convenient

and cost-effective method was a medium-scale Wittig reaction.¹¹

The only poor Wittig reaction was in the formation of the

tetraﬂuorinated stilbene (which was reacted on to diether 11)

which was formed in only 21% yield. The equilibration of the

mixture of cis- and trans-stilbenes into trans-stilbene was achieved

using iodine and sunlight and proved most convenient.† We were

thus able to make trans-stilbenes in 40 gram batches.

Compounds 3–11 were prepared by standard methods from

the corresponding diols with a view to constructing a range of

thiepines (Fig. 1).

Lithiation of compounds

The lithiation of the compounds was achieved using either

halogen–lithium exchange or ortho-lithiation. The excellent regio-

selection of diﬂuoride 3 at the 2-position rather than the 4-

position was reﬂected in the lithiation of the related MOM ether

Scheme 1 Formation of thiepines.

† The one day of equilibration noted in the reference referred to Californian

sunlight which translated to seven days of sunlight in Bristol.

School of Chemistry, Cantock’s Close, Bristol, UK BS8 1TS

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was most reliable when it came to lithiation – diether 3. The usual

suspects of elemental sulfur, thionyl chloride, sulfuryl chloride

and SCl₂itself were tried. Although elemental sulfur did work to

a degree, giving the desired product in 10% yield, it also gave rise

to a host of other compounds and this lack of selectivity meant it

was not a useful reagent. Of all these reagents, the least bad results

were obtained with sulfuryl chloride which gave sulfone 12 in 19%

yield (Scheme 3).

Scheme 3

The main by-product was the chlorinated diether 13 (39%

yield). Given that sulfuryl chloride is a chlorinating agent this

was scarcely a surprise but it set us on the road to success. Clearly

a chloride leaving group was not suitable and we moved to using

an imidazole anion as the leaving group.

Sulfur diimidazole was readily prepared by the method of

Degen by the combination of SCl₂and TMSimidazole.¹²The

SIm₂precipitates from hexane solution and could be washed with

hexane and then used immediately as a solution in THF. It is not

especially soluble and so for larger scale reactions it was added

as a ﬁne suspension in THF. We were pleased to ﬁnd reaction of

lithiated 3 with SIm₂gave the thiepine 14 in 48% yield (Scheme 4).

Given the success of sulfuryl chloride over sulfur chloride we also

prepared SO₂Im₂(17) and SOIm₂but, in reaction with lithiated

3, these electrophiles gave us only starting material 3. If there is a

reaction at all with these two electrophiles perhaps the proton at

Fig. 1 Substrates for lithiation.

10. This regioselection was also present with the acetal 4 and

silyl ether 5 however, although the degree of bislithiation of

diether 3 was 96% (an improvement over the previously-reported

84%) it was 43% with silyl ether 5 and only 6% with acetal 4.

Unsurprisingly, lithation of the tetraﬂuorinated diether 11 was

completely regioselective for the 4-position (instead of the 2-

position) and was not useful for ring synthesis. The degree of

lithiation was detected in each case by quenching with methyl

iodide and analysing the degree and position of methylation.

Hence lithiation is at least as good as the ﬁgures indicated above

because methylation, although excellent, will not be quantitative.

All the bromine containing compounds (6–9) were lithiated with

four equivalents of tert-butyl lithium (two per reactive site) and

lithiated as expected.

The sulfur transfer reagent

During the early stages of the work we were concerned with

introducing sulfur by any means possible and at any oxidation

level. Experiments were conducted using the compound which

Scheme 4

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position-2 is being removed – after all, benzenesulfonylimidiazole

(16) lithiates at this position (Fig. 2).¹³

reactions of its chiral counterpart. In fact, we were to ﬁnd that

the behaviour of the precursor to the achiral thiepine (25) and

precursors to chiral thiepines (8 and 3) was radically different.

Reaction of lithiated bibenzyl 25 with sulfur diimidazole gave

only a 3% yield of simple thiepine 26. And this was on the best

occasion – usually it gave no thiepine at all. Given the success

of SIm₂with the other substrates we found this extraordinary;

particularly when heterocycles with other electrophiles have been

made with this substrate.¹⁵However, the result was entirely

reproducible. It is fortunate that we obtained this negative result

after we had already done a successful reaction with a chiral

substrate. It would have been tempting indeed to conclude that

SIm₂was ineffective as a double sulfur electrophile for use with

organolithium reagents and abandoned it. We were to ﬁnd on

other occasions that the reactivity of dibromide 25 did not mimic

the reactivity of chiral dibromides in the least.

Fig. 2 Alternative reagents to sulfur diimidazole.

In trying to improve on sulfur diimidazole as a way to introduce

sulfur, we investigated similar reagents (made in the same way

as SIm₂) but matters were not improved using sulfur ditriazole

18 (21% yield of thiepine 14) or sulfur bisbenzotriazole 19 (11%

yield). Hence we settled upon SIm₂as the reagent for all other

thiepine formation reactions. Using SIm₂a total of six novel chiral

thiepines from precursors 3 and 6–10 were prepared (Table 1).

Interestingly, treatment of thiepine 22 with a combination of

ethylene glycol and tosic acid (in an attempt to remove the acetal

function) allowed entry into the pharmaceutically important

thioxanthene ring system 24.¹⁴The mechanism presumably in-

volves a 1,2-sigmatropic shift to contract the seven membered ring

with the resulting aldehyde being trapped by the ethylene glycol.

NMR spectra

Thiepine 14 is C₂symmetrical and this is evident in the NMR

spectrum – a singlet is visible for the two benzylic protons and for

the two methyl groups. This symmetry is destroyed upon oxidation

to the sulfoxide. The difference in chemical shift between the two

diastereotopic benzylic protons of the sulfoxide is remarkable. To

the uninitiated it might appear that the expected AB quartet

is missing. In fact one of the doublets is so far downﬁeld it

masquerades as an aromatic signal (Fig. 3).

The X-ray crystal structure of thiepine 14 has been revealed

before.³The two benzene rings are not in the same plane but angled

so as to form a ‘butterﬂy’ arrangement (Fig. 4). They are twisted

so that (viewed from the sulfur atom) we see one leading edge

is slightly above the other. The anti-periplanar nature of the two

homotopic benzylic protons can also be seen. From the ¹³C satellite

Formation of achiral thiepines

We imagined, incorrectly as it turned out, that the achiral thiepine

26 would be easy to synthesise and serve as a useful model for

1

peaks detected in the H NMR spectrum we found the coupling

Table 1 New thiepines

Starting material

R¹

X

Equivalents of butyl lithium

E

Y

Yield

Compound

3

Me

OCH₂OMe

Me

SiMe₂Bu

CMe₂

OCH₂OMe

3-F

2-Br

2.2eq sec-BuLi

2.36 eq sec-BuLi

4 eq tert-BuLi

SIm₂

SCl₂

SIm₂

4,6-F

H

48%

3%

37%

38%

19%

12%

36%

14

20

15

21

22

23

3

10

8

t

7

6

9

H

Reagents and conditions: i, conditions in Table 1; ii, SIm₂.

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(which is on the other side of the ring). This accounts, perhaps,

for the dramatically different environments of the diastereotopic

protons. Fig. 5 shows only one of the two independent molecules

of sulfoxide 27.

Reactivity of the thiepines

Because the thiepines are C₂symmetrical, the two lone pairs on the

sulfur atom are homotopic and there is thus no concern over the

formation of diastereomers in any reaction. A reaction of thiepine

14thatcouldbeconductedreadilywasitsoxidationtosulfoxide27.

This was done in quantitative yield with mCPBA. Usually, the oxi-

dation of sulﬁdes to sulfoxides has to be conducted carefully to

avoid over-oxidation to the sulfone.¹⁶This was not the case here –

sulfoxide 27 could not be oxidized to the sulfone even under the

most forcing conditions. This lack of reactivity was a taste of things

to come as the sulfur atom of thiepine 14 was to prove remarkably

unreactive and known reactions of Ph₂S, which we could repeat

with ease, failed. Since most of our ﬁrst reactions were conducted

with thiepine 14, we initially considered that this might be due to

the electron-withdrawing nature of the ﬂuorine atoms. However,

reactivity was not improved with the analogous thiepine 15.

Yamamoto’s tetrabutylammonium salt of chloramine T§,¹⁷

worked nicely for us to turn diphenyl sulﬁde into its corresponding

tosylsulﬁmide. When this was treated with concentrated H₂SO₄,

the free sulﬁmide was produced in 93% yield (Scheme 5).¹⁸

However reaction of thiepine 15 and the salt of chloramine T was

not successful. Either there was no reaction at all or, under more

forcing conditions, destruction of the thiepine. It was a similar

Fig. 3 Detail of two NMR spectra contrasting homotopic and di-

astereotopic signals from benzylic protons.

=

story for the reaction of thiepine 15 with PhI NTs in the presence

of CuOTf.^{19, 20}Methylation failed with MeOTf,²¹MeI/AgBF₄²²or

Me₃OBF₄.²³

Fig. 4 ORTEP drawing of thiepine 14; 50% probability ellipsoids.‡

constant between these hydrogen atoms was 8.6 Hz. With sulfoxide

=

27, a view from the front (S O to backbone, Fig. 5a) shows a

slightly more pronounced butterﬂy arrangement and a view from

=

the side (Fig. 5b) shows how the S O bond bends back across

the seven membered ring and is in reasonably close proximity

˚

(2.3 A) to one of the benzylic hydrogen atoms but not the other

‡ Crystal data for (−)-14. Single crystals of 14 were grown from petroleum

ether (bp 40–60 ^◦C). C₁₆H₁₄F₂O₂S, M = 308.34, orthorhombic, a =

◦

˚

7.839(2) A, b = 11.645(2) A, c = 15.476(2) A, a = 90 , b = 90 , c =

Scheme 5 Reactions of Ph₂S and Ph₂SO that fail with thiepines.^24,25

◦

3

˚

90 , V = 1412.7(4) A , T = 173(2) K, space group P2₁2₁2₁, Z = 4, l =

0.253 mm⁻¹; 9132 reﬂections collected, 3223 [R_int= 0.0336] independent

reﬂections, R₁= 0.0264 [I > 2r(I)], wR₂= 0.0644. With a Flack parameter

of 0.02(6), the absolute stereochemistry is clearly established and is in

accord with the conﬁguration of the starting material. CCDC reference

number 290626. For crystallographic data in CIF or other electronic

format see DOI: 10.1039/b516606c

Mesitylenesulfonylhydroxylamine (MSH) 28 was prepared

from ethyl (O-mesitylenesulfonyl)acetohydroxamate (Scheme 5).²⁴

§ Reaction with normal chloramine T fails.

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Fig. 5 ORTEP drawings of thiepine oxide 27; 50% probability ellipsoids.¶

Diphenyl sulfoxide reacted with MSH 28 to give the aminated

product in 78% yield²⁵(Scheme 5) but thiepine oxide 27 did not

react.

to react with benzaldehyde or dicyanoethylene). Reaction with

tetracyanoethylene lead to the consumption of the ylide. Thiepine

15 was produced in the reaction and the formation of cyclopropane

31 suggested.²⁸

The reaction of sulﬁdes with diazo compounds to give sulfonium

ylides directly is a well known process and, with electron withdraw-

ing groups present to stabilise the negative charge, these ylides can

be stable isolable compounds.^{26, 27}Dimethyldiazomalonate 29 was

prepared by the reaction of dimethylmalonate with sodium azide.

Thiepine 15 was reacted with the diazomalonate in the presence of

5% Rh₂(OAc)₄to give ylide 30 in 75% yield (Scheme 6). The ylide

could be puriﬁed by column chromatography. Thiepine 15 also

reacted with dibenzyldiazomalonate under the same conditions to

give the corresponding ylide (32) in 63% yield.

Conclusions

Although sulfur diimidazole has been used a great deal for

the construction of, for instance, symmetrical trisulﬁdes²⁹it has

not previously been reported as a reagent in combination with

organolithium reagents. Clearly it is a very suitable reagent for

such reactions. The chiral thiepines we have investigated have very

unreactive sulfur atoms and we thus turned our attention to the

chiral disulﬁdes³⁰(dithiocines) and trisulﬁdes (trithionines) that

could be made using the same carbon backbone. Our ﬁndings in

this area will be reported in due course.

Experimental

General

Scheme 6

Flash chromatography was performed using Merck 9385 Kieselgel

60 according to Still et al.³¹Thin layer chromatography (TLC) was

performed using commercially available glass plates coated with

Merck silica Kieselgel 60F₂₅₄. The compounds were visualised

by a Mineralight UV lamp or by dipping into a potassium

permanganate solution in aqueous sodium hydroxide and heating

with a hot air gun. High performance liqiud chromatography

(HPLC) was performed using a Dynamax prepacked silica column

(25 cm × 21.4 mm internal diameter), a Gilson model 303 pump

and a Dynamax Rainin UV detector at 254 nm.

The ylide was stable to reﬂux conditions in dichloromethane

or toluene for several days. Unfortunately, the reactivity of

the stabilised sulfonium ylide is very limited and restricted to

exceptional Michael acceptors (unsurprisingly, the ylide failed

¶ Crystal data for (−)-27. Single crystals were grown from petroleum

ether (bp 40–60 ^◦C). C₁₆H₁₄F₂O₃S, M = 324.33, triclinic, a = 7.986(3)

◦

˚

A, b = 8_◦.7928(16) A, c = 11.254(3) A, a = 89.389(19) , b = 82.07(2) , c =

3

˚

67.49(2) , V = 722.3(4) A , T = 173(2) K, space group P1, Z = 2, l =

0.256 mm⁻¹; 7358 reﬂections collected, 5913 [R_int= 0.0289] independent

reﬂections, R₁= 0.0432 [I > 2r(I)], wR₂= 0.0912. With a Flack parameter

of −0.06(9), the absolute stereochemistry is clearly established and is in

accord with the conﬁguration of the starting material. CCDC reference

numbers 290627. For crystallographic data in CIF or other electronic

format see DOI: 10.1039/b516606c

Melting points were determined on a Gallenkemp melting point

apparatus and are uncorrected. Infra red spectra were recorded

on a Perkin Elmer 141 spectrophotometer as liquid ﬁlms or as

solutions in dichloromethane on sodium chloride plates. Optical

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rotations were recorded on a Perkin Elmer 241 MC polarimeter

irradiating with the sodium D line (k = 589 nm) and [a]_Dare given

in units of 10⁻¹deg cm²g⁻¹.

Protons and carbons which form part of a ring system are

numbered according to the numbering system indicated in Fig. 7.

The exo-cyclic portion is assigned using the labels ipso, ortho,

meta and para. In an instance when a compound contains an

exo-cyclic ring and it is clear which portion an atom belongs

to, but not the exact position, then the label exo is used in the

assignment. In addition if the spectroscopic data relating to, for

example, positions “1” and “9” are homotopic or enantiotopic

(Fig. 7), only position “1” is denoted in the assignment.

When coupling constants refer to the coupling between two

protons, or between two unassigned nuclei, then no subscripts

follow “J”. In NMR spectra of mixtures of compounds, peaks

assignable to each compound are denoted. All solids were white

and all oils colourless unless otherwise stated.

All nuclear magnetic resonance (NMR) spectra were recorded

as solutions using tetramethylsilane as the internal reference on a

Jeol GX270 MHz, GX400 MHz or k300 MHz spectrometer.

All mass spectra were recorded on a Fisons Autospec mass spec-

trometer and were determined by electron impact (EI), chemical

ionisation (CI) or fast atom bombardment (FAB) techniques.

When using alkyl lithium reagents, best results were obtained

using Hamilton 1700 series gas-tight Teﬂon tipped microsyringes

(<1000 ll), which did not require lubrication, and Hamilton

1700 series gas-tight Teﬂon tipped syringes (>1 ml) lubricated

R

ꢀ

with poly(dimethylsiloxane) 200 ﬂuid with a viscosity of 100

centistokes. All solvents were distilled before use; dry solvents were

purchased from Fluka. Distilled 40–60 ^◦C petroleum ether was

Stilbenes

◦

used for ﬂash chromatography and distilled 60–80 C petroleum

ether for recrystallisations.

(3-Fluorobenzyl)triphenylphosphonium

bromide. 3-Fluoro-

benzyl bromide (19.5 ml, 0.159 mol) was dissolved in DMF

(87 ml). Triphenylphosphine (45.8 g, 0.175 mol) was added to the

solution and the reaction vigorously stirred at room temperature

overnight. The mixture was poured into toluene (200 ml) and

the suspension ﬁltered. The solid product was dissolved in

dichloromethane (150 ml) and reprecipitated by the addition of

diethyl ether (200 ml). The precipitate was isolated by vacuum

ﬁltration to yield the phosphonium salt as a ﬁne powder (66.3 g,

Key to assignments

The notation used for aromatic protons and carbon assignments

is as follows: aromatic protons are referred to by their ring

position followed by “-ArH”. An illustration is provided with 3,3^ꢀ-

diﬂuorostilbene 2 (Fig. 6). The proton which is meta to both ﬂuo-

rine and the oleﬁnic substituent is referred to as 5-ArH. Aromatic

carbons are referred to in a similar manner. The carbon assignment

for diﬂuorostilbene 2 (Fig. 7) is: 163.1 (¹J_CF246.6, 3-ArC), 139.2

(³J_CF8.1, 1-ArC), 130.2 (³J_CF8.7, 5-ArC), 128.8 (⁴J_CF2.5, ArCH),

122.6 (⁴J_CF2.5, 6-ArC), 114.8 (²J_CF21.1, 2-ArC) and 112.9 (²J_CF

17.2, 4-ArC). The “C” in “ArC” is the numbered carbon within

that ring and not a carbon attached to the ring. Carbons outside

the ring are italicised when “Ar” is included in the assignment

e.g. 78.4 (⁴J_CF1.2, ArCH). If there is possible ambiguity as to

which proton or carbon the assignment refers to the appropriate

atom is italicised. When a carbon nucleus is observed to couple

to one other nucleus then it is not referred to as a doublet. Any

greater multiplicity is noted. In some cases quaternary carbons

were not observed in the ¹³C-NMR spectrum and hence have not

been included in the assignment.

◦

92.6%); mp >250 C (lit.,³²mp 309–310 ^◦C); d_H(300 MHz;

DMSO) 7.96–7.89 (3 H, m, ArH), 7.81–7.68 (12 H, m, ArH),

7.36–7.26 (1 H, m, ArH), 7.20–7.11 (1 H, m, ArH), 6.91–6.75 (2

H, m, ArH) and 5.34 (2 H, d, ²J_PH15.9, ArCH); m/z (FAB) 371

(M⁺, 100%).

E-3,3^ꢀ-Diﬂuorostilbene 2. Sodium metal (1.12 g, 48.7 mmol)

dissolved in dry ethanol (50 ml) was added to (3-ﬂuorobenzyl)-

triphenylphosphonium bromide (20.0 g, 44.3 mmol) in dry ethanol

(150 ml) under an argon atmosphere. After the exothermic

reaction was complete the solution was allowed to cool to room

temperature and was then added dropwise to the phosphonium

suspension. The mixture was warmed to 40 ^◦C and stirred at this

temperature for 0.5 h to produce a deep orange solution. After

allowing the reaction mixture to cool to room temperature 3-

ﬂuorobenzaldehyde (4.70 ml, 44.3 mmol), dissolved in dry ethanol

(40 ml), was added dropwise to the solution. The reaction was

heated to reﬂux and stirred at this temperature for 0.5 h and

then allowed to cool to room temperature before the dropwise

addition of concentrated hydrochloric acid (30 ml). The solution

was concentrated under reduced pressure, water (50 ml) was added

and the mixture extracted with toluene (3 × 100 ml). The combined

organic extracts were dried (MgSO₄) and concentrated under re-

duced pressure. The residue was puriﬁed by ﬂash chromatography,

eluting with petroleum ether, to yield a colourless oil.

Fig. 6 Diﬂuorostilbene assignments.

The oil was dissolved in hot heptane (100 ml) to which a

few small crystals of iodine were added until a strong violet

colour remained. The solution was exposed to direct sunlight

for seven days during which time the solid product crystallised

out of the solution. The suspension was ﬁltered and the crystals

washed with heptane (50 ml). The residue was puriﬁed by ﬂash

chromatography, eluting with petroleum ether, and recrystallised

from petroleum ether to yield the trans-stilbene as needles (6.93 g,

Fig. 7 Thiepine assignments.

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72.4%). This compound was also made by McMurry coupling

(methods A and B).

of stilbene 2. No attempt was made to isomerise the E : Z mixture.

The crude product was puriﬁed by ﬂash chromatography,

eluting with petroleum ether, and recrystallised from petroleum

ether to yield the trans-stilbene as needles (1.29 g, 11.4%); mp

133.5–135 ^◦C (from petroleum ether); m_max(CHCl₃)/cm⁻¹1624

(Ar), 1600 (Ar) and 1456 (Ar); d_H(300 MHz; CDCl₃) 6.74–6.62

(6 H, m, ArH) and 6.66 (2 H, s, ArCH); d_C(75.5 MHz; CDCl₃)

Method A. Anhydrous 1,2-dimethoxyethane (350 ml) was

added to titanium(III) chloride (25.0 g, 0.162 mol) under an argon

atmosphere. The suspension was heated to reﬂux and stirred at

this temperature for 1.5 h, the reaction was vigorously mixed

throughout using an overhead mechanical stirrer. The suspension

was allowed to cool to room temperature before dry copper sulfate

(3.10 g, 4.88 mmol) and zinc powder (40.7 g, 0.623 mol) were

added, the reaction heated to reﬂux and the suspension was stirred

at this temperature for a further two days. The reaction was allowed

to cool to room temperature, 3-ﬂuorobenzaldehyde (4.29 ml,

40.5 mmol) was added and the reaction heated to reﬂux and stirred

at this temperature for 18 h. The reaction mixture was allowed to

cool to room temperature, diluted with ethyl acetate (3 × 200 ml),

ﬁltered through a pad of Florisil and concentrated under reduced

pressure. The solid residue was dissolved in dichloromethane

and passed through silica. Recrystallisation from petroleum ether

yielded the trans-stilbene as hexagonal plates (3_◦.77 g, 86.2%); mp

86–87 ^◦C (from petroleum ether) (lit.,⁸mp 86–87 C); d_H(300 MHz;

1

3

163.1 (dd, J_CF248.2 and J_CF13.0, 3-ArC), 139.5 (t, J_CF9.9,

4

2

4

1-ArC), 130.3 (t, J_CF2.5, ArCH), 111.7 (dd, J_CF17.4 and J_CF

2

8.1, 2-ArC) and 103.2 (t, J_CF25.4, 4-ArC); d_F(282.65 MHz,

CDCl₃) −109.5 (t, J_HF8.2); m/z (CI) 253.0633 (MH⁺. C₁₄H₈F₄

3

requires 253.0640), 252 (MH⁺− H, 100%), 233 (MH⁺− HF, 31)

and 127 (ArCH₂, 22); and the cis-stilbene as ﬁne needles (1.07 g,

9.5%); mp 114–114.5 ^◦C (from heptane); m_max(CHCl₃)/cm⁻¹1623

(Ar) and 1597 (Ar); d_H(300 MHz; CDCl₃) 7.02–6.99 (4 H, m,

3

ArH), 6.99 (2 H, s, ArCH) and 6.74 (2 H, tt, J_HF8.7 and J 2.2,

1

3

4-ArH); d_C(75.5 MHz; CDCl₃) 163.3 (dd, J_CF247.6 and J_CF

13.1, 3-ArC), 139.7 (t, ³J_CF9.4, 1-ArC), 129.0 (ArCH), 109.4 (dd,

²J_CF17.4 and J_CF8.1, 2-ArC) and 103.5 (t, J_CF26.0, 4-ArC);

4

2

3

d_F(282.65 MHz, CDCl₃) −109.6 (t, J_HF8.7); m/z (EI) 252.0565

(M⁺. C₁₄H₈F₄requires 252.0565) and 232 (M⁺− HF, 51%).

4

CDCl₃) 7.33 (2 H, td, J 7.8 and J_HF5.7, 5-ArH), 7.27 (2 H, dt,

3

J 7.8 and 1.4, 6-ArH), 7.21 (2 H, ddd, J_HF7.8, J 2.5 and 1.4,

(2-Bromobenzyl)triphenylphosphonium

bromide. 2-Bromo-

3

2-ArH), 7.06 (2 H, s, ArCH) and 6.98 (2 H, tdd, J_HF7.8, J 7.8,

benzyl bromide (96.3 g, 0.385 mol) was reacted in a method

similar to that used in the synthesis of (3-ﬂuorobenzyl)-

triphenylphosphonium bromide. The product was dried under

vacuum to yield the phosphonium salt as a ﬁne powder (186 g,

2.5 and 1.4, 4-ArH); d_C(75.5 MHz; CDCl₃) 163.1 (¹J_CF246.6, 3-

ArC), 139.2 (³J_CF8.1, 1-ArC), 130.2 (³J_CF8.7, 5-ArC), 128.8 (⁴J_CF

2.5, ArCH), 122.6 (⁴J_CF2.5, 6-ArC), 114.8 (²J_CF21.1, 2-ArC) and

112.9 (²J_CF17.2, 4-ArC).

◦

94.3%); mp 163–168 C (from diethyl ether) (lit.,³³171–174 C);

d_H(300 MHz; CDCl₃) 7.99–7.90 (3 H, m, ArH), 7.80–7.54 (13 H,

m, ArH), 7.34–7.28 (2 H, m, ArH), 7.22–7.16 (1 H, m, ArH) and

5.21 (²J_PH14.5, ArCH); m/z (FAB) 433 (M⁺, 99%) and 431 (M⁺,

100).

Method B. Anhydrous 1,2-dimethoxyethane (350 ml) was

added to titanium powder (21.8 g, 0.454 mol) under an argon

atmosphere. Trimethylsilyl chloride (19.3 ml, 0.152 mol) was added

to the suspension, the reaction heated to reﬂux and vigorously

stirred for ﬁve days at this temperature using an overhead

mechanical stirrer. 3-Fluorobenzaldehyde (4.29 ml, 40.5 mmol)

was added to the suspension under reﬂux and the reaction stirred

at this temperature for a further 3 h. The suspension was allowed

to cool to room temperature. The same work up as previously

described in method A yielded the trans-stilbene as hexagonal

plates (4.84 g, 55.3%).

E-2,2^ꢀ-Dibromostilbene. (2-Bromobenzyl)triphenylphospho-

nium bromide (85 g, 0.166 mol) was reacted with 2-bromobenz-

aldehyde (17.6 ml, 0.151 mol) in a method similar to that used in

the synthesis of stilbene 2. The crude product was puriﬁed by ﬂash

chromatography, eluting with petroleum ether, and recrystallised

from petroleum ether to yield the trans-stilbene as needles (43.3 g,

78.1%).

In another experiment 2-bromobenzaldehyde (3.16 ml,

27.1 mmol) was reacted according to method A. The solid residue

was dissolved in dichloromethane and passed through silica.

Recrystallisation from petroleum ether yielded the trans-stilbene

as rectangular plates (3.33 g, 73.2%)_◦; mp 109–110 ^◦C (from

petroleum ether) (lit.,³⁴mp 108.0–108.5 C); d_H(300 MHz; CDCl₃)

7.69 (2 H, dd, J 7.6 and J 1.7, 3-ArH), 7.56 (2 H, dd, J 7.6 and 1.2,

6-ArH), 7.37 (2 H, s, ArCH), 7.30 (2 H, td, J 7.6 and 1.2, 4-ArH)

and 7.12 (2 H, td, J 7.6 and 1.7, 5-ArH); d_C(75.5 MHz; CDCl₃)

136.7 (1-ArC) 133.0, 130.0, 129.2, 127.6, 127.1 and 124.2 (2-ArC).

In another experiment 2-bromobenzaldehyde (3.16 ml,

27.1 mmol) was reacted in a similar way to method B used in the

synthesis of stilbene 2. The same work up as previously described

yielded the trans-stilbene as rectangular plates (2.01 g, 44.1%).

(3,5-Diﬂuorobenzyl)triphenylphosphonium bromide. 3,5-Di-

ﬂuorobenzyl bromide (10.0 g, 48.3 mmol) was reacted in a

method similar to that used in the synthesis of (3-ﬂuorobenzyl)-

triphenylphosphonium bromide. The product was dried under

vacuum to yield the phosphonium salt as a ﬁne powder (22.4 g,

98.8%); mp >250 ^◦C d_H(300 MHz; CDCl₃) 7.97–7.90 (5 H, m,

3

PPh₃), 7.82–7.70 (10H, m, PPh₃), 7.26 (1 H, tdd, J_HF8.7, J 4.7

and 2.3, 4-ArH), 6.70–6.64 (2 H, m, 2-ArH) and 5.27 (2 H, d, ²J_PH

1

16.0, ArCH); d_C(67.9 MHz; CDCl₃) 162.7 (dd, J_CF247.3 and

³J_CF4.1, 3 or 5-ArC), 135.9 (⁴J_CP2.6, para-ArC), 134.6 (³J_CP10.4,

meta-ArC), 132.9 (dd, ²J_CP18.3 and ³J_CF8.2, 1-ArC), 130.8 (²J_CP

12.3, ortho-ArC), 117.8 (¹J_CP86.2, ipso-ArC), 114.9 (m, 2-ArC)

2

and 104.7 (t, J_CF21.1, 4-ArC) and 27.5 (¹J_CP86.2, ArCH);

3

d_F(282.65 MHz, CDCl₃) −108.7 (t, J_HF8.7); d_P(121.6 MHz,

CDCl₃) 23.8; m/z (FAB) 389 (M⁺, 100%).

Diols and protection

E-3,3^ꢀ,5,5^ꢀ-Tetraﬂuorostilbene

and

Z-3,3^ꢀ,5,5^ꢀ-tetraﬂuoro-

stilbene. (3,5-Diﬂuorobenzyl)triphenylphosphonium bromide

(21.0 g, 44.7 mmol) was reacted with 3,5-diﬂuorobenzaldehyde

(5.82 g, 40.7 mmol) in a method similar to that used in the synthesis

(1R,2R)-1,2-Bis(3-ﬂuorophenyl)ethane-1,2-diol. (1R,2R)-1,2-

Bis(3-ﬂuorophenyl)ethane-1,2-diol was prepared by the reported

method⁸but was puriﬁed by ﬂash chromatography, eluting

2224 | Org. Biomol. Chem., 2006, 4, 2218–2232

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with petroleum ether–ethyl acetate, and recrystallised twice from

petroleum ether–ethyl acetate (70 : 30) to yield the diol as needles

(2.19 g, 95.4%); m_◦p 78–79.5 ^◦C (from petroleum ether–ethyl

acetate) (lit.,⁸79–80 C); [a]_D²²+ 103 (c 1.00 in CHCl₃) (lit.,⁸+ 112);

and recrystallised from petroleum ether–ethyl acetate (90 : 10) to

yield the diol as needles (404 mg, 73.4%). Characterisation data

were iden_◦tical to the enantiomerically pure compound except; mp

121–122 C (from petroleum ether–ethyl acetate) (lit.,³⁴118.5–

119.0 ^◦C).

3

4

d_F(282.65 MHz, CDCl₃) −112.8 (td, J_HF7.8 and J_HF6.2). The

400 MHz ¹H-NMR spectrum of the diol prior to recrystallisation

in comparison with a racemic sample, in the presence of Pirkle’s

reagent, indicated an enantiomeric excess of ≥99%.

(1R,2R)-1,2-Bis(3-ﬂuorophenyl)-1,2-dimethoxyethane

3.

was

3

prepared in the manner reported⁸but puriﬁed by ﬂash

chromatography, eluting with petroleum ether–ethyl acetate and

recrystallised from petroleum ether–ethyl acetate (90 : 10) to

yield the diether as needles (1.97 g, 97.9%); mp 87.5–88 ^◦C (from

(1RS,2RS)-1,2-Bis(3-ﬂuorophenyl)ethane-1,2-diol. 3,3^ꢀ-Di-

ﬂuorostilbene 2 (500 mg, 2.31 mmol) was reacted in a method

similar to that used in the synthesis of the above diol, except

quinuclidine was used instead of (DHQD)₂PHAL and the reaction

was stirred at room temperature throughout. The crude product

was puriﬁed by ﬂash chromatography, eluting with petroleum

ether–ethyl acetate, and recrystallised from petroleum ether–ethyl

acetate (90 : 10) to yield the diol as needles (452 mg, 78.1%). Data

were i_◦dentical to the optically pure compound except: mp 118–

118.5 C (from petroleum ether–ethyl acetate) (lit.,³⁵118–119 ^◦C).

◦

petroleum ether–ethyl acetate)(lit.,⁸88–88.5 C); [a]_D²²−48.2 (c

1.00 in CH₂Cl₂) (lit.,⁸−50.8) d_F(282.65 MHz, CDCl₃) −113.4 (td,

³J_HF8.4 and ⁴J_HF5.8).

(1R,2R)-1,2-Bis(3,5-diﬂuorophenyl)-1,2-dimethoxyethane

11.

(1R,2R)-1,2-Bis(3,5-diﬂuorophenyl)ethane-1,2-diol (190 mg,

0.664 mmol) was reacted in a method similar to that used in the

synthesis of diether 3. The crude product was puriﬁed by ﬂash

chromatography, eluting with petroleum ether, and recrystallised

from petroleum ether_◦to yield the diether as a powder (202 mg,

(1R,2R)-1,2-Bis(3,5-diﬂuorophenyl)ethane-1,2-diol. 3,3^ꢀ,5,5^ꢀ-

Tetraﬂuorostilbene (814 mg, 3.23 mmol) was reacted in a

method similar to that used in the synthesis of (1R,2R)-1,2-bis(3-

ﬂuorophenyl)ethane-1,2-diol. The crude product was puriﬁed by

ﬂash chromatography, eluting with petroleum ether–ethyl acetate,

and recrystallised from petroleum ether–ethyl acetate (80 : 20)

to yield the diol as ﬁne needles (861 mg, 93.2%); mp 103–

104.5 ^◦C (from petroleum ether–ethyl acetate); [a]²_D²+64.5 (c 1.00

in CH₂Cl₂); m_max(CHCl₃)/cm⁻¹3553 (OH), 3313 br (OH), 1626

(Ar) and 1600 (Ar); d_H(300 MHz; CDCl₃) 6.76–6.63 (6 H, m,

ArH), 4.62 (2 H, s, ArCH) and 2.68 (2 H, br s, OH); d_C(75.5 MHz;

CDCl₃) 162.9 (dd, ¹J_CF248.9 and ³J_CF12.4, 3-ArC), 143.4 (t, ³J_CF

96.8%); mp 54–55.5 C (from petroleum ether); [a]²_D²−58.4 (c

−1

1.00 in CH₂Cl₂); m_max(CDCl₃)/cm

2830 (CO), 1600 (Ar) and

3

1515 (Ar); d_H(300 MHz; CDCl₃) 6.64 (2 H, t, J_HF8.8, 4-ArH),

6.63–6.56 (4 H, m, ArH), 4.29 (2 H, s, ArCH) and 3.30 (6 H, s,

OMe); d_C(75.5 MHz; CDCl₃) 162.7 (dd, ¹J_CF248.9 and ³J_CF12.4,

3-ArC), 142.0 (t, J_CF8.0, 1-ArC), 110.4 (dd, J_CF17.4 and J_CF

8.1, 2-ArC), 103.3 (t, ²J_CF25.4, 4-ArC), 85.7 (t, ⁴J_CF1.8, ArCH)

and 57.5 (OMe); m/z (CI) 283.0746 ([MH]⁺− MeOH. C₁₅H₁₁F₄O

requires 283.0746) and 157 (100%).

3

2

4

2

4

(1R,2R)-1,2-Bis(2-bromophenyl)-1,2-dimethoxyethane

(1R,2R)-1,2-Bis(2-bromophenyl)ethane-1,2-diol (25.0

8.

g,

9.1, 1-ArC), 109.8 (dd, J_CF25.4 and J_CF8.1, 2-ArC), 103.7 (t,

²J_CF25.4, 4-ArC) and 77.9 (t, ⁴J_CF1.2, ArCH); m/z (CI) 270.0656

([MH]⁺− OH. C₁₄H₁₀F₄O requires 270.0668) and 269 ([MH]⁺−

H₂O, 100%).

67.6 mmol) was reacted in a method similar to that used in

the synthesis of diether 3. The crude product was puriﬁed by ﬂash

chromatography, eluting with petroleum ether–ethyl acetate, and

recrystallised from petroleum ether–ethyl acetate (95 : 5) to yield

the diether as rectangular prisms (26.7 g, 99.2%); mp 90–91 ^◦C

(1R,2R) - 1,2 - Bis(2 - bromophenyl)ethane - 1,2 - diol. 2,2^ꢀ- Di-

bromostilbene (65.0 g, 0.193 mol) was reacted in a method

similar to that used in the synthesis of (1R,2R)-1,2-bis(3-

ﬂuorophenyl)ethane-1,2-diol. The crude product was puriﬁed by

ﬂash chromatography, eluting with petroleum ether–ethyl acetate,

and recrystallised from petroleum ether–ethyl acetate (70 : 30)

to yield the diol as needles (68.7 g, 96.0%); mp 107–108.5 ^◦C

(from petroleum ether–ethyl acetate) (lit.,³⁴105.5–106.0 ^◦C); [a]²_D²

−37 (c 1.20 in ether) (lit.,³⁴+39.9 for (S,S) enantiomer) and

2,2^ꢀ-dibromobenzil as a yellow powder (1.49 g, 2.1%); mp 123–

◦

(from petroleum ether) (lit.,⁸85–85.5 C); [a]_D²²−107 (c 1.10 in

CH₂Cl₂) (lit.,⁸−109).

(1RS,2RS)-1,2-Bis(2-bromophenyl)-1,2-dimethoxyethane rac-8.

(1RS,2RS)-1,2-Bis(2-bromophenyl)ethane-1,2-diol (300 mg,

0.81 mmol) was reacted in a method similar to that used in the

synthesis of diether 3. The crude product was puriﬁed by ﬂash

chromatography, eluting with petroleum ether–ethyl acetate,

and recrystallised from petroleum ether–ethyl acetate (90 : 10)

to yield the diether as rectangular prisms (318 mg, 98.6%).

Characterisation data were identical to the enantiomerically pure

compound except; mp 1_◦21–122 ^◦C (from petroleum ether–ethyl

acetate) (lit.,⁸115.5–116 C).

◦

125 C (from petroleum ether–ethyl acetate) (lit.,³⁶115–120 C);

d_H(300 MHz; CDCl₃) 8.03–7.98 (2 H, m, ArH), 7.72–7.68 (2 H, m,

ArH), 7.51 (2 H, td, J 7.5 and 2.0, 4 or 5-ArH) and 7.47 (2 H, td,

J 7.5 and 2.0, 4 or 5-ArH); d_C(75.5 MHz; CDCl₃) 191.1 (ArCO),

1

134.6, 134.4, 134.1, 133.3, 127.6 and 123.2. The 400 MHz H-

NMR spectrum of the dimethyl ether derivative 8 in comparison

with a racemic sample (rac-8), in the presence of Pirkle’s reagent,³⁷

indicated an enantiomeric excess of ≥99%.

(1RS,2RS)-1,2-Bis(2-bromophenyl)ethane-1,2-diol. 2,2^ꢀ-Di-

bromostilbene (500 mg, 1.49 mmol) was reacted in a method

similar to that used in the synthesis of (1R,2R)-1,2-bis(3-

ﬂuorophenyl)ethane-1,2-diol. The crude product was puriﬁed by

ﬂash chromatography, eluting with petroleum ether–ethyl acetate,

(1R,2R)-1,2-Bis(3-ﬂuorophenyl)-1,2-bis(methoxymethoxy)-

ethane 10. Chloromethyl methyl ether (0.91 ml, 12.0 mmol) was

added dropwise to a solution of (1R,2R)-1,2-bis(3-ﬂuorophenyl)-

ethane-1,2-diol (1.50 g, 6.00 mmol) in dry dichloromethane (30 ml)

under an argon atmosphere. Hunig’s base (1.57 ml, 9.00 mmol) was

added to the solution and the reaction stirred for 72 h. The reaction

was quenched with 1 M hydrochloric acid (30 ml). The layers

were separated, the aqueous layer extracted with dichloromethane

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4

(3 × 15 ml) and the combined organic extracts washed with a

saturated sodium chloride solution (30 ml), dried (Na₂SO₄) and

concentrated under reduced pressure. The residue was puriﬁed by

ﬂash chromatography, eluting with petroleum ether–ethyl acetate,

to yield the acetal as an oil (1.71 g, 84.2%); [a]²_D²−130 (c 1.00

in CH₂Cl₂); m_max(ﬁlm)/cm⁻¹1614 (Ar), 1592 (Ar), 1488 (Ar) and

1103 (CO); d_H(300 MHz; CDCl₃) 7.20 (2 H, td, J 8.4 and ⁴J_HF5.7,

8.4 and J_HF5.5), m/z (CI) 275.0877 ([MH]⁺− Me. C₁₆H₁₃F₂O₂

requires 275.0844), 233 ([MH]⁺− (Me)₂CO, 4%) and 57 (100).

(4R,5R)-2,2-Dimethyl-4,5-bis(2-bromophenyl)-1,3-dioxolane

6. (1R,2R) - 1,2 - Bis(2 - bromophenyl)ethane - 1,2 - diol (5.00 g,

13.5 mmol) was reacted in a method similar to that used in the

synthesis of dioxolane 4. The crude product was puriﬁed by ﬂash

chromatography, eluting with petroleum ether–ethyl acetate, and

recrystallised from petroleum ether–ethyl acetate (95 : 5) to yield

the dioxolane as rectangular prisms (5.37 g, _◦96.4%); mp 112–

3

5-ArH), 7.04–6.98 (4 H, m, 2 and 6-ArH), 6.93 (2 H, tdd, J_HF

8.4, J 8.4, 2.6 and 1.1, 4-ArH), 4.82 (2 H, s, ArCH), 4.58 (2 H,

d, J 6.8, OCH_AH_BO), 4.54 (2 H, d, J 6.8, OCH_AH_BO) and 3.09

(6 H, s, OMe); d_C(75.5 MHz; CDCl₃) 162.6 (¹J_CF245.1, 3-ArH),

141.1 (³J_CF6.9, 1-ArC), 129.4 (³J_CF8.0, 5-ArC), 123.2 (⁴J_CF2.5,

6-ArC), 114.6 (²J_CF21.1, 2-ArC), 114.4 (²J_CF22.3, 4-ArC), 94.6

(OCH₂O), 80.1 (⁴J_CF1.9, ArCH) and 55.3 (OMe); d_F(282.65 MHz,

◦

113 C (from petroleum ether) (lit.,⁸114–115 C); [a]_D²²−11.7 (c

0.920 in CHCl₃) (lit.,⁸−11.4).

(1R,2R)-1,2-Bis(3-ﬂuorophenyl)-1,2-bis[(1,1-dimethylethyl)di-

methylsiloxy]ethane 5. (1R,2R)-1,2-Bis(3-ﬂuorophenyl)ethane-

1,2-diol (200 mg, 0.80 mmol) was dissolved in dry dichloro-

methane (10 ml) under an argon atmosphere. tert-Butyldi-

methylsilyl triﬂate (0.37 ml, 1.60 mmol) was added to the solution,

followed by 2,6-lutidene (0.279 ml, 2.40 mmol). The reaction was

stirred at room temperature overnight. The reaction was quenched

with saturated ammonium chloride solution (2 ml), the layers

separated and the aqueous layer extracted with dichloromethane

(3 × 5 ml). The combined organic extracts were washed with a

saturated sodium chloride solution (10 ml), dried (Na₂SO₄) and

concentrated under reduced pressure. The residue was puriﬁed by

ﬂash chromatography, eluting with petroleum ether-ethyl acetate,

and recrystallised twice from petroleum ether–ethyl acetate (95 :

5) to yiel_◦d the silyl ether as rectangular plates (284 mg, 97.8%); mp

87–87.5 C (from petroleum ether); [a]²_D²−48 (c 1.00 in CH₂Cl₂);

m_max(CH₂Cl₂)/cm⁻¹1588 (Ar), 1482 (Ar), 1366 (CMe₃) and 1260

3

4

CDCl₃) −113.2 (td, J_HF8.4 and J_HF5.7); m/z (CI) 339.1393

([MH]⁺. C₁₈H₂₁F₂O₄requires 339.1408), 323 ([MH]⁺− Me, 2%)

and 245 ([MH]⁺− Ar, 100).

(1R,2R) - 1,2 - Bis(2 - bromophenyl) - 1,2 - bis(methoxymethoxy) -

ethane

9. (1R,2R)-1,2-Bis(2-bromophenyl)ethane-1,2-diol

(1.21 g, 3.27 mmol) was reacted in a method similar to that used

in the synthesis of acetal 10. The crude product was puriﬁed by

ﬂash chromatography, eluting with petroleum ether–ethyl acetate,

and recrystallised from petroleum ether–ethyl acetate (90 : 10) to

yield the acetal as a powder (1.22 g, 81.6%); mp 76–77 ^◦C (from

petroleum ether–ethyl acetate); [a]²_D²−134.2 (c 1.00 in CH₂Cl₂);

−1

m_max(CH₂Cl₂)/cm

2844 (CO), 2825 (CO) 1592 (Ar) and 1568

(Ar); d_H(300 MHz; CDCl₃) 7.72 (2 H, dd, J 7.7 and 1.7, 3-ArH),

7.50 (2 H, dd, J 7.7 and 1.2, 6-ArH), 7.33 (2 H, td, J 7.7 and 1.2,

4-ArH), 7.12 (2 H, td, J 7.7 and 1.7, 5-ArH), 5.40 (2 H, s, ArCH),

4.40 (4 H, s, OCH₂O) and 2.87 (6 H, s, OMe); d_C(75.5 MHz;

CDCl₃) 137.9 (2-ArC) 132.6 (6-ArC), 131.0 (3-ArC), 129.2

(5-ArC), 127.0 (4-ArC), 123.2 (1-ArC), 95.0 (OCH₂O), 76.7

(ArCH) and 55.4 (OMe); m/z (CI) 458.9805 ([MH]⁺. C₁₈H₂₀Br₂O₄

requires 458.9807), 397 ([MH]⁺− MeOCH₂OH, 40%) and 367

(100).

4

(SiMe); d_H(300 MHz; CDCl₃) 7.12 (2 H, td, J 8.5 and J_HF5.6,

5-ArH), 7.98–6.75 (6 H, m, ArH), 4.71 (2 H, s, ArCH), 0.88

(9H, s, C(Me)₃), −0.08 (3 H, s, SiMe_AMe_B) and −0.20 (3 H, s,

SiMe_AMe_B); d_C(75.5 MHz; CDCl₃) 162.2 (¹J_CF243.9, 3-ArH),

143.7 (³J_CF7.5, 1-ArC), 128.5 (³J_CF8.4, 5-ArC), 122.9 (⁴J_CF2.5,

6-ArC), 114.3 (²J_CF21.7, 2 or 4-ArC), 113.9 (²J_CF21.1, 2 or

4-ArC), 78.4 (⁴J_CF1.8, ArCH), 25.8 (C(CH₃)₃), 18.1 (C(Me)₃),

−5.0 (SiMe_AMe_B) and −5.2 (SiMe_AMe_B); d_F(282.65 MHz, CDCl₃)

(4R,5R)-2,2-Dimethyl-4,5-bis(3-ﬂuorophenyl)-1,3-dioxolane

4. (1R,2R) - 1,2 - Bis(3 - ﬂuorophenyl)ethane - 1,2 - diol (1.05 g,

4.20 mmol), was dissolved in anhydrous toluene (30 ml) under

an argon atmosphere. Then 2,2-dimethoxypropane (2.50 ml,

20.4 mmol) and p-toluenesulfonic acid (30.0 mg, 0.174 mmol)

were added to the solution. The reaction was heated to 40 ^◦C

and stirred at that temperature for 2 h. 1.25 M sodium hydroxide

(4.2 ml) was added, the solution allowed to cool to room

temperature and stirred overnight. The mixture was extracted

with dichloromethane (3 × 20 ml), dried (MgSO₄) and concen-

trated under reduced pressure. The residue was puriﬁed by ﬂash

chromatography, eluting with petroleum ether–ethyl acetate, and

recrystallised from petroleum ether–ethyl acetate (95 : 5) to yield

the dioxolane as rectangular plates (1.17 g, 95.2%); mp 146–147 ^◦C

(from petroleum ether–ethyl acetate); [a]²_D²+40 (c 1.00 in CHCl₃);

m_max(CH₂Cl₂)/cm ⁻¹1615 (Ar) 1594 (Ar), 1453 (Ar), 1374 (CMe₂)

and 1142 (CO); d_H(300 MHz; CDCl₃) 7.33–7.24 (2 H, m, 5-ArH);

7.06–6.98 (4 H, m, 4 and 6-ArH), 6.92 (2 H, dt, ³J_HF8.4 and J 1.3,

2-ArH), 4.69 (2 H, s, ArCH) and 1.67 (6 H, s, OMe); d_C(75.5 MHz;

CDCl₃) 162.9 (¹J_CF245.7, 3-ArH), 139.2 (³J_CF7.4, 1-ArC), 130.0

(³J_CF8.7, 5-ArC), 122.4 (⁴J_CF3.1, 6-ArC), 115.4 (²J_CF21.1, 2 or

4-ArC), 113.4 (²J_CF22.3, 2 or 4-ArC), 109.9 (OCO), 84.7 (⁴J_CF1.8,

ArCH) and 27.1 (Me); d_F(282.65 MHz, CDCl₃) −112.4 (td, ³J_HF

−114.6 (td, J_HF8.5 and J_HF5.6); m/z (CI) 459 ([MH]⁺

−

3

4

HF, 10%), 421.1840 ([MH]⁺− (Me)₂CH. C₂₃H₃₃F₂O₂Si₂requires

421.1831), 347 ([MH]⁺− TBSOH, 26%), 217 ([MH]⁺− 2 ×

TBSOH, 28) and 85 (CH₂Cl₂, 100).

(1R,2R)-1,2-Bis(2-bromophenyl)-1,2-bis[(1,1-dimethylethyl)-

dimethylsiloxy]ethane

7. (1R,2R)-1,2-Bis(2-bromophenyl)-

ethane-1,2-diol (5.00 g, 13.5 mmol) was reacted in a method

similar to that used in the synthesis of silyl ether 5. The crude

product was puriﬁed by ﬂash chromatography, eluting with

petroleum ether–ethyl acetate, and recrystallised from petroleum

ether–ethyl acetate (90 : 10) to yield the silyl ether as rectangular

prisms (7.71 g_◦, 96.1%); mp 145–147 ^◦C (from petroleum ether)

(lit.,⁸140–141 C); [a]²_D²−40.7 (c 1.00 in CH₂Cl₂) (lit.⁸−39.5).

Lithiation experiments

Lithiation and methylation of (1R,2R)-1,2-bis(3-ﬂuorophenyl)-

1,2-dimethoxyethane 3. Diether 3 (28.0 mg, 0.10 mmol) was

dissolved in dry THF (1 ml) under an argon atmosphere and

cooled to −78 ^◦C. Then 1.25 M sec-BuLi (0.19 ml, 0.25 mmol)

was added dropwise to the stirred solution. After the addition

was complete the reaction was stirred for 3 h at this temperature.

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Methyl iodide (0.025 ml, 0.4 mmol.) was added, the reaction stirred

for a further 1 h at −78 ^◦C before the solution was allowed to

slowly warm to room temperature and stirred overnight. 2 M

potassium hydroxide (2 ml) was added, the solution stirred for

4 h and then diluted with diethyl ether (5 ml). The layers were

separated and the aqueous layer extracted with diethyl ether

(3 × 5 ml). The combined organic extracts were washed with

a saturated sodium chloride solution (25 ml), dried (MgSO₄)

and concentrated under reduced pressure. The solid residue was

dissolved in dichloromethane (5 ml), passed through a pad of silica

and concentrated under reduced pressure to yield a yellow oil.

¹H-NMR spectroscopy indicated the formation of dimethylated

species (96%); d_H(300 MHz; CDCl₃) 7.19 (2 H, dd, J 7.9 and 1.3,

6-ArH), 7.10 (2 H, td, J 7.9 and ⁴J_HF5.5, 5-ArH), 6.88 (2 H, ddd,

³J_HF9.6, J 7.9 and 1.3, 4-ArH), 4.66 (2 H, s, ArCH), 3.28 (6 H, s,

OMe) and 1.76 (6 H, d, ⁴J_HF2.2, ArCH₃); d_F(282.65 MHz, CDCl₃)

−115.9 (m), and starting material (4%).

stirred solution. After stirring at this temperature for a further

1 h, water (100 ml) was added and the reaction was allowed

to warm to room temperature. The layers were separated and

the aqueous layer extracted with diethyl ether (3 × 50 ml). The

combined organic extracts were washed with a saturated solution

of ammonium chloride (50 ml), dried (MgSO₄) and concentrated

under reduced pressure. The crude product was puriﬁed by ﬂash

chromatography, eluting with petroleum ether, and recrystallised

from petroleum ether to yield the citenzyl as platelets (22.3 g,

◦

91.1%); mp 81–83 C (from petroleum ether) (lit.,³⁴83–84 ^◦C);

d_H(300 MHz; CDCl₃) 7.55 (2 H, dd, J 7.9 and 1.6, 3-ArH), 7.26–

7.16 (4 H, m, ArH), 7.10–7.04 (2 H, m, ArH) and 3.04 (4 H, s,

ArCH₂); d_C(75.5 MHz; CDCl₃) 140.6 (1-ArC) 132.8 (ArC), 130.6

(ArC), 127.8 (ArC), 127.4 (ArC), 124.5 (2-ArC) and 36.4 (ArCH₂).

General methods

Sulfur diimidazole. Sulfur dichloride (1.72 ml, 27.1 mmol)

was added to dry hexane (30 ml) under an argon atmosphere.

The reaction mixture was cooled to 0 ^◦C before the dropwise

addition of 1-(trimethylsilyl)imidazole (6.32 ml, 43.2 mmol).

A white precipitate formed immediately. The suspension was

slowly allowed to warm to room temperature and stirred at this

temperature for 0.5 h. The suspension was ﬁltered under an argon

atmosphere and washed through with more dry hexane (20 ml).

The residual solvent was removed by passing a strong ﬂow of argon

through the precipitate for 0.1 h. Then dry THF (30 ml) was added

to the precipitate under an argon atmosphere. The ﬁne suspension

was immediately added to the prepared lithiated compound. The

yield of sulfur diimidazole was assumed to be quantitative.

Lithiation and methylation of (4R,5R)-2,2-dimethyl-4,5-bis(3-

ﬂuorophenyl)-1,3-dioxolane 4. Dioxolane 4 (35 mg, 0.121 mmol)

1

was reacted in a method similar to diether 3. H-NMR spectro-

scopy indicated the formation of monomethylated species (63%);

d_H(300 MHz; CDCl₃) 4.68 (d, J 8.4, ArCH_ACH_BAr) and 4.65 (d,

J 8.4, ArCH_ACH_BAr); d_F(282.65 MHz, CDCl₃) −112.5 (1F, td,

³J_HF9.0 and ⁴J_HF5.5) and −116.8 (1F, dd, ³J_HF9.0 and ⁴J_HF5.5),

dimethylated product (31%), d_H(300 MHz; CDCl₃) 4.64 (s, ArCH);

3

4

d_F(282.65 MHz, CDCl₃) −116.9 (td, J_HF9.0 and J_HF5.9),

and starting material (6%). A similar experiment, using tert-BuLi

instead of sec-BuLi, gave an identical distribution of products.

Lithiation and methylation of (1R,2R)-1,2-Bis(3-ﬂuorophenyl)-

1,2-bis[(1,1-dimethylethyl)dimethylsiloxy]ethane 5. Silyl ether 5

(30 mg, 0.0627 mmol) was reacted in a method similar to that

used in the reaction of diether 3. ¹H-NMR spectroscopy indicated

the formation of monomethylated species (65%), d_H(300 MHz;

CDCl₃) 4.72 (d, J 4.5, ArCH_ACH_BAr) and 4.70 (d, J 4.5,

Sulfur dibenzotriazole 19. Sulfur dichloride (0.18 ml,

2.26 mmol) was reacted with N-trimethylsilyl-1H-benzotriazole

(0.95 ml, 5.24 mmol) in a method similar to the preparation

of disulfur diimidazole. The yield of sulfur dibenzotriazole was

assumed to be quantitative.

3

ArCH_ACH_BAr); d_F(282.65 MHz, CDCl₃) −114.8 (1F, td, J_HF

Method C. General procedure for the preparation of the

sulﬁdes by ortho-lithiation. The thiepine precursor (1.80 mmol)

was dissolved in dry THF (5 ml) under an argon atmosphere and

4

3

4

9.0 and J_HF5.5) and −119.2 (1F, dd, J_HF9.0 and J_HF5.5),

dimethylated product (25%); d_H(300 MHz; CDCl₃) 4.64 (s, ArCH);

3

4

d_F(282.65 MHz, CDCl₃) −119.4 (dd, J_HF9.0 and J_HF5.4) and

◦

cooled to −78 C. Then sec-BuLi (3.60 ml of a 1.25 M solution,

starting material (10%).

4.5 mmol) was added dropwise to the stirred solution. After the

addition was complete the solution was stirred for a further 3 h

at −78 ^◦C. The electrophile (10.8 mmol) was then added and the

reaction was stirred for a further 1 h at this temperature before

being allowed to warm to room temperature overnight. Water

was added and the reaction stirred for 0.5 h. The layers were

separated and the aqueous layer extracted with dichloromethane

(3 × 10 ml). The combined organic extracts were washed with a

saturated solution of ammonium chloride (10 ml), dried (Na₂SO₄)

and concentrated under reduced pressure. The crude mixture was

subsequently puriﬁed.

(1R,2R)-1,2-Bis(3,5-diﬂuoro-4-methylphenyl)-1,2-dimethoxy-

ethane. Diether 11 (100 mg, 0.318 mmol) was reacted in a

method similar to that used in the lithiation and methylation of

diether 3, except that the crude product was puriﬁed by ﬂash

chromatography, eluting with petroleum ether, to yield the diether

as a yellow oil (92.1 mg, 84.6%); [a]²_D²−24.8 (c 1.00 in CH₂Cl₂);

m_max(CDCl₃)/cm ⁻¹2828 (CO), 1585 (Ar), 1559 (Ar) and 1500 (Ar);

d_H(270 MHz; CDCl₃) 6.56 (4 H, d, ³J_HF7.6, 2-ArH), 4.13 (2 H, s,

4

ArCH), 3.18 (6 H, s, OMe) and 2.06 (6 H, t, J_HF1.7, ArCH₃);

d_C(67.9 MHz; CDCl₃) 161.3 (dd, ¹J_CF246.5 and ³J_CF9.3, 3-ArC),

138.0 (t, ³J_CF9.1, 1-ArC), 110.0 (dd, ²J_CF17.1 and ⁴J_CF9.3, 2-ArC),

86.0 (ArCH), 57.5 (OMe) and 7.0 (t, ³J_CF3.6, ArCH₃); m/z (CI)

341.1164 ([MH]⁺. C₁₈H₁₇O₂F₄requires 341.1165), 323 ([MH]⁺−

HF, 26%), 311 ([MH]⁺− MeOH, 57), and 171 (100).

Method D. General procedure for the preparation of the

sulﬁdes by bromine–lithium exchange. The thiepine precursor

(1.25 mmol) was dissolved in dry THF (1 ml) under an argon

atmosphere and cooled to −78 ^◦C. Then tert-BuLi (2.94 ml of

a 1.70 M solution, 5.0 mmol) was added dropwise to the stirred

solution. After the addition was complete the solution was stirred

for a further 0.5 h at −78 ^◦C, allowed to slowly warm to −10 ^◦C

and stirred for 0.5 h at this temperature. The solution was recooled

1,2-Bis(2-bromophenyl)ethane 25. 2-Bromobenzyl bromide

(36.0 g, 0.144 mmol) was dissolved in dry THF (200 ml) under

an argon atmosphere and cooled to −78 ^◦C. Then n-BuLi (45 ml

of a 1.6 M solution, 0.072 mmol) was added dropwise to the

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to −78 ^◦C and stirred at this temperature for 0.5 h. The electrophile

(7.50 mmol) was then added and the reaction stirred for a further

1 h at this temperature before being allowed to warm to room

temperature overnight. Water was added and the reaction stirred

for 0.5 h. The layers were separated and the aqueous layer extracted

with dichloromethane (3 × 5 ml). The combined organic extracts

were washed with a saturated solution of ammonium chloride

(5 ml), dried (Na₂SO₄) and concentrated under reduced pressure.

The crude mixture was subsequently puriﬁed.

7.01–6.93 (2 H, m, 3-ArH), 5.46 (2 H, s, ArCH), 4.95 (2 H, d,

J 6.8, OCH_ACH_BO), 4.73 (2 H, d, J 6.8, OCH_ACH_BO) and 3.42

(6 H, s, OMe); d_C(75.5 MHz; CDCl₃) 161.1 (¹J_CF246.3, 4-ArH),

142.3 (³J_CF8.0, 11a-ArC), 129.5 (³J_CF8.1, 2-ArC), 126.2 (⁴J_CF3.7,

1-ArC), 123.2 (²J_CF19.2, 4a-ArC), 114.7 (²J_CF23.5, 3-ArC), 96.1

(OCH₂O), 79.6 (⁴J_CF3.1, ArCH) and 56.1 (OMe); d_F(282.65 MHz,

CDCl₃) −107.8 (dd, ³J_HF6.5 and ⁴J_HF3.7); m/z (EI) 368.0900 (M⁺.

C₁₈H₁₈O₄F₂S requires 368.0894), 307 (M⁺− CH₃OCH₂OH, 48%),

244 (M⁺− 2 × CH₃OCH₂OH, 28), and 233 (ArSArCH, 100).

(10R,11R)-4,6-Diﬂuoro-10,11-dimethoxy-10,11-dihydrodibenzo-

[b,f ]thiepine 5-oxide 27. Diether 3 (100 mg, 0.360 mmol) was

reacted according to method C using thionyl chloride (1.86 ll,

1.85 mmol) as the electrophile. Puriﬁcation by ﬂash chromato-

graphy, eluting with petroleum ether–ethyl acetate, and recrystal-

lisation from petroleum ether gave the sulfoxide as a powder

(9.8 mg, 8.4%); mp 87–89.5 ^◦C (from petroleum ether); [a]²_D²−15

(c 1.00 in CH₂Cl₂); m_max(CH₂Cl₂)/cm⁻¹1597 (Ar), 1574 (Ar) and

1042 (SO); d_H(300 MHz; CDCl₃) 7.60 (1 H, br d, J 8.2, 1 or

9-ArH), 7.49 (1 H, td, J 8.2 and ⁴J_HF5.5, 2 or 8-ArH), 7.46 (1 H,

Method E. General procedure for the preparation of the

unsubstituted sulﬁdes. 2-Bromobibenzyl 25 (2.10 g, 6.18 mmol)

was dissolved in dry THF (20 ml) under an argon atmosphere

and cooled to −78 ^◦C. Then n-BuLi (5.44 ml of a 2.5 M solution,

13.6 mmol) was added dropwise to the stirred solution. After the

addition was complete the reaction solution is stirred for a further

0.5 h at −78 ^◦C. The electrophile (37.1 mmol) was then added and

the reaction was stirred for a further 1 h at this temperature before

being allowed to warm to room temperature overnight. Water

(10 ml) was added and the reaction stirred for 0.5 h. The layers were

separated and the aqueous layer extracted with dichloromethane

(3 × 10 ml). The combined organic extracts were washed with a

saturated solution of ammonium chloride (10 ml), dried (Na₂SO₄)

and concentrated under reduced pressure. The crude mixture was

subsequently puriﬁed.

4

td, J 8.2 and J_HF5.5, 2 or 8-ArH), 7.34 (1 H, br d, J 8.2, 1 or

3

9-ArH), 7.10 (1 H, td, J_HF8.2, J 8.2 and 1.3, 3 or 7-ArH), 7.00

3

(1 H, br t, J_HF8.2 and J 8.2, 3 or 7-ArH), 6.75 (1 H, d, J 8.2,

ArCH_ACH_BAr), 4.65 (1 H, d, J 9.0, ArCH_ACH_BAr), 3.63 (3 H, s,

OMe_A) and 3.38 (3 H, s, OMe_B); d_C(75.5 MHz; CDCl₃) 159.3 (¹J_CF

252.0, 4 or 6-ArH), 158.2 (¹J_CF246.4, 4 or 6-ArH), 141.5 (³J_CF

8.1, 9a or 11a-ArC), 139.0 (³J_CF8.1, 9a or 11a-ArC), 134.2 (³J_CF

9.3, 2 or 8-ArC), 133.6 (³J_CF8.8, 2 or 8-ArC), 130.3 (⁴J_CF3.2, 1 or

9-ArC), 122.2 (⁴J_CF3.1, 1 or 9-ArC), 116.2 (²J_CF23.6, 3 or 7-ArC),

115.4 (²J_CF21.7, 3 or 7-ArC), 83.8 (⁴J_CF3.2, ArC_AH), 75.6 (⁴J_CF

3.2, ArC_BH), 58.8 (OC_AH₃) and 54.5 (C_BH₃); d_F(282.65 MHz,

CDCl₃) −110.9 (1F, dd, ³J_HF9.0 and ⁴J_HF5.5) and −113.2 (1F, dd,

³J_HF8.2 and ⁴J_HF5.4); m/z (CI) 325 ([M(C₂H₅)]⁺, 10%), 325.0703

([MH]⁺. C₁₆H₁₅F₂O₂S requires 325.0710), 293 ([MH]⁺− MeOH,

84) and 277 ([MH]⁺− SO, 12).

Thiepine syntheses

(10R,11R)-4,6-Diﬂuoro-10,11-dimethoxy-10,11-dihydrodibenzo-

[b,f ]thiepine 14. Diether 3 (500 mg, 1.80 mmol) was reacted

according to method C using sulfur diimidazole (1.79 g, 10.8 mmol)

as the electrophile. Puriﬁcation by ﬂash chromatography, eluting

with petroleum ether–ethyl acetate, and recrystallisation twice

from petroleum ether yielded the sulﬁde as a powder (265 mg,

◦

47.8%); mp 145–145.5 C (from petroleum ether); [a]²_D²+108 (c

1.00 in CH₂Cl₂); (Found: C, 62.27; H, 4.46; F, 12.66; S, 10.41.

(10R,11R)-4,6-Diﬂuoro-10,11-dimethoxy-10,11-dihydrodibenzo-

[b,f ]thiepine 5-dioxide 12. Diether 3 (100 mg, 0.36 mmol)

was reacted according to method C using sulfuryl dichloride

(0.17 ml, 2.16 mmol) as the electrophile. Puriﬁcation by ﬂash

chromatography, eluting with petroleum ether–ethyl acetate, and

recrystallisation from petroleum ether yielded the sulfone as a

ﬁne powder (23.0 mg, 18.8%); mp 87–89 ^◦C (from petroleum

ether); [a]_D²²+72 (c 1.00 in CH₂Cl₂); m_max(CH₂Cl₂)/cm⁻¹2828

(CO), 1597 (Ar) and 1574 (Ar); d_H(300 MHz; CDCl₃) 7.48 (2 H,

C₁₆H₁₄F₂O₂S requires C, 62.30; H, 4.50; F, 12.66; S, 10.49%);

−1

m_max(CH₂Cl₂)/cm

2853 (OC–H₃), 1573 (Ar) and 1122 (CO);

d_H(300 MHz; CDCl₃) 7.32–7.19 (4 H, m, 1 and 2-ArH), 6.98 (2 H,

td, ³J_HF8.4, J 8.4 and 1.8, 3-ArH), 5.09 (2 H, s, ArCH) and 3.48

(6 H, s, OMe); d_C(75.5 MHz; CDCl₃) 161.1 (¹J_CF246.4, 4-ArH),

142.5 (11a-ArC), 129.6 (³J_CF8.1, 2-ArC), 125.6 (⁴J_CF3.1, 1-ArC),

123.0 (²J_CF19.2, 4a-ArC), 114.7 (²J_CF23.6, 3-ArC), 83.1 (⁴J_CF3.1,

ArCH) and 57.1 (OMe); d_F(282.65 MHz, CDCl₃) −107.9 (dd,

³J_HF8.4 and ⁴J_HF5.0); m/z (EI) 308 (M⁺, 2%) 276 (M⁺− MeOH,

98), 244 (M⁺− 2 × MeOH, 40) and 233 (100).

4

td, J 8.1 and J_HF5.4, 2-ArH), 7.27–7.25 (2 H, m, 3-ArH), 6.81

(2 H, dt, J 8.1 and 1.2, 1-ArH), 5.98 (2 H, s, ArCH) and 3.29

(6 H, s, OMe); d_C(75.5 MHz; CDCl₃) 159.6 (¹J_CF260.7, 4-ArC),

138.7 (³J_CF8.1, 11a-ArC), 135.0 (³J_CF10.6, 2-ArC), 134.0 (²J_CF

19.2, 4a-ArC), 124.0 (⁴J_CF3.7, 1-ArC), 117.4 (²J_CF22.9, 3-ArC),

76.7 (⁴J_CF2.5, ArCH) and 57.9 (OMe); d_F(282.65 MHz, CDCl₃)

In another experiment diether 3 (500 mg, 1.80 mmol) was

reacted according to method C using sulfur dichloride (0.69 ml,

10.8 mmol) as the electrophile. The same puriﬁcation yielded the

sulﬁde as a powder (16.6 mg, 3.0%).

3

4

(10R,11R)-4,6-Diﬂuoro-10,11-di(methoxymethoxy)-10,11-di-

hydrodibenzo[b,f ]thiepine 20. Diether 10 (159 mg, 0.470 mmol)

was reacted according to method C using sulfur diimidazole

(430 mg, 2.59 mmol) as the electrophile. Puriﬁcation by ﬂash chro-

matography, eluting with petroleum ether–ethyl acetate yielded

the sulﬁde as a powder (64.2 mg, 37.1%); mp 122–122.5 ^◦C (from

−102.1 (dd, J_HF8.1 and J_HF5.4); m/z (CI) 341.0652 ([MH]⁺.

C₁₆H₁₅O₄F₂S requires 341.0659), 309 ([MH]⁺− MeOH, 10%),

277 ([MH]⁺− 2MeOH, 59) and 65 (100), (1R,2R)-1,2-bis(2-

chloro-3-ﬂuorophenyl)-1,2-dimethoxyethane 13 as a yellow powder

(48.7 mg, 39.0%); mp 67–71 ^◦C (from petroleum ether–ethyl

acetate); [a]_D²²−76.9 (c 1.00 in CH₂Cl₂); m_max(CH₂Cl₂)/cm⁻¹2829

(CO), 1594 (Ar) and 1576 (Ar); d_H(300 MHz; CDCl₃) 7.43

(2 H, dt, J 8.1 and 1.5, 6-ArH), 7.26 (2 H, td, J 8.1 and ⁴J_HF5.3,

5-ArH), 7.05 (2 H, td, ³J_HF8.1, J 8.1 and 1.5, 4-ArH), 4.93 (2 H, s,

petroleum ether–ethyl acetate); [a]²_D²+25.5 (c 1.00 in CH₂Cl₂);

−1

m_max(CH₂Cl₂)/cm

2825 (CO), 1610 (Ar), 1576 (Ar) and 705

(C–S); d_H(300 MHz; CDCl₃) 7.29–7.21 (4 H, m, 1 and 2-ArH),

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ArCH) and 3.18 (6 H, s, OMe); d_C(75.5 MHz; CDCl₃) 157.7 (¹J_CF

247.6, 3-ArC), 138.0 (³J_CF6.9, 1-ArC), 127.3 (³J_CF8.1, 5-ArC),

124.9 (⁴J_CF2.5, 6-ArC), 121.2 (⁴J_CF21.0, 2-ArC), 115.7 (²J_CF21.1,

4-ArC), 81.0 (⁴J_CF2.5, ArCH) and 57.7 (OMe); d_F(282.65 MHz,

OCH_ACH_BO), and 3.42 (6 H, s, OMe); d_C(75.5 MHz; CDCl₃)

139.1 (4a or 11a-ArC), 136.5 (4a or 11a-ArC), 132.4 (1 or 4-ArC),

130.8 (1 or 4-ArC), 127.9 (2 or 3-ArC), 127.3 (2 or 3-ArC), 96.1

(OCH₂O), 80.1 (ArCH) and 56.0 (OMe); m/z (EI) 332.1083 (M⁺.

C₁₈H₂₀O₄S requires 332.1082), 301 (M⁺− MeOH, 15%), 271 (M⁺−

CH₃OCH₂OH, 86) and 197 (100).

3

4

CDCl₃) −114.0 (dd, J_HF8.1 and J_HF5.4); m/z (CI) 347.0420

([MH]⁺. C₁₆H₁₄Cl₂F₂O₂requires 347.0417), 315 ([MH]⁺− MeOH,

25%) and 85 (CH₂Cl₂, 100), and (1R,2R)-1-(2-chloro-3-ﬂuoro)-

2-(3-ﬂuorophenyl)-1,2-dimethoxyethane as a yellow oil (7.7 mg,

6.9%); [a]²_D²−93.7 (c 1.00 in CH₂Cl₂); m_max(ﬁlm)/cm⁻¹2828 (CO),

1599 (Ar) and 1576 (Ar); d_H(300 MHz; CDCl₃) 7.72–7.60 (2 H,

m, ArH), 7.30–7.20 (3 H, m, ArH), 7.09–7.02 (2 H, m, ArH), 5.84

(1 H, d, J 6.0, ArCH_A), 5.03 (1 H, d, J 6.0, ArCH_B), 3.29 (3 H, s,

OMe_A) and 3.17 (3 H, s, OMe_B); d_C(75.5 MHz; CDCl₃) 159.5

(¹J_CF262.3, 3 or 3^ꢀ-ArC), 157.9 (¹J_CF255.3, 3 or 3^ꢀ-ArC), 140.1

(1-ArC), 137.5 (1-ArC), 135.8 (³J_CF9.9, 5 or 5^ꢀ-ArC), 127.4 (³J_CF

7.8, 5 or 5^ꢀ-ArC), 126.3 (⁴J_CF3.2, 6 or 6^ꢀ-ArC), 125.2 (⁴J_CF3.6, 6

or 6^ꢀ-ArC), 121.4 (²J_CF17.7, 2-ArC), 117.6 (²J_CF22.8, ArC), 115.9

(²J_CF21.3, ArC), 80.8 (ArC_AH), 78.8 (ArC_BH), 58.1 (OMe_A) and

( 10R,11R ) - 10,11 - Dimethylmethylenedioxy - 10,11 - dihydrodi -

benzo[b,f ]thiepine 22. Dioxolane 6 (500 mg, 1.76 mmol) was

reacted according to method D using sulfur diimidazole (1.75 g,

10.56 mmol) as the electrophile. Puriﬁcation by ﬂash chromatogra-

phy, eluting with petroleum ether–ethyl acetate, yielded the sulﬁde

as a powder (41.4 mg, 12.0%); mp 42–44 ^◦C; [a]_D²²−22.0 (c 1.00 in

CH₂Cl₂); m_max(CH₂Cl₂)/cm⁻¹1593 (Ar), 1566 (Ar) and 1126 (CO);

d_H(300 MHz; CDCl₃) 7.60 (2 H, dd, J 7.7 and 1.5, 1 or 4-ArH),

7.43 (2 H, dd, J 7.7 and 1.2, 1 or 4-ArH), 7.28 (2 H, td, J 7.7 and

1.5, 2 or 3-ArH), 7.19 (2 H, td, J 7.7 and 1.6, 2 or 3-ArH), 5.23

(2 H, s, ArCH) and 1.62 (6 H, s, C(Me)₂); d_C(75.5 MHz; CDCl₃)

138.4 (4a or 11a-ArC), 135.0 (4a or 11a-ArC), 129.3 (1 or 4-ArC),

127.6 (2 or 3-ArC), 127.3 (2 or 3-ArC), 126.4 (1 or 4-ArC), 109.6

(OCO), 78.7 (ArCH) and 27.1 (C(CH₃)₂); m/z (EI) 284.0875 (M⁺.

C₁₇H₁₆O₂S requires 284.0871), 226 (M⁺− (Me)₂CO, 81%), and

197 (100).

3

57.4 (OMe_B); d_F(282.65 MHz, CDCl₃) −102.0 (1F, dd, J_HF10.4

4

and J_HF5.1) and −113.5 (1F, m); m/z (CI) 281.0522 ([MH]⁺−

MeOH. C₁₅H₁₁ClF₂O requires 281.0545), 173 (FClArCHOMe,

32%) and 139 (ArCHOMe, 84).

(10R,11R)-10,11-Dimethoxy-10,11-dihydrodibenzo[b,f ]thiepine

15. Diether 8 (500 mg, 1.25 mmol) was reacted according to

method D using sulfur diimidazole (2.58 g, 7.50 mmol) as the

electrophile. Puriﬁcation by ﬂash chromatography, eluting with

petroleum ether–ethyl acetate, and recrystallisation from methanol

(10R,11R)-10,11-Bis[(1,1-dimethylethyl)dimethylsiloxy]-10,11-

dihydrodibenzo[b,f ]thiepine 21. Disilyl ether

7

(800 mg,

1.33 mmol) was reacted according to method D using sulfur

diimidazole (1.33 g, 8.00 mmol) as the electrophile. Puriﬁcation by

ﬂash chromatography (loaded as a solution in petroleum ether),

eluting with petroleum ether–ethyl acetate, and recrystallisation

from petroleum ether yielded the sulﬁde as needles (118 mg,

18.8%); mp 90–91.5 ^◦C (from petroleum ether); [a]²_D²+3.3 (c 1.00 in

CH₂Cl₂); m_max(CH₂Cl₂)/cm⁻¹1589 (Ar), 1564 (Ar), 1434 (Si–CH₃),

1265 (Si–CH₃), and 705 (C–S); d_H(300 MHz; CDCl₃) 7.79 (2 H, dd,

J 7.6 and 1.0, 1 or 4-ArH), 7.49 (2 H, dd, J 7.6 and 1.4, 1 or 4-ArH),

7.40 (2 H, td, J 7.6 and 1.4, 2 or 3-ArH), 7.26 (2 H, td, J 7.6 and 1.3,

2 or 3-ArH), 5.12 (2 H, s, ArCH), 0.79 (2 H, s, C(Me)₃), 0.34 (6 H, s,

SiMe_AMe_B) and 0.13 (6 H, s, SiMe_AMe_B); d_C(75.5 MHz; CDCl₃)

149.2 (4a or 11a-ArC), 136.4 (1 or 4-ArC), 136.3 (4a or 11a-

ArC), 129.8 (2 or 3-ArC), 126.8 (2 or 3-ArC), 126.6 (1 or 4-ArC),

74.7 (ArCH), 27.0 (C(CH₃)₃), 17.5 (C(Me)₃), −2.4 (SiMe_AMe_B)

and −2.9 (SiMe_AMe_B); m/z (CI) 473.2362 ([MH]⁺. C₂₆H₄₁O₂SSi₂

requires 473.2366) and 205 (100%), 1-(2-bromophenyl)-2-phenyl-

1-[(1,1-dimethylethyl) dimethylsiloxy]ethylene 33 as a yellow oil

ꢀ

ꢀꢀ

and (a,a ,a )-triﬂuorotoluene, _◦yielded the sulﬁde as ﬁne needles

(130 mg, 38.2%); mp 63–64.5 C (from methanol); [a]²_D²−33.2 (c

1.00 in CH₂Cl₂); m_max(CH₂Cl₂)/cm⁻¹2821 (CO), 1588 (Ar), 1573

(Ar) and 700 (C–S); d_H(300 MHz; CDCl₃) 7.53 (2 H, dd, J 7.6 and

1.0, 1 or 4-ArH), 7.44 (2 H, dd, J 7.6 and 1.6, 1 or 4-ArH), 7.28 (2

H, td, J 7.6 and 1.3, 2 or 3-ArH), 7.13 (2 H, td, J 7.6 and 1.6, 2 or

3-ArH), 5.11 (2 H, s, ArCH) and 3.46 (6 H, s, OMe); d_C(75.5 MHz;

CDCl₃) 139.4 (4a or 11a-ArC), 136.5 (4a or 11a-ArC), 132.3 (1

or 4-ArC), 130.2 (1 or 4-ArC), 128.2 (2 or 3-ArC), 127.4 (2 or

3-ArC), 83.0 (ArCH) and 56.7 (OMe); m/z (CI) 273.0942 ([MH]⁺.

C₁₆H₁₇O₂S requires 273.0949) and 241 ([MH]⁺− MeOH, 100%).

A

similar experiment, but using sulfur dibenzotriazole

(990 mg, 3.75 mmol) as the electrophile, yielded (1R,2R)-

1,2-diphenylethane-1,2-dimethoxyethane as a powder (88.6 mg,

◦

29.3%); mp 93–95 C (from petroleum ether) (lit.,³⁸94–95 ^◦C);

[a]²_D²+90 (c 1.00 in EtOH); d_H(300 MHz; CDCl₃) 7.18–7.12 (6

H, m, ArH), 7.02–6.95 (4 H, m, ArH), 4.30 (2 H, s, ArCH) and

3.26 (6 H, s, OMe); d_C(75.5 MHz; CDCl₃) 138.1 (1-ArC), 127.9

(ArC), 127.8 (ArC), 127.5 (ArC), 87.7 (ArCH) and 57.2 (OMe),

and sulﬁde 212 as a powder (53.0 mg, 15.6%).

(43.9 mg, 8.5%); m_max(ﬁlm)/cm⁻¹3054 (C C–H), 2955 (SiC–

=

H₃), 2928 (SiC–H₃), 1585 (Ar), 1557 (Ar) and 1361 (CMe₃);

d_H(300 MHz; CDCl₃) 7.72 (1 H, br d, J 7.7, ArH), 7.59 (2 H,

td, J 8.0 and 1.3, ArH), 7.53 (1 H, dd, J 7.9 and 1.3, ArH),

7.44–7.23 (3 H, m, ArH), 7.32 (1 H, s, ArCH), 7.11 (1 H, br

d, J 7.6 and 1.6, ArH), 0.92 (9 H, s, C(Me₃)₃and 0.39 (6 H, s,

Si(CH₃)₂); d_C(75.5 MHz; CDCl₃) 143.3 (ArC), 137.4 (ArC), 136.8

(ArC), 136.3 (ArC), 133.9 (ArC), 133.2 (ArC), 128.6 (ArC), 128.3

(ArC), 128.2 (ArC), 127.6 (ArCH), 126.7 (ArC), 126.3 (ArC),

126.0 (ArC), 124.2 (ArC), 27.0 (C(CH₃)₃), 18.0 (C(Me)₃) and

−2.9 (Si(Me)₂); m/z (CI) 389.0941 ([MH]⁺. C₂₀H₂₆OBrSi requires

389.0936), 359 ([MH]⁺− 2 × Me, 10%), 317 ([MH]⁺− OSi(Me)₂,

61), and 73 (100), and another unidentiﬁed compound as plates

(35 mg); mp 107–108.5 ^◦C (from petroleum ether); [a]²_D²−44.5 (c

1.00 in CH₂Cl₂); m_max(CH₂Cl₂)/cm⁻¹3427, 1591, 1586, 1434, 1265,

(10R,11R)-10,11-Di(methoxymethoxy)-10,11-dihydrodibenzo-

[b,f ]thiepine 23. Acetal 9 (538 mg, 1.17 mmol) was reacted

accordingto methodD using sulfur diimidazole(1.16g, 7.02mmol)

as the electrophile. Puriﬁcation by ﬂash chromatography, eluting

with petroleum ether–ethyl acetate, yielded the sulﬁde as an oil

(139 mg, 35.8%); [a]²_D²+0.9 (c 4.82 in CH₂Cl₂); m_max(ﬁlm)/cm⁻¹

2823 (CO), 1590 (Ar), 1567 (Ar) and 701 (C–S); d_H(300 MHz;

CDCl₃) 7.52 (2 H, dd, J 7.7 and 1.2, 1 or 4-ArH), 7.47 (2 H,

dd, J 7.7 and 1.5, 1 or 4-ArH), 7.26 (2 H, td, J 7.7 and 1.3, 2

or 3-ArH), 7.11 (2 H, td, J 7.7 and 1.5, 2 or 3-ArH), 5.45 (2 H,

s, ArCH), 4.97 (2 H, d, J 6.8, OCH_ACH_BO), 4.74 (2 H, d, J 6.8,

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657; d_H(300 MHz; CDCl₃)* 7.80 (2 H, br d, J 7.8), 7.51–7.46 (2 H,

m), 7.42 (1 H, td, J 7.5 and 1.5), 7.35 (1 H, dd, J 7.5 and 1.2), 7.30

(1 H, dd, J 7.5 and 1.2), 7.13 (1 H, td, J 7.9 and 1.6), 5.31 (1 H,

d, J 4.1), 5.15 (1 H, d, J 4.1), 0.82 (9 H, s), 0.32 (3 H, s) and 0.13

(3 H, s); d_C(75.5 MHz; CDCl₃) 127.8, 127.5, 127.1, 126.3, 123.9,

75.3, 75.1, 27.0, 17.6, −2.1 and −2.9 m/z (CI) 505.1545 ([MH]⁺.

C₂₅H₃₇O₁S₃Si₂requires 505.1541), 391 (50%), 381 (48), 333 (91),

331 (86) and 73 (100).

temperature, washed with water, dried (Na₂SO₄) and concentrated

under reduced pressure. The crude product was recrystallised from

methanol to yield the sulﬁmide as needles (773 mg, 72.5%); mp

◦

123–124 C (from methanol) (lit.,⁴²113 ^◦C); m_max(CH₂Cl₂)/cm⁻¹

=

1556 (Ar) and 930 (S N); d_H(300 MHz; CDCl₃) 7.75 (2 H, d,

J 8.1, SO₂ArH), 7.65–7.58 (4 H, m, ArH), 7.53–7.40 (6 H, m,

ArH), 7.14 (2 H, d, J 8.1, SO₂ArH) and 2.33 (3 H, s, SO₂ArCH₃);

d_C(75.5 MHz; CDCl₃) 141.7 (ArC), 141.3 (ArC), 136.5 (ArC),

132.3 (ArC), 129.9 (ArC), 129.1 (ArC), 127.2 (ArC), 126.3 (ArC)

and 21.4 (ArCH₃).

In a similar experiment diphenyl sulﬁde (0.50 ml, 3.01 mmol)

was reacted with chloramine-T trihydrate to yield the sulﬁmide as

needles (64.0 mg, 6.0%).

In another experiment, to a solution of copper triﬂate benzene

complex (333 mg, 0.663 mmol, 25 mol%) in dry acetonitrile

10,11-Dihydrodibenzo[b,f ]thiepine 26. Bibenzyl 25 (2.10 g,

6.18 mmol) was reacted according to method E using sulfur

diimidazole (6.16 g, 37.9 mmol) as the electrophile. Puriﬁcation by

ﬂash chromatography, eluting with petroleum ether–ethyl acetate,

and recrystallisation from petroleum ether yielded the sulﬁde as

yellow needles (34.0 mg, 2.6%); mp 47–48 ^◦C (from petroleum

=

(10 ml) was added PhI NTs (1.09 g, 2.92 mmol) under an argon

atmosphere. Then diphenyl sulﬁde (0.44 ml, 2.65 mmol) was added

and the solution stirred at room temperature for 48 h. Water (10 ml)

was added, the layers separated and the aqueous layer extracted

with diethyl ether (3 × 10 ml). The combined organic extracts

were dried (MgSO₄) and concentrated under reduced pressure.

The crude material was puriﬁed by ﬂash chromatography, eluting

with petroleum ether–ethyl acetate, to yield the sulﬁmide as needles

(586 mg, 62.4%).

◦

ether) (lit.,³⁹47–50 C); m_max(CH₂Cl₂)/cm⁻¹1584 (Ar), 1571 (Ar)

and 703 (C–S); d_H(300 MHz; CDCl₃) 7.45 (2 H, dd, J 7.9 and

1.1, 4-ArH), 7.20–6.87 (6 H, m, ArH) and 3.04–2.92 (4 H, m,

ꢀ

CH_AH_ACH_BH_B).

Reactions of diphenyl sulﬁde

Diphenyl sulﬁmine. Diphenyl-N-p-tosylsulﬁmine (250 mg,

70.4 mmol) was dissolved in concentrated sulfuric acid (1 ml). As

soon as the sulﬁmide dissolved the solution was poured into ice

water (10 ml) and sodium hydroxide solution (10 ml) added until

the solution became alkaline. The solution was extracted with

chloroform (2 × 5 ml) and concentrated under reduced pressure.

The residue was once again dissolved in concentrated sulfuric acid

(5 ml). The solution was decolourised with charcoal and sodium

hydroxide added until the solution became alkaline whereupon the

product precipitated out of solution. The suspension was ﬁltered

to yield the free sulﬁmide as needles (131 mg, 93.2%); mp 56–59 ^◦C

(from toluene) (lit.,¹⁸74 ^◦C); m_max(CH₂Cl₂)/cm⁻¹1557 (Ar) and 934

Methyldiphenylsulfonium tetraﬂuoroborate. Diphenyl sulﬁde

(0.41 ml, 2.46 mmol) was stirred with silver tetraﬂuoroborate

(0.50 g, 2.46 mmol) in acetonitrile (2 ml) for 1 h. The suspension

was cooled to 0 ^◦C before the dropwise addition of methyl iodide

(0.48 ml, 7.38 mmol). The reaction was stirred at room temperature

for 48 h. The suspension was ﬁltered and the ﬁltrate concentrated

under reduced pressure. Trituration with diethyl ether (5 ml)

yielded the salt as off-white platelets _◦(300 mg, 42.3%); mp 61–

63 ^◦C (from diethyl ether) (lit.,⁴⁰61–62 C); d_H(300 MHz; DMSO)

7.39–7.25 (10 H, m, ArH) and 3.30 (3 H, s, SCH₃); d_F(282.65 MHz,

DMSO) −147.9 (s, BF₄).

Methyldiphenylsulfonium triﬂuoromethanesulfonate. Methyl

triﬂuoromethanesulfonate (1.36 ml, 12.0 mmol) was added drop-

wise to a solution of diphenyl sulﬁde (1.0 ml, 6.0 mmol) in

dry dichloromethane (10 ml) under an argon atmosphere. The

reaction was stirred at room temperature for 48 h. Then 1.25 M

sodium hydroxide (15 ml) was added and the solution stirred

overnight. The layers were separated and the aqueous layer

extracted with dichloromethane (3 × 10 ml). The combined

organic extracts were dried (MgSO₄) and concentrated under

reduced pressure. Recrystallisation from_◦ethanol yielded the salt

as platelets (1.94 g, 92.4%); mp 95–96.5 C (from ethanol) (lit.,⁴¹

94–97.5 ^◦C); d_H(300 MHz; DMSO) 7.47–7.32 (10 H, m, ArH) and

3.23 (3 H, s, SMe); d_F(282.65 MHz, DMSO) −77.7 (s, CF₃).

=

(S N); d_H(300 MHz; CDCl₃) 7.65–7.40 (m, ArH); d_C(75.5 MHz;

CDCl₃) 145.5 (ArC), 141.1 (ArC), 131.0 (ArC), 131.0 (ArC), 130.4

(ArC), 129.3 (ArC), 129.3 (ArC), 129.2 (ArC), 125.9 (ArC) and

124.7 (ArC).

Diphenylsulfoxamide (2,4,6-trimethyl)phenylsulfonate.Diphenyl

sulfoxide (500 mg, 0.0248 mmol) was dissolved in dry

dichloromethane (20 ml). MSH (800 mg, 37.1 mmol) was added

and the reaction stirred at room temperature overnight. The

residue was washed with water (10 ml), dried (Na₂SO₄) and

concentrated under reduced pressure. The crude product was

triturated with diethyl ether (5 ml) and ﬁltered to yield the

aminated sulﬁde as a gum (806 mg, 78.1%); mp 169–173 ^◦C (lit.,⁴³

179–183 ^◦C); d_H(300 MHz; DMSO) 7.40 (4 H, dd, J 7.9 and 3.6,

ArH), 7.27–7.24 (6 H, m, ArH), 6.67 (2 H, s, (CH₃)₃ArH), 2.43

(6 H, s, ArCH₃) and 2.07 (6 H, s, ArCH₃).

Diphenyl-N-p-tosylsulﬁmide. Diphenyl sulﬁde (0.50 ml,

3.01 mmol) and the tetrabutylammonium salt of chloramine-T

(1.42 g, 3.01 mmol) were dissolved in dichloromethane (30 ml)

and the solution heated to 40 ^◦C. The reaction was stirred at

this temperature for 5 h. The solution was allowed to cool to room

Reactions of thiepines

(10R,11R)-4,6-Diﬂuoro-10,11-dimethoxy-10,11-dihydrodibenzo-

[b,f ]thiepine 5-oxide 27. Sulﬁde 14 (30 mg, 0.097 mmol) was

dissolved in dichloromethane (10 ml). 57–86% m-CPBA (32.4 mg)

was dissolved in dichloromethane (5 ml) and dried (MgSO₄)

* Coupling constants veriﬁed by comparison to a spectrum of the

compound run at 400 MHz.

2230 | Org. Biomol. Chem., 2006, 4, 2218–2232

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before its addition to the reaction solution. The reaction was

stirred at room temperature for 2 h. Then 1.25 M sodium

hydroxide (10 ml) was added and the reaction stirred for a further

1 h. The layers were separated and the aqueous layer extracted

with dichloromethane (3 × 30 ml). The combined organic extracts

were dried (MgSO₄) and concentrated under reduced pressure.

Puriﬁcation by ﬂash chromatography, eluting with petroleum

ether–ethyl acetate, and recrystallisation from petroleum ether

yielded the sulfoxide as a powder (31.0 mg, 99%) (characterised in

a previous experiment).

(10R,11R)-10,11-Dimethoxy-10,11-dihydrodibenzo[b,f ]thiepine-

5-ylidene malonic acid dibenzyl ester 32. Sulﬁde 15 (1.21 g,

4.45 mmol) and diazodibenzylmalonate (1.49 g, 5.34 mmol) were

reacted using a similar method to that used in the synthesis of

the ylide 30. The crude mixture was subsequently puriﬁed by

ﬂash chromatography, eluting with ethyl acetate. The product

was dissolved in a minimum amount of ethyl acetate (10 ml) and

the impurities reprecipitated by the addition of petroleum ether

(50 ml). The suspension was ﬁltered and the ﬁltrate concentrated

under reduced pressure to yield the sulfonium ylide as a powder

(1.69 g, 67.7%); mp 117–118 ^◦C (from petroleum ether–ethyl

acetate); [a]_D²²−9 (c 1.00 in CH₂Cl₂); m_max(CH₂Cl₂)/cm⁻¹2820

2-Diazomalonic acid dimethyl ester 29. Dimethylmalonate

(5.36 g, 40.6 mmol), triethylamine (5.7 ml, 41.2 mmol) and tosyl

azide (8.0 g, 40.6 mmol) were dissolved in acetonitrile (60 ml).

The solution was stirred at room temperature overnight. The

solution was concentrated under reduced pressure, partitioned

between dichloromethane (100 ml) and water (100 ml) and the

resulting mixture stirred for 1 h at room temperature. The organic

layer was separated, dried (MgSO₄) and concentrated under

reduced pressure. Puriﬁcation by ﬂash chromatography, eluting

with petroleum ether–ethyl acetate, yielded the diazomalonate as

a yellow oil (5.33 g, 83.1%); d_H(300 MHz; CDCl₃) 3.85 (s, OMe);

m/z (CI) 159 ([MH]⁺, 35%), 127 ([MH]⁺− MeOH, 32) and 101

([MH]⁺− CO₂Me, 100).

=

(CO), 1717 (C O), 1557 (Ar), 1519 (Ar) and 1454 (OCH₂);

d_H(300 MHz; CDCl₃) 7.78 (1 H, d, J 7.9, ArH), 7.69 (1 H, d, J

7.8, ArH), 7.46 (2 H, td, J 7.4 and 1.1, ArH), 7.41 (2 H, td, J 7.4

and 1.1, ArH), 7.33–7.27 (2 H, m, ArH), 7.19 (10H, m, exo-ArH),

5.11 (4 H, br s, OCH₂Bn), 5.02 (1 H, d, J 7.7, ArCH_A), 4.79 (1 H,

d, J 7.7, ArCH_B), 3.34 (3 H, s, OMe_A) and 3.22 (3 H, s, OMe_B);

d_C(75.5 MHz; CDCl₃) 166.8 (CO₂Bn), 137.2 (ipso-ArC), 136.1 (4a

or 5a-ArC), 135.5 (4a or 5a-ArC), 133.2 (ArC), 132.7 (ArC), 132.6

(ArC), 130.7 (ArC), 130.2 (ArC), 128.9 (ArC), 128.1 (exo-ArC),

127.6 (ArC), 127.3 (ArC), 127.2 (exo-ArC), 126.9 (ArC), 83.7

(ArC_AH), 80.8 (ArC_BH), 65.2 (OCH₂Bn), 57.5 (OC_AH₃), 56.9

(OC_BH₃) and 55.0 (SC(CO₂Me)₂); m/z (CI) 555.1850 ([MH]⁺.

C₃₃H₃₁O₆S requires 555.1841), 447 ([MH]⁺− BnOH, 28%), 241

([MH]⁺− CH₂(CO₂Bn)₂, 58) and 91 (Bn, 72).

(10R,11R)-10,11-Dimethoxy-10,11-dihydrodibenzo[b,f ]thiepine-

5-ylidene malonic acid dimethyl ester 30. Sulﬁde 15 (600 mg,

2.21 mmol) and diazodimethylmalonate 29 (418 mg, 2.65 mmol)

were dissolved in dichloromethane (20 ml). Rhodium(II) acetate

(49 mg, 0.111 mmol, 5 mol%) was added and the reaction stirred

at room temperature for 72 h. The reaction was washed with

a saturated sodium chloride solution (20 ml), dried (MgSO₄)

and concentrated under reduced pressure. The crude mixture

was subsequently puriﬁed by ﬂash chromatography, eluting with

ethyl acetate. The crude material was dissolved in a minimum

amount of ethyl acetate (4 ml) and the impurities reprecipitated

by the addition of petroleum ether (15 ml). The suspension was

ﬁltered and the ﬁltrate concentrated under reduced pressure

to yield t_◦he sulfonium ylide as a powder (662 mg, 74.6%); mp

203–204 C (from petroleum ether–ethyl acetate); [a]²_D²−118

(c 1.00 in CH₂Cl₂); m_max(CH₂Cl₂)/cm⁻¹2951 (COO–CH₃), 2830

9-(1,3-Dioxolane)-9H-thioxanthene 24. Dioxolane 22 (137 mg,

0.413 mmol) was dissolved in ethylene gylcol (5 ml). Toluene-

p-sulfonic acid (156 mg, 0.907 mmol) was added and the

solution heated to 80 ^◦C. The reaction was stirred at this

temperature overnight. The solution was allowed to cool to

room temperature, washed with water (5 ml), dried (MgSO₄)

and concentrated under reduced pressure. Puriﬁcation by ﬂash

chromatography, eluting with petroleum ether–ethyl acetate, and

recrystallisation from petroleum ether yielded the sulﬁde as a

powder (76.1 mg, 68.3%); mp 160–161 ^◦C (from petroleum

ether); m_max(CH₂Cl₂)/cm⁻¹2891 (CO), 1616 (Ar) and 1588 (Ar);

d_H(300 MHz; CDCl₃) 7.40–7.35 (4 H, m, ArH), 7.26–7.21 (4 H,

m, ArH), 5.21 (1 H, dd, J 6.6, ArCH), 4.13 (1 H, dd, J 6.6,

ꢀ

CH(OCH₂)₂) 3.91–3.81 (2 H, m, OCH_AH_BCH_AH_BO) and 3.79–

=

(C–O ether), 1716 (C O), 1475 (OCH₂), 1434 (OCH₂) and 704

ꢀ

3.76 (2 H, m, OCH_AH_BCH_AH_BO); d_C(75.5 MHz; CDCl₃) 133.1

(4a or 10a-ArC), 132.6 (4a or 10a-ArC), 130.7 (ArC), 127.4 (ArC),

126.5 (ArC), 126.3 (ArC), 101.9 (ArCH), 65.2 (CH₂CH₂) and

53.9 (CH(OCH₂)₂); m/z (EI) 270.0710 (M⁺. C₁₅H₁₄O₂S requires

270.0715), 197 (M⁺− CH(OCH₂)₂, 88%) and 73 (100).

(C–S); d_H(300 MHz; CDCl₃) 7.77 (1 H, br d, J 8.5, ArH), 7.70

(1 H, br d, J 8.1, ArH), 7.53–7.35 (6 H, m, ArH), 5.07 (1 H, d, J

7.9, ArCH_A), 4.82 (1 H, d, J 7.9, ArCH_B), 3.62 (6 H, br s, CO₂Me)

and 3.30 (6 H, s, OMe); d_C(75.5 MHz; CDCl₃) 166.8 (CO₂Me),

136.2 (4a or 5a-ArC), 135.5 (4a or 5a-ArC), 133.1 (ArC), 132.8

(ArC), 130.2 (ArC), 128.9 (ArC), 127.1 (ArC), 126.7 (ArC),

83.8 (ArC_AH), 80.8 (ArC_BH), 57.4 (OC_AH₃), 57.0 (OC_BH₃), 55.1

(SC(CO₂Me)₂) and 51.1 (CO₂CH₃); m/z (CI) 403.1207 ([MH]⁺.

C₂₁H₂₃O₆S requires 403.1207), 371 ([MH]⁺− MeOH, 100%), 339

([MH]⁺− 2 × MeOH, 12) and 271 ([MH]⁺− H₂C(CO₂Me)₂, 72).

Acknowledgements

Andrew Hudson thanks the Univerisity of Bristol for a Univer-

sity Scholarship. Hirihattaya Phetmung thanks the Royal Thai

Government for a Scholarship. Paul Wyatt thanks the School of

Chemistry for generous support.

2-Diazamalonic acid dibenzyl ester. Dibenzylmalonate (12.5 g,

47.7 mmol) was reacted in a similar way to dimethylmalonate.

Puriﬁcation by ﬂash chromatography, eluting with petroleum

ether–ethyl acetate, yielded the diazomalonate as an off-white

powder (12.1 g, 88.1%); d_H(300 MHz; CDCl₃) 7.39–7.30 (5 H,

m, ArH), 5.27 (2 H, s, ArCH); m/z (EI) 181 (M⁺− BnOH, 12%),

107 (BnO, 46) and 91 (Bn, 100).

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Synthesis and chemistry of enantiomerically pure 10,11-dihydrodibenzo[b,f] thiepines

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