Fluorination of sulfanyl amides using difluoroiodoarene reagents

Article abstract of DOI:10.1039/b209078c

A range of sulfur-containing amides have been fluorinated with the hypervalent iodine difluoride reagents 1, and two principal reaction pathways identified. Cephalosporin esters 2 having a heteroatom in the α-position to sulfur undergo fluorination in DCM with cleavage of the carbon-sulfur bond to form novel fluorinated β-lactams 4. Sulfides with electron-withdrawing groups in the α-position undergo α-fluorination in a process analogous to the classical Pummerer reaction. This Fluoro-Pummerer reaction has been exemplified for a range of simple α-phenylsulfanylacetamides 14-19. When β-hydrogens are present in the substrate a different route is followed, with deprotonation by basic fluoride taking place to yield vinyl sulfides 41-43. When an excess of the fluorinating reagent is used these vinyl sulfides can undergo further reaction in a novel tandem Pummerer-Additive-Pummerer process to yield α,β-difluoro sulfides 45-47.

Full text of DOI:10.1039/b209078c

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Fluorination of sulfanyl amides using difluoroiodoarene reagents
William B. Motherwell,*a Michael F. Greaney,†a Jeremy J. Edmunds‡b and Jonathan W. Steedc
a Department of Chemistry, Christopher Ingold Laboratories, University College London,
20 Gordon Street, London, UK WC1H OAJ. E-mail: w.b.motherwell@ucl.ac.uk;
Fax: 44 207679 7524; Tel: 44 20767 97533
1
b Department of Chemistry, Imperial College of Science, Technology and Medicine,
South Kensington, London, UK SW7 2AY
c Department of Chemistry, Kings College London, Strand, London, UK WC2R 2LS
Received (in Cambridge, UK) 18th September 2002, Accepted 6th November 2002
First published as an Advance Article on the web 22nd November 2002
A range of sulfur-containing amides have been fluorinated with the hypervalent iodine difluoride reagents 1, and
two principal reaction pathways identified. Cephalosporin esters 2 having a heteroatom in the α-position to sulfur
undergo fluorination in DCM with cleavage of the carbon–sulfur bond to form novel fluorinated β-lactams 4.
Sulfides with electron-withdrawing groups in the α-position undergo α-fluorination in a process analogous to
the classical Pummerer reaction. This Fluoro-Pummerer reaction has been exemplified for a range of simple
α-phenylsulfanylacetamides 14–19. When β-hydrogens are present in the substrate a different route is followed,
with deprotonation by basic fluoride taking place to yield vinyl sulfides 41–43. When an excess of the fluorinating
reagent is used these vinyl sulfides can undergo further reaction in a novel tandem Pummerer-Additive-Pummerer
process to yield α,β-difluoro sulfides 45–47.
difficult than, for example, the case of dithioketals3 or phenyl-
Introduction
thioglycosides.4 In similar fashion, the electron withdrawing
group which is required to enhance the acidity of the protons
Hα for the Type 2 reaction resides in a vinylogous ester which
also has enamide double bond character.
In the preceding paper we described the fluorination of a range
of α-phenylsulfanylated esters with difluoroiodotoluene 1a
(Fig. 1).1 Fluorination was observed to give the α-fluoro sulfides
In the event, treatment of benzyhydryl ester 2a with one
equivalent of p-tert-butyliodobenzene difluoride 1b in DCM
afforded the chromatographically unstable fluoroazetidinone
disulfide 4a in up to 30% yield (Scheme 1).
Fig. 1
through a Fluoro-Pummerer reaction, and we defined the
mechanism as being of Type 2. The present paper presents, in
full detail, our results from fluorinating two different classes of
amido-sulfides with difluoroiodoarenes 1.2 The first study
describes the reactions of some cephalosporin esters which
exhibit Type 1 behaviour, where fluorination occurs through
cleavage of the carbon–sulfur bond, whilst the second reports
on the behaviour of α-phenylsulfanylated amides and lactams
which follow a Type 2 pathway.
Results and discussion
The highly functionalised cephalosporin esters 2 were initially
selected for study as an intriguing test bed for probing the
reactivity of hypervalent iodoarene difluorides. In this particu-
lar instance, both Type 1 and Type 2 reactions are theoretically
possible but the major directing influence for each pathway is
attenuated by the overall connectivity within the molecular
architecture. Thus, the carbonyl group of the β-lactam will, to
some extent, diminish the nucleophilicity of the nitrogen atom
and hence render direct participation by the Type 1 path more
Scheme 1
† Current address: Department of Chemistry, University of Edinburgh,
King’s Buildings, West Mains Rd, Edinburgh, UK EH9 3JJ.
‡ Current address: Pfizer Global Research, 2800 Plymouth Rd, Ann
Arbor, MI 48105-2430, U.S.A.
The stereochemistry of 4 was readily deduced from the
proton and fluorine NMR spectra which indicated the absence
of cis-vicinal coupling between the azetidinone ring protons.
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This journal is © The Royal Society of Chemistry 2002
DOI: 10.1039/b209078c

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The methyl ester 2b led to the analogous derivative 4b in similar
yield. By contrast, the reaction with acetonitrile as solvent led
to the isolation of the oxazoline derivative 3 in 33% yield, most
certainly as a result of the precedented participation of the side
chain amide.5
The simplest mechanistic rationale for this solvent-
dependant divergence of behaviour is that the iodine difluoride
is first activating the sulfide leading to cleavage of the carbon–
sulfur bond, with Type 1 anchimeric assistance from nitrogen
(Scheme 2). The resultant acyl iminium ion is then trapped by
Scheme 2
the amide carbonyl group to produce intermediate 7. Use of
dichloromethane as solvent then permits nucleophilic attack
of fluoride on 7, forming 4, whereas the reduced nucleophilicity
of fluoride in acetonitrile6 precludes the fluorination of 7,
deprotonation giving the oxazoline 3.
Cephalosporin() esters with non-nucleophilic amide side-
chains have been reported to undergo the Pummerer reaction
when treated with NCS, forming the 2-chloro cephems 13, via
12, in a Type 2 “Chloro-Pummerer” reaction.7 In order to
investigate whether a change of nucleophile could alter the
course of our iodoarene mediated halogenation, we therefore
treated 2a with p-tert-butyliodobenzene dichloride under
anhydrous conditions. The rearranged isothiazole 11 was iso-
lated as the major product in 31% yield, (52% based on
recovered starting material). Isothiazole formation has been
observed for cephalosporins with nucleophilic amide side
chains when treated with NCS.7 An analogous mechanism,
via 9 and 10 and involving initial oxazolone participation is
presumably operating here (Scheme 3).
The striking differences in the behaviour of the iodoarene
difluoride relative to the dichloride may be understood in terms
of the relative leaving group ability of the initially formed
halogeniodoarene sulfonium salt 8. The chlorosulfonium
salt (G = Cl), as evidenced by sulfoxide formation,8 must be
considered as a relatively long-lived entity. In the absence of
water either isothiazole formation (path A) or Pummerer
reaction (path B) is possible, depending on side-chain partici-
pation. The absence of these products in reactions of the
iodoarene difluoride is indicative of a rapid cleavage of the
C6–S bond triggered by a superior leaving group (path C).
Although yields of fluorides were modest, we were encour-
aged by the compatibility of the fluorinating agent with a
complex substrate as well as the mildness of the reaction condi-
tions. We elected to synthesise a simpler set of substrates that
might be used to examine the Type 2 behaviour of the difluoro-
iodoarenes, in analogy to our work on the Fluoro-Pummerer
reaction of α-phenylsulfanyl esters.
Scheme 3
critically dependent on the nature of the substituents attached
to the nitrogen atom of the amide and also on the reaction
conditions employed. The series of allylic amides 14, 15, and
16 (Entries 1–4) were initially selected in order to investigate
the possibility of intercepting the cationic acyl sulfonium
intermediate 23 through intramolecular cyclisation to give
fluorinated heterocycles 24 which retain the pattern of
functionality required for further Fluoro-Pummerer chemistry
(Scheme 4). In all cases however, no evidence for cyclisation was
adduced, even when the potential carbocationic intermediate
would have been either benzylic (Entry 3) or tertiary (Entry 4).
The failure of substrates 14–16 to undergo cyclisation is in
line with literature reports where secondary α-methylsulfinyl
acetamides were found to be poor substrates for Pummerer
cyclisations,9 and it will therefore be of interest to prepare the
tertiary amide analogues in order to examine the desired fluoro-
cyclisation.
It was nevertheless pleasing to note that clean α-fluorination
of these amides takes place in good overall yield. Moreover,
and in contrast to Pummerer chemistry with sulfoxides using
DAST, the use of a second equivalent of DFIT (Entry 2) leads
to a very simple one-pot method for α, α-difluorination.
Although no competing cyclisation reactions were observed at
Our investigations into the Type 2 reaction were initiated
by preparing a simple range of α-phenylsulfanyl acetamides.
The results of treating these amides with DFIT 1a are shown
in Table 1 which reveals that the outcome of the reaction is
J. Chem. Soc., Perkin Trans. 1, 2002, 2816–2826
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Table 1 Treatment of α-phenylsulfanylacetamides with DFIT
Entry
1
Amide
Methoda
Product
Yield (%)b
14
14
15
16
17
17
A
2510
26
71
2
3
4
5
6
C
A
A
B
61
27
55
28
25
29
68
A
30: 47, 29: 25
7
18
A
31: 11, 32: 35
8
9
19
19
A
B
33
34
59
86
10
11
20
21
C
B
35
36
86
78
a Method A: DFIT (1 eq.), DCM, reflux; B: DFIT (1 eq.), DCM, 0 ЊC; C: DFIT (2 eq.), DCM, 0 ЊC. b Isolated yields.
0 ЊC presumably as a consequence of the preferred transoid con-
formation of the amide linkage, comparison of entries 5 and 6
for the benzylamine derivative 17 indicates that π-participation
from the aromatic ring can intervene at higher temperatures.
This phenomenon can also be seen in the case of the secondary
benzylic amide 18 (Entry 7) and in the case of the amide 19
(Entry 8), where the exclusive formation of the benzo fused
heterocycle 33 (Entry 8) can be considered to result from the
faster rate of 5-exo-trig ring closure relative to the 6-exo-trig
process required for substrates 17 and 18.11 The yields of hetero-
cycles in Entries 6–8 are moderate, and poorer than those
recorded by Tamura for similar cyclisations of α-phenylsulfanyl
acetamides mediated by iodobenzene(bistrifluoroacetate).12
In that system however, cyclisation is heavily favoured as the
labile α-acetoxy sulfide Pummerer products are themselves sub-
strates for cyclisation, whereas in our system the strength of
the carbon–fluorine bond precludes displacement by intra-
molecular cyclisation of the olefin.
In stark contrast to the above examples, Entries 9, 10 and 11
indicate that DFIT can also function as a simple reagent for
Scheme 4
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oxidation of sulfide functionality to sulfoxide. Treatment of 20
with DFIT and caesium fluoride in acetonitrile in an attempt to
increase the basicity of the medium led to the same sulfoxide,
but with a reduced yield of 53%. Although these results clearly
indicate that the hypervalent iodine reagent continues to func-
tion as a thiophilic oxidant, the subtle nature of the sub-
stituents around the nitrogen atom in controlling product
evolution is far from clear at present, as for instance in com-
parison of Entries 2 and 10.
We extended the methodology to lactams 38–40 with a view
to examining whether the presence of β hydrogens would lead
to alternative products in the Fluoro-Pummerer reaction with
DFIT. This proved to be the case, as treatment of the lactams
with one equivalent of DFIT in DCM at 0 ЊC led to the novel
unsaturated heterocycles 41–43 in moderate to high yield, by a
β-elimination pathway (Scheme 5).
Scheme 6
Pummerer reaction. This reaction involves sequential addition
of two nucleophiles across the double bond of an α,β-unsaturated
sulfoxide, generating the saturated α,β-difunctionalised sulfide,
and as such is a powerful, though under-utilised synthetic
method. The proposed mechanism for DFIT is shown in
Scheme 7, whereby the first equivalent of fluorinating agent
generates α,β-unsaturated sulfide 41 as previously discussed.
Scheme 5
The possibility of fluorination–dehydrofluorination was
rejected on the basis that the α-fluoride of 38 has been prepared
by electrochemical means in Et3Nؒ3HF and no elimination was
reported to occur upon product isolation.13 Fluoride is thus
acting as a base, and not as a nucleophile in this reaction. The
high yield of 41 starting from the bis-phenylsulfanylated com-
pound 44 is presumably a consequence of the substantially
easier generation of the sulfonium intermediate through thio-
ketal cleavage with DFIT by the Type 1 mechanism.3 Interest-
ingly, we observed small amounts of fluorinated side-products
in the above reactions, but were unable to characterise them at
this stage. We were aware however, that vinyl sulfides can them-
selves be substrates for the so-called Additive-Pummerer reac-
tion,14 and that such a precursor could be the source of the
fluorinated material. In order to test this theory, we therefore
treated the starting lactams with an excess of DFIT. When
treated with two equivalents of DFIT the pyrrolidinone 38 and
piperidinone 39 were both fluorinated in the α and β positions
to produce the diastereomeric difluorides 45 and 46 (Scheme 6).
The syn and anti diastereomers were separable by column
chromatography and a single crystal could be grown for both
syn-45 and anti-46, thus unambiguously characterising the
difluoride products by X-ray crystallography (Fig. 2).
Scheme 7
The second equivalent of reagent then activates the vinyl
sulfide towards conjugate addition of fluoride at the β position
forming the β-fluoro sulfonium species 49, which can then
capture a second fluoride nucleophile to provide the difluoride
45. The success of this tandem process is due to the ability of
the hypervalent iodine reagent to oxidise the sulfide in situ,
allowing the two consecutive Pummerer processes to take place
in one-pot. The modest stereoselectivity observed in these
transformations presumably arises as a consequence of the
small size of the initially introduced fluorine atom in the
4-position having little influence on the steric approach control
of the second fluoride nucleophile.
Fluorination of the bis-phenylsulfanylated compound 44
with DFIT produced difluoride 47 as a diastereomeric mixture.
In this instance, the strongly nucleophilic thiophenoxide anion
generated upon thioketal cleavage of 44 with DFIT will add to
the β-position of 41 upon DFIT activation in preference to
fluoride. Basic fluoride then regenerates the α,β-unsaturation,
presumably as a consequence of the now increased acidity of
the β-proton, and an Additive-Pummerer reaction furnishes the
observed difluoride. This mechanism dictates the consumption
of three equivalents of DFIT, accordingly an improved yield of
46% was obtained with this stoichiometry.
Introduction of fluoride to the apparently unactivated
β-position is readily understood by analogy with the Additive-
We were surprised to find that treating the unsaturated
sulfides 41 and 42 directly with one equivalent of DFIT led to
Fig. 2 ORTEP of syn-45.
J. Chem. Soc., Perkin Trans. 1, 2002, 2816–2826
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the difluorides being formed in comparable to lower yields than
those obtained through the tandem process. The generation of
two equivalents of HF in the first Pummerer reaction may be
important in this regard, as it may have a catalytic effect on the
second Additive process. However, attempts at promoting the
direct fluorination of 41 and 42 with DFIT using pyؒ9HF or
Et3Nؒ3HF as additives were not generally successful,15
although in one case the yield of 45 from the sulfide 41 was
improved to 59% through the addition of 25 mol% of Et3Nؒ
3HF to the reaction.
The reaction was extended to azetidinone 50, as the four-
membered ring would be expected to preclude α,β-unsaturated-
sulfide formation and possibly lead to alternative products. Two
equivalents of DFIT transformed 50 into the fluoro-sulfoxide
52 in 46% yield as a mixture of sulfoxide diastereomers, along
with a small amount of the known16 fluoro-sulfide 51 (Scheme
8).
The contrasting behaviour of some amides, and especially
lactams, therefore requires some explanation and it is interest-
ing to speculate that this could possibly reside in a competing
path leading to the formation of an intermediate such as 57
which is much more likely to form from an amide than an ester
by virtue of the more nucleophilic nitrogen atom. Given the
relatively electron rich nature of the carbon–carbon double
bond in 57, attack of fluoride anion as a nucleophile at the α
carbon is disfavoured and the reaction then evolves via the
β-elimination pathway with fluoride anion functioning as a
base. The relative ease of formation of 56 will of course be a
function of the substituents attached to the nitrogen atom
of the amide and α-fluorination without amide participation
is also possible.
In conclusion, we have demonstrated in the present paper
that hypervalent iodine difluorides are effective reagents for
the fluorination of a variety of sulfur-containing amides, with
most of the work being carried out on α-acyl sulfides. The
α-fluoroacetamides synthesised through the Fluoro-Pummerer
reaction are potentially versatile fluorinated synthons, and
may be elaborated into more complex systems using the rich
chemistry of sulfur. The most interesting chemistry from
a mechanistic perspective is the tandem Pummerer-Additive-
Pummerer fluorination reaction. The success of this reaction,
which applies to those α-phenylsulfanyl acetamides having
β-hydrogens, is due to the ability of the hypervalent iodine
reagent to oxidise sulfur in situ thus allowing sequential Pum-
merer reactions to take place in one-pot. Furthermore, fluoride
always acts first as a base, and second as a nucleophile, to form
the novel α,β-difluorides. We are currently examining the scope
and utility of this transformation in related systems.
Scheme 8
Characterisation of 52 was secured by oxidation to the
sulfone, whereby the two signals in the 19F NMR of the starting
material collapsed to one in the product. As expected, the
Additive-Pummerer reaction is not observed in this case due to
the prohibitively large ring-strain associated with formation of
a double bond in the four-membered azetidinone ring.
Experimental
See reference 1 for general experimental procedures.
Overview and conclusions
At this stage, it is also perhaps appropriate to provide a com-
parative overview of the essential difference in the reactivity of
esters and lactones on one hand,1 and amides and lactams on
the other, as far as product evolution via Fluoro-Pummerer
chemistry (the Type 2 mechanism) is concerned. In essence, the
selection of an α-phenylsulfanyl ester or lactone can always be
said to follow the “ideal” pathway and will always involve the
intermediacy of an α-acylsulfonium cation which is apparently
predisposed to capture fluoride anion as a nucleophile (Scheme
9). Thus, in our studies with ester and lactone functionality as
the electron-withdrawing group, β-elimination was never
observed as a competing process.
p-tert-Butyldifluoroiodobenzene 1b
p-tert-Butyliodobenzene dichloride17 (4.02 g, 12 mmol) was
dissolved in DCM (40 mL) in a polyethylene erlenmeyer
flask. Yellow mercuric oxide (5.5 g, 25 mmol) and 48% aq.
hydrofluoric acid (6 mL, 12 eq.) were then added. The slurry
was vigorously shaken periodically over 10 min, after which
time the almost colourless organic layer was decanted onto
MgO, swirled briefly, then decanted into a polyethylene vessel.
Argon was passed over the solution for 4 h to afford a white
solid. Trituration with dry hexane yielded the title compound
1b (2.6 g, 70%) which was collected and stored under argon in a
Scheme 9
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J. Chem. Soc., Perkin Trans. 1, 2002, 2816–2826

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polyethylene vessel at Ϫ20 ЊC; mp 40 ЊC (decomp.) (hexane); IR
(KBr/cmϪ1): νmax 2962, 1522, 1392, 818, 788, 770, 750, 538, 466;
1H NMR (90 MHz, CDCl3): δH 1.38 (9H, s, (CH3)3C), 7.60 (2H,
AAЈBB d J 9 Hz, 3-H, 5-H), 7.90 (2H, AAЈBBЈ d J 9 Hz, 2-H,
6-H); 13C NMR (23 MHz, CDCl3): δC 31.1 (C-8), 34.9 (C-7),
128.1 (C-1), 128.5 (C-3), 130.1 (C-2) 155.4 (C-4); 19F NMR
to afford an oil which could be crystallised from benzene:petrol
to give an orange solid. The solid was dissolved in DCM,
shaken with decolourising charcoal, filtered then concentrated
in vacuo to afford the title fluoride 4b (220 mg, 21%) as a cream
powder; mp 68–69 ЊC (benzene:petrol); IR (CCl4/cmϪ1): νmax
3414 (NH), 2956, 1792 (β-lactam), 1725 (ester carbonyl), 1697,
1599; 1H NMR (270 MHz, CDCl3): δH 2.32 (3H, s, 3-Me), 3.45
(1H, d J 14 Hz, 2-H), 3.78 (3H, s, OMe), 3.80 (1H, d J 14 Hz,
2-H), 4.38 (1H, d J 14 Hz, 15-H), 4.47 (1H, d, J 14 Hz, 15-H),
5.00 (1H, dd J 7, 7 Hz, 7-H), 6.05 (1-H, d J 73 Hz, 6-H),
6.90–7.30 (5H, m, Ar–H); 13C NMR (126 MHz, CDCl3): δC 19.3
(C-9), 44.0 (C-2), 52.3 (C-12), 63.2 (d J 23 Hz, C-7), 67.5 (C-15),
98.4 (d J 242 Hz, C-6), 115.0 (C-18), 121.0 (C-3), 122.5 (C-20),
129.9 (C-14), 151.8 (C-4), 157.3 (C-17), 162.7 (d J 11 Hz, C-10),
163.6 (C-14), 169.4 (C-8); 19F NMR (84.3 MHz, CDCl3):
(84 MHz, CD3CN): δF Ϫ176.8; MS (EI): m/z 298 (M ϩ), 283
ؒ
(M Ϫ Me), 260 (M Ϫ 2F); HRMS (EI) calcd. for C10H13F2I:
298.0030. Found: 298.0038.
Bis(benzhydryl 2-{(1ЈR,5ЈS )-3Ј-phenoxymethyl-7Ј-oxo-4Ј-oxa-
2Ј,6Ј- diazabicyclo[3.2.0]hept-2Ј-en-6Ј-yl}-3-methylbut-2-
enoate)-4-disulfide 3
To a stirred solution of cephalosporin() benzhydryl ester 2a
(1.506 g, 2.93 mmol) in dry acetonitrile (45 mL) was added a
solution of p-tert-butyliodobenzene difluoride (900 mg, 3.02
mmol) in dry acetonitrile (9 mL) via a polyethylene syringe
dropwise over 10 min. After 4.5 h the orange reaction mixture
was concentrated in vacuo, applied to a pad of silica and diluted
initially with petrol to remove starting material (33 mg, 2%) and
finally with ether to obtain the title compound 3 (400 mg, 27%).
An analytical sample was prepared by dissolving in benzene
and precipitating the required compound with petrol; mp 70 ЊC
(benzene:PE 30–40); [α]2D5 ϩ25.77Њ (c. 0.98, CHCl3); IR (CH2Cl2/
cmϪ1): νmax 3066, 2871, 1780 (β-lactam), 1719 (ester carbonyl),
δF Ϫ151.0 (dd J 73, 7 Hz); MS (EI): m/z 362 [M/2-F] ϩ, 349
ؒ
[M/2-S]ϩ, 303 [M/2-F
Ϫ
CO2Me]ϩ; Anal. calcd. for
C34H36N4O10S2F2: C, 53.68; H, 4.50; N, 7.37%. Found: C, 53.22;
H, 4.77; N, 7.11%.
Benzhydryl 4-methyl-2H,4H-isothiazole-3-carboxylate 11
To a stirred solution of cephalosporin() benzhydryl ester 2a
(1.0 g, 1.95 mmol) in acetonitrile (30 mL) was added a solution
of p-tert-butyliodobenzene dichloride (660 mg, 2.00 mmol) in
acetonitrile (7 mL) via a polyethylene syringe dropwise over 5
min. After 2 h silica was added and the orange reaction mixture
was concentrated in vacuo. Flash chromatography (SiO2, PE
30–40:ether 100:0 grading to 30:70) afforded the isothiazole 11
(190 mg, 31%), plus recovered starting material (400 mg, 40%).
Recrystallisation from PE:ether afforded an analytical sample;
mp 89–90 ЊC (PE:ether); IR (CH2Cl2/cmϪ1): νmax 3100–2900,
1598 (N᎐C), 1493, 1370, 1217, 1040; 1H NMR (250 MHz,
᎐
CDCl3): δH 2.18 (3H, s, 3-Me), 3.38 (1H, d J 13 Hz, 2-H), 3.50
(1H, d J 13 Hz, 2-H), 4.28 (1H, d J 12 Hz, 17-H), 4.40 (1H, d,
J 12 Hz, 17-H), 5.16 (1-H, d J 4 Hz, 7-H), 5.82 (1H, d J 4 Hz,
6-H), 6.75–7.30 (15H, m, Ar–H); 13C NMR (62.6 MHz,
CDCl3): δC 19.8 (C-9), 45.1 (C-2), 62.4 (C-17), 79.0 (C-11), 81.3
(C-7), 88.7 (C-6), 114.5 (C-20), 121.5 (C-3), 121.8 (C-21), 126.9,
127.1, 128.16, 128.21, 129.5 (Benzhy. and C-20), 139.1 and
139.4 (C-13 and C-13Ј), 151.6 (C-4), 157.6 (C-18), 162.0 (C-16),
165.5 (C-10), 166.5 (C-8); MS (FAB): m/z 407 [M/2-PhOCH2]ϩ;
Anal. calcd. for C58H50N4O10S2: C, 67.82; H, 4.91; N, 5.46%.
Found: C, 67.4; H, 4.9; N, 5.4%.
1
1725(ester carbonyl), 1410, 1340, 1235, 1150, 1080; H NMR
(90 MHz, CDCl3): δH 2.51 (3H, d, J 0.8 Hz, 4-Me), 7.1–7.5
(11H, m, Ph2CH ), 8.28 (1H, d J 0.8 Hz, 5-H); 13C NMR
(68 MHz, CDCl3): δC 14.3 (C-6), 78.0 (C-9), 128.6–127.3 (Ph),
138 (C-4), 147 (C-5), 160.5 (C-3), 189 (C-7); MS (EI): m/z 309
M
ϩ, 183 (Ph2CHO), 167 (Ph2CH)ϩ, 126 (M Ϫ Ph2CHO); Anal.
ؒ
calcd. for C18H15NO2S: C, 69.88; H, 4.89; N, 4.53%. Found: C,
69.88; H, 4.84; N, 4.40%.
Bis[benzhydryl 2ꢀ-fluoro-4-oxo-3ꢁ-(2-phenoxyacetamido)-1-
azetidine-3Ј-methylbut-2Ј-enoate]-4Ј-disulfide 4a
General procedure for the synthesis of ꢀ-phenylsulfanyl-
acetamides
To a stirred solution of cephalosporin() benzhydryl ester 2a
(500 mg, 0.97 mmol) in DCM (25 mL) was added a solution of
p-tert-butyliodobenzene difluoride (300 mg, 1.00 mmol) in
DCM (9 mL) via a polyethylene syringe dropwise over 7 min.
After 3 h the orange reaction mixture was concentrated in
vacuo, and filtered through a short pad of silica to remove
p-tert-butyliodobenzene, affording the fluoride 4a as a solid;
mp 79–80 ЊC; IR (CCl4/cmϪ1): νmax 3426 (NH), 3065, 1793
(β-lactam), 1724 (ester carbonyl), 1695, 1599; 1H NMR
(270 MHz, CDCl3): δH 2.25 (3H, s, 3-Me), 3.38 (1H, d J 14 Hz,
2-H), 3.80 (1H, d J 14 Hz, 2-H), 4.38 (1H, d J 14 Hz, 22-H),
4.47 (1H, d, J 14 Hz, 22-H), 4.90 (1H, dd J 7, 7 Hz, 7-H), 5.92
(1-H, d J 65 Hz, 6-H), 6.80–7.60 (15H, m, Ar–H); 13C NMR
(126 MHz, CDCl3): δC 19.6 (C-9), 43.4 (C-2), 62.9 (d J 23 Hz,
C-7), 67.1 (C-22), 78.8 (C-12), 98.7 (d J 242 Hz, C-6), 114.8
(C-25), 120.6 (C-3), 122.3 (C-27), 127–130 (C-26 ϩ other Ar),
139.4 (C-13), 153.6 (C-4), 156.9 (C-24), 162.05 (C-21), 162.8
(d J 11 Hz, C-10), 169.5 (C-8); 19F NMR (84.3 MHz, CDCl3): δF
Ϫ150.5 (dd J 65, 6 Hz); MS (FAB): m/z 501 [M/2-S]ϩ; Anal.
calcd. for C58H52N4O10S2F2: C, 65.27; H, 4.91; N, 5.25%.
Found: C, 65.90; H, 4.99; N, 5.22%.
Triethylamine or pyridine (1 eq.) was added to a stirred solution
of amine (1 eq.) in DCM (ca. 3 mL mmolϪ1). The mixture was
cooled in an ice–salt bath (<0 ЊC) and phenylsulfanylacetyl
chloride was added dropwise. Consumption of starting amine
was monitored by TLC and the reaction was quenched with
water upon completion. The aqueous phase was extracted with
DCM (×2), the combined extracts dried (MgSO4) and concen-
trated in vacuo. Flash chromatography followed by Kugelröhr
distillation or recrystallisation afforded pure products.
N-Allyl(phenylsulfanyl)acetamide 14
Colourless oil; Rf 0.22 (SiO2, PE 30–40:ether 50:50); IR (thin
film/cmϪ1): νmax 3289s (NH), 3075s, 2919s (CH), 1650 (amide I),
1537s (amide II), 1439s, 1311s, 1218s, 1154s, 1098m, 989m,
1
921m, 739s, 690s; H NMR (400 MHz, CDCl3): δH 3.61 (2H,
s, SCH2), 3.80–3.84 (2H, m, 1-H), 4.94–5.02 (2H, m, 3-H),
5.65–5.73 (1H, 2-H), 6.81 (1H, br, NH), 7.15–7.26 (5H, m,
Ar–H); 13C NMR (100 MHz, CDCl3): δC 37.7 (SCH2), 42.4
(1-C), 116.7 (3-C), 127.1, 128.4, 129.7, 134.0, 135.0 (Cipso), 168.0
Bis[methyl 2ꢀ-fluoro-4-oxo-3ꢁ-(2-phenoxyacetamido)-1-
azetidine-3Ј-methylbuten-2Ј-oate]-4Ј-disulfide 4b
(C᎐O); MS (FAB): m/z 208 (MHϩ, 100%); HRMS (FAB) calcd.
᎐
for C11H14NOS (MHϩ): 208.0796. Found: 208.0793.
To a stirred solution of cephalosporin() methyl ester 2b
(500 mg, 1.40 mmol) in DCM (25 mL) was added a solution of
p-tert-butyliodobenzene difluoride (425 mg, 1.43 mmol) in
DCM (9 mL) via a polyethylene syringe dropwise over 7 min.
After 3 h the orange reaction mixture was concentrated in vacuo
N-Cinnamyl(phenylsulfanyl)acetamide18 15
White solid; mp 101–102 ЊC (PE 30–40:ether); Rf 0.21 (SiO2, PE
30–40:ether 50:50); IR (thin film/cmϪ1): νmax 3295m (NH),
3057w, 2915m, 1646s (C᎐O), 1578m, 1524m, 1483m, 1436m,
᎐
J. Chem. Soc., Perkin Trans. 1, 2002, 2816–2826
2821

View Article Online
1
1320m, 1246w, 1022w, 968w, 737s, 689s; H NMR (300 MHz,
(57); HRMS (FAB) calcd. for C12H17NOS: 224.1109. Found:
CDCl3): δH 3.62 (2H, s, SCH2), 3.97 (2H, td J 6, 1 Hz, 1-H), 5.99
224.1120.
trans
trans
(1H, dt
J
16 Hz, 3J2,1 6 Hz, 2-H), 6.30 (1H, d
J
16 Hz,
AB
AB
3-H), 7.12–7.27 (10H, m, Ar–H); 13C NMR (75 MHz, CDCl3):
N-Phenyl(phenylsulfanyl)acetamide 21
δC 37.7, 42.0, 125.3, 126.7, 127.1, 128.1, 128.4, 128.9, 129.8,
Pink needles; mp 80–81 ЊC (DCM:hexane); Rf 0.68 (SiO2, PE
30–40:ethyl acetate 40:60); IR (KBr disc/cmϪ1): νmax 3311s
132.4, 135.0 (Cipso), 136.8 (Cipso), 168.0 (C᎐O); MS (FAB): m/z
᎐
306 (MNaϩ, 25%), 284 (MHϩ, 100); Anal. calcd. for
C17H17NOS: C, 72.05; H, 6.05; N, 4.96%. Found: C, 71.73; H,
5.89; N, 4.87%.
(NH), 3055w, 2924w, 1665s (C᎐O), 1599m, 1524s, 1439m,
᎐
1386m, 1317w, 1237m, 1152w, 1078w, 1025w, 888w, 749s, 688s,
1
485m; H NMR (400 MHz, CDCl3): δH 3.78 (2H, s, SCH2),
7.11–7.50 (10H, m, Ar–H), 8.59 (1H, br, NH); 13C NMR
N-(3-Methylbut-2-enyl)(phenylsulfanyl)acetamide 16
(75 MHz, CDCl3): δC 38.8 (SCH2), 120.3, 125.2, 127.5, 128.8,
White solid; mp 72–73 ЊC (ether); Rf 0.43 (SiO2, ether); IR (thin
129.5, 129.9, 134.5 (Cipso), 137.6 (Cipso), 166.4 (C᎐O); MS (EI):
᎐
film/cmϪ1): νmax 3286s (NH), 2967w (CH), 1649s (C᎐O), 1544w,
m/z 244 (M ϩ, 90%); Anal. Calcd. for C14H13NOS: C, 69.11; H,
ؒ
᎐
1480w, 735m, 693m; 1H NMR (300 MHz, CDCl3): δH 1.75 (3H,
s, CH3), 1.83 (3H, s, CH3), 3.78 (2H, s, SCH2), 3.97 (2H, t J 6
Hz, 1-H), 5.23 (1H, t J 7 Hz, 2-H), 6.84 (1H, br, NH), 7.34–7.48
(5H, m, Ar–H); 13C NMR (75 MHz, CDCl3): δC 18.3, 26.0,
37.7, 38.3, 119.8, 127.0, 128.6, 129.7, 135.0, 137.5, 168.3; MS
(FAB): m/z 258 (MNaϩ, 20%), 236 (MHϩ, 100); HRMS calcd.
for C13H18NOS (MHϩ): 236.1109. Found: 236.1093.
5.38; N, 5.76; S, 13.18%. Found: C, 68.90; H, 5.33; N, 5.67; S,
12.85%.
General procedure for the fluorination of substrates using DFIT
Reactions conducted at 0 ЊC: a solution of DFIT1 in DCM
was prepared in a 25 mL polypropylene flask protected from
light by aluminium foil. The solution was cooled to 0 ЊC in an
ice–salt bath and a solution of the substrate in DCM was then
added via cannula. The mixture was left to stir at this temper-
ature. Upon completion (TLC) the reaction was quenched
with water and extracted with DCM. The combined extracts
were dried (MgSO4) and concentrated in vacuo. Flash chroma-
tography yielded pure materials.
Reactions conducted at reflux: a solution of DFIT in DCM
was prepared in a 25 mL glass round-bottomed flask equipped
with a water-cooled reflux condenser. A solution of the sub-
strate in DCM was added via cannula and the mixture stirred at
reflux. Upon completion (TLC) the reaction was cooled to
room temperature and worked up as above.
N-Benzyl-N-methyl(phenylsulfanyl)acetamide 17
Colourless oil; Rf 0.51 (SiO2, PE 30–40:ether 60:40); IR (thin
film/cmϪ1): νmax 3058w, 3028w, 2924w, 1649s (C᎐O), 1582w,
᎐
1
1480, 1446m, 1400m, 1267w, 1092m, 738m, 696m; H NMR
(300 MHz, CDCl3): (E/Z) δH 2.82 and 2.83 (2 × 3H, 2 × s,
NCH3), 3.66 and 3.69 (2 × 2H, 2 × s, SCH2), 4.45 (2 × 2H, s,
NCH2), 7.04–7.43 (10H, m, Ar–H); 13C NMR (75 MHz,
CDCl3): (E/Z) δC 34.7 and 35.8 (NCH3), 37.3 and 37.5 (2-C),
51.6 and 54.3 (NCH2), 126.4, 126.9 (2C), 127.4, 127.7, 128.0,
128.6, 128.9, 129.0, 130.2, 130.3, 135.4 (Cipso), 135.5 (Cipso),
136.5 (Cipso), 137.3 (Cipso), 169.0 and 169.3 (C᎐O); MS (FAB):
᎐
m/z 272 (MHϩ, 100%); HRMS (FAB) calcd. for C16H17NOS
(MHϩ): 272.1109. Found: 272.1106.
N-Allyl(2-fluoro-2-phenylsulfanyl)acetamide 25 and N-allyl-
(2,2-diphenylsulfanyl)acetamide 37
N-Benzyl(phenylsulfanyl)acetamide 18
A solution of DFIT (91%, 294 mg, 1.1 mmol) and N-allyl-
(phenylsulfanyl)acetamide 14 (200 mg, 0.97 mmol) in DCM
(7 mL) refluxing for 2 h. Work-up according to the general
procedure followed by flash chromatography (SiO2, PE
30–40:ether 70:30) afforded the fluoride 25 (168 mg, 71%) as a
colourless oil; Rf 0.22 (SiO2, PE 30–40:ether 40:60); IR (thin
film/cmϪ1): νmax 3296m (NH), 3077m, 2924w (CH), 1669s
White solid; mp 52–54 ЊC (PE 30–40:ether); Rf 0.49 (SiO2, PE
30–40:ethyl acetate 40:60); IR (thin film/cmϪ1): νmax 3287m
(NH), 3063w, 2923w, 1651s (C᎐O), 1532m, 1476w, 1434w,
᎐
1315w, 1224w, 1155w, 1085w, 1022w, 742s, 686s; 1H NMR
(300 MHz, CDCl3): δH 3.84 (2H, s, SCH2), 4.58 (2H, d J 6 Hz,
NCH2), 7.20–7.46 (10H, m, Ar–H); 13C NMR (75 MHz,
CDCl3) δC 37.7 (SCH2), 44.1 (NCH2), 127.1, 127.9 (2C), 128.5,
(C᎐O), 1534s (amide II), 1478m, 1437m, 1272m, 1202w, 1070w,
᎐
992m, 923m, 825w, 746s, 691s; 1H NMR (300 MHz, CDCl3): δH
3.71 (2H, t J 6 Hz, 1Ј-H), 4.92–5.02 (2H, m, 3Ј-H), 5.46–5.59
(1H, m, 2Ј-H), 6.07 (1H, d 2JHF 53 Hz, 2-H), 6.22 (1H, br, NH),
7.27–7.55 (5H, m, Ar–H); 13C NMR (100 MHz, CDCl3): δC 41.6
129.7, 129.8, 134.9, 138.1, 168.1 (C᎐O); MS (FAB): m/z 280
᎐
(MNaϩ, 15%), 258 (MHϩ, 100); HRMS (FAB) calcd. for
C15H16NOS (MHϩ): 258.0953. Found: 258.0958.
N-Phenyl-N-methyl(phenylsulfanyl)acetamide 19
1
(1Ј-C), 97.5 (d JCF 234 Hz, 2-C), 116.9 (3Ј-C), 129.1, 129.3,
132.8, 132.9 (Cipso), 134.5, 164.7 (d 2JCF 24 Hz, C᎐O); 19F NMR
Yellow crystals; mp 70 ЊC (DCM:PE 30–40); Rf 0.53 (SiO2, PE
30–40:ether 60:40); IR (KBr disc/cmϪ1): νmax 2923w, 1651s
᎐
(282 MHz, CDCl3): δF Ϫ156.5 (d 2JFH 53 Hz). Recrystallisation
1
from DCM:PE 30–40 or MS analysis gave the amide 37: H
(C᎐O), 1588s, 1383s, 1297s, 1233s, 1118m, 895w, 743s, 697s,
᎐
1
NMR (500 MHz, CDCl3): δH 3.77–3.80 (2H, m, 1-H), 4.89
(1H, s, PhS2CH), 4.98–5.05 (2H, m, 3-H), 5.60–5.65 (1H, m,
2-H), 6.35 (1H, br, NH), 7.26–7.46 (10H, m, Ar–H); 13C NMR
(100 MHz, CDCl3): δC 42.6 (1-C), 58.3 (PhS2C), 117.2 (2-C),
556s; H NMR (400 MHz, CDCl3): δH 3.29 (3H, s, CH3), 3.52
(2H, s, SCH2) 7.14–7.40 (10H, m, Ar–H); 13C NMR (100 MHz,
CDCl3): δC 37.2 (SCH2), 37.9 (NCH3), 126.7, 127.4, 128.2,
128.9, 129.9, 130.2, 135.6 (SCipso), 143.4 (NCipso) 168.7 (C᎐O);
᎐
MS (EI): m/z 257 (M ϩ, 50%); Anal. Calcd. for C15H15NOS: C,
ؒ
128.9, 129.6, 132.6, 133.2, 133.6 (Cipso), 167.4 (C᎐O); MS
᎐
(FAB): m/z 316 (MHϩ, 60%), 231 ([(PhS)2CH]ϩ, 55), 206 ([M
Ϫ PhS]ϩ, 90), 178 (90), 153 (45), 123 (100); Anal. Calcd. for
C17H17NOS2: C, 64.73; H, 5.43; N, 4.44%. Found: C, 64.44; H,
5.37; N, 4.46%.
70.00; H, 5.87; N, 5.44%. Found: C, 69.91; H, 5.91; N, 5.34%.
N-Butyl(phenylsulfanyl)acetamide 20
Colourless oil; Rf 0.46 (SiO2, ether); IR (thin film/cmϪ1): νmax
3290s (NH) 2931m, 2869s (CH), 1653s (C᎐O), 1558s, 1442m,
1308m, 1152w, 1038s, 918w; H NMR (400 MHz, CDCl3): δH
᎐
N-Allyl(2,2-difluoro-2-phenylsulfanyl)acetamide 26
1
0.85 (3H, t J 7 Hz, CH3), 1.16–1.26 (2H, m, CH2CH3),
1.36–1.42 (2H, m, NCH2CH2), 3.24 (2H, m, NCH2), 3.64
A solution of DFIT (494 mg, 1.9 mmol) and N-allyl-
(phenylsulfanyl)acetamide 14 (200 mg, 0.97 mmol) in DCM
(7 mL) refluxing for 16 h. The mixture was diluted with
DCM and bound to SiO2. Flash chromatography (SiO2, PE
30–40:ether 70:30) afforded the difluoride 26 (129 mg, 61%) as
a colourless oil; Rf 0.13 (SiO2, PE 30–40:ether 50:50); IR (thin
(2H, s, SCH2), 6.81 (1H, br NH), 7.19–7.32 (5H, m, Ar–H); 13
C
NMR (75 MHz, CDCl3): δC 13.5 (CH3), 19.8 (CH2CH3), 31.2
(NCH2CH2), 37.1 (SCH2), 39.4 (NCH2), 126.4, 127.8, 129.2,
134.6 (Cipso), 167.4 (C᎐O); MS (FAB): m/z 224 (Mϩ, 100%), 123
᎐
2822
J. Chem. Soc., Perkin Trans. 1, 2002, 2816–2826

View Article Online
film/cmϪ1): νmax 3312s (NH), 3090w (CH), 1678s (C᎐O), 1538s
m/z 290 (MHϩ, 20%), 270 ([M Ϫ F]ϩ, 30); HRMS (FAB) calcd.
᎐
(amide II), 1436w, 1343w, 1265w, 1129w, 1084m, 1031w, 928m,
805w, 746m, 689m; 1H NMR (300 MHz, CDCl3): δH 3.85 (2H, t
J 6 Hz, 1Ј-H), 5.09–5.15 (2H, m, 3Ј-H), 5.63–5.76 (1H, m,
2Ј-H), 6.27 (1H, br, NH), 7.32–7.65 (5H, m, Ar–H); 13C NMR
(75 MHz, CDCl3): δC 42.5 (1Ј-C), 118.1 (3Ј-C), 122.8 (t
for C16H17FNOS (MHϩ): 290.1015. Found: 290.1007.
2-Methyl-3-oxo-4-phenylsulfanyl-1,2,3,4-tetrahydroisoquinoline
30
A solution of DFIT (91%, 337 mg, 1.2 mmol) and N-benzyl-N-
methyl(phenylsulfanyl)acetamide 17 (300 mg, 1.1 mmol) in
DCM (6 mL) at reflux for 3 h. Work-up according to the
general procedure followed by flash chromatography (SiO2, PE
30–40:ether 70:30) gave the tetrahydroisoquinoline 30 (140 mg,
47%) as a yellow oil; Rf 0.32 (SiO2, PE 30–40:ethyl acetate
40:60); IR (thin film/cmϪ1): νmax 3058m, 2926m, 1651s, 1439m,
1402m, 1139m, 1261m, 1087m, 747s, 695s; 1H NMR (300 MHz,
CDCl3): δH 2.90 (3H, s, CH3), 3.71 (1H, d JAB 13 Hz, 1-H), 3.87
(1H, d JAB 16 Hz, 1-H), 4.63 (1H, s 3-H), 6.87–7.24 (9H, m,
Ar–H); 13C NMR (75 MHz, CDCl3): δC 35.1 (CH3), 51.6 (4-C),
52.4 (1-C), 124.6, 127.3, 127.6, 128.3, 128.5, 129.0, 130.9, 132.0,
1JCF 289 Hz, 2-C), 125.3 (Cipso), 129.7, 131.0, 132.7, 137.2, 161.9
2
(t JCF 28 Hz, C᎐O); 19F NMR (282 MHz, CDCl3): δF Ϫ82.8;
᎐
MS (FAB): m/z 244 (MHϩ, 100%); HRMS (FAB) calcd.
for C11H12F2NOS (MHϩ): 244.0608. Found: 244.0613; plus
N-allyl(2-fluoro-2-phenylsulfanyl)acetamide 25 (22 mg, 10%).
N-Cinnamyl(2-fluoro-2-phenylsulfanyl)acetamide 27
A solution of DFIT (270 mg, 0.97 mmol) and N-cinnamyl-
(phenylsulfanyl)acetamide 15 (250 mg, 0.88 mmol) in DCM
(5 mL) refluxing overnight. Work-up according to the general
procedure followed by flash chromatography (SiO2, PE 30–
40:ether 50:50) afforded the fluoride 27 (146 mg, 55%) as a
white solid; mp 74–78 ЊC (DCM:PE 30–40); Rf 0.52 (SiO2, PE
30–40:ether 85:15); IR (thin film/cmϪ1): νmax 3391m (NH),
133.0, 135.6, 167.2 (C᎐O); MS (FAB): m/z 292 (MNaϩ, 15%),
᎐
270 (MHϩ, 100); HRMS (FAB) calcd. for C16H15NOS (MHϩ):
270.0952. Found: 270.0958; and the fluoride 29 (94 mg, 25%)
as a colourless oil.
3025w, 2925w, 1666s (C᎐O), 1519s, 1441w, 1362w, 1303w,
᎐
1
1261w, 1011m, 980m, 800w, 746s, 689s; H NMR (300 MHz,
3-Oxo-4-phenylsulfanyl-1,2,3,4-tetrahydroisoquinoline 31 and
N-benzyl(2-fluoro-2-phenylsulfanyl)acetamide 32
trans
CDCl3): δH 3.74–3.92 (2H, m, 1-H), 5.77 (1H, dt
J
16 Hz,
AB
3J2,1 6 Hz, 2-H), 6.05 (1H, d JHF 53 Hz, SCHF), 6.09 (1H, br,
2
trans
A solution of DFIT (91%, 474 mg, 1.76 mmol) and N-benzyl-
(phenylsulfanyl)acetamide 18 (400 mg, 1.55 mmol) in DCM
(10 mL) at reflux for 1 h. Work-up according to the general
procedure followed by flash chromatography (SiO2, PE 30–
40:ether 80:20) isolated the tetrahydroisoquinoline 31 (45 mg,
11%) as a colourless oil; Rf 0.21 (SiO2, PE 30–40:ether 50:50);
NH), 6.30 (1H, d
J
16 Hz, 3-H), 7.15–7.79 (10H, m, Ar–
AB
H); 13C NMR (75 MHz, CDCl3): δC 41.8 (1-C), 97.9 (d 1JCF 235
Hz, SCHF), 124.6, 126.8, 128.3, 129.0, 129.6, 130.0, 133.3,
135.26, 135.28, 136.6, 165.2 (d 2JCF 24 Hz, C᎐O); 19F NMR (282
᎐
2
MHz, CDCl3): δF Ϫ156.5 (d JFH 53 Hz); MS (FAB): m/z 302
(MHϩ, 100%); HRMS (FAB) calcd. for C17H17FNOS (MHϩ):
302.1015. Found: 302.1017.
IR (thin film/cmϪ1): νmax 3248m (NH), 3082w (CH), 1644s (C᎐
᎐
1
O), 1468w, 1420w, 1024w, 730m, 693m; H NMR (400 MHz,
CDCl3): δH 4.33 (2H, d J 6 Hz, 1-H), 4.94 (1H, s, 4-H), 6.72 (1H,
br, NH), 6.83–7.61 (9H, m, Ar–H); 13C NMR (75 MHz,
CDCl3): δC 43.9 (1-C), 57.7 (4-C), 127.5, 127.7, 128.4, 128.6,
N-(2-Fluoro-2-phenylsulfanyl)acetyl-3-methylbut-2-enylamine
28
A solution of DFIT (90 mg, 0.35 mmol) and N-(3-methylbut-2-
enyl)(phenylsulfanyl)acetamide 16 (75 mg, 0.32 mmol) in DCM
(4 mL) refluxing overnight. The reaction mixture was diluted
with DCM and bound to SiO2. Flash chromatography (SiO2,
PE 30–40:ether 50:50) afforded the fluoride 28 (20 mg, 25%) as
a colourless oil; Rf 0.33 (SiO2, PE 30–40:ether 50:50); IR (thin
129.2, 129.7, 132.3, 132.7, 137.3, 167.1 (C᎐O); MS (FAB): m/z
᎐
256 (MHϩ, 60%), 231 (55), 199 (40), 146 (100); HRMS (FAB)
calcd. for C15H13NOS (MHϩ): 256.0800. Found: 256.0796; and
the fluoride 32 (152 mg, 35%) as colourless crystals; mp 65 ЊC
(DCM:PE 30–40); Rf 0.22 (SiO2, PE 30–40:ether 50:50); IR
(thin film/cmϪ1): νmax 3391s (NH), 1669s (C᎐O), 1516m (amide
᎐
film/cmϪ1): νmax 3299m (NH), 2923w, 1667s (C᎐O), 1531m,
᎐
II), 1420w, 1300w, 1268w, 1065w, 1022w, 983m, 742m, 692m;
1442w, 1274w, 978m, 746m, 691m; 1H NMR (500 MHz,
CDCl3): δC 1.56 (CH3), 1.65 (CH3), 3.62–3.69 (2H, m, 1-H),
4.83–4.86 (1H, m, 2-H), 5.89 (1H, br, NH), 6.06 (1H, d 2JHF 53
Hz, SCHF), 7.31–7.56 (5H, m, Ar–H); 13C NMR (75 MHz,
1H NMR (300 MHz, CDCl3): δH 4.18–4.32 (2H, m, NCH2),
2
6.02 (1H, d JHF 52 Hz, 2-H), 6.35 (1H, br, NH), 6.90–7.55
(10H, m, Ar–H); 19F NMR (282 MHz, CDCl3): δF Ϫ156.8 (dd J
53, 3 Hz); MS (FAB): m/z 298 (MNaϩ, 20%), 276 (MHϩ, 90);
Anal calcd. for C15H14FNOS: C, 65.43; H, 5.12; N, 5.09; S,
11.65%. Found: C, 65.35; H, 5.00; N, 4.98; S, 11.89%.
1
CDCl3): δC 18.2, 26.0, 37.7, 98.0 (d JCF 235 Hz), 119.3, 129.5,
2
129.8, 135.1 (2C), 137.6, 165.0 (d JCF 24 Hz, C᎐O); 19F NMR
᎐
2
(282 MHz, CDCl3): δF Ϫ156.2 (d JFH 53 Hz); MS (FAB): m/z
1-Methyl-3-phenylsulfanylindol-2(3H)-one 3319
254 (MHϩ, 100%), 234 ([M Ϫ F]ϩ, 30); HRMS (FAB) calcd. for
C13H17FNOS (MHϩ): 254.1015. Found: 254.1030.
A solution of DFIT (91%, 237 mg, 0.86 mmol) and N-methyl-
N-phenyl(phenylsulfanyl)acetamide 19 (200 mg, 0.78 mmol)
in DCM (7 mL) at reflux for 4 h. Work-up according to the
general procedure followed by flash chromatography (SiO2, PE
30–40:ether 70:30) afforded the indolone 33 (117 mg, 59%) as a
red solid; Rf 0.53 (SiO2, PE 30–40:ether 80:30); IR (thin film/
N-Benzyl-N-methyl(2-fluoro-2-phenylsulfanyl)acetamide 29
A solution of DFIT (91%, 233 mg, 0.83 mmol) and N-benzyl-
N-methyl(phenylsulfanyl)acetamide 17 (207 mg, 0.76 mmol) in
DCM (6 mL) was stirred overnight. Work-up according to the
general procedure followed by flash chromatography (SiO2, PE
30–40:ether 70:30) gave the fluoride 29 (150 mg, 68%) as a col-
ourless oil; Rf 0.49 (SiO2, PE 30–40:ether 60:40); IR (thin film/
cmϪ1): νmax 3056m, 2932m (CH), 1715s (C᎐O), 1611s, 1470s,
᎐
1345s, 1308m, 1258m, 1162m, 1087s, 1021s, 922m, 865w, 746s,
1
691s; H NMR (300 MHz, CDCl3): δH 2.95 (3H, s, CH3), 4.49
cmϪ1): νmax 3061m, 2930m, 1666s (C᎐O), 1449s, 1265m, 1182m,
(1H, s 3-H), 6.56 (1H, d J 8 Hz, 7-H), 6.90–7.31 (8H, m, Ar–H);
13C NMR (75 MHz, CDCl3): δC 26.7 (CH3), 49.6 (3-C), 108.5
(7-C), 123.2, 125.6, 126.6, 129.0, 129.4, 131.3, 134.6, 144.3
᎐
1115m, 1025s, 913m, 742s, 696s; 1H NMR (300 MHz, CDCl3):
δH (E/Z) 2.85 and 2.96 (2 × 3H, s, CH3), 4.27–4.74 (2 × 2H, m,
NCH2), 6.24 and 6.25 (2 × 1H, d 2JHF 55 Hz, 2-H), 7.12–7.51 (2
× 10H, m, Ar–H); 13C NMR (75 MHz, CDCl3): δC (E/Z) 34.0
and 34.5 (CH3), 51.5 and 53.1 (NCH2), 96.8 and 97.8 (d 2JCF 232
Hz, 2-C) 127.4, 128.1, 128.4, 128.6, 129.2, 129.4, 129.5 (2C),
(7a-C), 174.7 (C᎐O); MS (FAB): m/z 256 (MHϩ, 40%), 159
᎐
(146, 100); HRMS (FAB) calcd. for C15H14NOS (MHϩ):
256.0796. Found: 256.0801.
N-Methyl-N-phenyl(phenylsulfinyl)acetamide 34
129.8, 131.8 (2 × Cipso), 132.0, 133.4 (2C), 136.0 (Cipso), 136.5
2
(Cipso), 164.5 and 164.8 (d JCF 24 Hz, C᎐O); 19F NMR (282
A solution of DFIT (219 mg, 0.85 mmol) and N-methyl-N-
phenyl(phenylsulfanyl)acetamide 19 (200 mg, 0.78 mmol) in
᎐
MHz, CDCl3): δF Ϫ153.8 and 151.8 (d 2JFH 53 Hz); MS (FAB):
J. Chem. Soc., Perkin Trans. 1, 2002, 2816–2826
2823

View Article Online
DCM (5 mL) was stirred for 5 h. Work-up according to the
general procedure followed by flash chromatography (SiO2, PE
40–60:ether 50:50 grading to 10% MeOH) yielded the sulfoxide
34 (176 mg, 86%) as a white solid; mp 100–101.5 ЊC (DCM:PE
30–40); Rf 0.15 (SiO2; ether); IR (thin film/cmϪ1): νmax 3058w,
64.47; H, 5.32; N, 6.88; S, 15.78%; plus 3,(syn/anti)-4-difluoro-
1-methyl-3-phenylsulfanyl-2-pyrrolidinone 46 (29 mg, 12%) as
a side product.
2) From 1-methyl-3,3-diphenylsulfanyl-2-pyrrolidinone 44
A solution of DFIT (325 mg, 1.27 mmol) and 1-methyl-3,3-
diphenylsulfanyl-2-pyrrolidinone21 44 (380 mg, 1.21 mmol) in
DCM (5 mL) was stirred for 18 h. The crude mixture was
diluted with DCM and absorbed onto SiO2. Flash chroma-
tography (SiO2, PE 30–40:ether 20:80) afforded the pyrroline 41
(202 mg, 82%) as a red solid, identical to material previously
prepared.
2923w, 1650s (C᎐O), 1593m, 1496m, 1383m, 1297w, 1116m,
᎐
1
1085m, 1047s, 749m, 698s; H NMR (400 MHz, CDCl3): δH
3.14, (3H, s, CH3), 3.42 (1H, AB d JAB 14 Hz, SCH2), 3.76 (1H,
AB d JAB 14 Hz, SCH2), 6.84 (2H, d J 8 Hz, Ar–H), 7.24–7.54
(8H, m, Ar–H); 13C NMR (75 MHz, CDCl3): δC 37.3 (CH3),
62.1 (SCH2), 124.3, 127.2, 128.4, 129.1, 129.9, 131.4, 142.5,
(Cipso), 143.6 (Cipso), 163.9 (C᎐O); MS (EI): m/z 273 (M ϩ, 80%),
ؒ
᎐
225 (40), 148 (100); Anal. Calcd. for C15H15NO2S: C, 65.91; H,
5.53; N, 5.12; S, 11.73%. Found: C, 65.94; H, 5.50; N, 5.12; S,
11.67%; plus 17 mg (9% recovery) of starting material.
1-Methyl-3-phenylsulfanyl-5,6-dihydro-2(1H)-pyridone 42
A solution of DFIT (54%, 463 mg, 0.98 mmol) and 1-methyl-3-
phenylsulfanyl-2-piperidinone21 39 (200 mg, 0.90 mmol) in
DCM (6 mL) was stirred for 24 h. Work-up according to the
general procedure followed by flash chromatography (SiO2, PE
30–40:ether 20:80) yielded the pyridone 42 (114 mg, 58%) as a
white solid mp 95–96 ЊC (DCM:PE 30–40); Rf 0.32 (SiO2, ethyl
acetate); IR (thin film/cmϪ1): νmax 3053w, 2932m, 2851m, 1635s
N-Butyl(phenylsulfinyl)acetamide 35
A solution of DFIT (468 mg, 1.8 mmol) and N-butyl(phenyl-
sulfanyl)acetamide 20 (186 mg, 0.83 mmol) in DCM (4 mL) was
stirred for 1.5 h. Work-up according to the general procedure
followed by flash chromatography (SiO2, PE 40–60:ether 50:50
grading to 10% MeOH) yielded the sulfoxide 35 (170 mg, 86%)
as a yellow oil, solidifying in the cold; Rf 0.08 (SiO2, ether); IR
(KBr disc/cmϪ1): νmax 3300s (NH) 3074m, 2957m, (CH), 1650s
(C᎐O), 1602s, 1480s, 1434s, 1400s, 1347s, 1306m, 1266m, 1212s,
᎐
1
1078s, 1024s, 930w, 856m, 823m, 755m, 695s; H NMR (400
MHz, CDCl3): δH 2.27–2.33 (2H, m, 5-H), 3.00 (3H, s, NCH3),
3.36 (2H, t J 7 Hz, 6-H), 5.76 (1H, t J 5 Hz, 4-H), 7.30–7.46
(5H, m, Ar–H); 13C NMR (100 MHz, CDCl3): δC 24.6 (5-C),
34.9 (CH3), 47.6 (6-C), 128.5, 129.4, 130.8 (4-C), 132.0, 134.5,
(C᎐O), 1544s, 1479m, 1222m, 1026w; 1H NMR (300 MHz,
᎐
CDCl3): δH 0.91 (3H, t J 7 Hz, CH3), 1.30–1.46 (4H, m,
CH2CH2), 3.19–3.23 (2H, m, NCH2), 3.50 (1H, AB d JAB 14 Hz,
SCH2), 3.71 (1H, AB d JAB 14 Hz, SCH2), 6.86 (1H, br NH),
7.53–7.62 (5H, m, Ar–H); 13C NMR (75 MHz, CDCl3): δC 13.6
(CH3), 19.9 (CH2CH3), 31.3 (NCH2CH2), 39.4 (NCH2), 58.6
136.8, 162.8 (C᎐O); MS (FAB): m/z 220 (MHϩ, 100%); Anal.
᎐
Calcd. for C12H13NOS: C, 65.72; H, 5.97; N, 6.39; S, 14.62%.
Found: C, 65.69; H, 5.99; N, 6.35; S, 14.93%; plus 3,(syn/anti)-
4-difluoro-1-methyl-3-phenylsulfanyl-2-piperidinone 47 (8 mg,
3%) as a side product.
(SCH2), 123.8, 129.3 131.5, 141.4 (Cipso), 163.4 (C᎐O); MS
᎐
(FAB): m/z 262 (MNaϩ 80%), 240 (MHϩ, 100); HRMS (FAB)
calcd. for C12H17NO2S: 239.0980; Found: 239.0971.
1-Methyl-3-phenylsulfanyl-1,5,6,7-tetrahydroazepine-2-one 43
A solution of DFIT (240 mg, 0.94 mmol) and 1-methyl-3-
phenylsulfanylcaprolactam 4021 (200 mg, 0.85 mmol) in DCM
(6 mL) was stirred 48 h. Work-up according to the general pro-
cedure followed by flash chromatography (SiO2, PE 30–40:ether
50:50) the tetrahydroazepin-2-one 43 (87 mg, 44%) as a yellow
oil; Rf 0.24 (SiO2, PE 30–40:ethyl acetate 40:60); IR (thin film/
N-Phenyl(phenylsulfinyl)acetamide 3620
A solution of DFIT (231 mg, 0.9 mmol) and N-phenyl(phenyl-
sulfanyl)acetamide 21 (200 mg, 0.82 mmol) in DCM (5 mL) was
stirred for 5 h. Work-up according to the general procedure
followed by flash chromatography (SiO2, PE 30–40 grading to
ether) yielded the sulfoxide 36 (165 mg, 78%) as a white solid;
mp 165–166 ЊC (DCM:PE 30–40); Rf 0.19 (SiO2, ether); IR
cmϪ1): νmax 3059m, 2950w, 2892m (CH), 1640s (C᎐O), 1476m,
᎐
1
1439m, 1396m, 1090m, 918w, 841w, 762m, 691m; H NMR
(KBr disc/cmϪ1): νmax 3454s (NH) 1679s (C᎐O), 1599m, 1539s,
(500 MHz, CDCl3): δC 1.94–2.00 (2H, m), 2.20–2.28 (2H, m),
3.06 (3H, s, CH3), 3.38 (2H, t J 6 Hz, 7-H), 6.21 (1H, t J 7 Hz,
4-H), 7.26–7.50 (5H, m, Ar–H); 13C NMR (126 MHz, CDCl3):
δC 24.8, 28.8, 35.2, 48.6, 128.1, 129.6, 132.9, 133.9, 134.1, 135.5,
᎐
1
1443m, 1326m, 1016s (S᎐O), 745s, 689s; H NMR (400 MHz,
᎐
CDCl3): δH 3.61 (1H, AB d JAB 14 Hz, SCH2), 3.94 (1H, AB d
JAB 14 Hz, SCH2), 7.08–7.65 (10H, m, Ar–H), 9.07 (1H, br
NH); 13C NMR (75 MHz, CDCl3): δC 58.9 (SCH2), 120.3,
124.0, 124.7, 129.0, 129.6, 131.8, 137.4 (Cipso), 140.9 (Cipso),
168.2 (C᎐O); MS (FAB): m/z 234 (MHϩ, 100%); HRMS (FAB)
᎐
calcd. for C13H16NOS (MHϩ): 234.0953. Found: 234.0936.
161.7 (C᎐O); MS (EI): m/z 259 (M ϩ, 50%), 211 (20), 106 (100);
ؒ
᎐
Anal. Calcd. for C14H13NO2S: C, 64.84; H, 5.05; N, 5.40; S,
12.36%. Found: C, 64.79; H, 5.03; N, 5.38; S, 12.08%; plus 41
mg (21% recovery) of starting material.
3,(anti/syn)-4-Difluoro-1-methyl-3-phenylsulfanyl-2-pyrrolidinone
45
A solution of DFIT (82%, 640 mg, 2.1 mmol), Et3Nؒ3HF (0.03
mL, 0.19 mmol) and 1-methyl-3-phenylsulfanyl-2-pyrrolidinone
38 (200 mg, 0.97 mmol) in DCM (6 mL) was stirred for 16 h.
Work-up according to the general procedure followed by flash
chromatography (SiO2, PE 30–40:ether 20:80) afforded 3,(anti/
syn)-4-difluoro-1-methyl-3-phenylsulfanyl-2-pyrrolidinone 45
(139 mg, 59%) as a colourless oil; syn:anti 1.75:1, from which
pure syn-45 could be crystallised: mp 91.5–93 ЊC (DCM:PE); Rf
1-Methyl-2-oxo-3-phenylsulfanyl-3-pyrroline 41
1) From 1-methyl-3-phenylsulfanyl-2-pyrrolidinone 38
A solution of DFIT (54%, 494 mg, 1.0 mmol) and 1-methyl-
3-phenylsulfanyl-2-pyrrolidinone21 38 (200 mg, 0.96 mmol) in
DCM (6 mL) was stirred for 18 h. Work-up according to the
general procedure followed by flash chromatography (SiO2, PE
30–40:ether 20:80) afforded the pyrroline 41 (110 mg, 56%) as a
red solid, mp 75–76 ЊC (hexane:ethyl acetate); Rf 0.18 (SiO2,
0.30 (SiO2, ether); IR (thin film/cmϪ1): νmax 2927w (CH), 1717s
1
(C᎐O), 1436m, 1307m, 1149m, 1053s, 756m, 694s; H NMR
᎐
ether); IR (thin film/cmϪ1): νmax 2920w, 1683s (C᎐O), 1597w,
(400 MHz, CDCl3): δH 2.96 (3H, s, CH3), 3.49 (1H, ddd 3JHF 22
᎐
1475m, 1443m, 1401m, 1291w, 1231w, 1036m, 933m, 801m,
Hz, 2JHH 12 Hz, 3JHH 1 Hz, 5-H), 3.80 (1H, ddd 3JHF 32 Hz, 2JHH
1
3
2
3
761m, 690m; H NMR (400 MHz, CDCl3): δH 3.02 (3H, s,
12 Hz, JHH 3 Hz, 5-H), 4.85 (1H, dd JHF 53 Hz, JHH 3 Hz,
CH3), 3.84 (2H, d J5,4 2 Hz, 5-H), 6.20 (1H, t J4,5 2 Hz, 4-H),
7.31–7.50 (5H, m, Ar–H); 13C NMR (100 MHz, CDCl3): δC 29.7
(CH3), 53.6 (5-C), 128.8, 129.5, 130.7, 131.5, 133.7, 137.6, 168.2
4-H), 7.28–7.62 (5H, m, Ar–H); 13C NMR (100 MHz, CDCl3):
2
1
δC 30.2 (CH3), 51.9 (d JCF 24 Hz, 5-C), 87.3 (dd JCF 199 Hz,
2JCF 19 Hz, 4-C), 99.6 (dd 1JCF 238 Hz, 2JCF 17 Hz, 3-C), 127,2
(C᎐O); MS (FAB): m/z 206 (MHϩ, 100%); Anal. Calcd. for
(Cipso), 129.5, 130.2, 135.3, 164.6 (d 2JCF 27 Hz, C᎐O); 19F NMR
᎐
᎐
C11H11NOS: C, 64.36; H, 5.40; N, 6.82; S, 15.66%. Found: C,
(564 MHz, CDCl3): δF Ϫ190.6–190.8 (m, 4-F), Ϫ155.9 (d JFF 17
2824
J. Chem. Soc., Perkin Trans. 1, 2002, 2816–2826

View Article Online
Hz, 3-F); MS (FAB): m/z 244 (MHϩ, 100%); Anal. Calcd. for
C11H11F2NOS: C, 54.31; H, 4.56; N, 5.76; S, 13.18%. Found: C,
54.17; H, 4.30; N, 5.70; S, 13.37%; anti-52: Rf 0.35 (SiO2, ether);
1H NMR (400 MHz, CDCl3): δH 2.87 (3H, s, CH3), 3.43–3.52
(1H, m, 5-H), 3.63–3.70 (1H, m, 5-H), 4.98–5.17 (1H, m, 4-H),
7.29–7.61 (5H, m, Ar–H); 19F NMR (564 MHz, CDCl3): δF
Ϫ191.64–191.46 (m, 4-F), Ϫ136.79 (dd J 17, 12 Hz, 3-F); plus
1-methyl-2-oxo-3-phenylsulfanyl-3-pyrroline 41 (20 mg, 8%) as
a side product.
H), 7.33–7.74 (10H, m, Ar–H); 19F NMR (376 MHz, CDCl3):
δF Ϫ154.0 (d 3JFF 17 Hz 3-F), Ϫ134.2 (m, 4-F).
(syn/anti)-1-n-Butyl-3-fluoro-3-phenylsulfinylazetidin-2-one 52
and 1-n-butyl-3-fluoro-3-phenylsulfanylazetidin-2-one 51
A solution of DFIT (304 mg, 1.2 mmol) and 1-n-butyl-3-
phenylsulfanylazetidin-2-one22 50 (127 mg, 0.54 mmol) in
DCM (4 mL) was stirred overnight. Work-up according to the
general procedure followed by flash chromatography (SiO2,
hexane:ether 50:50) yielded the fluoro-sulfide 51 16 (12 mg, 9%)
as a colourless oil; 1H NMR (400 MHz, CDCl3): δH 0.94 (3H, t
J 7 Hz, CH3), 1.31–1.57 (4H, m, CH2CH2), 3.22–3.32 (2H, m,
NCH2CH2), 3.49 (1H, t, 2JHH 6 Hz, 3JHF 6 Hz, 4-H), 3.63 (1H, t
2JHH 6 Hz, 3JHF 6 Hz, 4-H), 7.26–7.67 (5H, m, Ar–H); 19F NMR
(376 MHz, CDCl3): δF Ϫ137.9 (t, J 6 Hz); and the fluoro-
sulfoxide 52 (66 mg, 45%) as a colourless oil; [ca. 3:1 ratio of
diastereoisomers (unassigned)]; Rf 0.28 (SiO2, PE 40–60:ether
50:50); IR (thin film/cmϪ1): νmax 2928s and 2874s (CH), 1770
3,(anti/syn)-4-Difluoro-1-methyl-3-phenylsulfanyl-2-piperidinone
46
A solution of DFIT (510 mg, 1.8 mmol) and 1-methyl-3-
phenylsulfanyl-2-piperidinone 39 (200 mg, 0.9 mmol) in DCM
(6 mL) was stirred for 4 h. Work-up according to the general
procedure followed by flash chromatography (SiO2, PE:ether
20:80)
yielded
3,(anti/syn)-4-difluoro-1-methyl-3-phenyl-
sulfanyl-2-piperidinone 46 (88 mg, 39%) as a clear oil; anti:syn
2:1; IR (thin film/cmϪ1): νmax 2946m (CH), 1666s (C᎐O), 1501m,
(C᎐O), 1445m, 1404m, 1280m, 1182m, 1087s, 1055s, 876w,
᎐
᎐
750s, 689s; 1H NMR (300 MHz, CDCl3): δH 0.80 (3H, t J 7 Hz,
CH3 minor diastereoisomer), 0.90 (3H, t J 7 Hz, CH3 major),
1.06–1.60 (8H, m, 2 × CH2CH2), 2.99–3.35 (5H, m, 2 × NCH2,
1441m, 1405m, 1349m, 1212m, 1051m, 1024m, 970m, 842m,
753m. Pure anti-46 could be crystallised from the mixture: mp
1
83–84 ЊC (PE 30–40:ethyl acetate); Rf 0.29 (SiO2, ether); H
3
3
4-H major), 3.52 (1H, dd JHF 10 Hz, JHH 7 Hz, 4-H minor),
NMR (400 MHz, CDCl3): δH 2.20–2.32 (2H, m, 5-H), 2.97 (3H,
s, CH3), 3.24–3.35 (1H, m, 6-H), 3.52–3.63 (1H, m, 6-H), 4.50
(1H, dm 2JHF 47 Hz, 4-H), 7.26–7.63 (5H, m, Ar–H); 13C NMR
(100 MHz, CDCl3): δC 24.3 (d 2JCF 21 Hz, 5-C), 35.2 (CH3), 44.6
(d 3JCF 7 Hz, 6-C), 86.6 (dd 1JCF 183 Hz, 2JCF 36 Hz, 4-C), 102.0
2
3
3.81 (1H, dd, JHH 7 Hz, JHF 7 Hz 4-H minor), 3.85 (1H, dd
2JHH 7 Hz, JHF 7 Hz, 4-H major), 7.26–7.75 (10H, m, Ar–H);
3
13C NMR (151 MHz, CDCl3): δC (major diastereoisomer only)
13.5 (CH3), 19.9 (CH2CH3), 29.1 (NCH2CH2), 42.1
2
1
1
2
(NCH2CH2), 46.3 (d JCF 22 Hz, 4-C), 108.8 (d JCF 277 Hz,
3-C), 125.4, 129.1, 132.3, 137.6 (Cipso), 159.7 (d 2JCF 22 Hz, 2-C);
19F NMR (470 MHz, CDCl3): δF Ϫ168.9 (t, JFH 8 Hz, major),
Ϫ165.6 (t JFH 9 Hz, minor); MS (FAB): m/z 292 (MNaϩ, 25%),
270 (MHϩ, 100), 171 (95).
(dd JCF 224 Hz, JCF 25 Hz, 3-C), 127.8 (Cipso), 129.0, 129.9,
136.9, 162.3 (d 2JCF 23 Hz, C᎐O); 19F NMR (376 MHz, CDCl3):
᎐
δF Ϫ136.3–136.0 (m, 4-F), Ϫ72.0 (d, J 31 Hz, 3-F); MS (FAB):
m/z 258 (MHϩ, 100%), 210 (50); Anal. Calcd. for C12H13F2-
NOS: C, 56.02; H, 5.09; N, 5.44; S, 12.46%. Found: C, 56.03;
H, 4.93; N, 5.42; S, 12.27%; syn-46 (160): Rf 0.33 (SiO2, ether);
1H NMR (400 MHz, CDCl3): δH 2.15–2.24 (1H, m, 5-H),
2.63–2.83 (1H, m, 5-H), 2.98 (3H, s, CH3), 3.34 (1H, dd J 12, 7
An analytical sample of fluorosulfoxide 52 (ca. 20 mg) was
dissolved in DCM (1 mL) at 0 ЊC was treated with mCPBA
(68%, 50 mg). After stirring for 1 h sat. aq. NaHSO3 solution
(1 mL) was added and the mixture stirred a further 3 h. The
organic phase was separated, washed with sat. aq. NaHSO3
solution, brine, then dried (MgSO4) and concentrated in vacuo
to afford the sulfone derivative contaminated with mCBA as a
white solid; 1H NMR (300 MHz, CDCl3): δH 0.98 (3H, t J 7 Hz,
CH3), 1.34–1.68 (4H, m, CH2CH2), 3.29–3.46 (2H, m, NCH2),
2
Hz, 6-H), 3.59 (1H, td J 12, 5 Hz, 6-H), 4.76 (1H, dm JHF 51
Hz, 4-H), 7.26–7.63 (5H, m, Ar–H); 13C NMR (100 MHz,
CDCl3): δC 25.8 (d 2JCF 23 Hz, 5-C), 35.0 (CH3), 44.6 (6-C), 88.7
(dd 1JCF 185 Hz, 2JCF 22 Hz, 4-C), 97.6 (dd 1JCF 238 Hz, 2JCF 20
Hz, 3-C), 127.1 (Cipso), 129.5, 130.3, 136.0, 163.3 (d 2JCF 25 Hz,
C᎐O); 19F NMR (376 MHz, CDCl3): δF Ϫ145.3–145.0 (m, 4-F),
᎐
3
3
2
3.66 (1H, dd JHF 10 Hz, JHH 7 Hz, 4-H), 4.18 (1H, dd JHH
7
Ϫ93.4 (d, J 18 Hz, 3-F).
Hz, 3JHF 7 Hz, 4-H), 7.28–8.12 (5H, m, Ar–H); 19F NMR (470
MHz, CDCl3): δF Ϫ165.8 (t, JFH 8 Hz); MS (FAB): m/z 286
(MHϩ, 70%); HRMS (FAB) calcd. for C13H17FNO3S (MHϩ):
286.0913. Found: 286.0923.
3,(syn/anti)-4-Difluoro-1-methyl-3,(syn/anti)-4-diphenylsulfanyl-
2-pyrrolidinone 47
A solution of DFIT (402 mg, 1.57 mmol) and 1-methyl-3,3-
diphenylsulfanyl-2-pyrrolidinone 44 (150 mg, 0.47 mmol) in
DCM (6 mL) was stirred for 1 h. The reaction was quenched
with sat. aq. NaHCO3 solution and worked up as normal. Flash
chromatography (SiO2, PE 30–40:ether 75:25) yielded 3,(syn/
anti)-4-difluoro-1-methyl-3,(syn/anti)-4-diphenylsulfanyl-2-
pyrrolidinone 47 (75 mg, 45%) as a clear oil; anti:syn 2:1. Pure
anti-47 could be crystallised from the mixture: mp 126–128 ЊC
(DCM:PE 30–40); Rf 0.33 (SiO2, PE 30–40:ether 60:40); IR
Crystal data for syn-45
C11H11F2NOS, M = 243.37, 0.50 × 0.50 × 0.40 mm3,
monoclinic, space group P21/n, a = 7.5687(4), b = 13.7172(7),
c = 10.6303(5) Å, V = 1103.62(10)Å3, Z = 4, Dc = 1.464 g cmϪ3
,
F000 = 504, MoKα radiation, λ = 0.71070 Å, T = 100(2) K, 2θmax
= 52.0Њ, 9585 reflections collected, 2163 unique (Rint = 0.0259).
Final GoF = 1.050, R1 = 0.0344, wR2 = 0.0830, R indices based
on 1882 reflections with I > 2σ(I ) (refinement on F 2), 146
(thin film/cmϪ1): νmax 1734s (C᎐O), 1475w, 1439w, 1404w,
᎐
parameters, 0 restraints. µ = 0.297 mmϪ1
.
1283w, 1209w, 1045m, 995w, 929w, 893w, 728m, 690m; 1H
NMR (300 MHz, CDCl3): δC 2.81 (3H, s, CH3), 3.27 (1H, dd
Crystal data for anti-46
3
2JHH 11 Hz, JHF 2 Hz, 5-H), 3.57 (1H, t J 11 Hz, 5-H), 7.33–
7.74 (10H, m, Ar–H); 13C NMR (75 MHz, CDCl3): δC 30.4
(NCH3), 54.5 (d 2JCF 34 Hz, 5-C), 103.7 (dd 1JCF 242 Hz, 2JCF 19
Hz, 4-C) 106.8 (dd 1JCF 242 Hz, 2JCF 19 Hz, 3-C), 126.7 (Cipso),
128.4 (Cipso), 129.4, 129.9, 130.5, 130.6, 136.4, 136.9, 163.6 (dd
C12H13F2NOS, M = 257.29, 0.40 × 0.30 × 0.25 mm3, ortho-
rhombic, space group Pnma (No. 62), a = 14.3816(12), b =
9.2890(9), c = 9.0729(4) Å, V = 1212.05(16) Å3, Z = 4, Dc = 1.410
g cmϪ3, F000 = 536, Nonius KappaCCD, MoKα radiation, λ =
0.71073 Å, T = 100(2) K, 2θmax = 55.0Њ, 2617 reflections col-
lected, 1457 unique (Rint = 0.0517). Final GoF = 1.102, R1 =
0.0514, wR2 = 0.1049, R indices based on 1129 reflections with
I > 2σ(I ) (refinement on F 2), 150 parameters, 0 restraints. Lp
and absorption corrections applied, µ = 0.275 mmϪ1. CCDC
197047. See http://www.rsc.org/suppdata/p1/b2/b209078c/ for
crystallographic files in CIF or other electronic format.
3
2JCF 30 Hz, JCF 4 Hz, 2-C); 19F NMR (376 MHz, CDCl3): δF
Ϫ144.2 (d 3JFF 9 Hz 3-F), Ϫ132.9 (t, J 10 Hz, 4-F); MS (FAB):
m/z 484 (MCsϩ, 100%), 393 (33), 352 (MHϩ, 35%); Anal. Calcd.
for C17H15F2NOS2: C, 58.10; H, 4.30; N, 3.98; S, 18.25%.
Found: C, 58.11; H, 4.11; N, 4.05; S, 18.40%; syn-78: 1H NMR
3
(300 MHz, CDCl3): δC 2.81 (3H, s, CH3), 3.34 (1H, dd JHF 14
Hz, 2JHH 11 Hz, 5-H), 3.75 (1H, dd 2JHF 25 Hz, 3JHH 11 Hz, 5-
J. Chem. Soc., Perkin Trans. 1, 2002, 2816–2826
2825

View Article Online
formation to N-allyl(2,2-diphenylsulfanyl)acetamide, a reaction
which occurred during recrystallisation from DCM:PE mixtures. We
are currently investigating this behaviour and will report our results
in due course.
Acknowledgements
We are grateful to the EPSRC for the award of studentships to
M.F.G. and J.J.E.
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1985, 542; (d ) D. Craig, K. Daniels and A. Roderick-Mackenzie,
Tetrahedron, 1993, 49, 11263.
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