A radical based addition-elimination route for the preparation of indoles

Article abstract of DOI:10.1039/b002565h

Indoles, including tricyclic derivatives, are produced by cyclisations of aryl radicals onto vinyl halides followed by elimination of halide radical and tautomerism of the resulting product; the aryl radicals are produced using "clean methodology" either by reaction of iodide ions with arenediazonium salts or by reaction of phosphorus-centred radicals with aryl iodides. The Royal Society of Chemistry 2000.

Full text of DOI:10.1039/b002565h

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A radical based addition–elimination route for the preparation of
indoles
John A. Murphy,*a Karen A. Scott,a Rhona S. Sinclair,a Concepcion Gonzalez Martin,a
Alan R. Kennedya and Norman Lewisb
1
a Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street,
Glasgow, UK G1 1XL
b SmithKline Beecham Pharmaceuticals, Old Powder Mills, Leigh, Tonbridge, Kent,
UK TN11 9AN
Received (in Cambridge, UK) 31st March 2000, Accepted 3rd May 2000
Published on the Web 10th July 2000
Indoles, including tricyclic derivatives, are produced by cyclisations of aryl radicals onto vinyl halides followed by
elimination of halide radical and tautomerism of the resulting product; the aryl radicals are produced using “clean
methodology” either by reaction of iodide ions with arenediazonium salts or by reaction of phosphorus-centred
radicals with aryl iodides.
radical generation. Furthermore, indoles in which the pyrrole
Introduction
ring is fused to another ring e.g. 2, n = 0, 1, 2, could not be
generated in this manner since an alkyne cannot be conveni-
ently present in a ring smaller than eight atoms.
The preparation of the indole nucleus has inspired numerous
different synthetic approaches, but, surprisingly, few use the
chemistry of free radicals.1–4 A notable recent exception is
depicted in Scheme 12 featuring cyclisation onto the alkyne 1.
Accordingly, our proposal envisaged5 a very direct and
simple addition–elimination route to indoles involving 5-exo-
trig cyclisation of an aryl radical 3 (generated from the corre-
sponding arenediazonium salt or aryl iodide) onto a suitably
substituted olefin to give alkyl radical 4. Then, if X is a good
radical leaving group, β-elimination should occur resulting in
the formation of the exocyclic alkene 5, which should possess a
strong driving force to tautomerise to its more stable aromatic
tautomer, the indole 6. This approach should permit simple
access to a very wide range of indoles including the tricyclic
indoles 2.
Discussion
Two considerations are central to this work: (i) the method of
radical generation and (ii) the nature of the leaving group in
the addition–elimination reaction. To make radical chemistry
applicable to pharmaceutical preparation, it is necessary that
tin-based methods are avoided, and extensive research is
underway in this area.6 This consideration governed our selec-
tion of two methods for radical generation. Arenediazonium
salts7 afford aryl radicals when reacted with electron donors,
and this has recently been used for extensive studies on the
tetrathiafulvalene-triggered radical–polar crossover reaction.7a
The second method involved aryl iodides, which are converted
to aryl radicals on reaction with AIBN and hypophosphorous
acid8 and its salts. This method has recently been used for the
formation of carbon–carbon bonds, and Fukuyama et al. have
elegantly deployed4c,d the method for the formation of indoles.
However their approach is quite different from that proposed
here, involving thioamides 7 as substrates (Scheme 2).
Selection of these methods in turn influenced our choice of
leaving group, X . For the aryl iodide reactions, it is appropriate
Scheme 1
ؒ
This example provides a background for our study. The current
drive to make radical chemistry more environmentally accept-
able would preclude the use of the radioactive samarium
diiodide or a carcinogenic reagent like hexamethylphospho-
ramide. Our wish was to extend the scope of radical approaches
to the synthesis of indoles to include alternative methods of
to choose bromine as the leaving group, since it has been shown
that aryl carbon–bromine bonds are far less reactive to the
phosphorus-centred radicals than aryl carbon–iodine bonds;4,8
extrapolation suggests that vinyl bromides should also be
relatively unreactive. The alternative leaving groups which were
considered were sulfur leaving groups, i.e. thiyl, sulfenyl and
DOI: 10.1039/b002565h
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This journal is © The Royal Society of Chemistry 2000
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sulfinyl radicals arising from the corresponding sulfide, sulf-
oxide and sulfone respectively.9 Hypophosphorous acid is a
dibasic acid, and its commerically available N-ethylpiperidine
salt is still a monobasic acid, so the most acid-sensitive of the
three groups, the vinyl sulfide was not selected. A vinyl sulfone
was ultimately selected, and its synthesis and reactions are
described below.
In planning the use of arenediazonium salts as aryl radical
precursors, the vinyl sulfones are not so appropriate, since the
diazonium salt would be prepared from the corresponding
amine 8, and such an amine could undergo intermolecular
or intramolecular nucleophilic attack on the vinyl sulfone. On
the other hand, vinyl bromides appeared quite appropriate
radicophiles for the diazonium salt substrates.
MCPBA.11 Subsequent elimination of hydrogen bromide from
this intermediate compound was effected with sodium acetate
at ambient temperature, affording the desired 1-(bromomethyl)-
vinyl methyl sulfone 14 in 48% over three steps from 12.
Coupling of N-(2-iodophenyl)methanesulfonamide 16 with
1-(bromomethyl)vinyl methyl sulfone 14, afforded 15 (47%).
This compound showed restricted rotation in its 1H NMR spec-
trum where the two protons of the CH2 group resonated at
δ 4.57 and 4.91. This restricted rotation was a general feature of
the N-alkyl o-nitro- (or o-iodo)-arenesulfonamides in this study.
Sulfonamide 15 was then reacted with N-ethylpiperidine hypo-
phosphite (EPHP) and AIBN. This did not afford the expected
indole, however, but rather the iodophenylmethanesulfonamide
16 and its de-iodinated analogue. No sulfone-containing
product was isolated. The observed fragmentation may have
occurred either by addition of a phosphorus radical to the
unsubstituted alkene terminus in 15 followed by loss of the
arenesulfonamidyl radical—or by attack of hypophosphite
anion as a nucleophile expelling the sulfonamide anion. Hence,
it was clear that exploring the chemistry of vinyl sulfones was
not the best way forward, and so, vinyl bromides were explored.
Vinyl sulfone substrate 15
The target indole was N-methylsulfonyl-3-methylindole 11
which might be produced by the cyclisation shown in Scheme 3.
Although possible complications with the regiochemistry
of cyclisation could arise, we were confident that the 5-exo-
cyclisation should be more rapid than the potential 6-endo
alternative in the light of the work of Harvey and Whitham10
who had shown that 9 afforded 10 selectively. Aryl radicals are
normally more selective than alkyl radicals for 5-exo over
6-endo cyclisation.
Vinyl bromide substrates
Initially, three simple substituted vinyl bromides 17a–c were
selected for synthesis (Scheme 4). Bromination of alkenes 18
was effected using 0.9 equiv. of bromine at Ϫ10 ЊC, the low tem-
perature being required in order to minimise side-reactions.
Dehydrobromination of the intermediate dibromo compound
occurred cleanly on treatment with base. Luche reduction12
of the ketones 19a, 19b or DIBAL-H reduction of the ester
19c afforded the allylic alcohols 20. These were subjected to
Mitsunobu reaction13 with the sulfonamide 21 affording the
nitroarenes 22 efficiently. The product from coupling of alcohol
20a appeared to be more complex than expected, with four sets
of signals being visible in the NMR spectra for many of its
To prepare the desired diazonium salt, allyl methyl sulfide 12
was converted to the intermediate dibromo compound, which
was then oxidised to the corresponding sulfone 13 using
1
protons (e.g. 4 methyl resonances in the H NMR spectrum).
Our suspicions that the Mitsunobu coupling of this alcohol
1
were not regiospecific were confirmed by H–13C correlation
spectroscopy. This showed that the upfield two quartets in the
proton NMR spectrum mapped onto aliphatic methine signals,
while the downfield pair of quartets mapped onto vinyl methine
signals. As the mixture was inseparable, we proceeded to use
this for the transformations described below.
Reduction was achieved using sodium borohydride and
copper() acetylacetonate in ethanol.14 Care had to be taken at
Scheme 2
Scheme 3 Reagents and conditions: (i) Br2, CCl4, Ϫ10 ЊC→rt, 15 min, then MCPBA, Ϫ10 ЊC to rt, 6 h, then NaOAc, Et2O, rt, 48%; (ii) NaH,
IC6H4NHMs (16), DMF, rt, 47%; (iii) AIBN, EPHP, PhH, reflux.
2396
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Scheme 4 Reagents and conditions: (i) Br2, CCl4, Ϫ10 ЊC, then Et3N, CH2Cl2, rt; (ii) NaBH4, CeCl3ؒ7H2O, MeOH, 0 ЊC for conversion of 19a, 19b,
DIBAL-H, THF, Ϫ78 ЊC for conversion of 19c; (iii) DEAD, Ph3P, THF, 0 ЊC; (iv) NaBH4, Cu(acac)2, EtOH, rt; (v) NOBF4, CH2Cl2, rt; (vi) NaI,
AR acetone, rt.
this stage to ensure reduction of the olefin was avoided. Thus, if
any starting material was still present by TLC analysis (even
after longer reaction times) then, rather than adding more
sodium borohydride, the reaction was simply worked up and
the two compounds separated by column chromatography. It
should also be noted that washing the organic extracts of the
reaction mixture with ammonia solution during work-up
allowed the facile removal of any copper residues that were
often otherwise difficult to remove from the desired compound,
even by column chromatography. It was noteworthy that the
NMR spectrum of the purified amine 23a was simpler than its
precursor nitro compound; for example, only two doublets were
present for its CH–CH3 methyl group (4 doublets had been
present at the preceding nitro stage which had comprised 22a
and 22aЈ). The chemical shifts were consistent with pure 23a
rather than the reduction product of 22aЈ.
The aryl amines 23 were subsequently subjected to diazotis-
ation. This procedure gave dry diazonium salts 17, and as such
was preferred to the aqueous fluoroboric acid and sodium nitrite
conditions used by Beckwith and Meijs.7f The intermediate
diazonium salts were isolated simply by evaporation of the
reaction solvent and treated with sodium iodide to induce rad-
ical cyclisation7f onto the pendant vinyl bromide. A vigorous
evolution of gas accompanied this reaction which afforded the
indole products 24 directly when prolonged reaction times were
used, tautomerism occurring in situ.
Having completed the synthesis of the simple indoles, atten-
tion focused on the more complex tricyclic products 24d and
24e (Scheme 5). The precursor diazonium salts were prepared
from cyclohexenone and cyclopentenone in an analogous
manner to the previous examples. Restricted rotation was seen
in compounds 22d and 22e by 1H NMR, with the two rotamers
being present in these compounds in ratios of 2:1 and 7:1
respectively. Compound 22e afforded the indole product
(54%) following tautomerisation. However, the exocyclic alkene
intermediate 25e could be isolated when the reaction was
worked up immediately after adding the iodide ion. Thus the
intermediate 25e was isolated in 15% yield, as well as the desired
indole 24e in 35% yield. The alkene 25e was then efficiently
converted to the indole 24e by treatment with acid. The com-
bined yield of indole by this method was thus 49%.
Attention now turned to the synthesis of indole 24f (Scheme
6). This molecule was of interest because the important anti-
cancer drugs vinblastine15 and vincristine contain such a system
where the fused-ring is nine-membered. Since cyclonon-2-en-1-
one is not commercially available, and seemed difficult to pre-
pare, the alcohol, 20f, required for the Mitsunobu reaction was
prepared by the known procedure from 9,9-dibromobicyclo-
[6.1.0]nonane 26, using a silver ion-promoted ring expansion.16
The 1H NMR spectrum of alcohol 20f was intriguing, since it
showed three sets of peaks for every proton. The smallest peak
1
(~7% by H NMR) represents the (E)-isomer. The other two
peaks (37% and 56%) represent the (Z)-isomer, which existed as
two separate conformers at room temperature. This result is in
agreement with the previously reported analysis of this com-
pound.16 The isomers of the alcohol could not be separated, but
in principle this did not pose a problem, since all the isomers
should react to give the same intermediate radical during the
final cyclisation. The Mitsunobu reaction to form 22f was
initially attempted using triphenylphosphine and diethyl azodi-
carboxylate (DEAD) in THF at 0 ЊC, but only a trace amount
of the nitro product was obtained. The reaction was then
repeated using the smaller phosphine, diphenyl(methyl)phos-
phine, and a significant increase in yield was seen (16%). Again,
purification of the nitro compound proved to be difficult and
time-consuming, but eventually gave microanalytically pure
crystals. Surprisingly, the 1H NMR spectrum was very simple to
interpret, and showed the presence of only one “isomer” of the
nitro product 22f, the isomer being one form of the (Z)-isomer.
Even more interestingly, some alcohol 20f (41%) was recovered
from the reaction, and the relative proportions of the alcohol
isomers had changed, with the major (Z)-isomer now present
at 82% (56% before the reaction), the minor form of the
(Z)-isomer present at only 14% (37% prior to reaction), and the
(E)-isomer present at 4% (7% before the reaction). This indi-
cates that the Mitsunobu reaction was preferentially taking
place via one isomer of the (Z)-alkene. It was therefore thought
that higher temperatures might effect the conversion of the
major (Z)-conformer to the minor (Z)-conformer, thus allow-
ing coupling to take place. Alternatively, the increased temper-
ature should allow the less reactive (Z)-conformer or the
(E)-isomer to become more reactive. As a result, the reaction
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Scheme 5
reflux. Pleasingly, a substantial increase in the yield of the
nitro compound 22f was seen (41%). Copper acetylacetonate–
sodium borohydride–ethanol was used to reduce the nitro
compound 22f to the desired aniline 23f (74% yield).
1
The H NMR and 13C NMR spectra of 23f were compli-
cated, which was surprising, because the precursor nitro com-
pound 22f had been present as a single “isomer”. Diazotisation
of the aniline 23f was effected using nitrosonium tetrafluoro-
borate in DCM at 0 ЊC. The diazonium salt was isolated as a
fluffy yellow solid by precipitation in diethyl ether. Unfortu-
nately, the solid started to decolorise and became oily almost
immediately, even before the solvent could be removed by
decanting. As a result, no yield was obtained, and the salt was
immediately taken onto the next stage. Cyclisation was achieved
by stirring the diazonium salt in acetone under N2 at 0 ЊC with
sodium iodide. After work-up, column chromatography gave
the desired indole 24f (20%). Intriguingly, two isomers of the
unexpected iodo side-product 27 were also isolated (27a,
13% and 27b, 10%). The identity of the iodo products 27 was
initially confusing, because although 1H and 13C NMR spectra,
mass spectral analysis and elemental analysis indicated that
the structure of each of the two products was consistent
with the proposed structure, their mechanism of formation was
puzzling. Finally, X-ray crystallography of one of the products
confirmed the structure as the 9-membered iodo compound
27a17 (Fig. 1).
Compounds 27a and 27b may arise following the initial
cyclisation giving the desired β-bromoalkyl radical, 28 (Scheme
7). It may be that conformational peculiarities of the nine-
membered ring inhibit the desired elimination reaction, allow-
ing the observed alternative reactions to occur.
1,2-Bromine shift reactions of β-bromoalkyl radicals are
known in simple substrates,18 and it is thought that such a
rearrangement may have occurred here. This would give a
relatively stable benzylic radical, which could then abstract
a hydrogen atom from solvent, to give a nine-membered bromo
compound, 29. Displacement of bromide by an iodide anion
could then give the iodo product 27.
Scheme 6 Reagents and conditions: (i) Br3CH, KOt-Bu, hexane, 0 ЊC;
(ii) AgClO4, H2O, acetone, 0 ЊC; (iii) DEAD, Ph2MeP, THF, (21), 0 ЊC
then ∆; (iv) Cu(acac)2, NaBH4, EtOH, 0 ЊC; (v) NOBF4, DCM, 0 ЊC;
NaI, acetone.
was repeated, this time with heating. The reagents were added
at 0 ЊC, and then the solution was allowed to warm to room
temperature and stirred for 30 minutes, before being heated to
Alternatively, after initial cyclisation, loss of a bromine rad-
ical could occur as expected, to give the desired alkene inter-
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8). The alkene 25e was isolated in 60% yield, along with
recovered starting material. Acid-catalysed conversion of
the alkene 25e to the desired indole 24e occurred in high
yield (94%). The successful formation of indole 24e con-
firmed the potential of the phosphorus reagents in this new
synthesis.
For comparison, the radical cyclisation was repeated, this
time using tributyltin hydride as reagent (and using a full
equivalent of AIBN, since this reaction may not be a chain
reaction). The desired indole 24e was isolated in 49% yield,
along with the intermediate unrearranged alkene 25e, which
was isolated in 26% yield. Acid-catalysed conversion of the
alkene 25e to the desired indole 24e occurred in high yield,
giving the indole in 72% overall yield. Although the tin reagent
gives a slightly higher yield in the formation of this indole, its
toxicity drawbacks remain.
Finally, alcohol 20a was coupled under Mitsunobu con-
ditions with N-(2-iodophenyl)methanesulfonamide 16. This
alcohol had afforded a regioisomeric mixture of Mitsunobu
coupling products when coupled with the nitrosulfonamide 21.
A similar result was observed here, and once again four doub-
lets were present for the CHCH3 methyl group and four quar-
1
tets for the corresponding methine proton. Once again H–13C
Fig. 1 X-Ray crystal structure of 27a.
correlation spectroscopy indicated that two of the quartets were
associated with aliphatic carbons and two with vinyl carbons,
and so this Mitsunobu reaction afforded a mixture of 31 and
31Ј. This inseparable mixture was subjected to cyclisation.
When the reaction was first conducted, using AIBN (0.4
equiv.), only a single indole, 24a, was isolated in 45% yield
following tautomerism induced by toluene-p-sulfonic acid.
Because we were uncertain that the radical reaction would pro-
ceed by a proper chain mechanism in which bromine atoms
abstract a hydrogen from tributyltin hydride, the experiment
was repeated with a full equivalent of AIBN. [We recognise that
the 0.4 equiv. of AIBN used could afford 0.8 equiv. of iso-
butyronitrile radicals—but not all of these would be used in
initiating the desired reaction by abstraction of hydrogen from
tributyltin hydride]. This led to a decrease in yield of indole 24a
(41%), but the elusive isomeric indole 24aЈ was isolated in low
yield (4%).
mediate. Then, perhaps due to conformational peculiarities of
the nine-membered ring, the intermediate might be attacked by
iodine atoms, again giving relatively stable benzylic radicals.
Abstraction of a hydrogen atom would be required to form the
iodo product 27. The two proposed mechanisms are given in
Scheme 7.
In conclusion, an addition–elimination strategy has been
used to prepare indole products by radical methodology using
arenediazonium salts and using phosphorus-centred radicals.
The methods used avoid the difficulties associated with tributyl-
tin reagents or samarium diiodide.
Experimental
Melting points were measured on a Kofler hot stage apparatus
and are uncorrected. Microanalyses were determined using a
Perkin-Elmer 240B elemental analyser. Infrared spectra were
obtained on a Perkin-Elmer 1720-X FTIR or a Pye-Unicam
SP3-100 spectrometer. Ultraviolet spectra were recorded on a
Philips PU8700 series instrument. 1H NMR spectra were
recorded at 250 MHz on a Bruker WM250, at 270 MHz on a
JEOL EX270 or at 400 MHz on a Bruker DPX400 machine. 13
C
NMR spectra were recorded at 62.9 MHz on a Bruker WM250,
at 67.8 MHz on a JEOL EX270 or at 100 MHz on a Bruker
DPX400 machine. NMR experiments were carried out in
deuterochloroform, d4-methanol, or d6-acetone with tetra-
methylsilane as an internal reference. Chemical shifts are
quoted in parts per million (ppm). The following abbreviations
are used for multiplicities: s, singlet; d, doublet; t, triplet; q,
quartet; m, multiplet. Coupling constants are reported in hertz
(Hz). In cases where superimposition of the signals of two, or
more, isomers occurred, the signals have been reported as
multiplets (m), unless the coupling constants of each isomer
could be ascertained. Mass spectra were recorded at the EPSRC
Mass Spectrometry Service Centre, Swansea or using a JEOL
JMS-AX505HA at Strathclyde.
Scheme 7
Having successfully prepared these indoles using diazonium
salts as precursors, attention moved towards the synthesis of
aryl iodides and their cyclisation using tributyltin radicals.
Coupling of the alcohol 20e with the N-mesyl derivative of
iodoaniline 16 was achieved using Mitsunobu conditions. The
product, 30, was firstly treated with N-ethylpiperidine hypo-
phosphite (EPHP), and the radical initiator, AIBN (Scheme
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Scheme 8
Where necessary, solvents were dried and/or distilled before
methane to 100% dichloromethane gradient elution) to yield
use. Tetrahydrofuran was distilled from sodium–benzophenone.
Dichloromethane and dimethylformamide were distilled from
calcium hydride. Diethyl ether, toluene and benzene were dried
over sodium wire. Unless otherwise stated all petrol was of
boiling range 40–60 ЊC and was distilled before use. Chromato-
graphy was performed using Sorbsil C60 (May and Baker),
Kieselgel 60 (Art 9385) or Kieselgel HF254 silica gels.
1-(bromomethyl)vinyl methyl sulfone 14 (5.741 g, 0.0288 mol,
48%) as a yellow oil which solidified on cooling, mp 35–
36.5 ЊC (Found: C, 23.9; H, 3.5. C4H7BrO2S requires C, 24.1;
H, 3.5%); νmax(KBr disc)/cmϪ1 3037, 2927 (CH), 1630 (C᎐C),
᎐
1415 (CH), 1321, 1143 (SO2); δH(250 MHz, CDCl3) 3.09 (3H,
s, CH ), 4.29 (2H, s, CH ), 6.25 (1H, d, J 0.9, ᎐CH), 6.45
᎐
3
2
(1H, d, J 0.9, ᎐CH); δ (62.9 MHz, CDCl ) 25.8 (CH ), 43.8
᎐
C
3
2
(CH3), 130.5 (CH2), 147.0 (C).
1-(Bromomethyl)vinyl methyl sulfone 14
2-Iodo-N-methylsulfonylaniline 16
To a solution of allyl methyl sulfide 12 (6.7 ml, 60 mmol, 1.0
equiv.) in carbon tetrachloride (160 ml) was added a solution of
bromine (3.1 ml, 0.60 mmol, 1.0 equiv.) in carbon tetrachloride
(25 ml), dropwise via syringe whilst stirring constantly under
nitrogen at Ϫ10 ЊC. Once the addition was complete the mix-
ture was allowed to warm to room temperature over a period
of 15 min, before cooling to Ϫ10 ЊC again. m-Chloroperoxy-
benzoic acid (25.0 g, 14.5 mmol, 2.4 equiv.) in dichloromethane
(120 ml) was added to the mixture a little at a time. Each
addition was accompanied by an exotherm to ca. 10 ЊC. The
mixture was left to stir at room temperature for 6 h before
washing with saturated sodium bicarbonate solution (3 × 300
ml). The organic phase was dried over anhydrous magnesium
sulfate, filtered through kieselguhr and evaporated in vacuo to
yield an off-white solid. To this was added diethyl ether (300 ml)
(dried over sodium wire) and the solution treated with
sodium acetate (6.15 g, 0.075 mol, 1.5 equiv.). The mix-
ture was stirred under nitrogen at room temperature for
5 h. Ethyl acetate (200 ml) was added and the mixture washed
with water (2 × 300 ml). The organic phase was dried over
anhydrous magnesium sulfate, filtered through kieselguhr and
evaporated in vacuo to yield a yellow oil. This was purified by
column chromatography (silica; 10% hexane in dichloro-
2-Iodoaniline (50 g, 228 mmol, 1 equiv.), N,N-dimethyl-
aminopyridine (2.78 g, 22.8 mmol, 0.1 equiv.) and methanesul-
fonyl chloride (21.1 ml, 31.24 g, 274 mmol, 1.2 equiv.) were
stirred in pyridine (160 ml) under nitrogen and heated under
reflux for 18 h. Dichloromethane (400 ml) was added and the
mixture was washed with hydrochloric acid (2 M, 3 × 250 ml).
The organic solution was then extracted with sodium hydroxide
(2 M, 3 × 200 ml). The combined aqueous portions were acid-
ifed with conc. hydrochloric acid, and extracted into dichloro-
methane (3 × 150 ml). The combined organic portions were
dried over magnesium sulfate and the solvent removed to give a
brown oil. Recrystallisation from ethyl acetate and hexane
gave 2-iodo-N-methylsulfonylaniline 16 as a pale brown solid
(48.96 g, 72%), mp 94–95 ЊC (Found: C, 28.1; H, 2.4; N, 4.6.
C7H8INO2S requires C, 28.3; H, 2.7; N, 4.7%); νmax(KBr
disc)/cmϪ1 3283, 1582; δH(CDCl3, 400 MHz) 3.02 (3H, s,
SO2CH3), 6.68 (1H, br s, NH), 6.93 (1H, ddd, J 8.0, 7.3, 1.5,
ArH), 7.37 (1H, ddd, J 8.2, 7.2, 1.4, ArH), 7.64 (1H, dd, J 8.2,
1.5, ArH), 7.82 (1H, dd, J 8.0, 1.4, ArH); δC(CDCl3, 100 MHz)
40.4 (CH3), 92.4 (C), 122.7 (CH), 127.4 (CH), 130.0 (CH),
137.8 (C), 139.6 (CH); m/z (EI) 297 (Mϩ, 93%), 218 (100),
91 (89), 64 (60).
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N-(2-Iodophenyl)-N-[2-(methylsulfonyl)prop-2-enyl]methane-
sulfonamide 15
dropwise via syringe, while stirring under nitrogen at room
temperature. White fumes were liberated during the addition,
and a white precipitate gradually appeared. After the addition
was complete, the mixture was left to stir under nitrogen at
room temperature for a further 16 h. More dichloromethane
(10 ml) was added and the mixture washed with hydrochloric
acid (2 M, 2 × 30 ml) and water (30 ml). The organic layer
was dried over anhydrous magnesium sulfate, filtered through
kieselguhr and evaporated in vacuo to yield a brown oil. This
was purified by column chromatography (silica; 5% ethyl
acetate in hexane elution) to yield (E)-3-bromo-4-phenylbut-
3-en-2-one 19a (2.518 g, 0.0112 mol, 92%) as a yellow oil,
A suspension of sodium hydride (0.091 g, 3.8 mmol, 1.5 equiv.)
in dry N,N-dimethylformamide (10 ml) was treated with a solu-
tion of N-(2-iodophenyl)methanesulfonamide 16 (0.746 g, 2.5
mmol, 1.0 equiv.) in dry N,N-dimethylformamide (2 ml),
dropwise via syringe whilst stirring under nitrogen at room
temperature. Bubbles of gas were evolved and the solution
became yellow in colour. After 15 min, a solution of 1-(bromo-
methyl)vinyl methyl sulfone 14 (0.5 g, 2.5 mmol, 1.0 equiv.)
in dry N,N-dimethylformamide (2 ml) was added dropwise
via syringe while stirring under nitrogen at room temper-
ature. The solution became dark brown in colour. After 4 h,
ethyl acetate (40 ml) was added and the mixture washed with
water (6 × 40 ml). The organic phase was dried over anhydrous
magnesium sulfate, filtered through kieselguhr and evaporated
in vacuo to yield a dark yellow oil. This was purified by column
chromatography (silica; 50% ethyl acetate in hexane to 60%
ethyl acetate in hexane gradient elution) to afford N-(2-iodo-
phenyl)-N-[2-(methylsulfonyl)prop-2-enyl]methanesulfonamide
15 (0.486 g, 1.2 mmol, 47%) as a yellow solid, mp 121–122.5 ЊC
[Found: Mϩ (EI), 414.9409. C11H14O4NS2I requires M,
414.9409]; νmax(KBr disc)/cmϪ1 3011, 2927, 1478 (CH), 1342
(N–SO2), 1300 (SO2), 1159 (N–SO2), 1133 (SO2), 798 (Ar ring);
δH(270 MHz, CDCl3) 2.88 (3H, s, CH3), 3.15 (3H, s, CH3), 4.57
(1H, d, J 16.7, CH2), 4.91 (1H, d, J 16.7, CH2), 6.12 (1H, d,
νmax(film)/cmϪ1 3073, 3026, 2933, 2855 (CH), 1679 (C᎐O),
᎐
1607, 1503, 1457 (CH), 757, 685, 612; δH(250 MHz, CDCl3)
2.61 (3H, s, CH3), 7.45 (3H, m, ArH), 7.87 (2H, m, ArH),
8.04 (1H, s, ᎐CH); δ (67.8 MHz, CDCl ) 27.1 (CH ), 123.4
᎐
C
3
3
(C), 128.6 (CH), 130.6 (CH), 133.8 (C), 140.1 (CH), 193.2
(C᎐O); m/z 226 (Mϩ, 60%), 225 (60), 224 (Mϩ, 60), 223 (60),
᎐
145 (100), 102 (100).
3-Bromobut-3-en-2-one 19b.20 [Prepared using same pro-
cedure as for 19a] 3-Bromobut-3-en-2-one 19b (4.158 g, 0.0279
mol, 98%) as a yellow oil, νmax(film)/cmϪ1 3011, 2917, 2854
(CH), 1703 (C᎐O), 1619 (C᎐C), 612 (C–Br); δ (270 MHz,
᎐
᎐
H
CDCl ) 2.47 (3H, s, CH ), 6.43 (1H, d, J 2.4, ᎐CH), 6.81 (1H, d,
᎐
3
3
J 2.4, ᎐CH); δ (67.8 MHz, CDCl ) 26.1 (CH ), 129.6 (CH ),
᎐
C
3
3
2
132.0 (C), 192.0 (C᎐O).
᎐
J 1.1, ᎐CH), 6.45 (1H, br s, ᎐CH), 7.12 (1H, ddd, J 8.1, 7.1, 1.6,
᎐
᎐
ArH), 7.42 (1H, ddd, J 7.8, 7.1, 1.4, ArH), 7.51 (1H, dd, J 7.8,
1.6, ArH), 7.97 (1H, dd, J 8.1, 1.4, ArH); δC(67.8 MHz, CDCl3)
41.4 (CH3), 41.5 (CH3), 49.6 (CH2), 100.0 (C), 129.7 (CH),
130.1 (CH2), 131.0 (CH), 133.52 (CH), 140.0 (C), 141.2 (CH),
145.4 (C); m/z (EI) 415 (Mϩ, 5%), 336 (57), 256 (55) and 130
(100).
Ethyl (E/Z)-2-bromobut-2-enoate 19c21
A solution of ethyl but-2-enoate 18c (5.45 ml, 0.044 mol, 1.0
equiv.) in dry dichloromethane (40 ml) was treated dropwise
with a solution of bromine (2.3 ml, 0.044 mol, 1.0 equiv.) in
carbon tetrachloride (5 ml), whilst stirring under nitrogen at
ca. Ϫ10 ЊC. The mixture was left to stir for 2 h before adding
dry triethylamine (7.4 ml, 0.053 mol, 1.2 equiv.) dropwise via
syringe, whilst cooling at 0 ЊC. This mixture was stirred for 1 h
before washing with 2 M hydrochloric acid (3 × 50 ml). The
combined aqueous layers were washed with dichloromethane
(100 ml), and the combined organic layers were washed with
water (50 ml), dried over anhydrous magnesium sulfate, filtered
through kieselguhr and evaporated in vacuo to yield a dark oil.
This was purified by column chromatography (silica; 5% ether
in hexane elution) to afford ethyl (E/Z)-2-bromobut-2-enoate
19c (8.494 g, 0.044 mol, 100%) as a yellow oil [Found:
(M ϩ NH4)ϩ (CI), 210.0130. C6H9O2Br requires (M ϩ NH4)ϩ,
Reaction of 1-ethylpiperidine hypophosphite (EPHP) with N-(2-
iodophenyl)-N-[2-(methylsulfonyl)prop-2-enyl]methanesulfon-
amide 15
EPHP (1.3 g, 7.2 mmol, 10 equiv.) was added to a solution of
N-(2-iodophenyl)-N-[2-(methylsulfonyl)prop-2-enyl]methane-
sulfonamide (300 mg, 0.72 mmol, 1 equiv.) in dry benzene
(8 ml) and the reaction was heated at reflux for 30 min. AIBN
(47 mg, 0.3 mmol, 0.4 equiv.) was added in two portions over
30 min and the reaction was refluxed for 1 h. The reaction was
cooled before diluting with dichloromethane and extracted with
water (50 ml). The organic phase was dried over sodium sulfate
and removed under vacuum. The residue obtained was purified
by column chromatography (5% ethyl acetate in hexane and
gradient elution to 50% ethyl acetate) to afford 2-iodo-N-
methylsulfonylaniline 16 (45 mg, 0.15 mmol, 23.3%) (data as
reported above) and N-methylsulfonylaniline (30 mg, 0.17
mmol, 24.3%), δH(CDCl3, 400 MHz) 3.04 (3H, s, CH3), 6.94
(1H, br s, NH), 7.19–7.28 (3H, m, ArH), 7.35–7.40 (2H, m,
ArH); δC(CDCl3, 100 MHz) 39.3 (q, CH3), 120.8 (d), 125.4 (d),
129.7 (d), 136.7 (s).
210.0130]; νmax(film)/cmϪ1 2990, 2933 (CH), 1729 (C᎐O), 1635
᎐
(C᎐C), 1457 (CH), 1253, 1059 (C–O); δ (250 MHz, CDCl )
᎐
H
3
1.33, 1.35 (3H, 2 × t, J 7.1, CH3), 1.95, 2.05 (3H, 2 × d, J 7.5,
CH3), 4.28 (2H, q, J 7.1, CH2), 6.77, 7.39 (1H, 2 × q, J 7.5,
᎐CH); δ (67.8 MHz, CDCl ) 15.7 (CH ), 15.8 (CH ), 19.1
᎐
C
3
3
3
(CH3), 19.5 (CH3), 63.6 (CH2), 63.9 (CH2), 113.7 (C), 119.3 (C),
142.8 (CH), 145.0 (CH), 164.0 (C), 164.6 (C); m/z (CI) 212
[(M ϩ NH4)ϩ, 12%], 210 [(M ϩ NH4)ϩ, 12%], 164 (62), 148
(100).
2-Bromocyclopent-2-en-1-one 19d.22 [Prepared using same
procedure as for 19a] 2-Bromocyclopent-2-en-1-one 19d (4.99 g,
(E)-3-Bromo-4-phenylbut-3-en-2-one 19a19
62%) as white needles, mp 37–38 ЊC (lit.,22d 39–39.5 ЊC); νmax
-
A solution of bromine (0.63 ml, 0.0122 mol, 0.9 equiv.) in
carbon tetrachloride was added dropwise via syringe to a solu-
tion of (E)-4-phenylbut-3-en-2-one 18a (2.00 g, 0.0136 mol, 1.0
equiv.) in carbon tetrachloride (5 ml) while stirring under nitro-
gen at Ϫ10 ЊC. The bromine solution was added at a rate that
did not allow the temperature to exceed ca. Ϫ2 ЊC. As the brom-
ine solution was added it decolorised, and an off-white precipi-
tate formed. Carbon tetrachloride (15 ml) was added during the
course of the reaction to aid stirring. After 0.5 h, the solvent was
evaporated in vacuo to yield an off-white solid. This was dis-
solved in dry dichloromethane (20 ml) and the solution was
treated with dry triethylamine (2.0 ml, 0.0146 mol, 1.2 equiv.)
(KBr disc)/cmϪ1 3055, 2921, 1708, 1663, 1584; δH(CDCl3, 250
MHz) 2.52–2.56 (2H, m, CH2), 2.68–2.73 (2H, m, CH2), 7.79
(1H, m, CH᎐); δ (CDCl , 63 MHz) 28.0 (CH ), 32.4 (CH ),
᎐
C
3
2
2
125.9 (C), 162.1 (CH), 201.7 (C); m/z 162, 160 (Mϩ, 100%), 134,
132 (66), 84 (79).
2-Bromocyclohex-2-en-1-one 19e.22a [Prepared using same
procedure as for 19a] 2-Bromocyclohex-2-en-1-one 19e (9.00 g,
51%) as white needles, mp 75–76 ЊC (lit.,22a 75–76 ЊC); νmax(KBr
disc)/cmϪ1 2959, 2941, 2872, 1681, 1597; δH(CDCl3, 250 MHz)
2.08 (2H, m, CH2), 2.46 (2H, m, CH2), 2.64 (2H, t, J 6.5, CH2),
J. Chem. Soc., Perkin Trans. 1, 2000, 2395–2408
2401

View Article Online
7.44 (1H, t, J 4.0, ᎐CH); δ (CDCl , 63 MHz) 22.7 (CH ), 28.4
(CH2), 38.4 (CH2), 123.7 (C), 151.5 (CH), 191.4 (C).
major; dd, J 7.5, 7.5, CHOHZ major), 6.01 (1HZ minor, dd,
J 10.3, 5.3, CH᎐Z minor), 6.17 (1HZ major, dd, J 9.0, 9.0, CH᎐Z
᎐
C
3
2
᎐
᎐
major), 6.37 (1HE, dd, J 5.5, 10.5, CH᎐E); δ (CDCl , 63 MHz)
᎐
C
3
(E)-3-Bromo-4-phenylbut-3-en-2-ol 20a11
22.7 (CH2), 23.0 (CH2), 24.7 (CH2), 24.8 (CH2), 25.8 (CH2),
26.7 (CH2), 27.1 (CH2), 27.3 (CH2), 28.1 (CH2), 29.3 (CH2),
29.5 (CH2), 29.6 (CH2), 29.9 (CH2), 31.4 (CH2), 33.6 (CH2),
35.0 (CH2), 35.7 (CH2), 69.5 (CH), 75.6 (CH), 77.1 (CH), 127.9
(CH), 128.2 (CH), 130.9 (C), 132.3 (C), 133.3 (CH); m/z 220
(Mϩ, 46%), 218 (Mϩ, 46), 150 (100), 148 (100).
To a solution of cerium() chloride heptahydrate (2.481 g, 6.6
mmol, 1.0 equiv.) in methanol (20 ml) was added a solution of
(E)-3-bromobut-3-en-2-one 19a (1.50 g, 6.6 mmol, 1.0 equiv.) in
methanol (10 ml). The mixture was stirred under nitrogen at
0 ЊC, and sodium borohydride (0.252 g, 6.6 mmol, 1.0 equiv.)
was added a little at a time. Each addition was accompanied by
a vigorous evolution of gas and an exotherm to ca. 15–20 ЊC.
Once the addition was complete, the mixture was left to stir
under nitrogen at this temperature for 2 h. Water (15 ml) was
added and the mixture extracted with diethyl ether (3 × 30 ml).
The combined organic layers were dried over anhydrous sodium
sulfate, filtered through kieselguhr and evaporated in vacuo to
yield (E)-3-bromo-4-phenylbut-3-en-2-ol 20a (1.114 g, 4.9
mmol, 74%) as a pale yellow oil (Found: C, 53.0; H, 4.4.
C10H11BrO requires C, 52.9; H, 4.9%); νmax(film)/cmϪ1 3363
N-(2-Nitrophenyl)methanesulfonamide 2125
To a solution of 2-nitroaniline (276.25 g, 2.0 mol, 1.0 equiv.)
and 4-dimethylaminopyridine (24.00 g, 0.2 mol, 0.1 equiv.) in
pyridine (690 ml) was added methanesulfonyl chloride (185 ml,
2.4 mol, 1.2 equiv.) slowly. After heating at reflux for 18 h, the
solution was allowed to cool before diluting with dichloro-
methane (1500 ml). The mixture was washed with 2 M hydro-
chloric acid (4 × 600 ml). The combined aqueous layers were
cooled to 0 ЊC and acidified to pH 6 using concentrated hydro-
chloric acid. A dense precipitate appeared. The mixture was
then extracted with dichloromethane (3 × 600 ml). The com-
bined organic layers were washed with water (2 × 800 ml), dried
over anhydrous magnesium sulfate, filtered through kieselguhr
and evaporated in vacuo. The residual solid was recrystallised
from ethyl acetate to yield N-(2-nitrophenyl)methanesulfon-
amide 21 (183.45 g, 0.9959 mol, 50%) as a yellow crystalline
solid, mp 101–103 ЊC (Found: C, 39.0; H, 3.8; N, 12.8. Mϩ,
216.0203. C7H8N2O4S requires C, 38.9; H, 3.7; N, 13.0%. Mϩ
216.0205); νmax(KBr disc)/cmϪ1 3266, 1615, 1578; δH(CDCl3,
400 MHz) 3.17 (3H, s, SO2CH3), 7.23 (1H, ddd, J 8.4, 8.4, 1.0,
ArH), 7.68 (1H, ddd, J 8.5, 8.5, 1.0, ArH), 7.86 (1H, dd, J 8.4,
1.0, ArH), 8.23 (1H, dd, J 8.5, 1.0, ArH), 9.70 (1H, br s, NH);
δC(CDCl3, 100 MHz) 41.1 (CH3), 119.9 (CH), 124.0 (CH), 127.0
(CH), 134.7 (C × 2), 136.8 (CH); m/z (EIϩ) 216 (Mϩ, 62%), 138
(100), 108 (36), 91 (22).
(OH), 3068, 3021, 2974, 2933, 2871 (CH), 1643, 1498 (C᎐C),
᎐
1452 (CH), 1084 (C–O), 763, 700 (Ar ring), 600; δH(270 MHz,
CDCl3) 1.48 (3H, d, J 6.2, CH3), 2.03 (1H, br s, OH), 4.48 (1H,
q, J 6.2, O-CH), 7.07 (1H, s, ᎐CH), 7.34 (3H, m, ArH), 7.60
᎐
(2H, d, J 8.4, ArH); δC(67.8 MHz, CDCl3) 22.8 (CH3), 73.8
(CH), 127.2 (C), 128.4 (CH), 129.3, (CH), 131.6 (CH), 135.3
(C); m/z 228 (Mϩ, 17%), 226 (Mϩ, 21), 147 (92), 84 (100).
3-Bromobut-3-en-2-ol 20b. [Prepared using same procedure
as for 20a] 3-Bromobut-3-en-2-ol 20b (1.855 g, 0.0123 mol,
61%) was obtained as a pale yellow oil, νmax(film)/cmϪ1 3373
(O–H), 2985 , 2938, 2886 (CH), 1638 (C᎐C), 1452 (CH), 1094
᎐
(C–O); δH(250 MHz, CDCl3) 1.39 (3H, d, J 6.3, CH3), 1.99 (1H,
br s, OH), 4.33 (1H, q, J 6.4, O-CH), 5.53 (1H, d, J 2.0, ᎐CH),
᎐
5.90 (1H, d, J 2.0, ᎐CH); δ (67.8 MHz, CDCl ) 23.7 (CH ),
᎐
C
3
3
73.7 (CH), 117.4 (CH2), 140.1 (C).
(E/Z)-2-Bromobut-2-en-1-ol 20c.21 (E/Z)-2-Bromobut-2-en-
1-ol 20c (0.787 g, 5.2 mmol, 52%) as a pale yellow oil, νmax(film)/
N-(2-Bromo-1-methyl-3-phenylprop-2-enyl)-N-(2-nitrophenyl)-
methanesulfonamide 22a and N-(2-bromo-1-phenylbut-2-enyl)-
N-(2-nitrophenyl)methanesulfonamide 22aЈ
cmϪ1 3351 (OH), 2933, 2865 (CH), 1656 (C᎐C), 1441 (CH),
᎐
1242, 1054 (C–O); δH(250 MHz, CDCl3) 1.77 (3H, m, CH3),
2.11 (1H, br s, OH), 4.25, 4.32 (2H, 2 × s, CH2), 6.08 (1H, q,
To a solution of (E)-3-bromo-4-phenylbut-3-en-2-ol 20a (1.0 g,
4.4 mmol, 1.0 equiv.), N-(2-nitrophenyl)methanesulfonamide
21 (0.952 g, 4.4 mmol, 1.0 equiv.) and triphenylphosphine
(1.616 g, 6.2 mmol, 1.4 equiv.) in dry tetrahydrofuran (10 ml)
was added a solution of diethyl azodicarboxylate (1.0 ml, 6.2
mmol, 1.4 equiv.) in dry tetrahydrofuran (2 ml) dropwise via
syringe whilst stirring under nitrogen at 0 ЊC. Once the addition
was complete, the mixture was left to stir under nitrogen at room
temperature for 20 h. Water (10 ml) was added to quench the
reaction and the mixture evaporated to dryness in vacuo. The
residue was partitioned between water (25 ml) and ethyl acetate
(25 ml). The aqueous phase was washed with more ethyl acetate
(2 × 25 ml). The combined organic layers were washed sequen-
tially with 2 M sodium hydroxide solution (25 ml) and water (25
ml), dried over anhydrous magnesium sulfate, filtered through
kieselguhr and evaporated in vacuo to yield a yellow oil–white
solid mixture. This was purified by column chromatography
(silica; 45% dichloromethane in hexane to 100% dichloro-
methane gradient elution) to yield N-(2-bromo-1-methyl-
3-phenylprop-2-enyl)-N-(2-nitrophenyl)methanesulfonamide
22a and N-(2-bromo-1-phenylbut-2-enyl)-N-(2-nitrophenyl)-
methanesulfonamide 22aЈ (1.248 g, 3.0 mmol, 67%) as an
inseparable mixture and as a sticky yellow oil [Found: Mϩ (EI),
426.0065. C17H1781BrN2O4S requires M, 426.0072]; νmax(film)/
J 7.2, ᎐CH); δ (62.9 MHz, CDCl ) 15.0 (CH ), 16.3 (CH ), 61.9
᎐
C
3
3
3
(CH2), 67.9 (CH2), 124.4 (C), 124.5 (CH), 127.6 (C), 129.8
(CH).
2-Bromocyclopent-2-en-1-ol 20d.23 [Prepared using same pro-
cedure as for 20a] 2-Bromocyclopent-2-en-1-ol 20d (3.35 g,
76%) as a clear oil, νmax(film)/cmϪ1 3354, 3069, 2969, 2934, 2852,
1618; δH(CDCl3, 250 MHz) 1.83–1.88 (1H, m, CH2), 2.22–2.43
(3H, m, CH2), 2.82 (1H, br s, OH), 4.63–4.70 (1H, m, CHOH),
6.02 (1H, m, CH᎐); δ (CDCl , 63 MHz) 30.4 (CH ), 32.0 (CH ),
᎐
C
3
2
2
79.3 (CH), 125.1 (C), 134.3 (CH); m/z (EI) 164, (Mϩ, 20%), 162
(Mϩ, 20), 86 (97), 84 (100), 83 (100).
2-Bromocyclohex-2-en-1-ol.24 [Prepared using same pro-
cedure as for 20a] 2-Bromocyclohex-2-en-1-ol 20e (6.44 g, 73%)
as a yellow oil, νmax(film)/cmϪ1 3364, 2945, 2862, 2836, 1641;
δH(CDCl3, 250 MHz) 1.65–2.12 (6H, m, 3CH2), 2.10 (1H, s,
OH), 4.19 (1H, t, J 4.7, CHOH), 6.20 (1H, t, J 4.0, CH᎐);
᎐
δC(CDCl3, 63 MHz) 17.6 (CH2), 27.8 (CH2), 32.2 (CH2), 70.2
(CH), 125.7 (C), 132.8 (CH); m/z (EI) 178, 176 (M Ϫ H)ϩ
(25%), 150, 148 (85), 97 (100), 79 (100).
2-Bromocyclonon-2-enol 20f. [Prepared as in ref. 16] 2-Bromo-
cyclonon-2-enol 20f (2.13 g, 82%) as a clear oil and as an
11:9:2 mixture of the 2 Z rotamers and the E isomer,
νmax(film)/cmϪ1 3357, 2939, 2861, 1639; δH(CDCl3, 250 MHz)
0.88–2.51 (13H, m, 6 CH2, OH), 4.00 (1HZ minor, dd, J 10.5,
4.3, CHOHZ minor), 4.49–4.53 (1HE, m, CHOHE), 4.71 (1HZ
cmϪ1 3062, 3026, 2990, 2933, 2876 (CH), 1602 (C᎐C), 1540
᎐
(ON᎐O), 1486, 1446 (CH), 1371 (ON᎐O), 1348, 1161 (N–SO ),
᎐
᎐
2
778, 700 (Ar ring), 607 (C–Br); δH(400 MHz, CDCl3) 1.26
(J 6.8), 1.51 (J 6.8), 1.74 (J 6.0) and 1.75 (J 6.0) (4 × d, CH3),
2.97, 2.99, 3.03 and 3.35 (3H, 4 × s, CH3), 5.04 (1H, J 6.8), 5.34
(1H, J 6.8), 6.42 (1H, J 6.0), 6.54 (1H, J 6.0), (4 × q, N-CH),
2402
J. Chem. Soc., Perkin Trans. 1, 2000, 2395–2408

View Article Online
5.96, 6.07, 6.77 (3 × s, ᎐CH), 7.19–8.07 (10H, m, ᎐CH, ArH);
133.3 (CH minor), 133.6 (CH), 134.4 (CH minor), 139.0 (CH),
᎐
᎐
δC(62.9 MHz, CDCl3) 14.0 (CH3), 16.7 (CH3), 19.5 (CH3), 20.2
(CH3), 41.7 (CH3), 42.6 (CH3), 63.7 (CH), 65.4 (CH), 72.1
(CH), 72.7 (CH), 124.4 (C), 124.8 (CH), 124.9 (CH), 125.4
(CH), 125.6 (CH), 126.9 (C), 127.6 (C), 127.9 (CH), 128.0 (CH),
128.1 (CH), 128.1 (CH), 128.4 (CH), 128.5 (CH), 128.5 (CH),
128.9 (CH), 129.0 (CH), 129.3 (CH), 129.4 (CH), 129.5 (CH),
129.9 (CH), 130.0 (CH), 130.1 (CH), 130.6 (C), 131.5 (CH),
132.0 (C), 132.2 (C), 132.3 (CH), 132.4 (CH), 132.6 (CH), 133.1
(CH), 133.2 (CH), 133.4 (CH), 134.5 (C), 134.5 (CH), 134.6
(CH), 134.9 (C), 135.2 (CH), 135.7 (CH), 136.1 (C), 149.9 (C);
m/z (EI) 426 (Mϩ, 5%), 424 (Mϩ, 6), 345 (48), 129 (86), 79 (100).
139.7 (CH minor), 149.7 (C); m/z (EI) 362 (Mϩ, 1%), 360 (Mϩ,
1%), 283 (100), 281 (100).
N-(2-Bromocyclohex-2-en-1-yl)-N-(2-nitrophenyl)methane-
sulfonamide 22e. [Prepared using same procedure as for 22a]
N-(2-Bromocyclohex-2-en-1-yl)N-(2-nitrophenyl)-methane-
sulfonamide 22e (3.54 g, 56%), as a 7:1 mixture of rotamers by
1H NMR, and as off-white needles, mp 152–153 ЊC [Found: C,
41.68; H, 4.08, N, 7.47. C13H15BrN2O4S requires C, 41.61; H,
4.03; N, 7.47%] [Found (CI): (M ϩ NH4)ϩ 392.0285. C11H15-
BrN2O4S requires (M ϩ NH4)ϩ, 392.0280]; νmax(KBr disc)/cmϪ1
1600, 1543, 1362, 1341, 1150; δH(CDCl3, 250 MHz) 1.08–2.70
(6H, br m, CH2), 3.16 (3H major, br s, SO2CH3 major), 3.38 (3H
minor, br s, SO2CH3 minor), 4.75–5.02 (1H, br m, CHN), 6.35–
N-(2-Bromo-1-methylprop-2-enyl)-N-(2-nitrophenyl)methane-
sulfonamide 22b. [Prepared using same procedure as for 22a]
N-(2-Bromo-1-methylprop-2-enyl)-N-(2-nitrophenyl)methane-
sulfonamide 22b (1.315 g, 3.9 mmol, 78%) as a pale yellow solid,
mp 92.5–94 ЊC (Found: C, 37.9; H, 3.7; N, 7.8. C11H13BrN2O4S
requires C, 37.8; H, 3.8; N, 8.0%) [Found: (M ϩ NH4)ϩ (CI),
366.0123. C11H13BrN2O4S requires (M ϩ NH4)ϩ, 366.0123];
νmax(KBr disc)/cmϪ1 3109, 3071, 2990, 2938, 2876 (CH), 1625,
6.42 (1H, br m, CH᎐), 7.50–7.65 (2H, m, ArH), 7.76–7.79 (1H,
᎐
m, ArH), 7.96–7.99 (1H, m, ArH); δC(CDCl3, 63 MHz) 17.4
(CH2), 27.4 (CH2), 31.3 (CH2), 40.6 (CH), 63.0 (CH3), 121.0
(C), 126.2 (CH), 129.9 (CH), 130.2 (C), 132.9 (CH), 133.4 (CH),
138.8 (CH), 150.0 (C); m/z (CI) 394 [(M ϩ NH4)ϩ, 60%], 392
[(M ϩ NH4)ϩ, 55], 347 (100), 345 (86), 269(35), 267 (53), 265
(64).
1601 (C᎐C), 1540 (ON᎐O), 1483, 1450 (CH), 1371 (ON᎐O),
᎐
᎐
᎐
1348, 1161 (N–SO2), 773 (Ar ring), 621 (C–Br); NMR spectra
show a mixture of rotamers—the chemical shifts of the major
rotamer are reported here. δH(270 MHz, CDCl3) 1.16 (3H, d,
J 6.8, CH3), 3.01 (3H, s, CH3), 5.16 (1H, q, J 6.8, N-CH), 5.77
N-[(Z)-2-Bromocyclonon-2-enyl]-N-(2-nitrophenyl)methane-
sulfonamide 22f
2-Nitro-N-methylsulfonylaniline 21 (2.59 g, 12 mmol, 1.5
equiv.) and methyldiphenylphosphine (2.40 g, 12 mmol, 1.5
equiv.) were stirred in tetrahydrofuran (50 ml) under nitrogen at
0 ЊC. 2-Bromocyclonon-2-enol16 20f (1.75 g, 8 mmol, 1 equiv.)
was added, followed by diethyl azodicarboxylate (2.09 g, 12
mmol, 1.5 equiv.), and the solution was allowed to warm to
room temperature and stir for 30 min. The mixture was then
heated under reflux and stirred for 48 h. The solvent was
removed in vacuo and the resultant oil was dissolved in ethyl
acetate (20 ml) and washed with sodium hydroxide (2 M, 3 × 20
ml), hydrochloric acid (2 M, 20 ml), and brine (20 ml). The
solution was dried over magnesium sulfate and the solvent
removed in vacuo to give a brown solid (4.0 g). Initial gradient
elution column chromatography using ~15 g of silica and 50%
dichloromethane–50% hexane to 100% dichloromethane
removed the bulk of triphenylphosphine oxide and reduced
DEAD impurities. Further purification using ~6 g of silica
and 50% diethyl ether–50% hexane to 100% diethyl ether gave
the trans diastereomer, present in only one rotameric form,
N-[(Z)-2-bromocyclonon-2-enyl]-N-(2-nitrophenyl)methane-
sulfonamide 22f (1.38 g, 41.2%) as yellow crystals, mp 167 ЊC
(Found: C, 45.9; H, 4.9, N, 6.59. C16H21BrN2O4S requires C,
46.1; H, 5.1; N, 6.7%); νmax(KBr disc)/cmϪ1 2929, 2919, 2906,
1602, 1540, 1355, 1340, 1154; δH(CDCl3, 250 MHz) 1.15–1.72
(8H, m, 4CH2), 1.78–2.09 (2H, m, CH2), 2.24–2.52 (2H, m,
CH2), 3.02 (3H, s, SO2CH3), 5.59 (1H, dd, J 4.5, 12.0, CHN),
(1H, d, J 2.2, ᎐CH), 6.15 (1H, d, J 2.0, ᎐CH), 6.49 (2H, d, J 2.0,
᎐
᎐
᎐CH), 7.58 (1H, dd, J 7.7, 7.7, ArH), 7.68 (1H, ddd, J 7.7, 7.7,
᎐
1.6, ArH), 7.87 (1H, dd, J 7.7, 1.6, ArH), 8.02 (1H, dd, J 7.7,
1.6, ArH); δC(67.8 MHz, CDCl3) 19.4 (CH3), 42.0 (CH3), 62.4
(CH), 122.3 (C), 122.7 (CH2), 126.0 (CH), 130.4 (CH), 130.6
(C), 133.7 (CH), 134.8 (C), 134.9 (CH); m/z (CI) 366
[(M ϩ NH4)ϩ, 100%], 321 (68), 319 (70), 239 (40).
N-[(E/Z)-2-Bromobut-2-enyl]-N-(2-nitrophenyl)methane-
sulfonamide 22c. [Prepared using same procedure as for 22a]
N-[(E/Z)-2-Bromobut-2-enyl]-N-(2-nitrophenyl)methane-
sulfonamide 22c (0.954 g, 2.7 mmol, 83%) as a yellow oil
[Found (CI): (M ϩ NH4)ϩ 366.0123. C11H13BrN2O4S requires
(M ϩ NH4)ϩ, 366.0123]; νmax(film)/cmϪ1 3079, 3037, 3011, 2943,
2886, 2859 (CH), 1609 (C᎐C), 1541 (ON᎐O), 1488, 1457 (CH),
᎐
᎐
1352 (ON᎐O, N–SO ), 1169 (N–SO ), 777 (Ar ring); δ (250
᎐
2
2
H
MHz, CDCl3) 1.41, 1.70 (3H, 2 × d, J 7.3, CH3), 3.12, 3.15 (3H,
2 × s, CH3), 4.62, 4.80 (2H, 2 × m, CH2), 5.88, 6.12 (1H, 2 × q,
J 7.3, ᎐CH), 7.60 (3H, m, ArH), 7.97 (1H, m, ArH); δ (62.9
᎐
C
MHz, CDCl3) 15.3, 17.3 (CH3), 41.8 (CH3), 41.8 (CH3), 54.5
(CH2), 60.8 (CH2), 119.0 (C), 122.8 (C), 126.0 (CH), 126.1
(CH), 130.3 (CH), 130.5, (CH), 131.7 (CH), 132.1 (C), 132.2
(C), 134.0 (CH), 134.6 (CH), 134.7 (CH), 135.1 (CH), 149.1 (C),
149.4 (C); m/z 368 (M ϩ NH4ϩ, 90%), 366 (M ϩ NH4ϩ, 90), 321
(100), 319 (100), 241 (37), 239 (36).
6.46 (1H, dd, J 8.9, 8.9, CH᎐), 7.56–7.76 (2H, m, ArH), 7.88
᎐
N-(2-Bromocyclopent-2-en-1-yl)-N-(2-nitrophenyl)methane-
sulfonamide 22d. [Prepared using same procedure as for 22a]
N-(2-Bromocyclopent-2-en-1-yl)-N-(2-nitrophenyl)methane-
sulfonamide 22d (4.39 g, 61%) as a 2:1 mixture of rotamers by
1H NMR, and as off-white needles, mp 148–149 ЊC (Found: C,
40.1; H, 3.5, N, 7.7. C12H13BrN2O4S requires C, 39.9; H, 3.6; N,
7.8%); νmax(KBr disc)/cmϪ1 2932, 2865, 1602, 1583, 1536, 1481,
1341, 1150; δH(CDCl3, 250 MHz) 1.81–1.88 (1H major, m, CH2
major), 2.04–2.18 (2H, m, CH2), 2.42–2.54 (1H major ϩ 2H
minor, m, CH2), 3.18 (3H major, s, SO2CH3), 3.21 (3H minor, s,
SO2CH3), 4.78–4.84 (1H minor, br m, CHN), 5.48–5.53 (1H
(1H, dd, J 7.7, 1.3, ArH), 8.05 (1H, dd, J 7.7, 1.5, ArH);
δC(CDCl3, 63 MHz) 22.2 (CH2), 26.1 (CH2), 27.8 (CH2), 28.9
(CH2), 30.6 (CH2), 30.6 (CH2), 42.2 (CH3), 60.4 (CH), 125.9
(CH), 127.0 (C), 130.2 (CH), 131.1 (C), 133.7 (CH), 134.9 (CH),
138.6 (CH), 150.3 (C); m/z (EI) 418 (Mϩ, 8%), 416 (Mϩ, 7), 337
(100), 258 (22), 257 (22).
N-(2-Aminophenyl)-N-[(E)-2-bromo-1-methyl-3-phenylprop-2-
enyl]methanesulfonamide 23a
A mixture of sodium borohydride (0.182 g, 4.8 mmol, 1.0
equiv.) and copper() acetylacetonate (0.254 g, 1.0 mmol, 0.2
equiv.) in ethanol (130 ml) was stirred under nitrogen at room
temperature until a black suspension formed in a clear solution.
Sodium borohydride (0.363 g, 9.6 mmol, 2.0 equiv.) was added,
followed by a solution of N-[(E)-2-bromo-1-methyl-3-phenyl-
prop-2-enyl]-N-(2-nitrophenyl)methanesulfonamide 22a (2.0 g,
4.8 mmol, 1.0 equiv.) in ethanol (130 ml), and the resultant
major, m, CHN), 6.15–6.16 (1H, m, CH᎐), 7.53–7.68 (2H
᎐
major ϩ 4H minor, m, ArH), 7.85 (1H major, dd, J 8.2, 8.2,
ArH), 7.99 (1H major, d, J 7.3, ArH); δC(CDCl3, 63 MHz) 28.0
(CH2), 29.8 (CH2 minor), 30.3 (CH2), 30.8 (CH2 minor), 41.6
(CH3 minor), 41.8 (CH3), 70.4 (CH), 73.8 (CH minor), 118.7
(C minor), 121.3 (C), 125.1 (CH minor), 126.1 (CH), 128.8 (C),
129.9 (CH minor), 130.2 (CH), 132.2 (C minor), 133.2 (CH),
J. Chem. Soc., Perkin Trans. 1, 2000, 2395–2408
2403

View Article Online
mixture stirred under nitrogen at room temperature overnight.
Water (200 ml) was added to quench the reaction, and the mix-
ture filtered through kieselguhr before evaporating to dryness in
vacuo. The residue was partitioned between water (100 ml) and
dichloromethane (100 ml). The aqueous layer was washed with
more dichloromethane (100 ml), and the combined organic
layers washed with water (100 ml). The organic phase was dried
over anhydrous magnesium sulfate, filtered through kieselguhr
and evaporated in vacuo to yield a yellow oil. This was purified
by column chromatography (silica; 100% dichloromethane elu-
tion) to yield N-(2-aminophenyl)-N-[(E)-2-bromo-1-methyl-3-
phenylprop-2-enyl]methanesulfonamide 23a (1.55 g, 4.0 mmol,
84%) as a pale yellow solid, mp 136–137.5 ЊC (Found: C, 51.5;
H, 4.8; N, 6.9. C17H19BrN2O2S requires C, 51.7; H, 4.8; N,
7.1%) [Found: Mϩ (EI), 394.0354. C17H19BrN2O2S requires M,
394.0351]; νmax(KBr disc)/cmϪ1 3472, 3383 (NH2), 3063, 3027,
43.34; H, 4.40, N, 8.21. C12H15BrN2O2S requires C, 43.51; H,
4.56; N, 8.46%] [Found: Mϩ, 331.9967. C12H1581BrN2O2S
requires M, 331.9987. Found: Mϩ, 330.0021. C12H1579BrN2O2S
requires M, 330.0038]; νmax(KBr disc)/cmϪ1 3460, 3371, 2964,
2932, 2917, 1624, 1498; δH(CDCl3, 250 MHz) 1.55–1.62 (1H, m,
CH2), 1.93–2.06 (1H, m, CH2), 2.06–2.41 (2H, m, CH2), 3.10
(3H minor, s, SO2CH3), 3.22 (3H major, m, SO2CH3), 3.52–
4.31 (2H, br s, NH2), 5.02–5.09 (1H minor, m, CHN), 5.43–
5.47 (1H major, m, CHN), 6.02–6.08 (1H, m, CH᎐), 6.71
᎐
(1H, dd, J 7.3, 7.3, ArH), 6.80 (1H, d, J 7.5, ArH), 7.15–7.21
(2H, m, ArH); δC(CDCl3, 63 MHz) 28.2 (CH2), 30.7 (CH2),
40.3 (CH3), 70.3 (CH), 117.8 (CH), 118.6 (CH), 121.1 (C),
121.2 (C), 130.5 (CH), 132.1 (CH), 138.7 (CH), 147.9 (C);
m/z (EIϩ) 332 (Mϩ, 33%), 330 (Mϩ, 28), 253 (41), 251 (42), 186
(100), 107 (100).
2953, 2927, 2880 (CH), 1619, 1504 (C᎐C), 1447 (CH), 1316,
N-(2-Aminophenyl)-N-(2-bromocyclohex-2-en-1-yl)methane-
sulfonamide 23e. [Prepared using same procedure as for 23a]
N-(2-Aminophenyl)-N-(2-bromocyclohex-2-en-1-yl)methane-
sulfonamide 23e (1.34 g, 93%), as a 4:1 mixture of rotamers by
1H NMR, and as off-white needles, mp 129–131 ЊC (Found: C,
45.35; H, 4.93, N, 7.93. C13H17BrN2O2S requires C, 45.23; H,
4.96; N, 8.11%); νmax(KBr disc)/cmϪ1 3472, 3430, 3384, 3358,
3316, 3011, 3037, 2933, 2902, 2866, 2829, 1628, 1597, 1312,
1146; δH(CDCl3, 250 MHz) 1.05–1.20 (1H, m, CH2), 1.42–1.53
(1H, m, CH2), 1.82–2.14 (3H, m, CH2), 2.26–2.38 (1H, m, CH2),
3.19 (3H minor, s, SO2CH3 minor), 3.21 (3H major, s, SO2CH3
major), 4.38 (2H, br s, NH2), 5.07 (1H, br t, CHN), 6.32 (1H, t,
᎐
1154 (N–SO2), 761 (Ar ring). NMR spectra showed a mixture
of rotamers—the chemical shifts of the protons of the major
rotamer are reported here. δH(270 MHz, CDCl3) 1.44 (3H, d,
J 7.0, CH3), 3.09 (3H, s, CH3), 4.16 (2H, br s, NH2), 5.35 (1H, q,
J 7.0, N–CH), 6.70–6.88 (3H, m, ArH ϩ ᎐CH), 7.17–7.49 (7H,
᎐
m, ArH); δC(67.8 MHz, CDCl3) 19.6 (CH3), 40.2 (CH3), 64.2
(CH), 117.4 (CH), 118.2 (CH), 121.1 (C), 126.8 (C), 128.3 (CH),
128.5 (CH), 129.1 (CH), 130.5 (CH), 132.3 (CH), 133.0 (CH),
135.2 (C), 148.5 (C).
N-(2-Aminophenyl)-N-(2-bromo-1-methylprop-2-enyl)-
methanesulfonamide 23b. [Prepared using same procedure as for
J 4.2, CH᎐), 6.76–6.92 (2H major ϩ 1H minor, m, 2ArH major,
᎐
23a]
N-(2-Aminophenyl)-N-(2-bromo-1-methylprop-2-enyl)-
1ArH minor), 7.17 (1H major, ddd, J 7.8, 7.8 1.6, ArH major),
7.33–7.37 (1H major ϩ 3H minor, m, ArH major, 3ArH
minor); δC(CDCl3, 63 MHz) 17.5 (CH2 minor), 17.6 (CH2), 27.0
(CH2 minor), 27.1 (CH2), 31.1 (CH2 minor), 31.8 (CH2), 38.9
(CH3), 40.4 (CH3 minor), 61.4 (CH minor), 61.6 (CH), 116.1
(CH minor), 117.4 (CH), 118.3 (CH), 121.1 (C minor), 121.7
(C minor), 121.8 (C), 122.1 (C), 130.2 (CH), 130.3 (CH minor),
131.0 (CH minor), 131.7 (CH), 137.0 (CH), 137.3 (CH minor),
148.2 (C), 151.3 (C minor); m/z (ESϩ) 347 (MHϩ, 93%), 345
(MHϩ, 100), 187 (38).
methanesulfonamide 23b (0.217 g, 0.7 mmol, 78%) as a pale
yellow solid, mp 113–114 ЊC [Found: Mϩ (EI), 318.0055.
C11H15BrN2O2S requires M, 318.0038]; νmax(KBr disc)/cmϪ1
3451, 3371 (NH ), 3074, 3037, 2990, 2927, 1621 (C᎐C), 1497,
᎐
2
1454 (CH), 1321, 1154 (N–SO2), 762; NMR spectra show a
mixture of rotamers—the chemical shifts of the major rotamer
are reported here. δH(400 MHz, CDCl3) 1.35 (3H, d, J 7.0,
CH3), 3.15 (3H, s, CH3), 3.90 (2H, br s, NH2), 5.19 (1H, q, J 7.0,
N-CH), 5.69 (1H, d, J 2.3, ᎐CH), 5.78 (1H, d, J 2.2, ᎐CH), 6.72
᎐
᎐
(1H, ddd, J 7.8, 7.8, 1.3, ArH), 6.80 (1H, dd, J 8.0, 1.3, ArH),
7.18 (1H, ddd, J 8.0, 8.0, 1.5, ArH), 7.32 (1H, dd, J 8.0, 1.5,
ArH); δC(100.6 MHz, CDCl3) 19.1 (CH3), 40.1 (CH3), 62.7
(CH), 117.6 (CH), 118.5 (CH), 121.0 (C), 121.8 (CH2), 130.6
(CH), 132.9 (CH), 134.0 (C), 148.5 (C); m/z 320 (Mϩ, 28%), 318
(Mϩ, 29), 241 (62), 239 (100), 185 (34), 159 (73).
Some separation of these rotameric diastereomers was pos-
sible by column chromatography, and as a result the H NMR
1
spectrum of the major diastereomer was obtained. The separ-
ated diastereomers quickly became a mixture again at room
temperature. Major rotameric diastereomer: δH(CDCl3, 250
MHz) 1.05–1.20 (1H, m, CH2), 1.42–1.53 (1H, m, CH2), 1.82–
2.14 (3H, m, CH2), 2.26–2.38 (1H, m, CH), 3.21 (3H, s, CH3),
4.38 (2H, br s, NH2), 5.07 (1H, br t, CHN), 6.32 (1H, t, J 4.2,
N-(2-Aminophenyl)-N-[(E/Z)-2-bromobut-2-enyl]methane-
sulfonamide 23c. [Prepared using same procedure as for 23a] N-
(2-Aminophenyl)-N-[(E/Z)-2-bromobut-2-enyl]methanesulfon-
amide 23c (0.204 g, 0.6 mmol, 58%) as a pale yellow oil
(Found: C, 41.7; H, 4.9; N, 8.5. C11H15BrN2O2S requires C,
41.4; H, 4.7; N, 8.8%) [Found: (M ϩ H)ϩ (CI), 319.0116.
C11H15BrN2O2S requires (M ϩ H)ϩ, 319.0116]; νmax(film)/cmϪ1
CH᎐), 6.69–6.80 (2H, m, ArH), 7.17 (1H, ddd, J 7.8, 7.8 1.6,
᎐
ArH), 7.35 (1H, dd, J 7.9, 1.5, ArH).
N-(2-Aminophenyl)-N-(2-bromocyclonon-2-enyl)methane-
sulfonamide 23f. [Prepared using same procedure as for 23a]
N-(2-Aminophenyl)-N-(2-bromocyclonon-2-enyl)methanesulf-
onamide 23f (428 mg, 73.7%), as a complicated mixture of
rotamers by 1H NMR, and as a yellow oil [Found: Mϩ,
388.0652. C16H2381BrN2O2S requires M, 388.0613] [Found: Mϩ,
386.0611. C16H2379BrN2O2S requires M, 386.0664]; νmax(KBr
disc)/cmϪ1 3454, 3366, 2929, 2859, 1623, 1334, 1153; δH(CDCl3,
250 MHz) 1.13–2.41 (12H, m, CH2), 2.95, 3.00, 3.13 (3H, 3 × s,
SO2CH3), 3.69–4.39 (2H, br s, NH2), 5.19–6.42 (2H, m, CHN,
3482, 3383 (NH ), 3032, 2927, 2854 (CH), 1619, 1504 (C᎐C),
᎐
2
1462 (CH), 1326, 1159 (N–SO2), 761 (Ar ring); δH(400 MHz,
CDCl3) 1.26, 1.66 (3H, 2 × d, J 7.3, CH3), 3.12, 3.17 (3H, 2 × s,
CH3), 4.03 (2H, br s, NH2), 4.55 (2H, s ϩ br m, CH2), 5.75, 6.04
(1H, 2 × q, J 7.3, ᎐CH), 6.75 (2H, m, ArH), 7.15 (2H, m, ArH);
᎐
δC(100.6 MHz, CDCl3) 14.6, 17.0, 39.7, 40.1 (CH3), 51.9, 58.9
(CH2), 117.2 (CH), 117.4 (CH), 118.7 (CH), 118.7 (CH), 119.1
(C), 122.9 (C), 123.6 (C), 123.8 (C), 130.2 (CH), 130.2 (CH),
130.3, (CH), 130.5 (CH), 134.1 (CH), 146.5 (C), 146.5 (C);
m/z 321, 319 [(M ϩ H)ϩ, 14%], 159 (77), 133 (74), 119 (100),
109 (72).
CH᎐), 6.70–6.82 (2H, m, Ar), 7.08–7.55 (2H, m, ArH);
᎐
δC(CDCl3, 63 MHz) 22.8 (CH2), 23.1 (CH2), 25.6 (CH2), 25.8
(CH2), 26.1 (CH2), 26.3 (CH2), 26.8 (CH2), 27.1 (CH2), 27.4
(CH2), 27.6 (CH2), 27.7 (CH2), 28.3 (CH2), 28.5 (CH2), 29.9
(CH2), 31.2 (CH2), 33.6 (CH2), 39.1 (CH3), 40. 5 (CH3), 40.7
(CH3), 57.2 (CH), 57.7 (CH), 116.5 (CH), 116.8 (CH), 117.6
(CH), 117.7 (CH), 117.9 (CH), 118.1 (CH), 121.5 (C), 121.8 (C),
122.4 (C), 127.4 (CH), 128.3 (CH), 129.9 (CH), 130.0 (CH),
130.5 (CH), 131.8 (CH), 132.2 (CH), 132.8 (CH), 133.1 (CH),
147.6 (C), 148.3 (C), 148.4 (C); m/z (EI) 388 (Mϩ, 6%), 386
N-(2-Aminophenyl)-N-(2-bromocyclopent-2-en-1-yl)methane-
sulfonamide 23d. [Prepared using same procedure as for 23a]
N-(2-Aminophenyl)-N-(2-bromocyclopent-2-en-1-yl)methane-
sulfonamide 23d (1.19 g, 90%) as an 8:1 mixture of rotamers by
1H NMR, and as off-white needles, mp 149–150 ЊC [Found: C,
2404
J. Chem. Soc., Perkin Trans. 1, 2000, 2395–2408

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(Mϩ, 6), 309 (49), 307 (57), 229 (60), 227 (51), 186 (71), 119 (76),
107 (100).
dichloromethane (10 ml) under nitrogen at 0 ЊC. Nitrosonium
tetrafluoroborate (211 mg, 1.8 mmol, 1.2 equiv.) was added and
the mixture was stirred for 60 min. TLC analysis showed that
some starting material remained, and so additional nitroso-
nium tetrafluoroborate (105 mg, 1.4 mmol, 0.6 equiv.) was
added. The mixture was stirred for a further 20 min, after which
time no starting material remained by TLC. The solvent was
removed in vacuo, and the resulting oil was dissolved in acetone
(5 ml), and added dropwise to vigorously stirring diethyl
ether (100 ml), causing immediate precipitation of the desired
diazonium salt, 2-[N-(2-bromocyclopent-2-en-1-yl)-N-(methyl-
sulfonyl)amino]benzenediazonium tetrafluoroborate 17d as a
cream solid. During filtration the solid quickly blackened and
became oily, and as a result, the salt was immediately taken on
to the next stage.
2-[N-(2-Bromocyclopent-2-enyl)-N-(methylsulfonyl)amino]-
benzenediazonium tetrafluoroborate 17d from the previous step
was dissolved in acetone (10 ml) and stirred under nitrogen at
room temperature. Sodium iodide (225 mg, 1.5 mmol, 1 equiv.)
was added and the mixture was stirred for 24 h. The solvent was
removed in vacuo giving a brown solid, which was partitioned
between dichloromethane (20 ml) and water (20 ml). The aque-
ous phase was extracted with dichloromethane (2 × 20 ml), and
the combined organic portions were washed with water (2 × 20
ml), sodium thiosulfate (sat. aq., 20 ml) and brine (20 ml). The
solution was dried over magnesium sulfate and the solvent was
removed in vacuo to give a brown solid (394 mg). Column
chromatography using ~12 g of silica and 30% diethyl ether–
70% hexane, gave the desired indole, 4-methylsulfonyl-1,2,3,4-
tetrahydrocyclopenta[b]indole 24d (230 mg, 65%) as a white
solid, mp 136–137 ЊC (Found: C, 61.35; H, 5.54, N, 5.84.
C12H13NO2S requires C, 61.25; H, 5.57; N, 5.95%) [Found: Mϩ,
235.0737. C12H13NO2S requires M, 235.0667]; νmax(KBr disc)/
cmϪ1 3022, 2963, 2917, 2863, 1611; δH(CDCl3, 250 MHz) 2.48–
2.57 (2H, m, CH2), 2.74–2.81 (2H, m, CH2), 3.01–3.08 (5H, m,
CH2, SO2CH3), 7.23–7.29 (2H, m, 2ArH), 7.39–7.42 (1H, m,
ArH), 7.87–7.91 (1H, m, ArH); δC(CDCl3, 63 MHz) 24.2 (CH2),
27.6 (CH2), 27.8 (CH2), 40.6 (CH3), 114.1 (CH), 119.4 (CH),
123.6 (CH), 123.7 (CH), 126.6 (C), 127.4 (C), 140.5 (C), 144.0
(C); m/z (EI) 235 (Mϩ, 46%), 156 (100), 128 (25).
3-Benzyl-2-methyl-1-(methylsulfonyl)-1H-indole 24a
A suspension of nitrosonium tetrafluoroborate (0.037 g, 0.3
mmol, 1.2 equiv.) in dry dichloromethane (3 ml) was treated
dropwise with a solution of N-(2-aminophenyl)-N-[(E)-2-
bromo-1-methyl-3-phenylprop-2-enyl]methanesulfonamide 23a
(0.103 g, 0.3 mmol, 1.0 equiv.) in dry dichloromethane (1 ml)
whilst stirring under nitrogen at room temperature. A dark red–
brown coloured solution formed. The mixture was stirred at
room temperature for 3.5 h before evaporating the solvent in
vacuo to yield a red–brown oil. This was dissolved in degassed
AR acetone (3 ml), and stirred under nitrogen at room tempera-
ture. Sodium iodide (0.040 g, 0.3 mmol, 1.0 equiv.) was added in
one portion. A vigorous evolution of gas was observed, along
with a colour change to dark brown. The resultant mixture was
left to stir under nitrogen for 16 h. The solvent was evaporated
in vacuo to yield a dark solid which was partitioned between
dichloromethane (10 ml) and water (10 ml). The organic
phase was washed with sodium thiosulfate solution (10 ml) and
brine (10 ml). The combined organic layers were dried over
anhydrous magnesium sulfate, filtered through kieselguhr and
evaporated in vacuo to yield a brown solid. This was purified by
column chromatography (silica; 20% ethyl acetate in hexane
elution) to yield 3-benzyl-2-methyl-1-(methylsulfonyl)-1H-
indole 24a (0.039 g, 0.1 mmol, 49%) as a pale yellow solid, mp
81.5–83 ЊC [Found: Mϩ (EI), 299.0966. C17H17NO2S requires
M, 299.0980]; νmax(KBr disc)/cmϪ1 3062, 3032, 2938, 2857
(CH), 1604 (C᎐C), 1498, 1457 (CH), 1363, 1180 (N–SO ), 772
᎐
2
(Ar ring); δH(400 MHz, CDCl3) 2.60 (3H, s, CH3), 3.03 (3H, s,
CH3), 4.07 (2H, s, CH2), 7.24 (7H, m, ArH) 7.39 (1H, dd, J 7.8,
1.0, ArH), 8.03 (1H, dd, J 8.0, 1.1, ArH); δC(100.6 MHz,
CDCl3) 13.0 (CH3), 30.2 (CH2), 40.7 (CH3), 114.3 (CH), 119.1
(C), 119.2 (CH), 123.8 (CH), 124.4 (CH), 126.5 (CH), 128.3
(CH), 128.8 (CH), 130.8 (C), 133.8 (C), 136.4 (C), 139.7 (C);
m/z (EI) 299 (Mϩ, 40%), 220 (70), 153 (100), 136 (79), 107 (66).
2,3-Dimethyl-1-(methylsulfonyl)-1H-indole 24b. [Prepared
using same procedure as for 24a] 2,3-Dimethyl-1-(methyl-
sulfonyl)-1H-indole 24b (0.093 g, 0.4 mmol, 83%) as an off-
white solid, mp 90–91 ЊC (Found: C, 58.9; H, 5.6; N, 6.2.
C11H13NO2S requires C, 59.2; H, 5.9; N, 6.3%) [Found: Mϩ
(EI), 223.0684. C11H13NO2S requires M, 223.0667]; νmax(KBr
disc)/cmϪ1 3048, 3011, 2927, 2854, 1457 (CH), 1352, 1174
(N–SO2), 777 (Ar ring); δH(400 MHz, CDCl3) 2.22 (3H, s,
CH3), 2.53 (3H, s, CH3), 2.97 (3H, s, CH3), 7.31 (2H, m, ArH),
7.46 (1H, m, ArH), 8.01 (1H, m, ArH); δC(100.6 MHz, CDCl3)
9.1 (CH3), 12.8 (CH3), 40.4 (CH3), 114.2 (CH), 116.2 (C), 118.7
(CH), 123.7 (CH), 124.3 (CH), 131.5 (C), 132.6 (C), 136.2 (C);
m/z (EI) 223 (Mϩ, 55%), 208 (18), 144 (100).
9-Methylsulfonyl-1,2,3,4-tetrahydro-9H-carbazole 24e (via
the diazonium salt 17e). N-(2-Aminophenyl)-N-(2-bromocyclo-
hex-2-enyl)methanesulfonamide 23e (0.518 g, 1.5 mmol, 1
equiv.) was stirred in dichloromethane (10 ml) under nitrogen at
0 ЊC. Nitrosonium tetrafluoroborate (0.211 g, 1.8 mmol, 1.2
equiv.) was added and the mixture was stirred for 40 min. The
solvent was removed in vacuo, and the resulting oil was dis-
solved in acetone (5 ml), and added dropwise to vigorously
stirring diethyl ether (100 ml), causing immediate precipitation
ofthediazoniumsalt,2-[N-(2-bromocyclohex-2-enyl)-N-methyl-
sulfonylamino]benzenediazonium tetrafluoroborate 17e, as a
cream solid. During filtration the solid quickly blackened and
became oily, and as a result was immediately taken on to the
next stage.
2-[N-(2-Bromocyclohex-2-en-1-yl)-N-methylsulfonylamino]-
benzenediazonium tetrafluoroborate 17e from the previous step
was dissolved in acetone (10 ml) and stirred under nitrogen at
room temperature. Sodium iodide (0.225 g, 1.5 mmol, 1 equiv.)
was added and the mixture was stirred for 24 h. The solvent was
removed in vacuo giving a brown oil, which was partitioned
between diethyl ether (20 ml) and water (20 ml). The aqueous
phase was extracted with diethyl ether (2 × 5 ml), and the com-
bined organic portions were washed with water (2 × 20 ml), aq.
sodium thiosulfate (20 ml) and brine (20 ml). The solution was
dried over magnesium sulfate and the solvent was removed to
give a brown oil. Column chromatography [8% ethyl acetate–
92% hexane] gave the desired indole, 9-methylsulfonyl-1,2,3,4-
tetrahydro-9H-carbazole 24e (185.2 mg, 54%) as an off-white
solid mp 104–105 ЊC (Found: C, 62.53; H, 5.86, N, 5.29.
3-Ethyl-1-(methylsulfonyl)-1H-indole 24c. [Prepared using
same procedure as for 24a] 3-Ethyl-1-(methylsulfonyl)-1H-
indole 24c (0.049 g, 0.2 mmol, 44%) as a yellow solid, mp 63.5–
65 ЊC (Found: C, 58.8; H, 5.8; N, 6.1. C11H13NO2S requires C,
59.2; H, 5.9; N, 6.3%) [Found: Mϩ (EI), 223.0667. C11H13NO2S
requires M, 223.0667]; νmax(KBr disc)/cmϪ1 3045, 3011, 2927,
2854, 1457 (CH), 1352, 1174 (N–SO2), 777 (Ar ring); δH(400
MHz, CDCl3) 1.35 (3H, t, J 7.6, CH3), 2.75 (2H, dq, J 7.6, 1.2,
CH2), 3.05 (3H, s, CH3), 7.21 (1H, t, J 1.2, ArH), 7.34 (2H, m,
ArH), 7.59 (1H, d, J 7.6, ArH), 7.92 (1H, d, J 7.7, ArH);
δC(100.6 MHz, CDCl3) 13.4 (CH3), 18.4 (CH2), 40.4 (CH3),
113.5 (CH), 119.9 (CH), 122.1 (CH), 123.4 (CH), 125.1 (CH),
125.4 (C), 131.3 (C), 135.7 (C); m/z (EI) 223 (Mϩ, 10%), 144
(100), 115 (47), 79 (53).
4-Methylsulfonyl-1,2,3,4-tetrahydrocyclopenta[b]indole 24d.
N-(2-Aminophenyl)-N-(2-bromocyclopent-2-en-1-yl)methane-
sulfonamide 23d (497 mg, 1.5 mmol, 1 equiv.) was stirred in
J. Chem. Soc., Perkin Trans. 1, 2000, 2395–2408
2405

View Article Online
C13H15NO2S requires C, 62.63; H, 6.06; N, 5.62%) (Found: Mϩ,
249.0805. C13H15NO2S requires M, 249.0824); νmax(KBr disc)/
cmϪ1 3031, 2933, 2840, 1612, 1457, 1358, 1224, 1152; δH(CDCl3,
250 MHz) 1.85–1.96 (4H, m, 2CH2), 2.65–2.71 (2H, m, CH2),
2.93–2.99 (5H, m, CH2, CH3), 7.28–7.31 (2H, m, ArH), 7.42–
7.46 (1H, m, ArH), 7.97–8.01 (1H, m, ArH); δC(CDCl3, 63
MHz) 21.2 (CH2), 22.2 (CH2), 23.3 (CH2), 24.5 (CH2), 40.3
(CH3), 113.9 (CH), 118.3 (CH), 118.6 (C), 123.5 (CH), 124.1
(CH), 130.4 (C), 135.5 (C), 136.1 (C); m/z (EI) 249 (Mϩ, 63%),
170 (100%).
2-[N-(2-Bromocyclonon-2-enyl)-N-methylsulfonylamino]-
benzenediazonium tetrafluoroborate 17f was dissolved in acet-
one (5 ml) and stirred under nitrogen at room temperature.
Sodium iodide (37.5 mg, 0.25 mmol, 1 equiv.) was added and
the mixture was stirred for 24 h. The solvent was removed in
vacuo giving a brown oil, which was partitioned between ethyl
acetate (20 ml) and water (20 ml). The aqueous phase was
extracted with ethyl acetate (2 × 5 ml), and the combined
organic portions were washed with water (2 × 20 ml), aq.
sodium thiosulfate (20 ml) and brine (20 ml). The solution was
dried over magnesium sulfate and the solvent was removed to
give a brown oil. Gradient elution column chromatography
using ~9 g of silica and ethyl acetate–hexane as the eluant,
gave the desired indole, 5-methylsulfonyl-5,6,7,8,9,10,11,12-
octahydrocyclonona[b]indole 24f (14.3 mg, 20%), as an off-white
solid and 2 separate diastereomers of 12-iodo-5-methylsulfonyl-
5,5a,6,7,8,9,10,11,12,12a-decahydrocyclonona[b]indole 27a and
27b as off-white solids (13.6 mg, 13%), and (16.7 mg, 16%).
Isolation of 9-methylsulfonyl-1,2,3,9a-tetrahydro-9H-carbazole
25e from diazonium salt reaction
2-[N-(2-Bromocyclohex-2-enyl)-N-methylsulfonylamino]-
benzenediazonium tetrafluoroborate 17e (0.5 mmol) was dis-
solved in acetone (10 ml) and stirred under nitrogen at room
temperature. Sodium iodide (75 mg, 0.5 mmol, 1 equiv.) was
added and the mixture was stirred for 5 min. The solvent was
removed in vacuo giving a brown oil, which was partitioned
between ethyl acetate (20 ml) and water (20 ml). The aqueous
phase was extracted with ethyl acetate (2 × 5 ml), and the
combined organic portions were washed with water (2 × 20
ml), aq. sodium thiosulfate (20 ml) and brine (20 ml). The
solution was dried over magnesium sulfate and the solvent
was removed to give a brown oil. Column chromatography
using ~9 g of silica and 20% diethyl ether–80% hexane, gave
the indole, 9-methylsulfonyl-1,2,3,4-tetrahydro-9H-carbazole
24e, as an off-white solid (43 mg, 35%) (data as reported
above) as well as the relatively unstable alkene intermediate,
9-methylsulfonyl-1,2,3,9a-tetrahydro-9H-carbazole 25e (19 mg,
15%), mp 95–97 ЊC, δH(CDCl3, 250 MHz) 1.57–1.79 (2H, m,
CH2), 1.95–2.01 (1H, m, CH2), 2.28–2.35 (2H, m, CH2), 2.65–
2.75 (1H, m, CH2), 2.72 (3H, s, SO2CH3), 4.34–4.40 (1H, m,
5-Methylsulfonyl-5,6,7,8,9,10,11,12-octahydrocyclonona[b]-
indole 24f. Mp 101–102 ЊC (Found: C, 65.4; H, 7.0; N, 4.8.
C16H21NO2S requires C, 65.9; H, 7.3; N, 4.8%) [Found: Mϩ,
291.1293. C16H21NO2S requires M, 291.1293]; νmax(KBr disc)/
cmϪ1 2926, 2856, 1455, 1362, 1184; δH(CDCl3, 250 MHz) 1.11–
1.33 (2H, m, CH2), 1.40–1.57 (4H, m, CH2), 1.64–1.89 (4H, m,
CH2), 2.79 (2H, m, CH2), 2.93 (3H, s, SO2CH3), 3.11 (2H, m,
CH2), 7.26–7.30 (2H, m, ArH), 7.44–7.50 (1H, m, ArH), 8.00–
8.04 (1H, m, ArH); δC(CDCl3, 63 MHz) 22.7 (CH2), 23.9 (CH2),
24.2 (CH2), 25.4 (CH2), 25.5 (CH2), 26.3 (CH2), 27.0 (CH2),
40.1 (CH3), 114.6 (CH), 118.6 (CH), 122.3 (C), 123.6 (CH),
124.3 (CH), 130.7 (C), 136.7 (C), 137.2 (C); m/z (EIϩ) 291 (Mϩ,
64%), 212 (100).
12-Iodo-5-methylsulfonyl-5,5a,6,7,8,9,10,11,12,12a-deca-
hydrocyclonona[b]indole 27a. Mp 138–140 ЊC [Found: C, 45.9;
H, 5.2; N, 3.3. C16H22INO2S requires C, 45.8; H, 5.3; N, 3.3%]
[Found: Mϩ, 419.0416. C16H22INO2S requires M, 419.0416];
νmax(film)/cmϪ1 2925, 2853, 1599, 1345, 1155; δH(CDCl3, 250
MHz) 1.50–1.89 (9H, m, CH2), 2.23–2.53 (3H, m, CH2), 3.12
(3H, s, SO2CH3), 3.23 (1H, dd, J 3.3, 3.3, CH), 4.39 (1H,
ddd, J 10.7, 3.4, 3.4, CH), 4.62 (1H, ddd, J 11.3, 3.2, 3.2, CH),
7.02–7.13 (2H, m, ArH), 7.27 (1H, m, ArH), 7.38 (1H, d, J 8.1,
ArH); δC(CDCl3, 63 MHz) 21.3 (CH2), 23.1 (CH2), 25.2 (CH2),
27.8 (CH2), 36.3 (CH2), 36.8 (CH2), 39.0 (CH3), 43.8 (CH), 48.9
(CH), 65.7 (CH), 113.6 (CH), 123.7 (CH), 124.4 (CH), 129.3
(CH), 133.9 (C), 141.1 (C); m/z (CI) 437 (M ϩ NH4ϩ, 8%), 311
(52), 309 (62), 292 (61), 214 (100).
CHN), 5.98 (1H, m, CH᎐), 7.06 (1H, dd, J 8.1, 7.0, ArH),
᎐
7.22 (1H, dd, J 7.0, 7.0, ArH), 7.37 (1H, d, J 7.0, ArH), 7.51
(1H, d, J 8.1, ArH); δC(CDCl3, 100 MHz) 20.2 (CH2), 24.7
(CH2), 29.4 (CH2), 34.1 (CH3), 65.1 (CH), 114.7 (CH), 118.9
(CH), 120.5 (CH), 124.3 (CH), 129.4 (CH), 129.6 (C), 135.6
(C), 143.6 (C).
Conversion of 9-methylsulfonyl-1,2,3,9a-tetrahydro-9H-
carbazole 25e to 9-methylsulfonyl-1,2,3,4-tetrahydro-9H-
carbazole 24e
9-Methylsulfonyl-1,2,3,9a-tetrahydro-9H-carbazole 25e (19 mg,
0.08 mmol, 1 equiv.) and toluene-4-sulfonic acid (10 mg) were
stirred in benzene (2 ml) under nitrogen and the mixture heated
under reflux for 2 h. TLC showed only the desired indole pres-
ent, and so the solution was washed with sodium hydroxide
(2 M, 5 ml) and water (5 ml) and dried over magnesium sulfate.
Removal of solvent in vacuo gave the indole, 9-methylsulfonyl-
1,2,3,4-tetrahydro-9H-carbazole 24e (18 mg, 95%) as a white
solid (data as reported above).
12-Iodo-5-methylsulfonyl-5,5a,6,7,8,9,10,11,12,12a-deca-
hydrocyclonona[b]indole 27b. Mp 144–145 ЊC [Found: C, 45.9;
H, 5.0; N, 3.2. C16H22INO2S requires C, 45.8; H, 5.3; N,
3.3%]; [Found: M ϩ NH4ϩ, 437.0760. C16H22INO2S requires
M ϩ NH4ϩ, 437.0760]; νmax(film)/cmϪ1 3054, 2932, 2854, 1604;
δH(CDCl3, 400 MHz) 1.41–1.89 (9H, m, CH2), 2.04–2.09 (1H,
m, CH2), 2.26–2.31 (1H, m, CH2), 2.38–2.42 (1H, m, CH2), 2.89
(3H, s, SO2CH3), 3.76 (1H, d, J 11.6, CHAr), 4.14 (1H, ddd,
J 11.7, 3.2, 3.2, CHI), 4.44 (1H, dm, J 12.1, CHN), 7.10 (1H,
dd, J 7.6, 7.6, ArH), 7.29 (1H, dd, J 8.0, 7.6, ArH), 7.41 (1H, d,
J 8.0, ArH), 7.93 (1H, d, J 7.6, ArH); δC(CDCl3, 63 MHz) 18.8
(CH2), 20.28 (CH2), 20.34 (CH2), 25.9 (CH2), 32.7 (CH2), 34.9
(CH2), 37.1 (CH3), 39.7 (CH), 48.1 (CH), 64.1 (CH), 115.6
(CH), 123.6 (CH), 128.5 (CH), 129.4 (CH), 132.1 (C), 141.4 (C);
m/z (EI) 419 (Mϩ, 100%), 340 (12), 292 (64), 291 (39).
5-Methylsulfonyl-5,6,7,8,9,10,11,12-octahydrocyclonona[b]-
indole 24f and 12-iodo-5-methylsulfonyl-5,5a,6,7,8,9,10,11,12,
12a-decahydrocyclonona[b]indole 27
N-(2-Aminophenyl)-N-(2-bromocyclonon-2-enyl)methane-
sulfonamide 23f (98 mg, 0.25 mmol, 1 equiv.) was stirred in
dichloromethane (30 ml) under nitrogen at 0 ЊC. Nitrosonium
tetrafluoroborate (35.1 mg, 0.3 mmol, 1.2 equiv.) was added
and the mixture was stirred for 50 min. The solvent was
removed in vacuo, and the resulting oil was dissolved in acetone
(3 ml), and added dropwise to vigorously stirring diethyl ether
(100 ml), causing immediate precipitation of 2-[N-(2-bromo-
cyclonon-2-enyl)-N-methylsulfonylamino]benzenediazonium
tetrafluoroborate 17f as a cream solid. During filtration the
solid quickly blackened and became oily, and as a result was
immediately taken on to the next stage.
N-(2-Bromocyclohex-2-enyl)-N-(2-iodophenyl)methane-
sulfonamide 30
[Prepared using same procedure as for 22a] N-(2-Bromocyclo-
hex-2-enyl)-N-(2-iodophenyl)methanesulfonamide 30 (1.94 g,
85%) as a 14:1 mixture of rotamers, and as a white solid, mp
2406
J. Chem. Soc., Perkin Trans. 1, 2000, 2395–2408

View Article Online
143–144 ЊC [Found: C, 34.37; H, 3.16, N, 2.97. C13H15BrINO2S
requires C, 34.23; H, 3.31; N, 3.07%]; νmax(KBr disc)/cmϪ1 2946,
2933, 2906, 1650, 1577, 1340, 1166, 751; δH(CDCl3, 250 MHz)
(peaks for only major rotamer mentioned in 1H spectrum) 1.05–
1.11 (1H, m, CH2), 1.49–1.56 (1H, m, CH2), 1.83–2.07 (3H, m,
CH2), 2.80–2.90 (1H, m, CH2), 3.23 (3H, s, SO2CH3), 4.97–4.99
mmol, 1.4 equiv.) in dry tetrahydrofuran (20 ml) was added
diisopropyl azodicarboxylate (0.83 ml, 4.2 mmol, 1.4 equiv.)
dropwise whilst stirring under nitrogen at 0 ЊC. Once the
addition was complete, the reaction was stirred at room
temperature for 16 h. Water (20 ml) was added to quench the
reaction and extracted with dichloromethane. The organic phase
was washed with sodium hydroxide (2 M, 2 × 25 ml) and dried
over anhydrous sodium sulfate, filtered and evaporated in vacuo
to yield a yellow oil. This was purified by column chrom-
atography (silica; 20% ethyl acetate in hexanes) to afford
N-(2-bromo-1-methyl-3-phenylprop-2-enyl)-N-(2-iodophenyl)-
methanesulfonamide 31 and N-(2-bromo-1-phenylbut-2-enyl)-
N-(2-iodophenyl)methanesulfonamide 31Ј (1.1 g, 2.18 mmol,
72%) as an inseparable mixture and as a viscous yellow oil
[Found: M ϩ NH4ϩ, 522.9563. C17H17BrINO2S requires M ϩ
NH4ϩ, 522.9552]; νmax (film)/cmϪ1 3065, 3029, 2981, 2934, 1641,
1583, 1458, 1338, 1159; NMR showed a complex mixture of
isomers: δH(CDCl3, 400 MHz) 1.38 (J 6.9), 1.69 (J 6.9), 1.76
(J 6.5), 1.92 (J 6.5) (3H, 4 × d, Me), 3.03, 3.11, 3.20, 3.35 (3H,
4 × s, CH3), 5.12 (J 6.9), 5.36 (J 6.9), 6.47 (J 6.5), 6.92 (J 6.5)
(1H, m, CHN), 6.34 (1H, t, J 4.3, CH᎐), 7.15 (1H, ddd, J 7.8,
᎐
7.8, 1.6, ArH), 7.36 (1H, ddd, J 7.8, 7.8, 1.5, ArH), 7.67 (1H,
dd, J 7.8, 1.5, ArH), 8.01 (1H, dd, J 7.8, 1.4, ArH); δC(CDCl3,
63 MHz) 17.0 (CH2), 17.9 (CH2), 27.0 (CH2), 27.1 (CH2), 30.7
(CH2), 32.2 (CH2), 41.0 (CH3), 42.9 (CH3), 62.2 (CH), 63.4
(CH), 101.3 (C), 106.3 (C), 119.8 (C), 121.8 (C), 128.7 (CH),
128.9 (CH), 130.1 (CH), 132.4 (CH), 135.3 (CH), 136.1 (CH),
138.4 (CH), 139.9 (C), 141.0 (CH), 142.0 (C); m/z 475
(M ϩ NH4ϩ, 94%), 473 (M ϩ NH4ϩ, 100), 458 (Mϩ, 12), 456
(Mϩ, 10).
9-Methylsulfonyl-1,2,3,9a-tetrahydro-9H-carbazole 25e
To
a solution of N-(2-bromocyclohex-2-enyl)-N-(2-iodo-
phenyl)methanesulfonamide 30 (200 mg, 0.44 mmol, 1 equiv.)
in dry benzene (5 ml), was added 1-ethylpiperidine hypophos-
phite (790 mg, 4.4 mmol, 10 equiv.) and the reaction was heated
under reflux for 30 min. AIBN (28 mg, 0.17 mmol, 0.4 equiv.)
was added in two portions over 30 min and the reaction was
refluxed for another 20 h. The reaction was cooled before dilut-
ing with dichloromethane and extracted with water (50 ml). The
organic phase was washed with aqueous hydrochloric acid,
sodium bicarbonate and dried over sodium sulfate. The solvent
was distilled under vacuum and the residue obtained was
purified by column chromatography (5–10% ethyl acetate in
hexanes) to afford a white solid identified as 9-methylsulfonyl-
1,2,3,9a-tetrahydro-9H-carbazole 25e (65 mg, 0.26 mmol, 60%)
and recovered starting material 30 (20 mg). Data as reported
previously.
(1H, 4 × q, CHN), 5.95 and 6.13 (2 × s, ᎐CH), 6.8–8.1 [m,
᎐
9 × ArH ϩ ᎐CH(partial)]; δ (CDCl , 100.6 MHz) 16.9 (CH ),
᎐
C
3
3
17.1 (CH3), 20.0 (CH3), 21.4 (CH3), 42.1 (CH3), 43.2 (CH3),
43.3 (CH3), 43.9 (CH3), 62.7 (CH), 65.6 (CH), 72.8 (CH), 73.7
(CH), 103.7 (C), 106.2 (C), 107.4 (2 × C), 125.2 (CH), 126.7
(C), 127.2 (C), 127.5 (C), 127.89 (CH), 127.94 (CH), 128.10
(CH), 128.16 (CH), 128.26 (CH), 128.3 (CH), 128.6 (CH), 128.8
(CH), 128.97 (CH), 129.06 (CH), 129.1 (CH), 129.5 (CH), 129.8
(CH), 130.1 (CH), 130.3 (CH), 130.5 (CH), 130.77 (CH),
130.8 (CH), 132.5 (CH), 132.9 (CH), 133.02 (CH), 133.07 (CH),
133.2 (CH), 133.5 (CH), 134.7 (C), 135.7 (C), 135.76 (C),
140.02 (CH), 140.1 (CH), 140.28 (C), 140.3 (CH), 140.5 (CH),
141.0 (C), 141.6 (C); m/z (CI) 525 (M ϩ NH4ϩ, 100%), 523
(M ϩ NH4ϩ, 90).
3-Benzyl-2-methyl-1-(methylsulfonyl)-1H-indole 24a
9-Methylsulfonyl-1,2,3,4-tetrahydro-9H-carbazole 24e and 9-
methylsulfonyl-1,2,3,9a-9H-tetrahydrocarbazole 25e via tri-n-
butyltin hydride reaction
To a solution of N-(2-bromo-1-methyl-3-phenylprop-2-enyl]-N-
(2-iodophenyl)methanesulfonamide 31 and N-(2-bromo-1-
phenylbut-2-enyl)-N-(2-iodophenyl)methanesulfonamide 31Ј
(450 mg, 0.89 mmol, 1 equiv.) in dry benzene (9 ml) was added
1-ethylpiperidine hypophosphite (1.6 g, 8.9 mmol, 10 equiv.)
and the reaction was heated to reflux. AIBN (58 mg, 0.36
mmol, 0.4 equiv.) was added in two portions over 30 min and
the reaction was refluxed for another 2 h. The reaction was
cooled before diluting with DCM and extracted with water (50
ml). The organic phase was washed with aqueous hydrochloric
acid, sodium bicarbonate and dried over anhydrous sodium
sulfate. The residue was partly purified by column chromato-
graphy and the appropriate fractions obtained were dissolved in
benzene (5 ml) and toluene-p-sulfonic acid (30 mg) was added.
The reaction was heated at reflux for 1 h before diluting with
dichloromethane and extracting with sodium bicarbonate solu-
tion (2 × 10 ml). The organic phase was washed with water,
dried over anhydrous sodium sulfate and distilled under
vacuum to yield a brown oil. This was purified by column
chromatography (silica; 10% ethyl acetate in hexanes elution) to
afford a single indole (24a) (120.5 mg, 0.40 mmol, 45.2%). Data
as reported previously.
N-(2-Bromocyclohex-2-enyl)-N-(2-iodophenyl)methanesulfon-
amide 30 (228 mg, 0.5 mmol, 1 equiv.) was stirred in benzene
(40 ml) under nitrogen and heated under reflux. AIBN (82 mg,
0.5 mmol, 1 equiv.) and tri-n-butyltin hydride (0.20 ml, 0.75
mmol, 1.5 equiv.) were dissolved in benzene (10 ml) under a
nitrogen atmosphere. The solution was added to the solution of
30 via a syringe pump over 3 h. Heating was continued for 12 h.
The solvent was removed in vacuo to give a brown oil. Column
chromatography using ~6 g of silica and ~1 l of hexane
removed the bulk of the tin residues. Column chromatogaphy
using 20% diethyl ether–80% hexane gave 9-methylsulfonyl-
1,2,3,4-tetrahydro-9H-carbazole 24e contaminated with the
unrearranged alkene 25e and some tin residues (256 mg). Fur-
ther column chromatography using ~6 g of silica and 4% diethyl
ether–96% hexane as the eluant gave the indole, 9-methyl-
sulfonyl-1,2,3,4-tetrahydro-9H-carbazole 24e (61 mg, 49%) as a
white solid and the intermediate, 9-methylsulfonyl-1,2,3,9a-
tetrahydro-9H-carbazole 25e (32 mg, 26%), as an unstable white
solid.
9-Methylsulfonyl-1,2,3,4-tetrahydro-9H-carbazole 24e: data
as described above.
9-Methylsulfonyl-1,2,3,9a-tetrahydro-9H-carbazole 25e: data
as described above.
When the reaction was repeated as above but using
N-(2-bromo-1-methyl-3-phenylprop-2-enyl-N-(2-iodophenyl)-
methanesulfonamide (31 ϩ 31Ј), (200 mg, 0.39 mmol, 1 equiv.),
and AIBN (64 mg, 0.39 mmol, 1 equiv.), the same indole (24a)
(50 mg, 0.16 mmol, 41%) was isolated as well as the isomeric
indole, 3-ethyl-2-phenyl-1-(methylsulfonyl)-1H-indole 24aЈ (5
mg, 0.017 mmol, 4%).
N-(2-Bromo-1-methyl-3-phenylprop-2-enyl)-N-(2-iodophenyl)-
methanesulfonamide 31 and N-(2-bromo-1-phenylbut-2-enyl)-N-
(2-iodophenyl)methanesulfonamide 31Ј
To a solution of (E)-3-bromo-4-phenylbut-3-en-2-ol 20a (681
mg, 3 mmol, 1 equiv.), 2-iodophenylmethanesulfonamide 16
(891 mg, 3 mmol, 1 equiv.) and triphenylphosphine (786 mg, 4.2
3-Ethyl-2-phenyl-1-(methylsulfonyl)-1H-indole 24aЈ. δH(CD-
Cl3, 400 MHz) 1.19 (3H, t, J 7.Hz, CH3), 2.59 (2H, q, J 7.6,
CH2), 2.79 (3H, s, CH3), 7.35–7.48 (7H, m, ArH), 7.60–7.64
J. Chem. Soc., Perkin Trans. 1, 2000, 2395–2408
2407

View Article Online
Patent No. 97–EP-2284970506, 1997; ( f ) D. H. R. Barton, D. O.
(1H, m, ArH), 8.12–8.15 (1H, m, ArH); δC(CDCl3, 100.6 MHz)
15.0 (CH3), 17.9 (CH2), 40.0 (CH3), 115.7 (CH), 119.7 (CH),
124.2 (CH), 125.3 (CH), 125.6 (C), 128.0 (CH), 128.9 (CH),
130.7 (C), 131.1 (CH), 131.6 (C), 136.3 (C), 137.2 (C); νmax
(CHCl3)/cmϪ1 3065, 2969, 2935, 2878, 1606, 1496, 1458, 1376,
1175.
Jang and J. Cs. Jaszberenyi, Tetrahedron Lett., 1992, 33, 5709; (g)
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17 X-Ray crystallographic data for compound 27a, C16H22INO2S,
M 419.31. A colourless crystal was cut to 0.47 × 0.35 × 0.25 mm
and mounted on a Rigaku AFC7S diffractometer at 293 K.
Measurements were made using the ω/2θ method and MoKα
radiation (0.71069 Å) to a maximum 2θ of 55Њ. Monoclinic, space
group P21/n, a = 8.451(2), b = 10.550(4), c = 19.373(4) Å, β =
93.57(2)Њ, V = 1723.9(9) Å3, Z = 4, µ = 1.983 mmϪ1, Dc = 1.616 g
cmϪ3. Of 4217 measured reflections, 3956 were unique (Rm = 4.07%)
and 2131 observed with I > 2σ(I). All the unique reflections were
used in final refinement to convergence against F 2. R1 = 0.0412,
wR2 = 0.1186, GOF = 0.985 for 190 parameters. Disorder in the 9-
membered ring at C-11, C-12 and C-13 was modeled with isotropic
atoms split over two sites. All other non-hydrogen atoms were
refined anisotropically. CCDC reference number 207/439. See http://
www.rsc.org/suppdata/p1/b0/b002565h/ for crystallographic files in
.cif format.
Acknowledgements
We thank the EPSRC, SmithKline Beecham, and the University
of Strathclyde for funding and EPSRC Mass Spectrometry
Service, Swansea, for high resolution mass spectra. We are
grateful to the Ministerio de Educación y Cultura (Spain) for a
Fellowship to C. G. M.
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