The Newman-Kwart rearrangement re-evaluated by microwave synthesis

Article abstract of DOI:10.1016/j.tet.2005.12.063

The Newman-Kwart rearrangement (NKR) has been re-evaluated by microwave heating. Microwave technology has proven to be ideal for investigating this high temperature rearrangement and facilitated the confirmation of many aspects of this valuable reaction.

Full text of DOI:10.1016/j.tet.2005.12.063

Tetrahedron 62 (2006) 4685–4689
The Newman–Kwart rearrangement re-evaluated
by microwave synthesis
*
Jonathan D. Moseley, Rosalind F. Sankey, Olivier N. Tang and John P. Gilday
AstraZeneca, Process Research and Development, Avlon Works, Severn Road, Hallen, Bristol BS10 7ZE, UK
Received 1 November 2005; revised 22 December 2005; accepted 22 December 2005
Available online 29 March 2006
Abstract—The Newman–Kwart rearrangement (NKR) has been re-evaluated by microwave heating. Microwave technology has proven
to be ideal for investigating this high temperature rearrangement and facilitated the confirmation of many aspects of this valuable reaction.
Comparisons between thermal and microwave results indicate no evidence of a significant microwave effect.
Ó 2006 Published by Elsevier Ltd.
1. Introduction
group (EDG) substituents slow the reaction. Ortho-substitu-
ents can enhance the reaction rate,9 but doubly ortho or very
sterically hindered substituents slow the reaction or stop it
altogether.1,9 The rearrangement is proposed to proceed
via a four-centre transition state 5 (Fig. 1), which is consis-
tent with these observations. Furthermore, comprehensive
kinetic and linear free energy relationships have been con-
ducted,9,10 which are also in agreement with this model.
This should give a first-order reaction, which Newman,1
Relles9 and Miyazaki10a have shown to be the case. Lastly,
this reactive intermediate (5) should be stabilised by polar
solvents, lowering the activation energy, and thus increasing
the reaction rate, but this does not appear to have been
studied in detail.10b
The Newman–Kwart rearrangement (NKR)1,2 is a valuable
synthetic technique for converting phenols 1 to thiophenols
4 via their O- (2) and S-thiocarbamates (3) (Scheme 1).
Indeed, such is the utility that other sulfur-containing func-
tional groups have been readily accessed through this meth-
odology, including thioethers, (homo-chiral) sulfoxides,
sulfones and sulfonic acids.3 Alternatively, this approach
can be used to access particular aromatic substitution pat-
terns without the phenol/sulfur function, starting from the
many widely available phenols, and de-sulfurizing the
hydrolysed thiol once the desired transformations are com-
plete. Consequently, the NKR has seen wide application in
synthesis,4 medicinal chemistry,5 materials and supramolec-
ular chemistry,6 agrochemicals7 and dyes.8
We were interested in investigating the NKR under micro-
wave irradiation11 for a number of reasons. It was a reaction
with which we had previous experience on scale-up12 and
knew was a sufficiently common motif in the pharmaceutical
industry to justify in-depth study.5 It also held wider syn-
thetic utility.4,6 Microwave technology provided convenient
access to the high temperatures generally required for this
reaction. Furthermore, a simple, first-order, unimolecular
The NKR proceeds via an O- to S-aryl migration, which has
a high activation energy. Many synthetically useful exam-
ples of the NKR require temperatures of 200–300 ꢀC. Elec-
tron withdrawing group (EWG) substituents are known to
aid the rearrangement, either reducing the reaction time or
lowering the required temperature, whilst electron-donating
SH
OH
S
NMe2
O
NMe2
i
ii
iii
O
S
X
X
X
X
1
2
3
4
Scheme 1. (i) DMTCC (1.1 equiv), DABCO (1.3 equiv), NMP, 50 ꢀC, then water; (ii) solvent, heat or MW; (iii) NaOH or KOH.
Supplementary data associated with this article can be found in the online version, at doi: 10.1016/j.tet.2005.12.063.
Keywords: Microwave; Newman–Kwart; Rearrangement.
* Corresponding author. Tel.: +44 117 938 5601; fax: +44 117 938 5081; e-mail: jonathan.moseley@astrazeneca.com
0040–4020/$ - see front matter Ó 2006 Published by Elsevier Ltd.
doi:10.1016/j.tet.2005.12.063

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J. D. Moseley et al. / Tetrahedron 62 (2006) 4685–4689
Table 1. Preparation of O-thiocarbamates 2a–o
NMe2
N+
O
O
O
NMe2
S
-
S
S
5
X
X
2a-f, h-o
Yield (%)
2g
Figure 1. Proposed four-centre transition state intermediate.
X¼
Quality (% LC)a
RRFb (2 vs 3)
model reaction would allow for a thorough and robust inves-
tigation of microwave heating. We were also hopeful that the
proposed polar transition state intermediate 5 might interact
favourably with microwaves,11d potentially giving rise to an
observable microwave effect, if there was one.
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2-NO2
3-NO2
4-NO2
4-CN
4-CO2Me
4-CF3
2-Naph
4-Br
4-Cl
4-H
4-Me
4-F
92
93
79
93
92
91
72
84
84
56c
66
80
49d
68c
75d
100.0
100.0
100.0
100.0
100.0
99.9
99.8
99.7
99.8
99.9
100.0
99.7
99.7
98.0
100.0
3.20
1.63
3.04
2.66
2.45
1.27
1.13
1.28
1.39
3.61
2.41
4.94
1.65
3.78
4.88
From a practical point, the starting O-thiocarbamates 2 could
be readily prepared from cheap phenols 1 in a single step. A
wide variety of substitution patterns was accessible for 2,
which meant that the reaction parameters could be ‘tuned’
as desired. All intermediates had good UV chromophores
and the NKR is ideal for analytical purposes in that it pro-
ceeds cleanly from starting material 2 to product 3 without
degradation or impurity formation in most cases. The NKR
can thus be readily followed by IR, LC, NMR or TLC as
preferred. It was also useful for our purposes that all of
substrates 2 and 3 were known; that thorough studies of
kinetics with Hammett plots had been conducted;9,10 and
that all these kinetic studies had been conducted with con-
ventional thermal heating;13 this would provide a secure
comparison for our own results.
4-MeO
3-MeO
2-MeO
a
Determined at 254 nm.
b
c
d
Relative response factor (RRF) at 254 nm.
Low melting solid purified by chromatography.
Recrystallised from MeOH/water.
appeared to show an additional steric rate acceleration com-
pared to the purely electronic effect of the para-substituents,
as reported by Relles.9 The meta-substituents 2b and 2n
also showed the trend expected relative to their ortho and
para regioisomers, given their respective electron withdraw-
ing and donating properties.
2. Results and discussion
For our initial investigations, we chose phenols 1a–o cover-
ing a range of EWG and EDG substituents from nitro- to
methoxyphenyl groups, including the electron neutral un-
substituted phenol (1j). To gauge the effect of aromatic sub-
stitution, we also included the ortho and meta nitro- and
methoxy-substituted compounds. The starting O-thiocarba-
mates 2a–o were readily prepared from phenols 1a–o
and dimethylthiocarbamoyl chloride (DMTCC) in fair-to-
excellent yields as predominantly crystalline compounds
of excellent quality (>98% by LC) (Table 1). We used our
previous method12 adapted from Sebok,7 which had the
advantage of direct isolation of 2 from the quenched aqueous
reaction mixtures, thus avoiding tedious chromatography in
the majority of cases. With quantities of substrates 2a–o
available, we conducted an initial screening in a focused
microwave reactor.
From this coarse screen, we were then quickly able to pin-
point the optimum temperature for a convenient 20 min mi-
crowave reaction that would give >95% conversion, in the
comparable manner reported by Newman.1 Reaction tem-
peratures and LC conversions for all substrates are collected
in Table 3, with Newman’s data alongside where available.
Generally the results are in good agreement, but some minor
differences will be noted, for which we offer the following
explanations.
Table 2. Conversion of 2 to 3 after 20 min in microwave at given tempera-
ture (20 min in 10 vol NMP)
X¼
Conversion at
180 ꢀC (%)a
Conversion at
220 ꢀC (%)a
Conversion at
280 ꢀC (%)a
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2-NO2
3-NO2
4-NO2
4-CN
4-CO2Me
4-CF3
2-Naph
4-Br
4-Cl
4-H
4-Me
4-F
98
4
68
19
4
>100b
45
—
—
—
—
—
—
97
98
95
78
53
51
27
92
76
>100b
99
75
We decided to conduct a coarse survey of reaction conver-
sion after 20 min for all compounds 2a–o, at 220 ꢀC for
EWG substituents and 280 ꢀC for EDG substituents, with
the relatively electron neutral compounds (2g–j) assayed at
both temperatures. The fast reacting nitro substituents had
to be reassessed at 180 ꢀC due to over-reaction, so the other
EWG compounds were also assayed at this temperature
(Table 2).
2
51
10
7
7
4
—
—
—
—
—
—
—
—
—
—
—
—
—
—
4-MeO
3-MeO
2-MeO
As can be seen, the trend is as expected when moving from
strong EWG to strong EDG substituents, with the latter
requiring higher temperatures for equivalent conversions.
The substituent effects for the nitro and methoxy com-
pounds were also largely as expected. The ortho-substituents
a
Determined by LC at 254 nm (RRF corrected).
Indicates all starting material converted and some product degradation
had occurred.
b

J. D. Moseley et al. / Tetrahedron 62 (2006) 4685–4689
4687
Table 3. Temperature required for >95% conversion of 2 to 3 in 20 min by
microwave (or conventionally)
Table 4. Conversion of 2a at 140 ꢀC in 10 vol of solvent under microwave
and thermal heating
X¼
Tempa
(ꢀC)
Conversionb
(%)
Tempc
(ꢀC)
Yieldd
(%)
Solvent
Time (min)
Conversion (%)a
Microwave Thermal
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2-NO2
3-NO2
4-NO2
4-CN
4-CO2Me
4-CF3
2-Naph
4-Br
4-Cl
4-H
4-Me
4-F
180
240
200
220
240
260
280
280
280
290
295f
295f
295f
295f
295
98
170
235
180
—
220
—
285
—
—
—
90
Dichlorobenzene
Diphenylether
30
60
15
28
15
27
77e
98
>95
>95
—
>95
—
80
—
—
—
—
—
83
—
99 (86)
99 (82)
98
30
60
12
23
15
27
Formic acidb
NMP
30
79
78
97
98 (83)
95 (82)
97 (82)
82 (83)
82
72
85 (86)
95 (80)
30
60
23
39
23
40
Trifluorotolueneb
Xylene
30
11
11
—
—
290
—
30
60
8
15
10
19
4-MeO
3-MeO
2-MeO
a
Conversion determined by LC at 254 nm (RRF corrected).
Conventional heating was conducted above the boiling point of the
solvent in a sealed tube in an oil bath.
280
90
b
a
MW, 20 min in 10 vol NMP.
b
Conversion determined by LC at 254 nm, RRF corrected with isolated
yields noted in brackets.
Thermal heating, 20–30 min neat.
Isolated yields except where >95% quoted (from TLC response at
254 nm).
Some decomposition seen above this temperature.
Higher temperatures could not be accessed to achieve >95% conversion
in 20 min.
tion state intermediate 5. To our knowledge this is the first
time such an effect has been confirmed experimentally.
c
d
e
f
3. Conclusions
In conclusion, we have shown that the NKR is a well-
behaved first-order reaction under microwave heating. We
have confirmed several known aspects of the reaction mech-
anism and provided the first experimental support for a sol-
vent rate effect. Furthermore, we find the reaction rate is
essentially unchanged compared to thermal heating under
all conditions. In short, we find no evidence for a significant
microwave effect in this case, although there may be a subtle
effect related to the reaction itself which we are currently
investigating.
Newman’s reactions were conducted neat whereas ours were
conducted in 10 vol of NMP (Relles and Kaji used 0.3 M
solutions in phenylether). For a first-order, unimolecular
reaction, rate should be independent of concentration. How-
ever, we know from our other results that there is a subtle
effect related to concentration, which we believe accounts
for the slight differences in the observed rate. Secondly,
the exact end-point of these reactions is difficult to ascertain
at 254 nm due to the generally stronger UV responses of
O-thiocarbamates 2 over their analogous S-thiocarbamates
3. Newman used IR but found this unreliable and reverted
to TLC, necessitating an additional 10 min heating time in
unspecified cases. We have determined the relative response
factors (RRFs) to give accurate LC results (see Table 1 for
data and Section 4 for method determination).
In addition, microwave technology has proven to be excep-
tionally convenient in a laboratory setting for accessing the
high temperatures required (200–300 ꢀC), both for the per-
sonal safety of the chemist and for rapid reactions. Further-
more, we found the IR temperature sensor to be very reliable
in our hands, confirmed by comparison to our thermal heat-
ing results. Opportunities for further exploitation of the NKR
as a probe to investigate microwave heating are ongoing and
results will be reported shortly.
Finally, we have briefly surveyed the solvent effect for one
substrate (2a) at one temperature (140 ꢀC) under both micro-
wave and thermal reaction conditions. The thermal tube
reactions were sealed with caps easily removed for sampling
purposes, except for the lower boiling solvents formic acid
and trifluorotoluene, where crimp caps were used; hence
only one time point was taken from these tubes. However,
being a rearrangement, no pressure is generated in this reac-
tion below the boiling point of the solvent used, and even
at the higher end of the temperature range (250–300 ꢀC),
pressures are still relatively modest. Data are shown for
both 30 and 60 min time points in Table 4. As can be seen,
there is an excellent correlation between microwave and
thermal results in all cases (the thermal figures are slightly
higher for two low polarity solvents, diphenylether and xy-
lene, the reasons for which are still being investigated).
Our studies with other substituted O-thiocarbamates (2)
and various solvents show this agreement between micro-
wave and thermal results to be general. The reaction rate
also fits the relative order of solvent polarity, supporting
the hypothesis that polar solvents can stabilise polar transi-
4. Experimental
4.1. General
Reaction mixtures and products were analysed by reverse
phase HPLC on an Agilent 1100 series instrument accord-
ing to the following conditions: column, Genesis C18
100ꢁ3.0 mm i.d.; eluent A, 95% purified water, 5% acetoni-
trile, 0.1% v/v formic acid; eluent B, 95% acetonitrile, 5%
purified water, 0.1% v/v formic acid; flow rate 0.75 ml/
min; wavelength 254 nm; temperature 35 ꢀC; injection
volume 10 ml; at t¼0 min, 40% eluent B; at t¼5 min, 70%
eluent B; at t¼7 min, 70% eluent B; 3 min post time. Typical
retention times (RT) are noted in each case. Melting points
were determined using a Griffin melting point apparatus
(aluminium heating block) and are uncorrected. 1H and

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J. D. Moseley et al. / Tetrahedron 62 (2006) 4685–4689
13C NMR spectra were recorded on a Varian Inova 400 spec-
trometer at 400 and 100.6 MHz, respectively, with chemical
shifts given in parts per million relative to TMS at d¼0. Elec-
trospray (ES+) mass spectra were performed on a Micromass
ZQ (O-thiocarbamates, 2a–o and S-thiocarbamates, 3d and
3f) or a Micromass Platform LC (all other S-thiocarbamates)
mass spectrometer. Analytical TLC was carried out on
commercially prepared plates coated with 0.25 mm of self-
indicating Merck Kieselgel 60 F254 and visualised by UV
light at 254 nm. Preparative scale silica gel flash chromato-
graphy was carried out by standard procedures using Merck
Kieselgel 60 (230–400 mesh). Otherwise wherever not
stated, assume standard practices have been applied.
dissolved in CDCl3 with an accurately weighed sample of
its respective analytically pure S-thiocarbamate analogue 3
in typicallyw1:1 ratio. The 1H NMR spectra were obtained
using a method with lengthened relaxation delay (for more
accurate integration) and the integration of the respective
NMe2 peaks in the 1H NMR spectra compared to the relative
responses in the LC spectra at 254 nm. Taking the 1H NMR
integration values as the correct ones allowed a correc-
tion factor to be determined for the relative response of the
O-thiocarbamates compared to the S-thiocarbamates when
using the LC according to the following equation:
Relative response factor ðO-thiocarbamateÞ
¼ ðNMR ratio ꢁ O-thiocarbamate LCÞ=
fS-thiocarbamate LC ꢁ ð1 ꢂ NMR ratioÞg
4.2. Typical microwave procedure
Microwave reactions were performed in 10 ml sealed tubes
in a regularly calibrated CEM Discover focused 300 W
microwave reactor with IR temperature monitoring and
non-invasive pressure transducer. In a typical procedure,
200 mg of O-thiocarbamate (2) was dissolved in NMP
(2.0 ml) and heated to the required temperature with stirring
for a fixed time. The heating time to reach the set tempera-
ture was typically 45–90 s, depending on the scale, the max-
imum wattage supplied (100–300 W) and the temperature
required (140–295 ꢀC) (typically 100 W to heat a 2 ml sam-
ple to 140 ꢀC inw45 s, or 300 W to heat to 295 ꢀC inw90 s).
The heating time is not included in the quoted hold time
for any given procedure; control studies show that the heat-
ing time is negligible for a 20 min reaction time. The
S-thiocarbamate (3) products were isolated either directly
by aqueous drown-out from NMP solutions, or by extraction
into MTBE followed by flash silica gel chromatography and/
or recrystallisation from methanol if required. Data only on
S-thiocarbamates (3a–o) can be found in the Supplementary
data. Yields are given only for preparative procedures, typi-
cally performed on 1.0 g of substrate 2 in 4.0 ml NMP (all
other parameters were kept constant).
So to determine the actual conversion to S-thiocarbamate
using the LC spectra, the following equation is used:
Actual S-thiocarbamate conversion
¼ ðS-thiocarbamate LCꢁRRFÞ=
fðS-thiocarbamate LCꢁRRFÞþO-thiocarbamate LCg
Several samples had RRFs determined at several ratios
(other than 1:1) to validate the consistency of this method.
4.5. Typical laboratory preparations
All the compounds (2a–o and 3a–o) were fully characterised
1
by LC/TLC, H and 13C NMR spectroscopy, MS, and mp
where applicable. The data are not reproduced here since
all compounds are known in the literature (see Supplemen-
tary data for full experimental conditions and characterisa-
tions in each case). A typical procedure is given below.
4.5.1. Preparation of an O-thiocarbamate (2-nitrophenyl-
O-thiocarbamate, 2a). 2-Nitrophenol (10.43 g, 75 mmol)
and DABCO (10.5 g, 93.8 mmol, 1.25 equiv) were heated
in NMP (52 ml) to 50 ꢀC with mechanical stirring to give
a dark yellow solution. Dimethylthiocarbamoyl chloride
(9.73 g, 78.8 mmol, 1.05 equiv) was dissolved in NMP
(8 ml) and added dropwise to the previous solution over
3–4 min. (N.B. A 6–8 K exotherm was typically seen on
this scale.) Some solid formed in the dark orange solution
during this addition. The reaction was monitored by LC
and was complete within 2–3 h at 50 ꢀC. Water (120 ml) was
added over 10–15 min at 50 ꢀC. The original solid dissolved
readily, but then a copious precipitate formed about halfway
through the addition, which persisted to the end. The reaction
mixture was cooled smoothly to 20 ꢀC and the precipitate
isolated by filtration. The product cake was displacement
washed twice with water (20 ml each) and dried in vacuo
at 50 ꢀC to yield the title compound as an off-white to pale
cream coloured crystalline solid (15.6 g, 92%). HPLC
(RT 2.1 min, 99.96%); mp 120–121 ꢀC (lit.1 112–113 ꢀC);
1H NMR (400 MHz, CDCl3) d 8.12 (1H, d, J¼8.4 Hz),
7.67 (1H, t, J¼7.8 Hz), 7.41 (1H, t, J¼7.8 Hz), 7.26 (1H,
d, J¼8.0 Hz), 3.46 (3H, s), 3.41 (3H, s); 13C NMR
(100.6 MHz, CDCl3) d 185.90, 147.21, 142.01, 134.42,
126.55, 126.49, 125.68, 43.50, 39.09; MS (ZQ) (ES+) 227
(M+1, 100%).
4.3. Typical oil bath procedure
For conventional (thermal) heating comparisons, identical
scales, temperatures and heating times were used. Proce-
dures were conducted in microwave test-tubes in oil baths
pre-heated to the set temperature. Heating times were deter-
mined on several control samples, being typically 60–120 s
depending on the exact conditions required. The heating
time is not included in the quoted hold time for any given
procedure; control studies show that the heating time is neg-
ligible for a 20 min reaction time. Tubes were generally
sealed with CEM’s Intellivent caps, except when working
close to or above the boiling point of a given solvent,
when crimp caps were used instead. However, control stud-
ies show that for high boiling solvents operating at modest
temperatures (e.g., 140 ꢀC), sealing tubes is not necessary
to mimic microwave reaction conditions, since no pressure
is developed. Work-up and isolation (if required) were per-
formed as for the microwave procedures as above.
4.4. Determination of relative response factors (RRF)
RRFs were determined as follows: an accurately weighed
sample of each analytically pure O-thiocarbamate 2 was

J. D. Moseley et al. / Tetrahedron 62 (2006) 4685–4689
4689
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S-thiocarbamate, 3a). (See Section 4.2, Typical Microwave
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(ES+) 227 (M+1, 100%).
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Acknowledgments
We thank CEM for technical advice and Simon Linke
(AstraZeneca, Avlon) for mass spectra.
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