A high temperature investigation using microwave synthesis for electronically and sterically disfavoured substrates of the Newman-Kwart rearrangement

Article abstract of DOI:10.1016/j.tet.2007.02.101

Electronically deactivated and/or sterically hindered substrates undergo the Newman-Kwart rearrangement (NKR) at around 300 °C, beyond the range of most convenient and safe, small-scale laboratory equipment. We report here the convenient conversions of several difficult substrates using modern microwave technology, which has proven ideal for investigating this high temperature reaction in all but the?most refractory of cases. In addition, several previously reported difficult examples were re-investigated, and found not to require high temperatures under these conditions, for various reasons which are elaborated upon.

Full text of DOI:10.1016/j.tet.2007.02.101

Tetrahedron 63 (2007) 4120–4125
A high temperature investigation using microwave synthesis for
electronically and sterically disfavoured substrates of the
Newman–Kwart rearrangement
*
Jonathan D. Moseley and Philip Lenden
AstraZeneca, Process Research and Development, Avlon Works, Severn Road, Hallen, Bristol, BS10 7ZE, UK
Received 5 December 2006; revised 8 February 2007; accepted 22 February 2007
Available online 25 February 2007
Abstract—Electronically deactivated and/or sterically hindered substrates undergo the Newman–Kwart rearrangement (NKR) at around
300 ꢀC, beyond the range of most convenient and safe, small-scale laboratory equipment. We report here the convenient conversions of several
difficult substrates using modern microwave technology, which has proven ideal for investigating this high temperature reaction in all but
the most refractory of cases. In addition, several previously reported difficult examples were re-investigated, and found not to require high
temperatures under these conditions, for various reasons which are elaborated upon.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
Having proven the utility of microwave technology for heat-
ing this high temperature rearrangement in the general case,1
we were interested to push the microwave capability above
the general limit of 250 ꢀC using difficult NKR substrates.6
Since many phenols bearing useful substituents are avail-
able, it would broaden the scope and utility of the procedure
by taking advantage of these substitution patterns. These dif-
ficult NKR compounds are electronically deactivated sub-
strates bearing one or more MeO groups (2a–f); sterically
crowded substrates (2h–n); or substrates incorporating
both features (2f, h–j). We also decided to investigate the
largely unknown fluoro series (2o–s) more comprehensively,
which had previously proven to be sluggish at ‘moderate’
temperatures (i.e., around 250 ꢀC).1 Finally, in addition to
examples 2d, h–k, we specifically re-investigated two com-
pounds in which the conversions were slow or the yields
were low for the O- to S-rearrangement, suggesting that
these might also be difficult substrates (2t–u).
In our first report1 on the Newman–Kwart rearrangement
(NKR),2 we commented that most synthetically useful ex-
amples require temperatures in the range of 200–300 ꢀC
since the NKR proceeds by an O- to S-aryl migration, which
has a high activation energy (Scheme 1). Many literature ex-
amples feature electron withdrawing group (EWG) substitu-
ents, which are known to aid this rearrangement. Typical
reaction temperatures for short reaction times are below
250 ꢀC in these cases.3 Substrates bearing electron-donating
group (EDG) substituents on the other hand tend to require
temperatures approaching 300 ꢀC.4 Furthermore, whilst
one ortho substituent can enhance the reaction rate, doubly
ortho and very sterically hindered substituents perturb the
reaction and also require typically high temperatures and/
or prolonged reaction times.5
+
NMe2
All these substrates were expected to require temperatures at
the upper end of the 250–300 ꢀC range, which one or two
modern scientific microwave instruments are capable of
achieving.7 Traditionally, many NKR reactions have been
performed as melts in oils baths, autoclaves,8 heating man-
tles,9 metal4c or salt baths,10 or under FVP conditions.11
FVP is too specialised for most organic chemists to use,12
and the other heating methods are also becoming less com-
mon due to their significant physical hazards. This is easily
avoided by the use of modern microwave instrumentation.13
Such microwaves effectively function as highly convenient,
small-scale autoclaves. Safety concerns are reduced to
O
S
NMe2
O
NMe2
S
-
O
S
X
X
X
Proposed four-centre
transition state intermediate
O-thiocarbamate
S-thiocarbamate
Scheme 1.
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 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.02.101

J. D. Moseley, P. Lenden / Tetrahedron 63 (2007) 4120–4125
4121
a minimum whilst accessing what are for the general organic
chemist, very high temperatures. Furthermore, the direct
heating capability of microwaves allows high temperatures
to be accessed rapidly, without the delay in heating a bath
or oven, or of conductive heating through a solid or molten
sample. Compressed air cooling at the end of the reaction
speeds up the cooling process. In addition, we were hopeful
that the rapid heating/rapid cooling capability provided by
microwave heating might also contribute to a cleaner reac-
tion profile. Finally, it is worth noting that near critical water
can be accessed in the 250–300 ꢀC temperature range, which
is of recent interest due to its unique reaction properties.14
solid 2g, where recovery was more difficult, and several of
the O-alkyl substituted compounds, where conversions
were lower although the products were highly crystalline.
The optimised conditions for conversion of each O- to S-
thiocarbamate were screened using microwave heating on
dilute samples, typically 0.4–1.2 M in NMP, and monitoring
by HPLC initially. Although NMP heats very efficiently in
the microwave field allowing high temperatures to be
achieved, the reaction solutions often became very dark,
which could complicate the workup; DMA was found to
be a better solvent in these cases. When NMP and DMA
both gave poorer impurity profiles, ortho-dichlorobenzene
(DCB) was found to be a suitable replacement capable of
reaching the high temperatures required (at high substrate
concentrations). Although we have reported that there is
a solvent dependency for this reaction,1 there is no practical
difference between NMP and DMA, and only a minor ad-
justment is required for the lower relative polarity of DCB.
There is also no practical difference on the rates of reaction
for the different concentrations used.
2. Results and discussion
The starting O-thiocarbamates 2 could be readily prepared
from available phenols in a single step, using our simplified
procedure in most cases (DABCO, DMTCC and NMP)
(Scheme 2).1 The sterically hindered compounds 2h–j could
not generally be prepared in good yield by this method, but
switching to the more forcing NaH/DMTCC conditions used
by other workers,2,4b,5 produced good yields for compounds
2h and i. By either method, direct aqueous drown-out of the
reaction mixtures gave high yields of highly crystalline com-
pounds in excellent purity in the majority of cases (Table 1).
Lower yields occurred only in the case of the low melting
Once ideal conditions had been determined for >95% con-
version after a 15–20 min heating time, purified samples
were isolated on 200–500 mg scale from preparative proce-
dures. Yields were comparable or better to existing literature
data in all cases. Pressures at the high temperatures of
w300 ꢀC were in the range 100–200 psi (7–14 bar) in most
cases, depending on the solvent and the actual temperature
required. This was well within the 300 psi (20 bar) operating
limit of the microwave. The results are collected in Table 1.
The unsubstituted compound 2g was included as a baseline
reference, showing >95% conversion at 290 ꢀC after
20 min.
S
NMe2
OH
O
NMe2
i or ii
iii
O
S
X
X
X
1
2
3
Scheme 2. (i) DMTCC (1.1 equiv), DABCO (1.3 equiv), NMP, 50 ꢀC, then
water; (ii) NaH, DMTCC, NMP, rt, then water and (iii) solvent, MW.
Table 1. Microwave conditions for conversion of 2 to 3
Substitution pattern (X¼)
Yielda 2 (%)
Yielda 3 (%)
Microwave conditions for conversion of 2 to 3
Conv.c (%)
Ref.
Tempb (ꢀC)
Time (min)
Solvent
Vold
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
s
2-MeO
3-MeO
4-MeO
3,5-DiMeO
3,4,5-TriMeO
2,6-DiMeO
4-H
2,6-DiMe
2,6-Di-i-Pr
2,6-Di-t-Bu-4-Mee
1-Naph
2-Naph
2-Ph
2,6-DiPh
2-F
3-F
4-F
2,4-DiF
3,4-DiF
2-Br-5-MeO
2,5-DiCl-4-I
75
68
67
66
81
77
56
70
64
n/a
77
72
76
88
87
93
80
94
90
n/a
93
80
86
79
86
64
78
82
86
91
n/a
84
75
80
75
75
92
72
71
89
89
85
300
295
>300
295
300
300
290
300
>300
335e
300
280
300
300
290
280
20
20
40
20
15
20
20
25
30
20e
15
20
15
25
20
20
20
20
20
20
20
99
98
99
99
100
100
97
NMP
NMP
NMP
NMP
NMP
DMA
NMP
DMA
DMA
Neate
NMP
DMA
DMA
DMA
DMA
NMP
DMA
DCB
DCB
DCB
DMA
10
10
10
4
4
4
10
10
4
n/a
4
4
4
4
4
4
4
4
4
2
4b
2
19
23
24
5
25
25
2,5
17
18
5
98
100
13e
100
97
100
96
96
100
97
100
100
100
97
5
—
—
1
21
—
9
>300
290
300
280
230
t
u
4
4
22
n/a Not applicable.
Isolated yields.
a
b
For >300 ꢀC, see text.
Determined by LC at 254 nm.
c
d
10 vol¼1 g in 10 mL.
e
Data from Ref. 2.

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J. D. Moseley, P. Lenden / Tetrahedron 63 (2007) 4120–4125
The results for singly and multiply substituted O-alkyl
substituted compounds (2a–f) were as expected, being con-
verted to their respective S-thiocarbamates in good yields in
15–20 min atw300 ꢀC. The conversion rates for the di- and
tri-substituted compounds 2d and e, and the doubly ortho
compound 2f, were equivalent to the mono-substituted 2a,
showing that meta-EWG substituents, and non-hindering or-
tho substituents do not make the reaction slower. However,
the para-methoxy substituted compound (2c) proved partic-
ularly refractory. Rather than lengthening the reaction time
significantly, however, 2c could be heated well above
300 ꢀC to achieve full conversion in 30–40 min by the expe-
diency of not stirring the homogeneous reaction mixture.
This lack of stirring means that the bulk heat in the unstirred
liquid column is not adequately dissipated throughout the
tube. This results in the microwave’s IR pyrometer at the
base of the microwave tube reading an artificially reduced
temperature, which tricks the magnetron into supplying more
power to the sample to reach the nominal set point of 300 ꢀC,
even though the bulk temperature above the pyrometer is
already >300 ꢀC. A semi-quantitative assessment from
known reaction conversions at lower temperatures indicates
that temperatures of w30–40 K higher can typically be
achieved by this procedure.15
above 300 ꢀC as for sterically hindered 2i to achieve
>95% conversion after 20 min. With additional fluorine,
the EWG effects appear to become dominant, and such ex-
treme temperatures, although high, are no longer quite
needed for compounds 2r and s. This trend appears to be
general, since the tetra fluoro-substituted bis-compound 2v
was reported to be converted at the relatively modest temper-
ature of 195 ꢀC after 45 min.3d
F
NMe2
F
O
F
S
2v
S
Me2N
O
F
Several compounds were studied in more detail, for which,
in our experience, over-long reaction times and/or low con-
versions had been reported. For example, a recent re-synthe-
sis of 2d following Wolfers’ procedure19 required 6 h at
285 ꢀC to give a modest yield of 47%.20 Wolfers obtained
72% after 90 min at 265 ꢀC, which compares well with our
86% yield after 20 min at 295 ꢀC. Compound 2r could
also be prepared in slightly improved yield and at faster con-
version in our hands than previously;21 and compound 2k
has already been discussed above.
The mildly electron-donating compounds 2h–i needed
slightly more forcing conditions, presumably due to their in-
creased steric hindrance around the reacting centre. A slight
lengthening of the reaction time to 25 min for 2h (2,6-diMe)
was required, and much more so for 2i (2,6-di-i-Pr). Rather
than increasing the reaction time excessively, which often
leads to some degradation, the reaction temperature was
again increased to >300 ꢀC, as described for 2c above. How-
ever, substrate 2j (2,6-di-t-Bu-4-Me) proved too bulky to be
synthesised in our hands, and it was not clear from the liter-
ature how this had been achieved in the past.2,5 Rundel
clearly had a similar problem with this and the simpler 2,6-
di-tert-butyl-substituted compound.16
Finally, we specifically investigated two additional com-
pounds for which long reaction times and/or low conversions
had been reported. Both were halogen-substituted com-
pounds, which should not have required particularly high
temperatures. The first was from our own laboratories,
whereby the 2-bromo-5-methoxy substrate (2t) had required
4 h at reflux in diethylaniline (bp 217 ꢀC) to achieve full con-
version with an isolated yield on scale-up of 90%.9 This
could be fully converted after 20 min in DCB at 280 ꢀC to
give an equivalent isolated yield. For an assumed first order
rearrangement,26 this increase in reaction rate at the higher
temperature is roughly what would have been predicted
from the Arrhenius equation. Comparison with the relevant
3-methoxy substituted analogue 2b shows that the weakly
EWG 2-bromo substituent does indeed facilitate this reac-
tion moderately.
O
NMe2
X = Me, 2j
X = H, ref. 16
S
X
O
NMe2
O
NMe2
MeO
Cl
I
S
S
The aromatic substituents 2k–n also proved to be readily
converted to their S-thiocarbamates, despite their relatively
bulky substituents. The sterically crowded 2m (2-Ph) and
n (2,6-diPh) were converted on a similar time scale to 2h
(2,6-diMe). The 1-naphthyl compound (2k) also underwent
good conversion within the scope of the instrument, despite
the expected steric constraint from the peri-proton and
previously reported unsuccessful preparation by NKR.17
The sterically unencumbered 2-naphthyl compound (2k)
showed that these aromatic rings can function like EWG sub-
stituents when steric factors do not intervene, being rela-
tively faster than the unsubstituted reference compound 2g.18
Br
Cl
2t
2u
The alternative 2,5-dichloro-4-iodo substrate (2u) was more
puzzling, giving an apparent isolated yield after reaction at
220 ꢀC for 2 h of only 33%.22 However, this yield was ob-
tained from the starting phenol 4, which required moderately
selective iodination to give 1u before formation of O-thiocar-
bamate 2u, and then rearrangement to the S-thioicarbamate
product 3u, without purification during the intermediate
steps (Scheme 3). The telescoped yield of 33% disguised
the apparently low quality of the iodination product 1u,
which was used crude to form 2u. We isolated and purified
iodophenol 1u in a modest 56% yield, from which the O-thio-
carbamate could then be prepared in an excellent 93% yield.
Conversion by NKR at the relatively modest temperature of
The fluoro-substituted compounds (2o–s) proved to be more
difficult than reference substrate 2g whilst exhibiting the
expected trend for a mono-substituted series, i.e., 3-F>2-F>
4-F. Indeed, compound 2q (4-F) had to be heated unstirred

J. D. Moseley, P. Lenden / Tetrahedron 63 (2007) 4120–4125
4123
X
NMe2
Cl
I
OH
Cl
Cl
I
OH
Cl
Cl
Y
ii, iii
i
Cl
4
1u
2u, X = O, Y = S
3u, X = S, Y = O
Scheme 3. (i) I2, Ag2SO4, CH2Cl2; (ii) DMTCC, DABCO, NMP and (iii) DMA, 230 ꢀC, MW.
230 ꢀC for 20 min gave 97% conversion with an isolated
yield of 85%. As with the other examples discussed above,
including our own,9 apparently lower than expected yields
for the NKR step were all due to poor yields or selectivities
in earlier chemistry steps whilst the NKR itself proved to
be high yielding.
Analytical TLC was carried out on commercially prepared
plates coated with 0.25 mm of self-indicating Merck Kiesel-
gel 60 F254 and visualised by UV light at 254 nm. Prepara-
tive scale silica gel flash chromatography was carried out
by standard procedures using Merck Kieselgel 60 (230–
400 mesh). Where not stated otherwise, assume standard
practices have been applied.
3. Conclusions
4.2. Typical microwave procedure
In summary, we have shown that electronically deactivated
and/or sterically hindered substrates, which undergo the
Newman–Kwart rearrangement (NKR) at w300 ꢀC can be
safely and conveniently transformed in short reaction times
using modern microwave technology. Significantly, micro-
wave heating allowed access to temperatures substantially
above solvent boiling points whilst under pressures that
were comfortably within the operating limits of the micro-
wave instrument. Of the substrates which could be prepared,
none of the examples tested were beyond the scope of avail-
able instruments. In addition, we have re-investigated several
examples which apparently required high temperatures and
gave modest yields. In each casewe found the NKR to be a re-
liable and high yielding reaction, often not requiring such
high temperatures. In every case, the previously reported
poor performance could be attributed to low conversions or
non-optimised isolations in earlier chemical steps unrelated
to the NKR.
Microwave reactions were exclusively 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 or 500 mg of O-thiocarbamate (2) was dissolved in
NMP, DMA or DCB (2.0 mL) and heated to the required
temperature with stirring for a fixed time. The heating time
to reach the set temperature was typically 90–120 s, depend-
ing on the maximum wattage supplied (250–300 W) and the
temperature required (230–300 ꢀC) (typically 300 W to heat
to 300 ꢀC inw120 s). The heating time is not included in the
quoted hold time for any given procedure; control studies
show that the heating time is negligible for a 20 min reaction
time. For substrates requiring more than 300 ꢀC (2c,i and q),
the same procedure was followed, except that the magnetic
stirring was switched off. Pressures at the high temperatures
ofw300 ꢀC were in the range 100–200 psi (7–14 bar) when
using DMA or NMP, and 200–250 psi (14–17 bar) when
once using DCB at 300+ ꢀC. This was well within the
300 psi (20 bar) operating limit of the microwave, and at
no time for any solvent/substrate/temperature combination
did the pressure exceed 250 psi (see also Ref. 15). The S-
thiocarbamate (3) products were isolated either by precipita-
tion by aqueous drown-out into water (for NMP and DMA
solutions) or by partition with water and extraction into
MTBE followed by flash silica gel chromatography. Yields
in Table 1 are of purified samples from preparative proce-
dures, typically performed on 200 or 500 mg of substrates
2 in 2.0 mL solvent.
4. Experimental
4.1. General
Reaction mixtures and products were analysed by reverse
phase HPLC on an Agilent 1100 series instrument as fol-
lows. Method A: column, Genesis C18 100 mmꢁ3.0 mm
i.d.; eluent A, 95% purified water, 5% acetonitrile, 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. For the non-polar,
sterically hindered substrates (2/3h–j and n), a longer run-
ning method was required. Method B: as for Method A, ex-
cept at t¼0 min, 0% eluent B; at t¼13 min, 100% eluent B;
at t¼15 min, 100% eluent B; 5 min post time. Typical reten-
tion times (tR) are noted in each case. Melting points were
determined using a Griffin melting point apparatus (alumin-
4.3. Typical laboratory preparations
All compounds (2a–u and 3a–u) were fully characterised by
LC/TLC, 1H and 13C NMR spectroscopy, MS, and mp where
applicable. The data are not reproduced here since most
compounds are known in the literature (see Supplementary
data for full experimental conditions and characterisations
for previously unreported compounds). Typical preparations
are given below.
1
ium heating block) and are uncorrected. H and 13C NMR
spectra were recorded on a Varian Inova 400 spectrometer
at 400 and 100.6 MHz, respectively, with chemical shifts
given in parts per million relative to TMS at d¼0. Electro-
spray (ES+) mass spectra were performed on Micromass
ZQ or Micromass Platform LC mass spectrometers.
4.3.1. Preparation of an O-thiocarbamate (2,6-dimethoxy-
phenyl-O-thiocarbamate, 2f). 2,6-Dimethoxyphenol
(11.76 g, 75 mmol) and DABCO (11.30 g, 97.5 mmol,
1.3 equiv) were heated in NMP (60 mL) to 50 ꢀC with me-
chanical stirring to give a dark brown solution. Dimethyl

4124
J. D. Moseley, P. Lenden / Tetrahedron 63 (2007) 4120–4125
thiocarbamoyl chloride (10.75 g, 82.5 mmol, 1.1 equiv) was
dissolved in NMP (15 mL) and added dropwise to the previ-
ous solution over 18 min (N.B. A 3 K exotherm was typically
seen on this scale). Some fine precipitate formed in the dark
red solution during this addition. The reaction was monitored
by LC and was complete within 90 min at 50 ꢀC. Water
(140 mL) was added over 15 min at 50 ꢀC. The original solid
dissolved readily, but a yellow precipitate formed later in 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 slurry washed twice
with water (24 mL each) and dried in vacuo at 50 ꢀC to yield
the title compound as a fine, off-white crystalline solid
(14.25 g, 77% yield). HPLC (method A, tR 2.53 min,
4.3.4. Preparation of an S-thiocarbamate (2,6-dimethyl-
phenyl-S-thiocarbamate, 3h). 2,6-Dimethylphenyl-O-thio-
carbamate (203 mg) was dissolved in DMA (2.0 mL) and
heated at 300 W in a microwave tube to 300 ꢀC for 25 min
with stirring. After compressed air cooling to rt, the dark
reaction mixture was diluted with water (15 mL), and
extracted with MTBE (1ꢁ15 mL, then 2ꢁ10 mL). The
combined MTBE extracts were dried over MgSO4 and con-
centrated to dryness to give an orange oil (709 mg), which
was purified by flash silica gel chromatography eluting
with 4:1 iso-hexane/ethyl acetate (Rf 0.27) to give the title
compound as a light oil (174 mg, 86%). HPLC (method A,
tR 4.75 min, 99%); mp oil; (lit.5 35–37 ꢀC (30–60 petrol
1
ether)); H NMR (400 MHz, CDCl3) d 7.18 (1H, m), 7.13
99.9%); mp 144–145.5 ꢀC (lit.24 144–146 ꢀC); H NMR
(2H, m), 3.16 (3H, br s), 3.02 (3H, br s), 2.42 (6H, s); 13C
NMR (100.6 MHz, CDCl3) d 165.95, 143.63, 129.48,
128.08, 118.85, 36.89, 22.01; MS (ES+) 210 (M+1, 100%).
1
(400 MHz, CDCl3) d 7.16 (1H, t, J¼8.7 Hz), 6.63 (2H, d,
J¼9.0 Hz), 3.83 (6H, s), 3.46 (3H, s), 3.36 (3H, s); 13C
NMR (100 MHz, CDCl3) d 187.69, 152.69, 132.21, 126.28,
105.01, 56.29, 43.35, 38.67; MS (ES+) 242 (M+1, 100%).
Acknowledgements
4.3.2. Preparation of a sterically hindered O-thiocarba-
mate (2,6-dimethylphenyl-O-thiocarbamate, 2h). 2,6-Di-
methylphenol (1.22 g, 10.0 mmol) was dissolved in NMP
(18 mL) with mechanical stirring at 20 ꢀC under N2 to give
a purple coloured solution over 30 min. Sodium hydride
(440 mg, 11.0 mmol) was added in several portions over
15 min, to give a dark brown solution. There was efferves-
cence on addition of each portion, and the temperature rose
to a maximum of 37 ꢀC. The reaction mixture was stirred
for 30 min during which time it cooled back to 20 ꢀC.
Dimethyl thiocarbamoyl chloride (1.66 g, 13.0 mmol) was
dissolved in NMP (6.0 mL) and added dropwise to the
sodium phenolate solution over 3 min. The reaction was
monitored by LC (method A) and judged complete after
60 min. Water (72 mL) was added over 15 min, which re-
sulted in some precipitation of a pale brown solid and an exo-
therm to 33 ꢀC on this scale. The reaction mixture was cooled
to 20 ꢀC and the precipitate isolated by filtration. The product
cake was slurry washed twice with water (24 mL each) and
dried in vacuo at 30 ꢀC to yield the title compound as a light
brown solid (2.11 g, 70% yield). HPLC (method B, tR
10.34 min, 95%); mp 72–74 ꢀC (lit.5 80–82 ꢀC (ethanol));
1H NMR (400 MHz, CDCl3) d 7.07 (3H, s), 3.48 (3H, s),
3.38 (3H, s), 2.17 (6H, s); 13C NMR (100.6 MHz, CDCl3)
d 186.23, 151.16, 130.87, 128.46, 125.81, 43.28, 38.40,
16.52; MS (ES+) 210 (M+1, 100%).
We thank Ros Sankey, Oli Tang and Anthony Thomson for
the preparation of several O-thiocarbamates.
Supplementary data
Supplementary data associated with this article can be found
in the online version, at doi:10.1016/j.tet.2007.02.101.
References and notes
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2. (a) Newman, M. S.; Karnes, H. A. J. Org. Chem. 1966, 31,
3980–3984; (b) Kwart, H.; Evans, E. R. J. Org. Chem. 1966,
31, 410–412.
3. For example, see: (a) Miyazaki, K. Tetrahedron Lett. 1968,
2793–2798; (b) Kaji, A.; Araki, Y.; Miyazaki, K. Bull. Chem.
Soc. Jpn. 1971, 44, 1393–1399; (c) Reineke, C.; Goralski,
C. T. J. Org. Chem. 1977, 42, 1139–1142; (d) Raasch, M. S.
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Scrowston, R. M. J. Chem. Soc., Perkin Trans. 1 1983, 2973–
2977; (f) Corral, C.; Lissavetzky, J.; Valedeolmillos, A. M.
Synthesis 1984, 172–173; (g) Hirano, M.; Miyashita, A.;
Nohira, H. Chem. Lett. 1991, 209–212; (h) Levai, A.; Sebok,
P. Synth. Commun. 1992, 22, 1735–1750; (i) Brooker, S.;
Croucher, P. D.; Roxburgh, F. M. J. Chem. Soc., Dalton
Trans. 1996, 3031–3037.
4. For example, see: (a) Cooper, J. E.; Paul, J. M. J. Chem. Eng.
Data 1970, 15, 586–588; (b) Kurth, H.-J.; Kraatz, U.; Korte,
F. Chem. Ber. 1973, 106, 2419–2426; (c) Hori, M.; Ban, M.;
Imai, E.; Iwata, N.; Suzuki, Y.; Baba, Y.; Morita, T.;
Fujimura, H.; Nozaki, M.; Niwa, M. J. Med. Chem. 1985, 28,
1656–1661; (d) Cossu, S.; De Lucchi, O.; Fabbri, D.; Cossu,
S.; De Lucchi, O.; Fabbri, D.; Valle, G.; Painter, G. F.; Smith,
R. A. J. Tetrahedron 1997, 53, 6073–6084; (e) Rao, P.;
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4.3.3. Preparation of an S-thiocarbamate (2,6-dimethoxy-
phenyl-S-thiocarbamate, 3f). 2,6-Dimethoxyphenyl-O-thio-
carbamate (500 mg) was dissolved in DMA (2.0 mL) and
heated at 300 W in a microwave tube to 300 ꢀC for 20 min.
After compressed air cooling to rt, the dark reaction
mixture was diluted with water (6 mL), from which a pre-
cipitate formed after about 5 min. The solid was isolated
by filtration, washed with water (2ꢁ6 mL, then 2ꢁ3 mL)
and dried in vacuo at 50 ꢀC to give the title compound as
a white solid (390 mg, 78%). HPLC (method A, tR
1
1.94 min, 96.5%); mp 127–128 ꢀC (lit.24 122–127 ꢀC); H
NMR (400 MHz, CDCl3) d 7.36 (1H, t, J¼8.5 Hz), 6.62
(2H, d, J¼8.5 Hz), 3.86 (6H, s), 3.18 (3H, s), 3.00 (3H, s);
13C NMR (100.6 MHz, CDCl3) d 165.68, 161.38, 131.67,
104.85, 104.24, 56.35, 36.93; MS (ES+) 242 (M+1,
100%).
5. Relles, H. M.; Pizzolato, G. J. Org. Chem. 1968, 33, 2249–2253.
6. It is worth noting the pioneering work of Strauss in the mid
1990s, who reported on the design of both prototype batch

J. D. Moseley, P. Lenden / Tetrahedron 63 (2007) 4120–4125
4125
and continuous flow microwave reactors, which were capable of
reaching 260 ꢀC. This was judged to meet the needs of most or-
ganic chemistry reactions and sow250 ꢀC is the limit that most
commercial microwave reactors have subsequently followed.
See: Roberts, B. A.; Strauss, C. R. Acc. Chem. Res. 2005, 38,
653–661.
Chem. Rev. 2002, 102, 2725–2750; (c) Kremsner, J. M.;
Kappe, C. O. Eur. J. Org. Chem. 2005, 3672–3679.
15. Caution: This procedure takes the temperature (and potentially
the pressure) above the standard operating limits of the CEM
Discover’s reaction tubes, which are rated to 300 ꢀC and
300 psi (20 bar). However, we have suffered no failures using
this technique on a small scale (2–4 mL), probably because
this reaction generates no pressure other than the mechanical
pressure of the solvent. This procedure is only possible on
the CEM Discover due to the placement of the IR pyrometer
at the base of the reaction tube. Some larger-scale instruments
also have IR pyrometers reading the temperature at the base of
their respective reaction tubes, but these are not intended to be
accurate, and are for approximate temperature monitoring
between reaction vessels in multiple vessel instruments (e.g.,
Anton Paar Synthos 3000, CEM Mars).
7. The only small-scale scientific microwave instrument capable
of reaching the 250–300 ꢀC window is the CEM Discover
(www.cem.com). The semi-preparative scale Anton Paar
Synthos 3000 has a set of quartz glass vessels capable of reach-
ing 300 ꢀC (www.anton-paar.com) (see Ref. 14c also).
Milestone has a special rotor, the NOVA-10, for use with the
Milestone Ethos, which will reach 280–300 ꢀC on a similar
scale (www.milestonsrl.com). Other microwave suppliers in-
clude Biotage (www.biotage.com).
8. Lau, C. K.; Belanger, P. C.; Dufresne, C.; Scheigetz, J. J. Org.
Chem. 1987, 52, 1670–1673.
€
16. Rundel, W.; Kohler, H. Chem. Ber. 1972, 105, 1087–1091.
9. Bowden, S. A.; Burke, J. N.; Gray, F.; McKown, S.; Moseley,
J. D.; Moss, W. O.; Murray, P. M.; Welham, M. J.; Young,
M. J. Org. Process Res. Dev. 2004, 8, 33–44.
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912.
17. Daub, G. H.; Whaley, T. W. J. Org. Chem. 1978, 43, 4659–
4661.
18. Newman, M. S.; Hetzel, F. W. Org. Synth. 1971, 51,
139–142.
19. Wolfers, H.; Kraatz, U.; Korte, F. Synthesis 1975, 43–44.
20. Gallardo-Godoy, A.; Fierro, A.; McLean, T. H.; Castillo, M.;
Cassels, B. K.; Reyes-Parada, M.; Nichols, D. E. J. Med.
Chem. 2005, 48, 2407–2419.
21. Scheigetz, J.; Zamboni, R.; Roy, B. Synth. Commun. 1995, 25,
2791–2806.
22. Springer, D. M.; Luh, B.-Y.; Goodrich, J.; Bronson, J. J. Bioorg.
Med. Chem. 2003, 11, 265–279.
23. Samreth, S.; Millet, J.; Bellamy, F.; Bajgrowicz, J.;
Barberousse, V.; Renaut, P. European Patent EP 0 365 397
B1, 1994.
24. Traxler, J. T. J. Org. Chem. 1979, 44, 4971–4973.
25. Cooper, J. E.; Paul, J. M. J. Org. Chem. 1970, 35, 2046–2048.
26. Newman and Karnes demonstrated that the rearrangement of
the 4-nitrophenyl-O-thiocarbamate was first order up to
w0.2 M, and assumed that this would be true for other sub-
strates (Ref. 2a). We have confirmed this for several other com-
pounds in dilute solutions (up tow0.4 M); Moseley, J. D.; Cox,
B. G. Unpublished results.
11. Nicholson, G.; Silversides, J. D.; Archibald, S. J. Tetrahedron
Lett. 2006, 47, 6541–6544.
12. For a recent modification on FVP conditions required for very
sterically hindered but temperature sensitive NKR substrates,
see: Higgs, T. C.; Carrano, C. J. Eur. J. Org. Chem. 2002,
3632–3645. Although successful in this case, this required
bespoke equipment to generate temperatures well above
300 ꢀC, and so has limited general utility for the organic chem-
ist at the present time.
13. (a) Kappe, O.; Stadler, A. Microwaves in Organic and
Medicinal Chemistry; Wiley-VCH: Weinheim, 2005; (b)
Microwave Assisted Organic Synthesis; Tierney, J. P.,
€
Lidstrom, P., Eds.; Blackwell: Oxford, 2005; (c) Microwaves
in Organic Synthesis; Loupy, A., Ed.; Wiley-VCH:
Weinheim, 2002; (d) Hayes, B. L. Microwave Synthesis:
Chemistry at the Speed of Light; CEM: Matthews, NC, 2002.
14. (a) Organic Synthesis in Water; Grieco, P. A., Ed.; Kluwer
Academic: Dordrecht, 1997; (b) Akiya, N.; Savage, P. E.