The Molecularity of the Newman-Kwart Rearrangement**

Matthew Burns, (a) Guy C. Lloyd-Jones,*, (a) Jonathan D. Moseley, (b) and Joseph S. Renny (a)
(a) School of Chemistry, University of Bristol, Cantocks Close, Bristol, BS8 1TS, UK;
Phone ++ (0)117 928 8165; Fax ++ (0)117 929 8611; e-mail: [email protected];
(b) AstraZeneca, Avlon Works, Severn Road, Hallen, Bristol BS10 7ZE, UK

Supporting Information

1 General Experimental Details ..................................................................................... 1

2 Analysis and Instrumentation ..................................................................................... 2
3 Preparation of Thiocarbamates .................................................................................. 4
Synthesis of Thiocarbamate Precursors ............................................................................. 4
Preparation of Aryl-O-thiocarbamates ............................................................................... 7
Preparation of Aryl-S-thiocarbamates .............................................................................. 10
4 The Molecularity of the Newman-Kwart Rearrangement ....................................... 14
Thermal NKR Kinetics Performed in an Oil Bath ............................................................ 14
Single Time Point Thermal NKR Kinetics Performed in a GC Oven ............................... 18
5 Cross-over Studies ..................................................................................................... 21
MacKinetics Simulation of Cross-over ............................................................................ 21
NKR Cross-over Study Performed Under Convective Heating Conditions ...................... 27
NKR Cross-over Study Performed in a CEM Discover Microwave Reactor ................. 28
6 The Microwave Assisted Newman-Kwart Rearranegement .................................... 31
Single Time Point Microwave Investigation .................................................................... 31
7 NMR Spectra ............................................................................................................. 35
8 References .................................................................................................................. 59
1 General Experimental Details

Standard Techniques: All air and moisture sensitive manipulations were conducted
employing standard Schlenk techniques, using vacuum lines attached to a double manifold
with greaseless PTFE valves equipped with an oil pump (0.1 mmHg) under an atmosphere of
dry nitrogen or under an argon atmosphere in an glovebox. Glassware (acid and base washed)
and needles were placed in an oven (200 C) for at least 2 hours prior to use and allowed to
cool under an atmosphere of dry nitrogen or under vacuum at 0.1 mmHg (oil pump). Liquid
reagents, solutions or solvents were added via cannula or gas-tight syringe (balanced by a
nitrogen inlet) through rubber septa; solid reagents were added via Schlenk type adapters.
The removal of solvents in vacuo was achieved using a rotary evaporator (bath temperatures
up to 40 C) at a pressure of 15 mmHg (diaphragm pump), or at 0.1 mmHg (oil pump) on a
vacuum line at room temperature.

Solvents: Commercial grade solvents were used for chromatography and extraction; petrol
refers to the fraction of petroleum-ether boiling in the range of 40-60 C. Commercial
anhydrous solvents were transferred into flasks equipped with greaseless PTFE valves
employing standard Schlenk techniques and stored over activated 3 molecular sieves.
Solvents were dried by distillation from the appropriate drying agent under an atmosphere of
dry nitrogen (THF from sodium benzophenone ketyl and tert-butanol from sodium metal); or
by passage through a column of anhydrous column of alumina[S1] from which solvents were
collected in Strauss flasks fitted with greaseless PTFE valves.

Materials and Reagents: Potassium tert-butoxide was purified by sublimation at 220 C

under vacuum (0.1 mmHg) in a Schlenk tube fitted with a cold finger.[S2]

Chromatography: TLC analysis was conducted employing commercially available glass

backed silica plates with flurescent indicator. Visualisation was achieved by either UV
fluorescence (254 nm) or basic KMnO4 solution and heat; relative front values (R F) are
quoted as the ratio between the distances from the baseline to the spot and the solvent front.
Column chromatography was performed on 230-400 mesh (40-63 m) silica-gel. The crude
material was applied to the column as a solution in the appropriate eluent or by pre-
adsorption onto silica gel, as appropriate.

S1
Kinetic Simulations: were performed employing MacKinetics v0.9.1b, Leipold Associates,
USA, 1997.

Microwave-Assisted Reactions: were performed in thick-walled glass sealed tubes in a CEM

Discover microwave reactor with IR temperature monitoring and non-invasive pressure
transducer.

2 Analysis and Instrumentation

NMR spectra: Chemical shifts are quoted in parts per million (ppm); 1H NMR spectra
(reported to the nearest 0.01 ppm) are referenced to TMS or residual protons of the deuterated
13
solvent; C NMR spectra (reported to the nearest 0.1 ppm, except where isotope shifts are
reported) are referenced to TMS or the deuterated solvent. Coupling constants (J) are quoted
to the nearest 0.1 Hz. Other abbreviations used are: s (singlet), d (doublet), t (triplet), q
(quartet), m (multiplet) and b (broad). Assignments of 1H NMR and 13
C{1H} NMR signals
were made where possible, using COSY, DEPT, HMQC, HMBC and H2BC experiments. In
some circumstances, coupling constants were extracted by spectral simulation, and in such
cases the assignment is denoted 'SIMUL'. Isotope shifts ( ) are quoted in parts per billion
(ppb). N.B. An isotope shift is defined as the chemical shift change caused by exchanging a
heavier nucleus for a lighter nucleus of the same element. Expressed as an equation this is:

n
(L, H) X(L) - X(H)
Equation S1: Nuclear isotope shielding

where n is the number of bonds between the exchanged isotope and the observed nucleus
(zero for a primary isotope shift), X is the observed nucleus, L is the lighter of the exchanged
isotope, H is the heavier of the exchanged isotope and is the chemical shift.

IR spectra: were recorded in the range 4000-600 cm-1 on an FT-IR spectrometer either as
neat films or solids compressed onto a diamond window. Abbreviations used are: w (weak,
0-40%), m (medium, 40-70%), s (strong, 70-100%) and br (broad).

Mass spectra: were aquired using either electron impact (EI) or chemical ionisation (CI)
techniques or by electro-spray ionisation (ESI+).

S2
HPLC Analysis: Relative response factors (RRF) reported by Moseley et al. were utilised to
determine the extent of conversion in the thermal reactions. [S3] Reaction mixtures and
products were analysed by reverse phase HPLC according to the following conditions:
column, C18 100 mm 3.0 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-1; wavelength 254 nm; temperature 35 C; injection volume 10 L; at t = 0 min,
40% eluent B; at t = 5 min, 70% eluent B; at t = 7 min, 70% eluent B; 3 min post time. In
some cases the chromatographic conditions employed were modified to: column, C18 100
mm 3.0 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-1;
wavelength 254 nm; temperature 35 C; injection volume 5 L; at t = 0 min, 30% eluent B; at
t = 5 min, 30% eluent B; at t = 7 min, 60% eluent B; 3 min post time.

LC MS Analysis: Relative response factors (RRF) reported by Lloyd-Jones et al. were utilised
to determine the extent of conversion in the thermal reactions. [S4] LC MS analysis was
determined with an MS scan (0.30 s with 0.05 s interscan) within a mass range of 100.00 to
1200.00 ES+ employing in source CID with a 70 V cone voltage, the total run time was 5.5
min. The following conditions were employed for chromatography: column, C18 50 mm 1
mm i.d.; eluent A, 90% purified water, 10% acetonitrile, 0.1% v/v formic acid; eluent B,
100% acetonitrile, 0.1% v/v formic acid; flow rate 0.18 mL min-1; wavelength 210-350 nm;
target column temperature 60 C; injection volume 10 L; at t = 0 min, 27.5% eluent B; at t =
2.5 min, 35.0% eluent B; at t = 4 min, 95.0% eluent B; 3 min post time.

S3
3 Preparation of Thiocarbamates

Synthesis of Thiocarbamate Precursors

[18O1]-4-nitrophenol[S5]

To a stirred slurry of 1-fluoro-4-nitrobenzene (4.7 g, 33.3 mmol, 3 eq.) in tert-butanol (40

mL) was added potassium tert-butoxide (3.73 g, 33.3 mmol, 3 eq.), at room temperature, and
the white slurry turned yellow (N.B. proceeds with slight exotherm, care should be taken
when performing this reaction on a larger scale). Water (200 mg, 11.1 mmol, 1 eq. 90% atom
18
O) was added drop wise over 5 minutes, a light brown colour slowly developed. After 1 h
the reaction was heated to 95 C for 24 h. The reaction was allowed to cool to room
temperature and water added until the entire solid had dissolved, which gave a vibrant yellow
solution. The organics were extracted into diethyl ether (4 80 mL), washed with aqueous
NaOH (1 M, 2 80 mL). The aqueous phases were combined, and acidified to pH = 1 (as
indicated by universal indicator paper) with HCl (5 M), and extracted into diethyl ether (4 80
mL). The combined organic fractions from the second extraction were dried over magnesium
sulfate, and reduced in vacuo to give long brown crystals which were purified by column
chromatography on silica-gel (petrol - ethyl acetate 3:1) to give light orange crystals (1.53 g,
98%; 88 atom % 18O incorporation based on ESI MS analysis of [18O1]-1a); Rf (0.32, petrol
ethyl acetate 1:1); Mpt. 110-112 C (literature 113 C);[S5] 1H NMR (270 MHz, CDCl3)
8.18 (second order AABB spin system, 3J(1H,1H) = 9.0 Hz, 4J(1H,1H) = 2.3 Hz, 5J(1H,1H) =
0.3 Hz, 2H, C(3,5)H))SIMUL, 6.92 (second order AABB spin system, 3J(1H,1H) = 9.0 Hz,
4
J(1H,1H) = 2.3 Hz, 5J(1H,1H) = 0.3 Hz, 2H, C(2,6)H))SIMUL, 5.69 (1H, bs, C(1)OH); 13C{1H}
NMR (100 MHz, d6-DMSO) 163.92 (1 C(18O1) = -10.5 ppb, C(1)), 139.6 (C(4)), 126.2
(C(3)), 115.81 (2 C(18O1) = -8.6 ppb, C(2)); HRMS (CI+): m/z found 142.039 [MH]+,
C6H5NO218O requires 142.039. This data is in accordance with that previously published.[S5]

S4
 18
An analgous procedure was performed with 70 atom % O water to furnish [18O1]-4-
nitrophenol with 65 atom % 18O incorporation based on ESI MS analysis of 18O1-1a.

[2H2]-4-Nitrophenol[S6]

4-Nitrophenol (200 mg, 1.44 mmol, 1 eq.) was dissolved in 35% 2HCl in 2H2O (1 mL) and
irradiated in a CEM Discover microwave reactor at 175 C for 20 minutes at medium
power (140 W). The resultant precipitate was dissolved in ethyl acetate (10 mL) and washed
with brine (10 mL). The aqueous phase was extracted with ethyl acetate (3 10 mL), the
organics were combined, dried over sodium sulfate, filtered and reduced in vacuo to afford
the title compound as a white crystalline solid (168 mg, 82%; 93% 2H2, 7% 2H1, based on ESI
MS analysis of [2H2]-1a); Rf (0.32, petrol ethyl acetate 1:1); Mpt. 111-113 C (literature
113 C);[S5] 1H NMR (270 MHz, CDCl3) 8.18 (s, 2H, C(3,5)H), 6.92 (m, C(2,6)H), residual
mono deuterated species); 13C{1H} NMR (100 MHz, d6-DMSO) 163.92 (2 C(2H1) = -46.5
ppb, 2 C(2H2) = -85.2 ppb, C(1)), 139.6 (C(4)), 126.19 (2 C(2H1,2H2) = -100.7 ppb, C(3)),
115.79 (1 C(2H1,2H2) = -240.0 ppb, t, 1J(13C,2H) = 25.7 Hz, C(2)); HRMS (CI+): m/z found
142.047 [MH]+, C6H32H2NO3 requires 142.050.

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 34
S1-4-Nitrobenzenethiol[S4]

Sodium sulphide nonahydrate (1.34 g, 5.58 mmol, 1 eq.) and elemental sulphur-34 (190 mg,
34
5.58 mmol, 1/8 S8, 1 eq. 90 atom % S) were weighed into a Schlenk tube under nitrogen,
degassed anhydrous ethanol (15 mL) was added via cannula and heated to reflux to give a
clear yellow solution. A solution of 4-nitrochlorobenzene (1.96 g, 12.48 mmol, 2.23 eq.) in
degassed anhydrous ethanol (20 mL) was added to the refluxing sodium disulfide solution via
cannula to give a red-brown solution. After 30 minutes sodium hydroxide (500 mg, 12.48
mmol, 2.23 eq.) in degassed anhydrous ethanol (20 mL) was added to the reaction mixture
via cannula. The resultant reaction mixture was then refluxed under nitrogen for a further 15
minutes, after which time the reaction mixture was cooled and the solvent reduced in vacuo.
Nitrogen sparged deionised water (100 mL) was added to the solid residue and the
supernatant then transferred to a Schlenk tube containing a rapidly stirred aqueous solution of
nitrogen sparged hydrochloric acid (50 mL, 1 M). A precipitate formed immediately which
was isolated via Bchner filtration and dried in vacuo to afford the title compound as a buff
34
solid (834 mg, 43 atom %, 52 atom % S based on ESI MS analysis of 2H634S1-2c)
contaminated with a small amount of the corresponding disulfide (ca. 5% as determined from
1
H NMR); Rf (0.32, petrol ethyl acetate 1:1); 1H NMR (400 MHz, CDCl3) 8.10 (second
order AABB spin system, 3J(1H,1H) = 8.0 Hz, 4J(1H,1H) = 3.0 Hz, 5J(1H,1H) = 0.3 Hz, 2H,
C(3,5)H))SIMUL, 7.36 (second order AABB spin system, 3J(1H,1H) = 8.00 Hz, 4J(1H,1H) =
3.0 Hz, 5J(1H,1H) = 0.3 Hz, 2H, C(3,5)H))SIMUL, 3.78 (1H, s); 13C{1H} NMR C(1/4)),
C(1/4)), C(2/3)), 124.4 (C(2/3)); HRMS (CI+): m/z found 158.006 [MH]+,
C6H5NO2S requires 158.007.

S6
 Preparation of Aryl-O-thiocarbamates

4-Nitrophenyl-O-N,N-dimethyl thiocarbamate, 1a[S3]

4-Nitrophenol (10.43 g, 75 mmol, 1 eq.) and DABCO (10.5 g, 93.8 mmol, 1.25 eq.) were
heated in DMF (52 mL) to 50 C with vigorous stirring to give a pale yellow solution.
Dimethyl thiocarbamoyl chloride (9.73 g, 78.8 mmol, 1.05 eq.) dissolved in DMF (10 mL)
was then added drop-wise to the reaction mixture, which became turbid. The resultant was
stirred at 50 C for 4 h; after which time water (120 mL) was added over 15-20 minutes at 50
C; a pale yellow precipitate formed approximately halfway through the addition which
persisted to the end. The reaction mixture was cooled slowly to room temperature and the
precipitate was isolated by filtration. The cake was washed with water (3 20 mL),
recrystallised from methanol and dried in vacuo at 50 C to yield the title compound as a
colourless crystalline solid (13.4 g, 80%); Rf (0.55, Toluene Ethyl acetate 6:1); HPLC (RT
3.43 min); Mpt. 150 152 C (literature 150-153 C);[S3] 1H NMR (500 MHz, CDCl3) 8.27
(second order AABB spin system, 3J(1H,1H) = 9.1 Hz, 4J(1H,1H) = 2.3 Hz, 5J(1H,1H) = 0.7
Hz, 2H, C(3,5)H))SIMUL, 7.24 (second order AABB spin system, 3J(1H,1H) = 9.1 Hz,
4
J(1H,1H) = 2.3 Hz, 5J(1H,1H) = 0.7 Hz, 2H, C(2,6)H))SIMUL, 3.46 (3H, s, NMe2), 3.38 (3H, s,
NMe2); 13C{1H} NMR (125 MHz, CDCl3) 186.1 (C(S)), 158.4 (C(1)), 145.3 (C(4)), 124.8
(C(3)), 123.8 (C(2)), 43.3 (NMe2), 38.9 (NMe2); MS (EI+): m/z found 226.1 [M] +

C9H11N203S requires 226.0. This data is in accordance with that previously published.[S3]

S7