S. W. J. Shields and J. M. Manthorpe
and the splitting abbreviations used are as follows: s, singlet; d, doublet; t, (s, 3H), 1.39 (s, 9H). Spectroscopic data were in good agreement with
triplet; q, quartet; m, multiplet. Chemical purity of compounds that were reported data.34
used without purification was determined by 1H NMR spectroscopy.
N-Methyl-d3 tert-butyl p-toluenesulfonylcarbamate (8-d3)
Deuterium incorporation of deuterated compounds was determined by
comparison of peak integrations of the labelled materials versus the
integration of the same peak(s) in the 1H NMR spectrum of the unlabelled
compound. 13C content of 13C-labelled compounds was determined by
integration of the methyl doublet resulting from 1J 13C–1H coupling versus
the singlet of the unlabelled methyl group in the same spectrum.
Finely ground tert-butyl p-toluenesulfonylcarbamate 7 (15.64 g, 57.6mmol),
methyl-d3 p-toluenesulfonate 5-d3 [9.82g (crude material, 91% purity),
47.2mmol], was dissolved in MeCN (230 mL). While the reaction solution
was stirring vigorously, powdered K2CO3 (13.23 g, 695.7 mmol) was added
in one portion (caution: if carbonate was added too slowly, the mixture
would gel and stirring would become very difficult). The flask was fitted
with a reflux condenser and heated to 80°C for 18 h. The mixture was
allowed to cool before adding H2O (100mL) to dissolve the salts. The
resultant biphasic mixture was transferred to a separatory funnel, and the
layers were separated. The aqueous layer was washed with ethyl acetate
(3× 75 mL), and the combined organic layers were dried over anhydrous
MgSO4, filtered and concentrated to afford a sludgy solid (19g). The crude
yellow solid was adsorbed onto Celite and purified by dry column vacuum
chromatography (0–16% EtOAc in hexanes) to afford N-methyl-d3 tert-butyl
p-toluenesulfonylcarbamate 8-d3 as a white solid (11.96 g, 90%).
Methyl-d3 p-toluenesulfonate (5-d3)
This protocol was adapted from the literature procedure reported by
Tanabe.25 Trimethylamine hydrochloride (1.18 g, 12.3 mmol) was suspended
in toluene (123 mL). Methanol-d4 (5 mL, 123 mmol, 99.8%D) and triethylamine
(19 mL, 136 mmol) were added to the suspension and cooled in an ice bath.
p-Toluenesulfonyl chloride (25.82 g, 135 mmol) was dissolved in toluene
(90 mL) and added in three 30 mL portions over 10 min to the cooled reaction
mixture. The mixture was allowed to stir for 1 h at 0 °C and filtered over Celite.
The filter cake was washed with ice-cold toluene (200 mL). Solvent was
removed under reduced pressure to give 5-d3 as an amber liquid (24.63 g,
106%, 91% purity) that was used without further purification.
mp 63.1–64.5 °C Rf 0.20 (10% EtOAc in hexanes, UV). 1H NMR (CDCl3,
300 MHz): δ 7.78 (d, 3J = 8.4 Hz, 2H), 7.31 (d, 3J = 8.4 Hz, 2H), 2.44 (s, 3H),
1.35 (s, 9H). 13C NMR (CDCl3, 75 MHz): δ 151.2, 144.2, 137.2, 129.3, 127.7,
84.1, 32.7 (septet, 1J = 21.7 Hz), 27.9, 21.6. IR (KBr pellet, cmÀ1): 3405,
3058, 2983, 2931, 2447, 2402, 2257, 2124, 2076, 1712, 1599, 1457, 1365,
1311, 1256, 1178, 1106, 870, 849, 817, 769, 734.
Rf 0.23 (10% EtOAc in hexanes; UV). 1H NMR (CDCl3, 400 MHz): δ 7.79
(d, 3J = 8.0 Hz, 2H), 7.36 (d, 3J = 8.0 Hz, 2H), 2.45 (s, 3H). 13C NMR (CDCl3,
100 MHz):δ 145.0, 132.2, 129.9, 128.0, 55.5 (septet, 1J = 23 Hz), 21.6. IR (NaCl
plate, cmÀ1): 3068, 2927, 2875, 2592, 2264, 2129, 2087, 1925, 1736, 1598,
1495, 1453, 1361, 1308, 1180, 1104, 1080, 996, 934, 817, 741, 704.
N-Methyl-13C tert-butyl p-toluenesulfonylcarbamate (8-13C)
Methyl p-toluenesulfonate-13C (5-13C)
Prepared analogously to the aforementioned compound 8-d3 to afford
8-13C (14.11 g, 95%, 99% 13C).
mp 61.1–62.0°C Rf 0.27 (10% EtOAc in hexanes, UV). 1H NMR (CDCl3,
300 MHz): δ 7.78 (d, 3J=8.1Hz, 2H), 7.31 (d, 3J=8.1, 2H), 3.35 (d, 1J= 143 Hz,
3H), 2.44 (s, 3H), 1.35 (s, 9H). 13C NMR (CDCl3, 75MHz): δ 151.2, 144.2, 137.2,
129.3, 127.7, 84.2, 33.3, 27.9, 21.6. IR (NaCl plate, cmÀ1): 2982, 1731, 1598,
1456, 1417, 1359, 1296, 1258, 1157, 1087, 967, 849, 804, 770, 723.
Prepared analogously to compound 5-d3 using the aforementioned
methanol-13C (5 mL, 99% 13C) to afford 5-13C (30.15 g, 106%, 90% purity,
99% 13C).
Rf 0.21 (10% EtOAc in hexanes; UV). 1H NMR (CDCl3, 300 MHz): δ 7.80
(d, 3J = 8.1 Hz, 2H), 7.36 (d, 3J = 8.1 Hz, 2H), 3.74 (d, 1J = 149 Hz, 3H), 2.46
(s, 3H). 13C NMR (CDCl3, 75 MHz): δ 145.0, 132.2, 129.9, 128.1, 56.2, 21.6.
IR (NaCl plate, cmÀ1): 2952, 1926, 1744, 1599, 1455, 1360, 1293, 1178,
1096, 1019, 979, 818, 765.
N-Methyl-d3-N-nitroso-p-toluenesulfonamide (9-d3)
This protocol was adapted from the literature procedure reported by de Boer
and Backer.28,29 TFA (45 mL) was cooled to 0 °C before adding d3-methyl
p-toluenesulfonylcarbamate 8-d3 (11.58g, 40.2mmol) slowly. The solution
was warmed to room temperature and stirred for 1 h. The TFA was removed
under reduced pressure, and the resulting residue was dissolved in acetic
acid (42 mL) and cooled to 5 °C (internal temp) in an ice/water bath. A
solution of NaCl (2.36 g, 40.4 mmol), NaOAc (0.14 g, 1.7 mmol) and NaNO2
(3.03g, 44.0mmol) in H2O (13 mL) was then added such that the internal
temperature was kept below 7 °C. After the addition was complete, the
reaction mixture was stirred for a further 15 min, ice-cold H2O (40 mL) was
added and stirring was continued for a further 5 min. The mixture was
allowed to stand without stirring for 20 min, filtered, washed with ice-cold
H2O (300 mL) and dried under high vacuum overnight to afford 9-d3 as a
light yellow solid (8.51g, 97%, 99%D).
p-Toluenesulfonamide (6)
Aqueous ammonium hydroxide (28% w/w, 82.0 g, 1.35 mol) was
combined with absolute ethanol (250 mL) and added via a dropping
funnel over 5 min to a solution of p-toluenesulfonyl chloride (50.0 g,
262 mmol) in THF (150 mL). The resulting mixture was stirred for 1 day
at room temperature. Solvents were removed under reduced pressure
and the off-white solid was washed with 200 mL of cold distilled water
and dried under high vacuum to give 6 as a white solid (43.5 g, 97%,
90% purity). This material was used without further purification.
mp 126–127 °C. Rf 0.21 (30% EtOAc in hexanes; UV,). 1H NMR (CDCl3,
3
3
300 MHz): δ 7.82 (d, J= 8.1 Hz, 2H), 7.32 (d, J=8.1Hz, 2H), 4.81 (br s, 2H),
2.44 (s, 3H). Spectroscopic data were in good agreement with reported data.33
1
mp 49.1–50.0 °C. Rf 0.57 (30% EtOAc in hexanes, UV). H NMR (CDCl3,
300 MHz): δ 7.87 (d, 3J= 8.4 Hz, 2H), 7.38 (d, 3J= 8.4, 2H), 2.46 (s, 3H). 13C
NMR (CDCl3, 75MHz): δ 146.2, 134.1, 130.4, 128.0, 28.4 (septet, 1J= 21.8 Hz),
21.7. IR (NaCl plate, cmÀ1): 3075, 2973, 2925, 2867, 2591, 2405, 2291, 2255,
2185, 2108, 1922, 1803, 1595, 1493, 1381, 1330, 1302, 1258, 1192, 1163,
1119, 1088, 1046, 910, 879, 812, 731.
tert-Butyl p-toluenesulfonylcarbamate (7)
N,N-Dimethylaminopyridine (3.14 g, 25.7 mmol), triethylamine (39 mL,
280 mmol) and p-toluenesulfonamide 6 (43.5g, 254 mmol) were combined
in DCM (300 mL) to give a suspension. Di-tert-butyl dicarbonate (66.68g,
305 mmol) was separately dissolved in DCM (510 mL) and added via
dropping funnel to the suspension of p-toluenesulfonamide (6) over
25 min, and the mixture was stirred for 2 h at room temperature. Solvent
N-Methyl-13C-N-nitroso-p-toluenesulfonamide (9-13C)
was removed under reduced pressure, and residue was dissolved in ethyl Prepared analogously to the aforementioned compound 9-d3 to afford
acetate (500 mL). The organic layer was washed with 1 M aqueous HCl 9-13C (10.03 g, 97%, 99% 13C)
1
(2 × 500 mL), H2O (500 mL) and brine (500 mL), then dried over anhydrous
mp 46.2–47.0 °C. Rf 0.23 (10% EtOAc in hexanes, UV). H NMR (CDCl3,
MgSO4, filtered and concentrated to give 7 as an off-white solid (68.5g, 300 MHz): δ 7.87 (d, 3J = 8.4 Hz, 2H), 7.38 (d, 3J = 8.4, 2H), 3.12 (d,
99%, 97% purity). This material was used without further purification.
1J = 144 Hz, 3H), 2.46 (s, 3H). 13C NMR (CDCl3, 75 MHz): δ 146.2, 134.1,
mp 102.0–103.7 °C. Rf 0.49 (30% EtOAc in hexanes; UV,). 1H NMR 130.4, 128.0, 28.9, 21.7. IR (NaCl plate, cmÀ1): 3075, 2980, 2925, 1922,
(CDCl3, 300 MHz): δ 7.90 (d, 3J = 8.3 Hz, 2H), 7.34 (d, 3J = 8.3 Hz, 2H), 2.45 1801, 1594, 1496, 1402, 1381, 1301, 1216, 1174, 1135, 1085, 860, 812.
J. Label Compd. Radiopharm 2014, 57 674–679
Copyright © 2014 John Wiley & Sons, Ltd.