Organic Process Research & Development
(13
C-enriched), 156.89, 154.92, 148.17, 144.07 (d, JCC = 3.5
Article
MTBE. The filtrate was concentrated, and the residue was
purified by column chromatography on silica gel (elution with
Hz), 138.78, 130.28 (d, JCC = 14.3 Hz), 116.69, 112.40, 111.18,
1
3
15
5
5.22, 26.43, 22.58. ESI HRMS m/z: calcd for C C H N O
100:1 to 10:1 hexane/EtOAc) to afford the desired N-labeled
1
13 18
4
2
+
15
1
(
M ), 275.1463; found, 275.1449. ESI HRMS m/z: calcd for
C C H N O ([M + H] ), 276.1536; found, 276.1519.
cyanomethylether ( N-labeled-2) as a colorless oil. H NMR
1
3
+
(500 MHz, CDCl ): δ 6.88 (d, J = 8.8 Hz, 1H), 6.85 (d, J = 3.1
1
13 19
4
2
3
Manufacture of CME (2). A 12 to 15 wt % solution of 2-
Hz, 1H), 6.71 (dd, J = 8.8, 3.1 Hz, 1H), 4.71 (d, JNH = 1.6 Hz,
2H), 3.79 (s, 3H), 3.29 (hept, J = 6.9 Hz, 1H), 1.23 (d, J = 7.0
isopropyl-4-methoxylphenol (314.3 kg, 12 wt %, 226.8 mol) was
concentrated to 45 to 60 wt % 2-isopropyl-4-methoxyphenol in
toluene under vacuum at 40 to 50 °C. To the solution was added
1
3
Hz, 6H). C NMR (126 MHz, CDCl ): δ 155.68, 148.12,
3
139.96, 115.66 (d, JCN = 16.1 Hz), 114.15, 113.44, 110.51, 55.54,
1
89 L of NMP, and the mixture was cooled to 5 °C. Sodium
55.12 (d, JCN = 2.9 Hz), 26.92, 22.85.
1
hydroxide (27.2 kg, 50 wt % in water, 340 mol) and
chloroacetonitrile (36 kg, 340 mol) were added sequentially to
the mixture while maintaining the internal temperature below 10
Spectral Data for 8a. H NMR (500 MHz, CDCl
): δ 6.89
3
(d, J = 8.8 Hz, 1H), 6.85−6.81 (m, 3H), 6.72 (dd, J = 8.8, 3.1 Hz,
1H), 6.66 (dd, J = 8.8, 3.1 Hz, 1H), 4.84 (s, 2H), 4.68 (br s, 2H),
3.80 (s, 3H), 3.78 (s, 3H), 3.38−3.24 (m, 2H), 1.26−1.23 (m,
°
C. The reaction was aged for 2 h and then diluted with 150 L of
1
3
toluene and 226 L of water while maintaining the temperature
below 10 °C. The mixture was warmed to 20 to 25 °C, the layers
were separated, and the organic layer was washed with 75 L of 20
wt % NaCl (aq). The organic layer was concentrated to roughly
two volumes and filtered to provide 2-(2-isopropyl-4-
methoxyphenoxy)acetonitrile (56.8 kg, 74.6 wt %) as a solution
in toluene. The filter was washed with NMP to provide
additional 2-(2-isopropyl-4-methoxyphenoxy)acetonitrile (27.1
12H). C NMR (126 MHz, CDCl ): δ 155.97, 155.09, 148.80,
3
147.02, 145.44, 139.30, 139.10, 116.04, 115.29, 113.57, 113.36,
110.86, 110.48, 103.84, 77.41, 77.16, 76.91, 65.50, 55.75, 27.31,
27.22, 23.00, 22.99. ESI HRMS m/z: calcd for C24
H
N
O
([M
31
2
4
+
+ H] ), 411.2278; found, 411.2279.
1
Spectral Data for 8b. H NMR (500 MHz, DMSO-d
): δ
6
6.80 (d, J = 8.9 Hz, 1H), 6.74 (d, J = 3.0 Hz, 1H), 6.64 (d, J = 3.1
Hz, 1H), 6.59 (dd, J = 7.0, 3.0 Hz, 1H), 6.58 (dd, J = 6.9, 3.1 Hz,
1H), 6.36 (d, J = 8.9 Hz, 1H), 6.27 (br s, 2H), 6.02 (s, 2H), 4.48
(s, 2H), 3.66 (s, 3H), 3.64 (s, 3H), 3.40−3.33 (m, 1H), 2.98−
2.79 (m, 1H), 1.10 (d, J = 6.8 Hz, 6H), 0.98 (d, J = 7.0 Hz, 6H).
kg, 5.0 wt %) as a solution in NMP. The combined yield of 2 was
1
about 94%. H NMR (400 MHz, CDCl ): δ 6.88 (d, J = 8.8 Hz,
3
1
(
H), 6.83 (d, J = 2.9 Hz, 1H), 6.70 (dd, J = 8.8, 3.0 Hz, 1H), 4.72
1
3
s, 2H), 3.79 (s, 3H), 3.27 (hept, J = 6.9 Hz, 1H), 1.22 (d, J = 6.9
C NMR (126 MHz, DMSO-d ): δ 160.06, 158.81, 154.22,
6
1
3
Hz, 6H). C NMR (126 MHz, CDCl ): δ 155.82, 148.24,
153.58, 149.84, 148.83, 138.01, 137.12, 125.61, 113.13, 112.61,
112.53, 112.33, 110.47, 110.19, 67.24, 55.30, 55.22, 26.22,
25.93, 22.67, 22.61. ESI HRMS m/z: calcd for C H N O ([M
3
1
2
40.13, 115.69, 114.27, 113.59, 110.61, 55.69, 55.30, 27.03,
2.98.
2
5
33
4
4
Synthesis of 15N-Labeled-2. To a cold (0 °C), stirred
+
+ H] ), 453.2496; found, 453.2483.
1
solution of KOt-Bu (2.4 g, 21.7 mmol) in NMP (15.0 mL) was
added a solution of 2-isopropyl-4-methoxyphenol (3.0 g, 18.1
mmol) in NMP (15.0 mL) over a period of 30 min. Neat
chloromethyl methyl sulfide (2.1 g, 21.7 mmol) was added
dropwise over a period of 15 min. The reaction mixture was
slowly warmed to room temperature and aged overnight. The
reaction was quenched with water (25 mL), followed by a
Spectral Data for 9. H NMR (500 MHz, DMSO-d ): δ
6
6.89−6.60 (m, 7H), 4.64 (s, 2H), 3.67 (s, 3H), 3.33−3.25 (m,
1
3
1H), 1.15 (d, J = 6.9 Hz, 6H). C NMR (126 MHz, DMSO-d ):
6
δ 173.61, 167.11, 153.59, 149.86, 137.90, 113.40, 112.42,
110.36, 71.42, 55.21, 26.19, 22.71. ESI HRMS m/z: calcd for
+
C
H
N
O
([M + H] ), 290.1612; found, 290.1616.
14
19
4
2
13
1
Spectral Data for 2,4- C
d ): δ 6.84−6.61 (m, 7H), 4.64 (s, 2H), 3.67 (s, 3H), 3.30 (hept,
6
J = 6.94 Hz, 1H), 1.15 (d, J = 6.9 Hz, 6H). C NMR (126 MHz,
-9. H NMR (500 MHz, DMSO-
2
saturated aqueous solution of NH Cl (25 mL). The resulting
4
1
3
layer was extracted with heptane (2 × 25 mL). The combined
organic layers were washed with 5 wt % aqueous solution of LiCl
1
3
DMSO-d
153.58, 149.86, 137.91, 113.41, 112.42, 110.35, 71.42 (t, JCC
5.1 Hz), 55.21, 26.20, 22.71. ESI HRMS m/z: calcd for
): δ 173.61 (t, J = 2.0 Hz), 167.09 ( C enriched),
6
(
20 mL), dried over MgSO , filtered, and concentrated to yield a
=
4
residue that was purified by column on silica (elution with 100:1
1
3
+
to 10:1 hexane/EtOAc) to yield the desired thiomethylether
C C H N O ([M + H] ), 292.1684; found, 292.1696.
Spectral Data for 10. H NMR (500 MHz, DMSO-d ): δ
6
7.93 (s, 1H), 6.66 (br s, 4H). C NMR (126 MHz, DMSO-d ):
δ 166.53, 166.03. GC LRMS m/z: calcd for C H N (M ),
2 12 19 4 2
1
1
intermediate as a colorless oil. H NMR (500 MHz, CDCl ): δ
3
1
3
6
8
.85 (d, J = 8.8 Hz, 1H), 6.81 (d, J = 3.1 Hz, 1H), 6.67 (dd, J =
.8, 3.1 Hz, 1H), 5.12 (s, 2H), 3.78 (s, 3H), 3.33 (hept, J = 6.9
6
+
3
5
5
13
Hz, 1H), 2.26 (s, 3H), 1.22 (d, J = 6.9 Hz, 6H). C NMR (126
111.0; found, 111.0.
1
MHz, CDCl ): δ 154.81, 148.41, 140.05, 114.94, 113.21, 110.31,
Spectral Data for 11. H NMR (600 MHz, DMSO-d ): δ
3
6
7
3.85, 55.70, 26.98, 23.05, 14.99. To a cold (0 °C), stirred
solution of the above intermediate (1.5 g, 6.6 mmol) in DCM
6.0 mL) was added a solution of sulfuryl chloride (6.96 mL of
.0 M solution in DCM, 6.96 mmol) dropwise. The resulting
10.53 (br s, 1H), 8.41 (br s, 4H), 7.64 (br s, 1H), 7.39 (br s, 1H),
7.28 (s, 1H), 6.89 (d, J = 3.1 Hz, 1H), 6.88 (d, J = 8.8 Hz, 1H),
6.77 (dd, J = 8.9, 3.0 Hz, 1H), 3.74 (s, 3H), 3.13 (hept, J = 6.9
(
1
3
1
Hz, 1H), 1.17 (d, J = 6.9 Hz, 6H). C NMR (151 MHz, DMSO-
d6): δ 156.34, 156.21, 155.50, 151.41, 145.88, 140.27, 138.79,
135.45, 119.75, 112.65, 111.82, 55.35, 26.65, 22.84. ESI HRMS
yellow solution was stirred at 0 °C for 1 h and then at room
temperature for 30 min. The mixture was concentrated, and the
residue was quickly filtered through a pad of silica, followed by
washing with 30:1 hexane/EtOAc (100 mL). The filtrate was
+
m/z: calcd for C H N O ([M + H] ), 317.1721; found,
1
5
21
6
2
317.1721.
1
1
concentrated to provide the α-chloro ether. H NMR (500
Spectral Data for 14a. H NMR (500 MHz, DMSO-d ): δ
6
MHz, CDCl ): δ 7.07 (d, J = 8.9 Hz, 1H), 6.82 (d, J = 3.1 Hz,
9.00 (d, J = 12.0 Hz, 1H), 7.78 (dt, J = 11.9, 2.5 Hz, 1H), 7.31 (s,
1H), 6.92−6.85 (m, 2H), 6.86 (d, J = 2.7 Hz, 1H), 6.78−6.71
(m, 2H), 3.73 (s, 3H), 3.35−3.29 (m, 2H), 3.22 (hept, J = 6.9
3
1
3
H), 6.72 (dd, J = 8.9, 3.1 Hz, 1H), 5.89 (s, 2H), 3.79 (s, 3H),
.29 (hept, J = 6.9 Hz, 1H), 1.20 (d, J = 6.9 Hz, 6H). This
intermediate was dissolved in acetone (6.0 mL). To the solution
Hz, 1H), 2.76 (s, 3H), 2.65 (ddd, J = 7.7, 6.3, 2.5 Hz, 2H), 1.19
1
5
13
was added KC N (0.43 g, 6.6 mmol) and heated to 60 °C
(d, J = 6.9 Hz, 6H). C NMR (126 MHz, DMSO-d ): δ 169.49,
6
overnight. The resulting slurry was filtered and washed with
156.91, 155.55, 154.15, 147.28, 142.01, 139.64, 133.23, 127.41,
M
Org. Process Res. Dev. XXXX, XXX, XXX−XXX