Organic Process Research & Development
C ), 130.2 (C ), 128.3, 127.1, 124.2, 120.0 (C ), 111.6, 20.0
Article
(
(C ), 132.9, 131.9 (C ), 130.3, 121.6, 120.9, 120.7, 108.8,
IV
IV
IV
IV
IV
+
ppm.
107.3, 101.4 ppm. HRMS (ESI ): calculated for C H NO [M +
13 9 4
+
2
-Cyano-benzenediazonium Tetrafluoroborate (1h). Pre-
H] 244.0604, found 244.0602.
pared according to the general diazotisation procedure with tert-
3′,3-Dinitro-biphenyl (3e). White solid, mp 207−208 °C. 688
1
butyl nitrite in 20 volumes of ethanol. The product was not
mg, 94% yield. H NMR (DMSO-d , 400 MHz): δ = 8.57 (s,
6
1
13
purified further. Pale-yellow solid, 86%−89% yield. H NMR
2H), 8.29 (t, 4H, J = 9.1 Hz), 7.83 (t, 2H, J = 8.0 Hz) ppm. C
(
DMSO-d , 400 MHz): δ = 9.00 (dd, 1H, J = 8.3 Hz, J = 1.0
NMR (DMSO-d , 100 MHz): δ = 148.5 (C ), 139.4 (C ),
6
1
2
6
IV
IV
+
Hz), 8.59 (dd, 1H, J = 7.9 Hz, J = 1.0 Hz), 8.46 (atd, 1H, J = 7.9
133.7, 130.7, 123.2, 121.8 ppm. HRMS (ESI ): calculated for
C H N O [M + H] 245.0557, found 245.0556.
1
2
1
13
+
Hz, J = 1.0 Hz), 8.32 (atd, 1H, J = 8.3 Hz, J = 1.0 Hz) ppm. C
2
1
2
12
8
2
4
NMR (DMSO-d , 100 MHz): δ = 141.0, 136.4, 135.6, 134.6,
3′-Nitro-4-N-methylsulfonamide-biphenyl (3f). Beige solid,
6
1
1
18.6 (C ), 113.8 (C ), 112.4 (C ) ppm.
Catalyst and Solvent Screening Reactions. To a glass
mp 145−150 °C. 612 mg, 90% yield. H NMR (DMSO-d , 400
IV
IV
IV
6
MHz): δ = 9.98 (s, 1H), 8.41 (t, 1H, J = 2 Hz), 8.19 (dd, 1H, J =
1
tube equipped with a stirrer bar were introduced 3-nitro-phenyl
boronic acid 2b (56 mg, 0.335 mmol), methyl 4-benzoatedia-
zonium tetrafluoroborate 1b (126 mg, 0.503 mmol), and
palladium catalyst (1.0 mol %). The air inside was replaced by
nitrogen via vacuum/nitrogen cycles. Solvent (5 mL) was then
injected into the glass tube, and the reaction mixture was stirred
under a nitrogen atmosphere at 25 °C for 24 h. Ethyl acetate was
then added to the mixture and the catalyst removed by filtration
over Celite. The filtrate was analysed by HPLC to determine a
solution yield (see SI) before being evaporated to dryness. The
crude product was purified by silica gel chromatography eluting
with a heptane/ethyl acetate mixture to give 3b as a white solid.
8.2 Hz, J = 1.5 Hz), 8.12 (d, 1H, J = 8.3 Hz), 7.79−7.73 (m, 3H),
2
13
7.35 (d, 2H, J = 8.7 Hz), 3.06 (s, 3H) ppm. C NMR (DMSO-d ,
6
100 MHz): δ = 148.5 (C ), 141.1 (C ), 138.9 (C ), 132.9
IV
IV
IV
(C ), 132.8, 130.5, 128.0, 121.8, 120.6, 119.7, 39.5 ppm. HRMS
IV
+
+
(ESI ): calculated for C H N O S [M + NH ] 310.0856,
13
12
2
4
4
found 310.0854.
4-(Benzofuran-2-yl)-benzonitrile (3g). White solid, mp 141−
1
144 °C. 237 mg, 35% yield. H NMR (DMSO-d , 400 MHz): δ =
6
8.10 (d, 2H, J = 8.4 Hz), 7.96 (d, 2H, J = 8.6 Hz), 7.74−7.66 (m,
3H), 7.40 (ddd, 1H, J = 8.0 Hz, J = 8.0 Hz, J = 1.3 Hz), 7.33
1
2
3
1
3
(ddd, 1H, J = 8.0 Hz, J = 8.0 Hz, J = 1.3 Hz) ppm. C NMR
1
2
3
(DMSO-d , 100 MHz): δ = 154.6 (C ), 153.2 (C ), 133.8
6
IV
IV
4
′-Methylbenzoate-3-nitro-biphenyl (3b). White solid, mp
(C ), 133.0, 128.4 (C ), 125.7, 125.2, 123.6, 121.8, 118.7 (C ),
IV IV IV
1
+
1
=
46−148 °C. H NMR (DMSO-d , 400 MHz): δ = 8.51 (at, 1H J
2.0 Hz), 8.28 (bd, 1H, J = 8.2 Hz), 8.22 (bd, 1H, J = 7.8 Hz),
111.4, 110.7 (C ), 105.3 ppm. HRMS (ESI ): calculated for
6
IV
+
C H NO [M + H] 220.0757, found 220.0756.
15
9
8
8
1
1
.08 (d, 2H, J = 8.4 Hz), 7.95 (d, 2H, J = 8.4 Hz), 7.80 (at, 1H J =
5-(3′,4′-Methylenedioxyphenyl)-2-trifluoromethyl-pyridine
1
3
1
.0 Hz), 3.89 (s, 3H) ppm. C NMR (DMSO-d , 100 MHz): δ =
(3h). Off-white solid, mp 117−125 °C. 7%−35% yield. H NMR
6
65.9 (C ), 148.5 (C ), 142.2 (C ), 140.4 (C ), 133.5, 130.7,
(DMSO-d , 400 MHz): δ = 9.05 (s, 1H), 8.30 (d, 1H, J = 8.0 Hz),
IV
IV
IV
IV
6
+
29.9, 129.5 (C ), 127.4, 123.0, 121.5, 52.3 ppm. HRMS (ESI ):
7.93 (d, 1H, J = 8.3 Hz), 7.47 (s, 1H), 7.34 (d, 1H, J = 8.1 Hz),
IV
+
13
calculated for C H NO [M + H] 258.0761, found 258.0761.
7.09 (d, 1H, J = 8.3 Hz), 6.12 (s, 2H) ppm. C NMR (DMSO-d ,
14
11
4
6
Design of Experiments Reactions. To a glass tube
equipped with a stir bar were introduced 3-nitro-phenyl boronic
acid 2b (1.0 equiv), methyl 4-benzoatediazonium tetrafluor-
oborate 1b (Factor A) and Johnson Matthey 5% Pd/C type 394
100 MHz): δ = 148.3 (C ), 148.2 (C ), 147.9, 144.6 (q, J = 33.8
IV
IV
Hz), 138.5 (C ), 135.5, 129.5 (C ), 121.8 (q, J = 273.4 Hz),
IV
IV
+
121.5, 120.7, 109.0, 107.5, 101.5 ppm. HRMS (ESI ): calculated
+
for C H F NO [M + H] 268.0580, found 268.0578.
13
8
3
2
(
moisture: 56.70%) (Factor C). The air inside was replaced by
7-(4′-N-Methylsulfonamid-phenyl)-2-methyl-chromone
1
nitrogen via vacuum/nitrogen cycles. Ethanol/water (Factor D
and E) was then injected into the glass tube, and the reaction
mixture was stirred under a nitrogen atmosphere at the indicated
temperature (Factor B) for 24 h. Ethyl acetate was then added to
the mixture, and the catalyst removed by filtration over Celite.
The filtrate was analysed by HPLC to determine a solution yield
(3i). Beige solid, mp 226−228 °C. 705 mg, 92% yield. H NMR
(DMSO-d , 400 MHz): δ = 10.00 (s, 1H), 8.01 (d, 1H, J = 8.3
6
Hz), 7.81−7.78 (m, 3H), 7.72 (d, 1H, J = 8.3 Hz), 7.34 (d, 2H, J =
1
3
8.5 Hz), 6.23 (s, 1H), 3.07 (s, 3H), 2.39 (s, 3H) ppm. C NMR
(DMSO-d , 100 MHz): δ = 176.4 (C ), 166.8 (C ), 156.4
6
IV
IV
(C ), 144.8 (C ), 139.2 (C ), 133.0 (C ), 128.2, 125.4, 123.2,
IV
IV
IV
IV
+
(see SI).
121.5 (C ), 119.5, 114.9, 110.0, 39.5, 20.0 ppm. HRMS (ESI ):
calculated for C H NO S [M + H] 330.0795, found 330.0794.
IV
+
General Cross-Coupling Procedure for Substrate
17
15
4
Scope. To a glass tube equipped with a stir bar were introduced
aryl boronic acid (500 mg, 1.0 equiv), aryldiazonium
tetrafluoroborate (1.1 equiv), and catalyst (Johnson Matthey
2′-Cyano-4-formyl-biphenyl (3j). White to beige solid, mp
1
164−165 °C. 18%−72% yield. H NMR (DMSO-d , 400 MHz):
6
δ = 10.13 (s, 1H), 8.08 (d, 2H, J = 8.0 Hz), 8.02 (d, 1H, J = 7.8
1
3
5% Pd/C type 394, moisture: 56.70%, 1.0 mol %). The air inside
Hz), 7.88−7.83 (m, 3H), 7.72−7.65 (m, 2H) ppm. C NMR
was replaced by nitrogen via vacuum/nitrogen cycles. Ethanol (5
mL, 10 vol) was then injected into the glass tube, and the reaction
mixture was stirred under a nitrogen atmosphere at 30 °C for 24
h. Ethyl acetate or acetone was then added to the mixture and the
catalyst removed by filtration over Celite. The filtrate was
evaporated to dryness, and the crude product was purified by
silica gel chromatography eluting with heptane/ethyl acetate or
heptane/acetone mixtures to give the biaryl product.
(DMSO-d , 100 MHz): δ = 192.8, 143.4 (C ), 143.3 (C ),
6
IV
IV
136.0 (C ), 134.0, 133.6, 130.2, 129.7, 129.6, 129.0, 118.2 (C ),
IV
IV
+
110.2 (C ) ppm. HRMS (ESI ): calculated for C H NO [M +
IV
14
9
+
H] 208.0757, found 208.0756.
3′-Carboxamido-4-nitro-biphenyl (3k). White solid, mp
1
182−186 °C. 529 mg, 72% yield. H NMR (DMSO-d , 400
6
MHz): δ = 8.35 (d, 2H, J = 8.5 Hz), 8.29 (s, 1H), 8.17 (bs, 1H),
8.06 (d, 2H, J = 8.8 Hz), 7.97 (t, 2H, J = 7.6 Hz), 7.64 (t, 1H, J =
7.8 Hz), 7.50 (bs, 1H) ppm. C NMR (DMSO-d , 100 MHz): δ
13
3
′-Nitro-3,4-methylenedioxy-biphenyl (3c). Beige solid, mp
6
1
1
=
19−120 °C. 6%−90% yield. H NMR (DMSO-d , 400 MHz): δ
8.33 (s, 1H), 8.14 (d, 1H, J = 8.1 Hz), 8.05 (d, 1H, J = 7.5 Hz),
= 167.4 (C ), 146.9 (C ), 146.0 (C ), 137.8 (C ), 135.2 (C ),
6
IV
IV
IV
IV
IV
+
130.0, 129.3, 128.1, 128.0, 126.2, 124.1 ppm. HRMS (ESI ):
calculated for C H N O [M + H] 243.0764, found 243.0761.
+
7
7
1
.69 (t, 1H, J = 7.8 Hz), 7.35 (s, 1H), 7.24 (d, 1H, J = 8.1 Hz),
13
10
2
3
1
3
.02 (d, 1H, J = 8.1 Hz), 6.09 (s, 2H) ppm. C NMR (DMSO-d ,
4′-Formyl-4-bromo-biphenyl (3l). White solid, mp 144−149
6
1
00 MHz): δ = 148.3 (C ), 148.2 (C ), 147.7 (C ), 141.5
°C. 366 mg, 42% yield. H NMR (DMSO-d , 400 MHz): δ =
IV
IV
IV
6
H
dx.doi.org/10.1021/op5002353 | Org. Process Res. Dev. XXXX, XXX, XXX−XXX