An efficient synthesis of biaryl diamides via Ullmann coupling reaction catalyzed by CuI in the presence of Cs2CO3 and TBAB

Article abstract of DOI:10.1007/s11164-018-3422-0

Abstract: CuI accompanyied by Cs₂CO₃ and TBAB was confirmed to be an efficient catalyst combination to promote an Ullmann coupling reaction. It facilitated 2-bromobenzamides to undergo a coupling reaction for the synthesis of symmetrical biaryldiamides in moderate yields at 120?°C under Pd-free conditions. Graphical Abstract: [Figure not available: see fulltext.].

Full text of DOI:10.1007/s11164-018-3422-0

Res Chem Intermed
https://doi.org/10.1007/s11164-018-3422-0
An efficient synthesis of biaryl diamides via Ullmann
coupling reaction catalyzed by CuI in the presence
of Cs2CO3 and TBAB
Fang Dong1 Jian-Quan Liu1 Xiang-Shan Wang1
•
•
Received: 12 January 2018 / Accepted: 27 March 2018
Ó Springer Science+Business Media B.V., part of Springer Nature 2018
Abstract CuI accompanyied by Cs2CO3 and TBAB was confirmed to be an efficient
catalyst combination to promote an Ullmann coupling reaction. It facilitated 2-bro-
mobenzamides to undergo a coupling reaction for the synthesis of symmetrical biaryl-
diamides in moderate yields at 120 °C under Pd-free conditions.
Graphical Abstract
Keywords Biaryldiamide Á 2-Bromobenzamide Á CuI Á Ullmann coupling Á Pd-free
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11164-
018-3422-0) contains supplementary material, which is available to authorized users.
&
Xiang-Shan Wang
xswang1974@yahoo.com
1
School of Chemistry and Materials Science, Jiangsu Key Laboratory of Green Synthesis for
Functional Materials, Jiangsu Normal University, Xuzhou, Jiangsu 221116, People’s Republic
of China
123

F. Dong et al.
Introduction
Symmetric biaryls are an important class of molecules in natural products, materials
science and pharmaceutical chemistry [1–4]. The main procedures for the
construction of their derivatives include the following four methods (Scheme 1):
(1) Ullmann reaction [5] using aryl halides as the reactants under higher
temperature; (2) Suzuki coupling reaction [6] including a Pd-catalyzed reaction of
arylboronic acid and aryl halide; (3) C–H activating reaction [7–11] which is a
direct arylation of an aryl halide with simple arene; and (4) oxidative coupling
dehydrogenation [12–17] which is a green and dream reaction which only requires
an external oxidant in order to scavenge the formal H2 by-product from two arenes.
Of these, the first reaction is a very classical and useful procedure [18–21] for the
construction of an Ar–Ar bond which has been developed for several known named
reactions, such as the Stille reaction [22], Kumada reaction [23] and Negishi
reaction [24]. In our recent study, 2-bromo-N-phenylbenzamide (1a) was prepared
to react with dimedone catalyzed by CuI and 1.0 equiv of Cs2CO3 (Scheme 2). As
our initial assumption, the a-arylation of carbonyl group should take place, or
further cyclization occurs to give tricyclic phenanthridine. To our surprise, the
dimedone did not affect the reaction and only 1a underwent a coupling reaction
2
2
0
giving N ,N -diphenyl-[1,10-biphenyl]-2,20-dicarboxamide. Although it is a known
reaction, it has always been promoted by a Pd-catalyst, and, further, 2-iodoben-
zamide was the common reactant, and in only a few examples was it 2-bromoben-
zamides [25–27]. As a continuous study of copper-catalyzed reactions [28–31], we
Scheme 1 Approach to biaryl subunits
123

An efficient synthesis of biaryl diamides via Ullmann…
O
O
O
O
O
Ph
Ph
O
N
N
H
N
H
or
Br
CuI/Cs2CO3
DMF
O
O
CuI/Cs2CO3, DMF
O
NHPh
PhNH
O
Scheme 2 Our original assumption and real reaction
would like to report here on the synthesis of symmetrical biaryldiamides catalyzed
by CuI under mild conditions.
Experimental
Melting points were determined in open capillaries and are uncorrected. IR spectra
were recorded on a TENSOR 27 spectrometer in KBr. NMR spectra were obtained
from solution in CDCl3 or DMSO-d6 with TMS as internal standard using a Bruker-
400 spectrometer. HRMS analyses were carried out using a Bruker-micro-TOF-Q-
MS analyzer.
General procedure for the synthesis of 2a–2r
A reaction flask with a high vacuum valve was charged with 2-bromobenzamides 1
(1.0 mmol), CuI (20 mg, 0.1 mmol), TBAB (32 mg, 0.1 mmol) and Cs2CO3
(325 mg, 1.0 mmol) in DMF (10.0 mL). After being degassed by three freeze–thaw
pump cycles with argon, the resulting mixture was stirred at 120 °C under an argon
atmosphere. After completion of the reaction, monitored by TLC, the insoluble
substance was filtered off by a fast hot-filtration, and the filtrate was concentrated
under reduced pressure. The resulting crude residue was purified by silica-gel
column chromatography using ethyl acetate and petroleum ether (1:4) as an eluent
to give the final products 2a–2r.
20
N2,N -diphenyl-[1,10-biphenyl]-2,20-dicarboxamide (2a) Yield 86% (169 mg);
yellow solid, m.p.: 234–236 °C (Lit [25]. 230–232 °C). 1H NMR (CDCl3,
400 MHz): dH 7.04–7.06 (m, 4H), 7.22–7.24 (m, 4H), 7.32–7.38 (m, 4H),
7.42–7.44 (m, 4H), 7.64–7.66 (m, 2H), 9.21 (s, 2H). 13C NMR (CDCl3,
100 MHz): dC 120.0, 124.5, 127.2, 128.1, 128.9, 129.7, 130.1, 136.1, 138.0,
123

F. Dong et al.
139.1, 168.4. IR (KBr): m 3269, 3238, 3124, 3033, 3014, 2973, 1654, 1644, 1575,
1550, 1499, 1488, 1440, 1331, 1266, 1106, 1045, 895, 837, 755, 719, 709 cm-1
.
HRMS (TOF, ESI, m/z): Calcd for C26H20N2NaO2 [M ? Na]? 415.1422, found
415.1455.
20
N2,N -bis(4-bromophenyl)-[1,10-biphenyl]-2,20-dicarboxamide (2b) Yield 65%
(179 mg); white solid, m.p.: 184–185 °C (Lit [25]. 182–183 °C). 1H NMR (CDCl3,
400 MHz): dH 7.02–7.05 (m, 2H), 7.30–7.38 (m, 12H), 7.60–7.64 (m, 2H), 9.25 (s,
2H). 13C NMR (CDCl3, 100 MHz): dC 117.2, 121.5, 127.2, 128.2, 129.6, 130.3,
131.9, 135.7, 136.9, 139.0, 168.5. IR (KBr): m 3230, 3174, 3102, 3039, 2929, 2866,
1645, 1604, 1588, 1541, 1395, 1332, 1072, 1008, 824, 755, 713 cm-1. HRMS
(TOF, ESI, m/z): Calcd for C26H18Br2N2NaO2 [M ? Na]? 570.9633, found
570.9644.
20
N2,N -bis(4-chlorophenyl)-[1,10-biphenyl]-2,20-dicarboxamide (2c) Yield 70%
(161 mg); white solid, m.p.: 221–223 °C. 1H NMR (CDCl3, 400 MHz): dH
7.09–7.11 (m, 2H), 7.19–7.21 (m, 4H), 7.36-7.39 (m, 8H), 7.63–7.66 (m, 2H), 9.09
(s, 2H). 13C NMR (CDCl3, 100 MHz): dC 121.1, 127.2, 128.2, 128.9, 129.5, 129.7,
130.4, 135.8, 136.4, 139.0, 168.4. IR (KBr): m 3231, 3177, 3107, 3034, 2867, 1646,
1593, 1543, 1491, 1399, 1335, 1236, 1092, 1012, 828, 754, 715 cm-1. HRMS
(TOF, ESI, m/z): Calcd for C26H18Cl2N2NaO2 [M ? Na]? 483.0643, found
483.0644.
20
N2,N -bis(4-isopropylphenyl)-[1,10-biphenyl]-2,20-dicarboxamide (2d) Yield
1
61% (145 mg); white solid, m.p.: 213–214 °C. H NMR (CDCl3, 400 MHz): dH
1.18–1.20 (m, 12H), 2.80–2.86 (m, 2H), 6.96–7.00 (m, 2H), 7.07–7.09 (m, 4H),
7.24–7.35 (m, 8H), 7.58–7.60 (m, 2H), 9.32–9.50 (m, 2H). 13C NMR (CDCl3,
100 MHz): dC 24.0, 33.6, 120.3, 126.7, 127.3, 128.0, 129.7, 130.0, 135.7, 136.2,
139.1, 145.1, 168.3. IR (KBr): m 3283, 3238, 3183, 3116, 3056, 2959, 2869, 1644,
1604, 1540, 1513, 1413, 1332, 1293, 1257, 1055, 1018, 903, 835, 756, 715 cm-1
.
HRMS (TOF, ESI, m/z): Calcd for C32H33N2O2 [M ? H]? 477.2537, found
477.2533.
20
N2,N -di-p-tolyl-[1,10-biphenyl]-2,20-dicarboxamide (2e) Yield 81% (170 mg);
white solid, m.p.: 181–183 °C (Lit [25]. 177–179 °C). 1H NMR (CDCl3, 400 MHz):
dH 2.27 (s, 6H), 7.03–7.05 (m, 4H), 7.14–7.16 (m, 2H), 7.28–7.30 (m, 4H), 7.37 (s,
4H), 7.65–7.67 (m, 2H), 8.95 (s, 2H). 13C NMR (CDCl3, 100 MHz): dC 20.9, 120.1,
127.2, 127.9, 129.3, 129.6, 129.9, 134.0, 135.4, 136.1, 139.1, 168.2. IR (KBr): m
3234, 3182, 3125, 3051, 3026, 2975, 1674, 1647, 1548, 1489, 1439, 1321, 1272,
1158, 1118, 997, 894, 756, 723 cm-1. HRMS (TOF, ESI, m/z): Calcd for
C28H24N2NaO2 [M ? Na]? 443.1735, found 443.1771.
20
N2,N -bis(3-nitrophenyl)-[1,10-biphenyl]-2,20-dicarboxamide (2f) Yield 75%
(181 mg); white solid, m.p.: 190–191 °C. 1H NMR (CDCl3, 400 MHz): dH
7.17–7.19 (m, 2H), 7.41–7.45 (m, 6H), 7.70–7.72 (m, 2H), 7.81–7.83 (m, 2H),
7.92–7.94 (m, 2H), 8.30–8.31 (m, 2H), 9.33 (s, 2H). 13C NMR (CDCl3, 100 MHz):
dC 114.6, 119.2, 125.6, 127.3, 128.5, 129.8, 129.9, 130.8, 135.3, 138.8, 138.9,
123

An efficient synthesis of biaryl diamides via Ullmann…
148.5, 168.8. IR (KBr): m 3237, 3184, 3122, 3057, 3019, 2867, 1653, 1602, 1526,
1481, 1431, 1352, 884, 821, 758, 737 cm-1. HRMS (TOF, ESI, m/z): Calcd for
C26H18N4NaO6 [M ? Na]? 505.1124, found 505.1136.
20
N2,N -bis(3,4-dimethoxyphenyl)-[1,10-biphenyl]-2,20-dicarboxamide (2g) Yield
1
77% (197 mg); white solid, m.p.: 226–228 °C. H NMR (CDCl3, 400 MHz): dH
3.80 (s, 6H), 3.82 (s, 6H), 6.71–6.73 (m, 2H), 6.78–6.81 (m, 2H), 7.14–7.17 (m,
4H), 7.37–7.42 (m, 4H), 7.66–7.68 (m, 2H), 8.93 (s, 2H). 13C NMR (CDCl3,
100 MHz): dC 55.9, 56.1, 105.0, 111.2, 112.3, 127.1, 128.1, 129.7, 130.1, 131.4,
136.2, 139.1, 146.0, 148.9, 168.1. IR (KBr): m 3225, 3134, 3057, 2999, 2934, 2830,
1640, 1607, 1513, 1452, 1266, 1236, 1236, 1203, 1170, 1130, 1025, 849, 762,
730 cm-1. HRMS (TOF, ESI, m/z): Calcd for C30H28N2NaO6 [M ? Na]?
535.1845, found 535.1873.
20
N2,N -di(naphthalen-1-yl)-[1,10-biphenyl]-2,20-dicarboxamide (2h) Yield 65%
(160 mg); white solid, m.p.: 254–256 °C. 1H NMR (CDCl3, 400 MHz): dH
7.33–7.39 (m, 6H), 7.42–7.46 (m, 2H), 7.47–7.51 (m, 4H), 7.54–7.59 (m, 4H),
7.65–7.67 (m, 2H), 7.77–7.80 (m, 4H), 9.08 (s, 2H). 13C NMR (CDCl3, 100 MHz):
dC 121.5, 121.7, 125.5, 125.9, 126.1, 126.3, 127.5, 127.9, 128.3, 128.4, 130.0,
130.2, 132.3, 134.0, 136.5, 139.4, 169.1. IR (KBr): m 3215, 3168, 3141, 3054, 3015,
2852, 1659, 1640, 1597, 1520, 1505, 1400, 1348, 1302, 803, 756, 722, 709 cm-1
.
HRMS (TOF, ESI, m/z): Calcd for C34H24N2NaO2 [M ? Na]? 515.1735, found
515.1765.
20
N2,N -di(pyridin-2-yl)-[1,10-biphenyl]-2,20-dicarboxamide (2i) Yield 60%
(118 mg); white solid, m.p.: 213–215 °C. 1H NMR (CDCl3, 400 MHz): dH
6.93–6.96 (m, 2H), 7.21–7.25 (m, 2H), 7.39–7.43 (m, 4H), 7.59–7.63 (m, 2H),
7.70–7.74 (m, 2H), 8.09–8.10 (m, 2H), 8.15–8.17 (m, 2H), 9.52 (s, 2H). 13C NMR
(CDCl3, 100 MHz): dC 112.5, 116.3, 125.3, 126.4, 126.7, 126.9, 127.3, 134.1,
135.1, 147.8, 148.6, 159.0. IR (KBr): m 3235, 3186, 3110, 3069, 3023, 2995, 2924,
2868, 1677, 1594, 1576, 1525, 1430, 1307, 1152, 1092, 993, 900, 789, 775,
728 cm-1. HRMS (TOF, ESI, m/z): Calcd for C24H18N4NaO2 [M ? Na]?
417.1327, found 417.1327.
20
N2,N -dibenzyl-[1,10-biphenyl]-2,20-dicarboxamide (2j) Yield 62% (130 mg);
1
yellow solid, m.p.: 218–219 °C. H NMR (CDCl3, 400 MHz): dH 4.23–4.44 (m,
4H), 6.89–6.90 (m, 4H), 7.05–7.08 (m, 2H), 7.16–7.22 (m, 6H), 7.31–7.38 (m, 4H),
7.44–7.50 (m, 2H), 7.52–7.54 (m, 2H). 13C NMR (CDCl3, 100 MHz): dC 43.6,
127.1, 127.2, 127.5, 127.8, 128.5, 129.55, 129.60, 136.0, 137.9, 139.0, 169.8. IR
(KBr): m 3067, 3030, 2977, 2950, 2918, 1644, 1613, 1523, 1443, 1406, 1337, 1211,
1140, 935, 904, 847, 812, 742, 731, 701 cm-1. HRMS (TOF, ESI, m/z): Calcd for
C28H24N2NaO2 [M ? Na]? 443.1735, found 443.1735.
20
N2,N -dipropyl-[1,10-biphenyl]-2,20-dicarboxamide (2k) Yield 63% (102 mg);
white solid, m.p.: 174–176 °C. 1H NMR (CDCl3, 400 MHz): dH 0.71–0.74 (m, 6H),
1.20–1.29 (m, 4H), 3.04–3.19 (m, 4H), 7.07–7.08 (m, 2H), 7.24 (s, 2H), 7.32–7.34
(m, 4H), 7.51–7.53 (m, 2H). 13C NMR (CDCl3, 100 MHz): dC 11.2, 22.5, 41.4,
123

F. Dong et al.
126.9, 127.7, 129.3, 129.4, 136.5, 139.0, 170.0. IR (KBr): m 3254, 3068, 2964, 2933,
2875, 1636, 1595, 1555, 1469, 1437, 1383, 1319, 1247, 1150, 756, 712 cm-1
.
HRMS (TOF, ESI, m/z): Calcd for C20H24N2NaO2 [M ? Na]? 347.1735, found
347.1733.
20
5,50-Dichloro-N2,N -diphenyl-[1,10-biphenyl]-2,20-dicarboxamide (2l) Yield
1
80% (184 mg); white solid, m.p.: 227–228 °C. H NMR (CDCl3, 400 MHz): dH
7.09–7.12 (m, 2H), 7.11–7.18 (m, 2H), 7.28–7.30 (m, 4H), 7.39–7.45 (m, 6H),
7.62–7.64 (m, 2H), 9.02 (s, 2H). 13C NMR (DMSO–d6, 100 MHz): dC 120.2, 124.8,
128.8, 129.3, 129.4, 130.1, 134.9, 135.1, 138.3, 139.6, 167.0. IR (KBr): m 3197,
3167, 3135, 3061, 2958, 1671, 1603, 1560, 1481, 1472, 1296, 1252, 1144, 942, 828,
769 cm-1. HRMS (TOF, ESI, m/z): Calcd for C26H18Cl2N2NaO2 [M ? Na]?
483.0643, found 483.0637.
20
4,40-Dimethoxy-N2,N -diphenyl-[1,10-biphenyl]-2,20-dicarboxamide (2m) Yield
1
85% (192 mg); yellow solid, m.p.: 231–232 °C. H NMR (CDCl3, 400 MHz): dH
3.72 (s, 6H), 6.76–6.78 (m, 2H), 6.82–6.84 (m, 2H), 7.05–7.09 (m, 2H), 7.14–7.15
(m, 2H), 7.24–7.27 (m, 4H), 7.48–7.50 (m, 4H), 9.44 (s, 2H). 13C NMR (CDCl3,
100 MHz): dC 55.4, 112.2, 116.6, 120.0, 124.4, 128.9, 131.0, 131.3, 137.2, 138.1,
158.9, 168.4. IR (KBr): m 3231, 3126, 3061, 2969, 2835, 1654, 1647, 1596, 1534,
1444, 1325, 1293, 1217, 1051, 1037, 827, 819, 767, 753 cm-1. HRMS (TOF, ESI,
m/z): Calcd for C28H24N2NaO4 [M ? Na]? 475.1634, found 475.1636.
20
4,40-Dimethyl-N2,N -diphenyl-[1,10-biphenyl]-2,20-dicarboxamide (2n) Yield
1
80% (168 mg); white solid, m.p.: 214–216 °C. H NMR (CDCl3, 400 MHz): dH
2.35 (s, 6H), 6.99–7.01 (m, 2H), 7.04–7.06 (m, 2H), 7.14–7.15 (m, 2H), 7.23–7.25
(m, 4H), 7.44–7.46 (m, 6H), 9.06 (s, 2H). 13C NMR (CDCl3, 100 MHz): dC 21.1,
119.9, 124.3, 127.8, 128.8, 129.8, 130.8, 136.0, 136.2, 137.8, 138.1, 168.6. IR
(KBr): m 3251, 3131, 3066, 3028, 2923, 2859, 1655, 1640, 1556, 1521, 1501, 1445,
1331, 1261, 1202, 908, 835, 756, 744 cm-1. HRMS (TOF, ESI, m/z): Calcd for
C28H25N2O2 [M ? H]? 421.1911, found 421.1905.
20
N2,N -bis(4-bromophenyl)-4,40-dimethyl-[1,10-biphenyl]-2,20-dicarboxamide (2o)
Yield 65% (188 mg); white solid, m.p.: 204–206 °C. 1H NMR (CDCl3, 400 MHz):
dH 2.33 (s, 6H), 6.91–9.93 (m, 2H), 7.13–7.15 (m, 2H), 7.34 (s, 8H), 7.41 (s, 2H),
9.17 (s, 2H). 13C NMR (CDCl3, 100 MHz): dC 21.1, 117.0, 121.4, 127.7, 129.8,
131.0, 131.8, 135.7, 136.1, 137.1, 138.0, 168.7. IR (KBr): m 3226, 3173, 3100, 3034,
2921, 2850, 1651, 1601, 1540, 1488, 1394, 1329, 1254, 1072, 1007, 939, 864, 771,
731 cm-1. HRMS (TOF, ESI, m/z): Calcd for C28H22Br2N2NaO2 [M ? Na]?
598.9946, found 598.9957.
20
N2,N -bis(4-chlorophenyl)-4,40-dimethyl-[1,10-biphenyl]-2,20-dicarboxamide (2p)
Yield 67% (164 mg); white solid, m.p.: 217–218 °C. 1H NMR (CDCl3, 400 MHz):
dH 2.33 (s, 6H), 6.91–6.93 (m, 2H), 7.13–7.15 (m, 2H), 7.18–7.21 (m, 4H),
7.38–7.42 (m, 6H), 9.19 (s, 2H). 13C NMR (CDCl3, 100 MHz): dC 21.1, 121.1,
127.7, 128.9, 129.3, 129.8, 131.0, 135.7, 136.1, 136.6, 137.9, 168.7. IR (KBr): m
3231, 3177, 3105, 3037, 2924, 2863, 1651, 1594, 1541, 1491, 1399, 1330, 1255,
123

An efficient synthesis of biaryl diamides via Ullmann…
1201, 1093, 1011, 940, 865, 772, 731 cm-1. HRMS (TOF, ESI, m/z): Calcd for
C28H22Cl2N2NaO2 [M ? Na]? 511.0956, found 511.0985.
20
4,40-Dimethyl-N2,N -di-p-tolyl-[1,10-biphenyl]-2,20-dicarboxamide (2q) Yield
1
78% (175 mg); white solid, m.p.: 235–237 °C. H NMR (CDCl3, 400 MHz): dH
2.27 (s, 6H), 2.32 (s, 6H), 6.93–6.96 (m, 2H), 7.02–7.04 (m, 4H), 7.10–7.12 (m,
2H), 7.31–7.33 (m, 4H), 7.42 (s, 2H), 9.08–9.12 (m, 2H). 13C NMR (CDCl3,
100 MHz): dC 20.8, 21.0, 120.0, 127.8, 129.3, 129.8, 130.7, 133.9, 135.5, 136.1,
136.2, 137.6, 168.5. IR (KBr): m 3234, 3178, 3031, 2957, 2886, 2779, 1635, 1615,
1575, 1559, 1489, 1450, 1345, 1241, 1186, 1039, 927, 846, 795, 717, 708 cm-1
.
HRMS (TOF, ESI, m/z): Calcd for C30H28N2NaO2 [M ? Na]? 471.2048, found
471.2058.
20
4,40-Dimethyl-N2,N -bis(3-nitrophenyl)-[1,10-biphenyl]-2,20-dicarboxamide (2r)
Yield 76% (194 mg); white solid, m.p.: 227–229 °C. 1H NMR (CDCl3, 400 MHz):
dH 2.31 (s, 6H), 6.96–6.98 (m, 2H), 7.16–7.18 (m, 2H), 7.40–7.46 (m, 4H),
7.80–7.82 (m, 2H), 7.89–7.92 (m, 2H), 8.32–8.34 (m, 2H), 9.58 (s, 2H). 13C NMR
(CDCl3, 100 MHz): dC 21.0, 114.7, 119.1, 125.7, 127.8, 129.7, 129.9, 131.4, 135.2,
136.0, 138.3, 139.0, 148.4, 169.2. IR (KBr): m 3229, 3238, 3180, 3119, 3089, 3022,
2925, 2869, 1655, 1600, 1528, 1481, 1432, 1347, 1301, 1272, 1257, 1204, 1089,
889, 835, 774, 738 cm-1. HRMS (TOF, ESI, m/z): Calcd for C28H22N4NaO6
[M ? Na]? 533.1437, found 533.1443.
General procedure for the synthesis of 2s
A reaction flask with a high vacuum valve was charged with 2-bromo-4-chloro-N-
phenylbenzamide 1l (155 mg, 0.5 mmol), 2-bromo-5-methyl-N-(3-nitrophenyl)
benzamide 1r (168 mg, 0.5 mmol), CuI (20 mg, 0.1 mmol), TBAB (32 mg,
0.1 mmol) and Cs2CO3 (325 mg, 1.0 mmol) in DMF (10.0 mL). After being
degassed by three freeze–thaw pump cycles with argon, the resulting mixture was
stirred at 120 °C under an argon atmosphere. After completion of the reaction
monitored by TLC, the insoluble substance was filtered off by a fast hot-filtration,
and the filtrate was concentrated under reduced pressure. The resulting crude residue
was purified by silica-gel column chromatography using ethyl acetate and petroleum
ether (1:4) as an eluent to give the products 21, 2r and 2s.
20
50-Chloro-4-methyl-N2-(3-nitrophenyl)-N -phenyl-[1,10-biphenyl]-2,20-dicar-
1
boxamide (2s): M.p. 231–232 °C; H NMR (CDCl3, 400 MHz): dH 2.41 (s, 3H,
CH3), 7.05 (d, J = 7.6 Hz, 1H, ArH), 7.13–7.17 (m, 1H, ArH), 7.23 (s, 1H, ArH),
7.26 (s, 1H, ArH), 7.30–7.34 (m, 2H, ArH), 7.49–7.43 (m, 2H, ArH), 7.46–7.48 (m,
2H, ArH), 7.52–7.54 (m, 1H, ArH), 7.61–7.64 (m, 1H, ArH), 7.83 (d, J = 7.6 Hz,
1H, ArH), 7.90 (d, J = 8.0 Hz, 1H, ArH), 8.29–8.30 (m, 1H, ArH), 8.36 (s, 1H,
NH), 9.78 (s, 1H, NH). 13C NMR (CDCl3, 100 MHz): dC 20.1, 113.4, 117.8, 119.2,
124.2, 124.4, 127.1, 127.3, 127.5, 127.1, 128.3, 128.7, 129.4, 130.3, 133.1, 133.4,
134.5, 135.4, 136.3, 137.8, 138.3, 140.1, 147.5, 166.9, 167.3. IR (KBr): m 3244,
3189, 3129, 3064, 3063, 3023, 2925, 2856, 1653, 1599, 1532, 1491, 1444, 1350,
123

F. Dong et al.
1330, 1302, 1261, 1102, 892, 825, 756, 738 cm-1. HRMS (TOF, ESI, m/z): Calcd
for C27H20ClN3NaO4 [M ? Na]? 508.1035, found 508.1021.
Results and discussion
2-bromo-N-phenylbenzamide (1a) has been used as a model to optimize the reaction
conditions including the catalyst, base and solvent. First, an attempt with previous
conditions [32] in the presence of Pd(PPh3)2Cl2, CuI and Et3N in refluxing
acetonitrile was conducted, affording 2a in 56% yield. Considering its lower
reactivity than that of aryl iodide, the solvent was changed to DMF in order to
further increase the reaction temperature. To our delight, it gave 2a in 87% yield at
90 °C. In view of the higher price for the Pd catalyst, we gradually reduced its dose.
It was found that 2a could be obtained in 66% yield in the absence ofthe Pd catalyst.
Inspired by this result, we further screened other copper sources, such as CuCl,
CuBr, Cu2O and Cu powder, but CuI still gave the best result. Then, inorganic
bases, for example, NaHCO3, K2CO3 and Cs2CO3, accompanied by the additive of
TBAB, especially for 1.0 equivalent of Cs2CO3/TBAB (10 mol%), gave 2a in 82%
yield. Subsequently, we found that the reaction temperature also played a key role in
this transition. Using amounts of 10 mol% CuI and 1.0 equivalent of Cs2CO3/TBAB
(10 mol%) at 120 °C in DMF, the coupling reaction gave the best yield of 86%,
which is almost the same effect as the Pd-Cu co-catalytic system. Finally, other
common solvents, such as xylene, DMA and DMSO, all gave 2a in slightly lower
yields. Therefore, 10 mol% CuI and 1.0 equivalent of Cs2CO3/TBAB (10 mol%), at
Table 1 The process of
optimizing the reactiona
Entry Cat. (mol%) Base
T (°C) Solvent Yields (%)b
1
Pd–Cu(15)c
Pd–Cu(15)
Pd–Cu(5)
CuI(20)
CuCl(20)
CuBr(20)
Cu2O(20)
Cu(20)
Et3N
80
90
MeCN
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
56
87
79
66
52
56
50
58
59
76
82
83
86
86
2
Et3N
3
Et3N
90
4
Et3N
90
5
Et3N
90
6
Et3N
90
7
Et3N
90
8
Et3N
90
9
CuI(10)
CuI(10)
CuI(10)
CuI(10)
CuI(10)
CuI(10)
CuI(10)
CuI(10)
CuI(10)
NaHCOd3
K2COe3
Cs2COe3
Cs2COe3
Cs2COe3
Cs2COe3
Cs2COe3
Cs2COe3
Cs2COe3
90
aReaction condition: 1a
(276 mg, 1.0 mmol), Base
(1.0 mmol), solvent (10.0 mL)
bIsolated yields
cPd(PPh3)2Cl2 (15 mol%), CuI
(15 mol%) and Et3N (0.5 mL)
dNaHCO3 (168 mg, 2.0 mmol),
TBAB (32 mg, 0.1 mmol)
eBase (1.0 mmol)/TBAB
(32 mg, 0.1 mmol)
10
11
12
13
14
15
16
17
90
90
110
120
130
120
120
120
Xylene 76
DMA 84
DMSO 85
123

An efficient synthesis of biaryl diamides via Ullmann…
Table 2 The diversity of biaryldiamides 2
aReaction conditions: 1 (1.0 mmol), Cs2CO3 (325 mg, 1.0 mmol)/TBAB (32 mg, 0.1 mmol), DMF
(10.0 mL), 120 °C; bIsolated yields
123

F. Dong et al.
120 °C in DMF was identified as the optimized reaction conditions for this
conversion (Tables 1, 2).
On the basis of the above optimal reaction conditions, we next examined the
application of the substrate 1. First, keeping the benzoyl the same, we altered the
various kinds of groups on the N-atom, such as phenyl, 4-methylphenyl,
4-isopropylphenyl and 3,4-methoxyphenyl, which were all in an aromatic group
with an electron-donating substituent giving 2 in good yields. A benzene ring
containing an electron-drawing group, for example, 4-chlorophenyl, 4-bromophenyl
and 3-nitrophenyl, could also proceed smoothly to give the desired biaryldiamides
in moderate yields. It should be noted that a condensed nucleus (e.g., 1-naphthyl),
heterocycle (e.g., pyridin-2-yl) and aliphatic substituents, such as benzyl and n-
butyl, all gave 2h–2k in moderate yields. Then, other benzoyls, such as benzene
bearing chloro, methoxy, and methyl, were also tested in our laboratory and they all
underwent the coupling reaction to provide biaryldiamides as we expected.
In order to confirm whether it was a homocoupling reaction, two different
2-bromobenzamides (1l and 1r) were performed in one-pot reaction under the same
reaction conditions. It was found that a mixture of 2l, 2r and 2s was obtained in 21,
20 and 26% yields, respectively (Scheme 3). These data indicated that it was not a
homocoupling reaction.
The structures of the products were fully characterized by NMR, IR and HRMS,
and their data were in good agreement with the corresponding structures. Of which
the structure of 2q was further confirmed by X-ray diffraction analysis (Fig. 1). The
two connected benzene rings make a dihedral angle of 77.7 (1)° to each other, which
is stabilized by the intra-molecular hydrogen bond of N1-H1…O1. The adjacent
molecules link via an inter-molecular hydrogen bond of N2–H1ÁÁÁO2 (x ? 1/2,
- y ? 1/2, z ? 1/2), forming the polymers along the c axis in a unit cell (Fig. 2).
According to the structure of the products, we think that CuI promotes the
subsequent oxidative addition and reductive elimination to give the final products 2.
The role of the base (Cs2CO3) is to help dehalogenation, and at the same time the
Scheme 3 The confirmative reaction
123

An efficient synthesis of biaryl diamides via Ullmann…
Fig. 1 The crystal structure of 2q
Fig. 2 The hydrogen bonds of 2q in a unit cell
123

F. Dong et al.
Scheme 4 The possible reaction mechanism
CuI is released to form the catalytic cycle. The probable reaction mechanism is
shown in Scheme 4.
Conclusion
In summary, 2-bromobenzamides were found to be aryl halides which underwent an
Ullmann reaction for the synthesis of symmetrical biaryldiamides. They proceeded
smoothly under mild conditions catalyzed by CuI and Cs2CO3 in moderate yields.
Acknowledgements This work was financially supported by NSFC of China (No. 21702078), the NSF of
Jiangsu Province (No. BK20170231), the Priority Academic Program Development of Jiangsu Higher
education Institutions and TAPP.
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