Scaled-up Negishi-coupling of aryl halides bearing unprotected amides with Knochel-type organozinc reagents

Article abstract of DOI:10.3184/174751917X15064232103038

Without the need of any protecting groups, aryl halides bearing acidic amides were coupled with several Knochel-type organozinc reagents by using Pd(OAc)₂ as catalyst and 2-dicyclohexylphosphino-2',6'-dimethoxy biphenyl (S-Phos) as ligand. The reactions were carried out on a large scale (30 mmol), furnishing the desired coupling products smoothly in excellent yields (70–98%).

Full text of DOI:10.3184/174751917X15064232103038

JOURNAL OF CHEMICAL RESEARCH 2017
VOL. 41 OCTOBER, 569–570
RESEARCH PAPER 569
Scaled-up Negishi-coupling of aryl halides bearing unprotected amides with
Knochel-type organozinc reagents
Jia-Chao Xiong, Wan Xu and Zhi-Bing Dong*
School of Chemistry and Environmental Engineering, Wuhan Institute of Technology, Wuhan 430205, P.R. China
Without the need of any protecting groups, aryl halides bearing acidic amides were coupled with several Knochel-type organozinc reagents
by using Pd(OAc)2 as catalyst and 2-dicyclohexylphosphino-2',6'-dimethoxy biphenyl (S-Phos) as ligand. The reactions were carried out
on a large scale (30 mmol), furnishing the desired coupling products smoothly in excellent yields (70–98%).
Keywords: palladium catalysis, Negishi-coupling, organozinc
Suzuki and Negishi cross-coupling reactions are the most
halides bearing acidic hydrogen atoms under very mild
conditions (1.5–2.5 h, 25 °C) on a large scale (30 mmol)
(Scheme 1) and the results are shown in Table 1. No excess of
the zinc reagent and no additional base for deprotonation of the
acidic proton prior to the cross-coupling were necessary. The
use of palladium(II) acetate (1 mol%) and S-Phos (2 mol%)5
allowed an efficient cross-coupling between various Knochel-
type organozinc reagents and aryl halides bearing relatively
acidic amide groups. By adding the organozinc reagent slowly
(typically over 120 min via a syringe pump), the acidic amide
groups were tolerated (Table 1). Thus, the sensitive cyano-
substituted alkylzinc reagent 1a, prepared by zinc insertion
into the corresponding alkyl bromide,6 reacted with 2a in the
presence of Pd(OAc)2 (1 mol%) and S-phos (2 mol%) in THF
powerful and widely used methods for making C –C 2 bonds.1,2
2
sp
sp
The resulting products find use in the pharmaceutical and
agrochemical industries, as well as being possible new materials.3
Recently, Knochel and Dong and co-workers4 reported palladium-
catalysed cross-couplings of unsaturated halides bearing acidic
hydrogen atoms by using Knochel-type organozinc reagents. As
part of our interest in developing new methods by using Knochel-
type organozinc reagents,4 we now report another application to
further illustrate its synthetic value.
Results and discussion
A variety of functionalised Knochel-type organozinc reagents
(prepared as reported previously4) were coupled with aryl
Z
Y
Z
2
RZnX.LiCl
Zn, LiCl
RX
°
THF, 25
24 h
C
R
1
Pd(OAc)2 (1 mol%)
S-Phos (2 mol%)
3
scale: 40 mmol
−
THF, 1.5 2.5 h, 25 °C
scale: 30 mmol
Scheme 1
Table 1 Yields of coupled products 3a–e formed from reaction of a zinc complex 1a–d with an aryl halide 2a–c in the presence of Pd(OAc)2 and
S-Phos (Scheme 1)a
Zinc reagent 1
R
R = NCCH2(CH2)2,
X = Br
Aryl halide 2
Y
Y = I, Z = EtCO2CH2NHSO2
Product 3
R
R = NCCH2(CH2)2,
Z = EtCO2CH2NHSO2
3a
Entry
1
Time (h)
2.5
Yield (%)b
70
X
Z
Z
1a
2a
R = 2-Cl–C6H4–CH2,
Y = I,
R = 2-Cl–C6H4–CH2,
2
3
4
5
X = Cl
Z = 4-Me–C6H4SO2NH
Z = 4-Me–C6H4SO2NH
3b
R = 3-CN–C6H4–CH2,
Z = 4-Me–C6H4SO2NH
3c
R = 3-CN–C6H4–CH2,
Z = 4-CH2CH2CHNHCO
3d
R =3-BuCO–C6H4–CH2,
Z = 4-Me–C6H4SO2NH
3e
2
98
98
1b
2b
R = 3-CN–C6H4–CH2,
X = Cl
Y = I,
Z = 4-Me–C6H4SO2NH
2
1c
2b
R = 3-CN–C6H4–CH2,
X = Cl
Y = Br,
Z = 4-CH2CH2CHNHCO
2.5
1.5
83
90
1c
2c
R =3-BuCO–C6H4–CH2,
X = Cl
Y = I,
Z = 4-Me–C6H4SO2NH
1d
2b
aReaction conditions: in a dried flask flushed with argon, an organozinc reagent 1 (33 mmol), an aryl halide 2 (30 mmol), Pd(OAc)2 (1 mol%) and S-Phos (2 mol%) were stirred in THF at
25 °C and left to stand for 1.5–2.5 h. bIsolated yield of analytically pure product.
* Correspondent. E-mail: dzb04982@wit.edu.cn

570 JOURNAL OF CHEMICAL RESEARCH 2017
(%): 238 (12), 237 (89), 209 (13), 208 (100), 173 (14), 144 (46), 116 (12),
102 (10), 91 (10); HRMS (ESI) calcd for C14H18N2O4S: 310.0987; found:
310.0980.
furnishing 3a in 70% yield within 2.5 h (entry 1). Gratifyingly,
the benzyl zinc reagent 1b reacted well with the acidic substrate
2b, giving the desired product 3b in excellent yield (98%, entry
2). The sensitive 3-cyanopropylzinc reagent 1c also coupled well
with 2b affording the corresponding product 3c in high yield
(98%, entry 3). Unprotected benzamide 2c was also suitable for
the cross-coupling, yielding 3d in a satisfying yield (83%, entry 4).
The zinc reagent 1d bearing a sensitive acyl group, reacted with 2b
smoothly, providing 3e within 1.5 h in 90% yield (entry 5).
N-[4-(2-Chlorobenzyl)-phenyl]-4-methylbenzenesulfonamide (Table 1,
entry 2, 3b): White solid; m.p. 127.6–128.8 °C; 1H NMR (300 MHz) δ 7.64
(ddd, J = 8.3, 2.0, 1.9 Hz, 2H), 7.37–7.31 (m, 1H), 7.20 (dd, J = 8.3, 0.8 Hz,
2H), 7.16–7.12 (m, 2H), 7.08–7.04 (m, 2H), 7.01 (ddd, J = 8.3, 2.0, 1.9 Hz,
2H), 6.98–6.96 (m, 1H), 6.92 (s, 1H), 4.00 (s, 2H), 2.36 (s, 3H); 13C NMR
(75 MHz) δ 143.7, 138.3, 136.7, 136.1, 134.7, 134.1, 130.1, 129.7, 129.6,
129.5, 127.7, 127.2, 126.8, 121.9, 38.5, 21.5; MS (EI, 70 eV), m/z (%): 371
(60) [M]+, 216 (100), 189 (10), 180 (24), 153 (20); HRMS (ESI) calcd for
C20H18ClNO2S: 371.0747; found: 371.0740.
Conclusion
In summary, an efficient scaled-up Negishi-coupling of several
functionalised Knochel-type organozinc reagents with unsaturated
halides bearing an acidic amide group was demonstrated. The use
of protecting groups was not required, and sensitive functional
groups, such as cyano and acyl groups could be tolerated. These
reactions could be performed with standard laboratory glassware
and did not require the use of expensive chemicals or catalysts,
which showed its practical synthetic value in organic synthesis.
N-[4-(3-Cyanobenzyl)-phenyl]-4-methylbenzenesulfonamide
(Table 1, entry 3, 3c): Colourless oil; H NMR (300 MHz) δ 7.66
1
(d, J = 8.4 Hz, 2H), 7.50–7.44 (m, 1H), 7.39–7.34 (m, 3H), 7.22 (dd,
J = 8.4, 0.5 Hz, 2H), 7.04–6.98 (m, 4H), 6.95 (s, 1H), 3.91 (s, 2H), 2.37 (s,
3H); 13C NMR (75 MHz) δ 143.9, 142.2, 136.4, 136.1, 135.2, 133.3, 132.2,
130.0, 129.8, 129.6, 129.2, 127.2, 122.0, 118.8, 112.5, 40.6, 21.5; MS (EI,
70 eV), m/z (%): 362 (65) [M]+, 207 (100), 180 (35), 155 (17), 91 (40);
HRMS (ESI) calcd for C21H18N2O2S: 362.1089; found: 362.1094.
4-(3-Cyanobenzyl)-N-cyclopropylbenzamide (Table 1, entry 4, 3d):
White solid; m.p. 136.5–138.1 °C; H NMR (300 MHz) δ 7.68 (ddd,
Experimental
1
Melting points were determined on a Kofler micro melting point apparatus
and are uncorrected. H and 13C NMR spectra were obtained in CDCl3
J = 8.3, 2.0, 1.9 Hz, 2H), 7.51–7.46 (m, 1H), 7.41 (m, 1H), 7.39–7.35
(m, 2H), 7.18 (ddd, J = 8.3, 2.0, 1.9 Hz, 2H), 6.30 (s, 1H), 4.02 (s, 2H),
2.92–2.83 (m, 1H), 0.87–0.81 (m, 2H), 0.59 (ddd, J = 7.0, 5.0, 4.1 Hz, 2H);
13C NMR (75 MHz) δ 168.5, 143.0, 141.8, 133.3, 132.9, 132.3, 130.1, 129.4,
129.1, 127.4, 118.7, 112.6, 41.1, 23.1, 6.8; MS (EI, 70 eV), m/z (%): 276
(10) [M]+, 220 (100), 160 (13), 165 (12), 116 (8); HRMS (ESI) calcd for
C18H16N2O: 276.1263; found: 276.1254.
4-Methyl-N-[4-(3-pentanoylbenzyl)phenyl]benzenesulfonamide
(Table 1, entry 5, 3e): Colourless semi-solid; 1H NMR (600 MHz) δ 7.78
(d, J = 7.8 Hz, 1H), 7.74 (s, 1H), 7.65 (d, J = 8.4 Hz, 2H), 7.35 (t, J = 7.2
Hz, 1H), 7.29 (d, J = 7.8 Hz, 1H), 7.20 (d, J = 8.4 Hz, 2H), 7.11 (s, 1H),
7.03–7.00 (m, 4H), 3.94 (s, 2H), 2.92 (t, J = 7.8 Hz, 2H), 2.36 (s, 3H),
1.71–1.66 (m, 2H), 1.42-1.36 (m, 2H), 0.93 (t, J = 7.2 Hz, 3H).; 13C NMR
(150 MHz) δ 200.7, 143.8, 141.3, 137.5, 137.3, 136.2, 134.8, 133.4, 129.7,
129.6, 128.7, 128.3, 127.2, 126.1, 122.0, 41.0, 39.4, 26.5, 22.4, 21.5, 14.0;
MS (70 eV, EI) m/z (%): 422 (25), 421 (90) [M]+, 380 (14), 379 (54), 365
(24), 364 (100), 266 (15), 224 (15), 210 (37), 209 (26), 182 (16), 181 (16),
180 (29), 155 (10), 153 (18), 152 (14), 106 (10), 91 (37), 57 (15); HRMS
(ESI) calcd for C25H27NO3S: 421.1712; found: 421.1671.
1
using TMS as internal standard on a Bruker 600 AC or a Bruker 300
AC NMR spectrometer. High-resolution mass spectra (ESI–HRMS) were
determined on an Ion Spec (7.0 T) spectrometer. All reactions were carried
out under an argon atmosphere in dried glassware. Starting materials
were purchased from commercial suppliers and used without further
purification unless otherwise stated. THF was continuously refluxed and
freshly distilled from sodium benzophenone ketyl under nitrogen. Yields
refer to isolated compounds estimated to be > 95% pure as determined by
1H NMR and capillary GC analysis.
Synthesis of organozinc reagent 1a; general procedure4
Anhydrous LiCl (44 mmol, 1.87 g) was placed in an argon-flushed flask
equipped with a condenser and dried for 30 min at 250 °C under high
vacuum (1 mbar). Zinc powder (90 mmol, 5.88 g) was added under argon
and the heterogenous mixture was dried again for 30 min at 250 °C under
high vacuum (1 mbar). After cooling to 25 °C, the flask was evacuated
and refilled with argon three times. THF (40 mL) was added and the zinc
was activated with 1,2-dibromoethane (5% mmol) and TMSCl (1–2%
mmol). 4-Bromobutylnitrile (40 mmol, 5.92 g) was added carefully
and the reaction mixture was stirred at 25 °C for 24 h. The solution of
1a was carefully separated from the zinc powder by using a syringe and
transferred to another dry and argon-flushed flask. Titration of the zinc
reagent (typically 1 mL) with iodine,2,4 indicated a concentration of 0.85
mol L–1.
Acknowledgements
We thank the National Natural Science Foundation of China
(21302150), the Hubei Provincial Department of Education
(D20131501), the Scientific Research Foundation for the Returned
Overseas Chinese Scholars, State Education Ministry [2012]1707,
the foundation of Chutian distinguished fellowship from Hubei
Provincial Department of Education and the foundation of
High-end Talent Cultivation Program from Wuhan Institute of
Technology for support. Z.B. Dong thanks Prof. Dr Paul Knochel
for his generous help during his stay in Germany.
Synthesis of ethyl [4-(3-cyanopropyl)-benzenesulfonylamino]acetate
(3a); general procedure
Ethyl (4-iodobenzenesulfonylamino)acetate (2a, 11.1 g, 30 mmol),
Pd(OAc)2 (67.35 mg,
1
mol%), 2-dicyclohexylphosphino-2',6'-
dimethoxybiphenyl (S-Phos, 246 mg, 2 mol%) and THF (40 mL) were
placed in a dry and argon-flushed 250 mL Schlenk-flask equipped
with a reflux condenser. The reaction mixture was stirred for 5 min,
and then 4-cyanobutylzinc bromide (1a, 40 mL, 0.85 mol L–1) in
THF (33 mmol) was added by using a syringe pump over 120 min.
The reaction mixture was stirred for 1 h at 25 °C and then quenched
with aqueous saturated NH4Cl solution, and extracted with ether.
The combined organic phases were dried with Na2SO4, the crude
residue obtained after evaporation of the solvent was purified by flash
chromatography (pentane/ether = 3:2) to yield 3a: Light yellow solid, yield
6.51 g, 70%; m.p. 65.9–67 °C; 1H NMR (300 MHz) δ 7.85–7.81 (m, 2H),
7.38–7.34 (m, 2H), 5.25 (t, J = 5.4 Hz, 1H), 4.10 (q, J = 7.2 Hz, 2H), 3.79 (d,
J = 5.7 Hz, 2H), 2.87 (t, J = 7.5 Hz, 2H), 2.37 (t, J = 7.2 Hz, 2H), 2.06–1.96
(m, 2H), 1.20 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz) δ 168.8, 145.4, 137.5,
129.2, 127.7, 119.1, 61.9, 44.2, 34.2, 26.5, 16.5, 14.0; MS (70 eV, EI) m/z
Received 3 August 2017; accepted 23 August 2017
Paper 1704925
https://doi.org/10.3184/174751917X15064232103038
Published online: 4 October 2017
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