Scaled-up transition-metal-catalyzed cross-coupling reactions of thioether-substituted N-heterocycles with organozinc reagents

Article abstract of DOI:10.1055/s-0030-1258145

A variety of functionalized methylthio-substituted N-heterocycles (pyridines, pyrimidines, pyrazines, pyridazines, triazines, quinazolines, benzothiazoles) undergo smooth palladium- or nickel-catalyzed cross-couplings with highly functionalized organozinc reagents at ambient temperature. No expensive copper(I) salts are required and the coupling reactions proceed readily in the range of up to 20 mmol scale. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0030-1258145

PRACTICAL SYNTHETIC PROCEDURES
2853
Scaled-Up Transition-Metal-Catalyzed Cross-Coupling Reactions of
Thioether-Substituted N-Heterocycles with Organozinc Reagents
S
caled-U
p
Cross-
C
l
ouplin
b
g
Reactionsrecht Metzger, Laurin Melzig, Paul Knochel*
Ludwig-Maximilians-Universität München, Department Chemie und Biochemie,
Butenandtstr. 5-13, Haus F, 81377 München, Germany
Fax +49(89)218077680; E-mail: Paul.Knochel@cup.uni-muenchen.de
PSP
Received 11 May 2010; revised 27 May 2010
No191
Abstract: A variety of functionalized methylthio-substituted N-heterocycles (pyridines, pyrimidines, pyrazines, pyridazines, triazines,
quinazolines, benzothiazoles) undergo smooth palladium- or nickel-catalyzed cross-couplings with highly functionalized organozinc re-
agents at ambient temperature. No expensive copper(I) salts are required and the coupling reactions proceed readily in the range of up to
20 mmol scale.
Key words: zinc organometallics, cross-coupling, thioether, palladium, nickel
Procedure 1
ZnI⋅LiCl
OMe
N
OMe
N
EtO2C
(1a; 1.5 equiv)
PCy2
OMe
N
N
MeO
Pd(OAc)2 (2.5 mol%)
S-Phos (5.0 mol%)
25 °C, 3 h
MeO
N
SMe
MeO
N
CO2Et
S-Phos
3a: 86%
(20 mmol scale)
2a
Procedure 2
ZnI⋅LiCl
PPh2
PPh2
Me2N
(1b; 1.5 equiv)
O
S
N
S
N
SMe
NMe2
Ni(acac)2 (2.5 mol%)
DPE-Phos (5.0 mol%)
25 °C, 5 h
DPE-Phos
2b
4a: 85%
(20 mmol scale)
Scheme 1 Typical procedures for the cross-coupling reactions of organozinc reagents with thioether-substituted N-heterocycles using either
Pd(OAc)2/S-Phos (Procedure 1) or Ni(acac)2/DPE-Phos (Procedure 2) as catalytic system.
pling reactions is an attractive alternative due to the easy
preparation of heterocyclic thioethers as well as their
Introduction
Transition-metal-catalyzed cross-coupling reactions be- long-time stability.2 The transition-metal-catalyzed cross-
tween unsaturated halides and organometallics of Zn, Mg, coupling reactions of unsaturated thioethers as well as thi-
and B are important tools in organic chemistry for the for- ols with Grignard reagents have been pioneered by
mation of carbon–carbon bonds.1 A major drawback is Wenkert and Takei in 1979.3 They represent attractive
that halogen-substituted heterocycles, which are used as methods for converting a carbon–sulfur bond into a car-
electrophiles in such cross-coupling reactions, are some- bon–carbon bond. Although great progress in this re-
times difficult to prepare and may be unstable. Therefore, search field has been achieved by Liebeskind4 using
the use of thioether-substituted heterocycles in cross-cou- organoboronic acids as nucleophilic coupling partners,
there are still some drawbacks related to these organome-
tallic reagents.5 One is their tendency to form nonstoichi-
ometric admixtures of boroxines. Moreover, harsher
reaction conditions are usually required for Suzuki cross-
SYNTHESIS 2010, No. 16, pp 2853–2858
Advanced online publication: 01.07.2010
DOI: 10.1055/s-0030-1258145; Art ID: T10210SS
x
x.
x
x
.
2
0
1
0
© Georg Thieme Verlag Stuttgart · New York

2854
A. Metzger et al.
PRACTICAL SYNTHETIC PROCEDURES
couplings compared to the related Negishi cross-coupling 4-(ethoxycarbonyl)phenylzinc iodide (1a; 1.5 equiv) with
reactions. Furthermore, stoichiometric amounts of expen- 2,4-dimethoxy-6-(methylthio)-1,3,5-triazine (2a; 1.0
sive copper(I) salts are required to perform these cross- equiv) using Pd(OAc)2/S-Phos (2.5 mol%/5.0 mol%) as
coupling reactions.4 Organozinc reagents tolerate a broad catalytic system, which was introduced by Buchwald,9 led
range of functional groups and have a good reactivity in to the desired cross-coupling product 3a within three
the presence of appropriate catalyst, and are therefore use- hours in 86% yield on a 20 mmol scale (Procedure 1 of
ful reagents for organic synthesis.6 However, organozinc Scheme 1; see also Table 1, entries 1–5). Similarly, the
compounds are only rarely used for cross-coupling reac- cross-coupling reaction of the ester-substituted arylzinc
tions with unsaturated thioethers to date.7 Recently, we iodide 1a with 4-methyl-2-(methylthio)pyrimidine (2c)
have reported a palladium- as well as a nickel-catalyzed provided the desired pyrimidine 3b in 91% yield
cross-coupling reactions of functionalized zinc reagents (10 mmol scale; Table 1, entry 1). By using the electron-
with methylthio-substituted N-heterocycles.8 Herein, we rich arylzinc reagent 1c and the methylthio-substituted
wish to report typical practical procedures illustrating quinazoline 2d under standard reaction conditions the ex-
these methods and their applications in scaled-up proto- pected N-heterocycle 3c was obtained within five hours in
cols.
71% yield (entry 2). Moreover, these palladium-catalyzed
cross-coupling reactions proceed also well with heterocy-
clic zinc reagents. Thus, 2-thienylzinc iodide (1d) led af-
ter cross-coupling reaction with pyridazine 2e to the
diheteroaryl compound 3d (91%; entry 3).
Scope and Limitation
A variety of functionalized organozinc reagents were cou-
pled with substituted heterocycles bearing the thioether
functionality. Thus, the palladium-catalyzed reaction of
Table 1 Transition-Metal-Catalyzed Cross-Coupling Reactions of Organozinc Reagents 1 with Methylthio-Substituted N-Heterocycles 2
Entry Zinc reagenta
Electrophile
Catalytic system
Time
(h)b
Product
Yield
(%)c
ZnI⋅LiCl
N
N
Pd(OAc)2/S-Phos
(2.5 mol%/5.0 mol%)
1
18
91d
N
EtO2C
N
SMe
1a
CO2Et
2c
3b
MeO
N
MeO
MeO
2d
N
N
MeO
ZnI⋅LiCl
Pd(OAc)2/S-Phos
(2.5 mol%/5.0 mol%)
N
2
10
71
91
MeO
1c
SMe
OMe
3c
MeO
MeO
Pd(OAc)2/S-Phos
(2.5 mol%/5.0 mol%)
N
3
5
ZnI⋅LiCl
N
N
N
S
N
SMe
S
1d
2e
2e
3d
MeO
F
ZnCl⋅LiCl
ZnCl⋅LiCl
Pd(OAc)2/S-Phos
(2.5 mol%/5.0 mol%)
4
5
5
73
68
N
F
1e
3e
N
N
F3C
Pd(OAc)2/S-Phos
(2.5 mol%/5.0 mol%)
18
N
CF3
N
SMe
1f
2f
3f
Synthesis 2010, No. 16, 2853–2858 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Scaled-Up Cross-Coupling Reactions
2855
Table 1 Transition-Metal-Catalyzed Cross-Coupling Reactions of Organozinc Reagents 1 with Methylthio-Substituted N-Heterocycles 2
(continued)
Entry Zinc reagenta
Electrophile
Catalytic system
Time
(h)b
Product
Yield
(%)c
CO2Et
CO2Et
EtO2C
ZnI⋅LiCl
Ni(acac)2/DPE-Phos
(2.5 mol%/5.0 mol%)
CO2Et
6
14
91
N
N
SMe
1g
2g
4b
MeO
N
MeO
MeO
2d
N
N
MeO
Ni(acac)2/DPE-Phos
(2.5 mol%/5.0 mol%)
N
7
8
1g
18
80
SMe
EtO2C
4c
ZnI⋅LiCl
N
Ni(acac)2/DPE-Phos
(2.5 mol%/5.0 mol%)
N
18
73
N
NC
N
SMe
1h
CN
2c
4d
CO2Et
F3C
EtO2C
F3C
ZnCl⋅LiCl
Ni(acac)2/DPE-Phos
(2.5 mol%/5.0 mol%)
9
24
15
74
N
SMe
N
1i
2h
4e
N
N
OMe
ZnCl⋅LiCl
Ni(acac)2/DPE-Phos
(2.5 mol%/5.0 mol%)
10
84d
MeO
N
SMe
N
1j
4f
2f
a The zinc reagents were prepared by zinc insertion into the corresponding aromatic iodides (ref. 6d) or the benzylic chlorides (ref. 6e) in the
presence of LiCl.
b Time for the cross-coupling reaction at 25 °C.
c Yield of isolated analytically pure product.
d Reaction carried out on a 10 mmol scale.
Moreover, functionalized benzylic zinc reagents were with the nicotinic acid derivative 2g or the quinazoline 2d
successfully used in the Pd-catalyzed cross-coupling pro- furnished the functionalized products 4b,c in 91 and 80%
cedure. Thus, reaction of 4-fluorobenzylzinc chloride (1e) yield, respectively (entries 6 and 7). Similarly, 4-cy-
with pyridazine 2e provided the heterodiarylmethane 3e anophenylzinc iodide (1h) provided the 2-aryl-substituted
in 73% yield (entry 4). Similarly, 3-(trifluoromethyl)ben- pyrimidine 4d within 18 hours at 25 °C in 73% yield (en-
zylzinc chloride (1f) led after palladium-catalyzed cross- try 8). The reaction protocol was also applied to benzylic
coupling reaction with pyrazine 2f to the desired cross- zinc reagents. Thus, the nickel-catalyzed cross-coupling
coupling product 3f within 18 hours in 68% yield (entry reaction of 3-(ethoxycarbonyl)benzylzinc chloride (1i)
5). The transition-metal-catalyzed cross-coupling reaction with 2-(methylthio)-5-(trifluoromethyl)pyridine (2h) pro-
of functionalized organozinc reagents with thioether-sub- vided the functionalized pyridine 4e in 74% yield (entry
stituted heteroaromatics was modified using a nickel cat- 9). Finally, 4-methoxybenzylzinc chloride (1j) underwent
alyst lowering the cost of the catalytic system. Thus, the smooth cross-coupling with 2-(methylthio)pyrazine (2f)
reaction of 4-(N,N-dimethylamino)phenylzinc iodide (1b; leading to the 2-benzylated pyrazine 4f within 15 hours at
1.5 equiv) with 2-(methylthio)benzothiazole (2b; 1.0 25 °C in 84% yield on a 10 mmol scale reaction
equiv) in the presence of Ni(acac)2 (2.5 mol%) and DPE- (entry 10).
Phos (5.0 mol%) provided smoothly the desired cross-
coupling product 4a within five hours at 25 °C on a 20
In summary, efficient palladium- and nickel-catalyzed
cross-coupling reactions of functionalized organozinc re-
mmol scale (85%; Procedure 2 of Scheme 1; see also
agents with thioether-substituted N-heterocycles were
Table 1, entries 6–10). Furthermore, a smooth cross-cou-
demonstrated. We have extended our previous work to the
pling reaction of the ester-substituted arylzinc reagent 1g
scaled-up procedures (10–20 mmol scale). These reac-
Synthesis 2010, No. 16, 2853–2858 © Thieme Stuttgart · New York

2856
A. Metzger et al.
PRACTICAL SYNTHETIC PROCEDURES
1018 (m), 880 (m), 850 (m), 838 (m), 760 (s), 698 (m), 610 cm–1
(w).
1H NMR (300 MHz, CDCl3): d = 8.66 (d, J = 5.1 Hz, 1 H), 8.54–
8.48 (m, 2 H), 8.18–8.08 (m, 2 H), 7.08 (dd, J = 5.1 Hz, 0.5 Hz, 1
H), 4.39 (q, J = 7.1 Hz, 2 H), 2.59 (s, 3 H), 1.41 (t, J = 7.1 Hz, 3 H).
tions can be performed with standard laboratory glass-
ware and do not require the use of expensive chemicals.
Further studies are underway to extend this method.
All reactions were carried out under an argon atmosphere in dried
glassware. All 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 N2. Yields refer to isolated com-
pounds estimated to be >95% pure as determined by 1H NMR and
capillary GC analysis.
13C NMR (75 MHz, CDCl3): d = 167.6, 166.4, 163.3, 156.7, 141.6,
132.1, 129.7, 128.1, 119.1, 61.1, 24.4, 14.3.
MS (EI, 70 eV): m/z (%) = 242 (M+, 45), 214 (38), 197 (100), 169
(25), 129 (3), 102 (4).
HRMS: m/z calcd for C14H14N2O2: 242.1055; found: 242.1051.
6,7-Dimethoxy-4-(4-methoxyphenyl)quinazoline (3c)
According to GP, 6,7-dimethoxy-4-(methylthio)quinazoline (2d;
236 mg, 1.00 mmol) in THF (1 mL) was reacted with 4-methoxy-
phenylzinc iodide (1c; 1.38 mL, 1.50 mmol, 1.09 M in THF),
Pd(OAc)2 (5.6 mg, 2.5 mol%), and S-Phos (20.5 mg, 5.0 mol%).
After 10 h at 25 °C, the reaction mixture was quenched with sat. aq
Na2CO3 (10 mL), followed by extraction with EtOAc (3 × 20 mL).
Purification by flash chromatography (silica gel, Et2O–EtOH, 10:1)
afforded the quinazoline 3c (211 mg, 71%) as a white solid; mp
149–150 °C.
Transition-Metal-Catalyzed Cross-Coupling Reaction of Orga-
nozinc Reagents with Methylthio-Substituted N-Heterocycles;
General Procedure (GP)
In a dry argon-flushed Schlenk flask, equipped with a magnetic stir-
ring bar and a septum, the heteroaromatic thioether (1.0 equiv) and
Pd(OAc)2/S-Phos (2.5 mol%/5.0 mol%) or Ni(acac)2/DPE-Phos
(2.5 mol%/5.0 mol%) were dissolved in THF. After stirring for 10
min, the zinc reagent (1.5 equiv) was added dropwise and the reac-
tion mixture was stirred for the given time at the required tempera-
ture until GC-analysis of a hydrolyzed aliquot showed full
consumption of the electrophile. The reaction mixture was
quenched with sat. aq Na2CO3 and extracted with EtOAc (3 ×). The
combined organic layers were dried (Na2SO4). Evaporation of the
solvents in vacuo and purification by flash column chromatography
afforded the expected products.
IR (Diamond-ATR, neat): 1608 (m), 1571 (w), 1516 (m), 1502 (vs),
1476 (m), 1458 (m), 1445 (m), 1412 (m), 1370 (m), 1300 (w), 1257
(s), 1236 (vs), 1218 (s), 1175 (s), 1137 (s), 1025 (s), 1004 (m), 860
(m), 831 (m), 816 (m), 792 cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 9.14 (s, 1 H), 7.77–7.72 (m, 2 H),
7.37 (s, 1 H), 7.36 (s, 1 H), 7.10–7.05 (m, 2 H), 4.06 (s, 3 H), 3.91
(s, 3 H), 3.89 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 164.7, 161.0, 155.7, 153.3, 150.2,
148.9, 131.1, 129.9, 118.6, 114.1, 106.8, 104.1, 56.4, 56.1, 55.4.
MS (EI, 70 eV): m/z (%) = 297 (21), 296 (M+, 100), 295 (43), 282
(17), 281 (86), 265 (37), 264 (54), 251 (10), 250 (11), 238 (11).
Ethyl 4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)benzoate (3a)
According to GP, 2,4-dimethoxy-6-(methylthio)-1,3,5-triazine (2a;
3.74 g, 20.0 mmol) in THF (10 mL) was reacted with 4-(ethoxycar-
bonyl)phenylzinc iodide (1a; 40.5 mL, 30.0 mmol, 0.74 M in THF),
Pd(OAc)2 (112 mg, 2.5 mol%), and S-Phos (411 mg, 5.0 mol%).
After 3 h at 25 °C, the reaction mixture was quenched with sat. aq
Na2CO3 (30 mL), followed by extraction with EtOAc (3 × 50 mL).
Purification by flash chromatography (silica gel, pentane–
Et2O, 7:3) afforded the triazine 3a (4.95 g, 86%) as a yellow solid;
mp 97–98 °C.
HRMS: m/z calcd for C17H16N2O3: 296.1161; found: 296.1152.
3-Methoxy-6-(2-thienyl)pyridazine (3d)
According to GP, 3-methoxy-6-(methylthio)pyridazine (2e;
156 mg, 1.00 mmol) in THF (1 mL) was reacted with 2-thienylzinc
iodide (1d; 1.94 mL, 1.50 mmol, 0.77 M in THF), Pd(OAc)2
(5.6 mg, 2.5 mol%), and S-Phos (20.5 mg, 5.0 mol%). After 5 h at
50 °C, the reaction mixture was quenched with sat. aq Na2CO3
(25 mL), followed by extraction with EtOAc (3 × 25 mL). Purifica-
tion by flash chromatography (silica gel, EtOAc) afforded the py-
ridazine 3d (175 mg, 91%) as a white solid; mp 79–80 °C.
IR (Diamond-ATR, neat): 2990 (w), 1714 (m), 1590 (m), 1541 (vs),
1496 (s), 1457 (s), 1354 (vs), 1274 (s), 1198 (m), 1128 (m), 1102
(s), 1034 (m), 1018 (s), 940 (m), 852 (w), 820 (m), 782 (m), 718
(m), 676 cm–1 (w).
1H NMR (300 MHz, CDCl3): d = 8.53 (d, J = 8.6 Hz, 2 H), 8.13 (d,
J = 8.6 Hz, 2 H), 4.40 (q, J = 7.2 Hz, 2 H), 4.12 (s, 6 H), 1.41 (t,
J = 7.2 Hz, 3 H).
IR (Diamond-ATR, neat): 3104 (w), 3068 (w), 3001 (w), 2958 (w),
1600 (w), 1550 (w), 1528 (w), 1462 (s), 1437 (m), 1409 (m), 1334
(m), 1301 (m), 1279 (m), 1228 (m), 1110 (m), 1025 (s), 852 (m),
830 (s), 812 (m), 707 (vs), 685 cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 7.68 (d, J = 9.2 Hz, 1 H), 7.49 (dd,
J = 3.6, 1.21 Hz, 1 H), 7.40–7.37 (m, 1 H), 7.89 (dd, J = 5.1, 3.6 Hz,
1 H), 6.96 (d, J = 9.2 Hz, 1 H), 4.13 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 163.9, 151.2, 140.7, 128.1, 127.7,
125.8, 125.0, 117.7, 54.8.
MS (EI, 70 eV): m/z (%) = 192 (M+, 100), 163 (23), 121 (60), 108
(19), 77 (8), 69 (7), 45 (8).
13C NMR (75 MHz, CDCl3): d = 174.0, 173.0, 166.0, 138.9, 134.0,
129.6, 128.8, 61.3, 55.3, 14.3.
MS (EI, 70 eV): m/z (%) = 290 (17), 289 (M+, 97), 288 (21), 261
(13), 259 (27), 245 (13), 244 (100), 216 (14), 186 (18), 159 (12).
HRMS: m/z calcd for C14H15N3O4: 289.1063; found: 289.1057.
Ethyl 3-(4-Methylpyrimidin-2-yl)benzoate (3b)
According to GP, 4-methyl-2-(methylthio)pyrimidine (2c; 1.40 g,
10.0 mmol) in THF (5 mL) was reacted with 4-(ethoxycarbon-
yl)phenylzinc iodide (1a; 20.0 mL, 15.0 mmol, 0.75 M in THF),
Pd(OAc)2 (56 mg, 2.5 mol%), and S-Phos (205 mg, 5.0 mol%). Af-
ter 18 h at 25 °C, the reaction mixture was quenched with sat. aq
Na2CO3 (250 mL), followed by extraction with EtOAc
(3 × 250 mL). Purification by flash chromatography (silica gel,
pentane–Et2O, 4:1) afforded the pyrimidine 3b (2.20 g, 91%) as a
yellow solid; mp 46–48 °C.
HRMS: m/z calcd for C9H8N2OS: 192.0357; found: 192.0352.
3-(4-Fluorobenzyl)-6-methoxypyridazine (3e)
According to GP, 3-methoxy-6-(methylthio)pyridazine (2e; 156
mg, 1.00 mmol) in THF (1 mL) was reacted with 4-fluorobenzyl-
zinc chloride (1e; 1.95 mL, 1.50 mmol, 0.77 M in THF), Pd(OAc)2
(5.6 mg, 2.5 mol%), and S-Phos (20.5 mg, 5.0 mol%). After 5 h at
25 °C, the reaction mixture was quenched with sat. aq Na2CO3 (10
IR (Diamond-ATR, neat): 2986 (w), 2904 (w), 1706 (s), 1586 (m),
1568 (m), 1550 (m), 1510 (w), 1480 (w), 1430 (w), 1400 (m), 1364
(m), 1304 (w), 1266 (vs), 1126 (m), 1106 (s), 1090 (m), 1026 (m),
Synthesis 2010, No. 16, 2853–2858 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Scaled-Up Cross-Coupling Reactions
2857
mL), followed by extraction with EtOAc (3 × 20 mL). Purification
by flash chromatography (silica gel, pentane–Et2O, 3:7) afforded
the pyridazine 3e (160 mg, 73%) as a white solid; mp 72–73 °C.
Ethyl 2-[3-(Ethoxycarbonyl)phenyl]nicotinate (4b)
According to GP, ethyl 2-(methylthio)nicotinate (2g; 197 mg,
1.00 mmol) in THF (1 mL) was reacted with 3-(ethoxycarbon-
yl)phenylzinc iodide (1g; 2.24 mL, 1.50 mmol, 0.67 M in THF),
Ni(acac)2 (6.4 mg, 2.5 mol%), and DPE-Phos (26.8 mg, 5.0 mol%).
After 14 h at 25 °C, the reaction mixture was quenched with sat. aq
Na2CO3 (25 mL), followed by extraction with EtOAc (3 × 25 mL).
Purification by flash chromatography (silica gel, pentane–
EtOAc, 4:1) afforded the pyridine 4b (273 mg, 91%) as a colorless
liquid.
IR (Diamond-ATR, neat): 1596 (m), 1508 (m), 1472 (s), 1463 (s),
1418 (s), 1308 (vs), 1286 (m), 1232 (s), 1157 (w), 1090 (m), 1011
(vs), 872 (m), 845 (s), 827 (s), 788 (m), 775 (m), 604 cm–1 (w).
1H NMR (300 MHz, CDCl3): d = 7.24–7.18 (m, 2 H), 7.14 (d,
J = 9.2 Hz, 1 H), 7.01–6.93 (m, 2 H), 6.86 (d, J = 9.2 Hz, 1 H), 4.21
(s, 2 H), 4.09 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 164.0, 161.8 (d, 1JC,F = 245.1 Hz),
IR (Diamond-ATR, neat): 2982 (w), 1713 (vs), 1582 (w), 1562 (m),
1439 (m), 1420 (m), 1391 (w), 1367 (m), 1283 (s), 1245 (vs), 1207
(s), 1170 (m), 1111 (s), 1097 (s), 1056 (s), 1015 (m), 855 (w), 822
(w), 787 (m), 753 (vs), 694 cm–1 (s).
4
3
157.8, 134.2 (d, JC,F = 3.4 Hz), 130.5 (d, JC,F = 8.0 Hz), 129.5,
117.9, 115.5, (d, 2JC,F = 21.4 Hz), 54.7, 40.9.
MS (EI, 70 eV): m/z (%) = 218 (M+, 29), 217 (100), 203 (3), 161 (4),
1H NMR (300 MHz, CDCl3): d = 8.78 (dd, J = 4.7, 1.7 Hz, 1 H),
8.22–8.19 (m, 1 H), 8.17 (dd, J = 7.9, 1.7 Hz, 1 H), 8.13–8.08 (m, 1
H), 7.77–7.71 (m, 1 H), 7.55–7.47 (m, 1 H), 7.38 (dd, J = 7.9, 4.7
Hz, 1 H), 4.37 (q, J = 7.0 Hz, 2 H), 4.16 (q, J = 7.2 Hz, 2 H), 1.37
(t, J = 7.2 Hz, 3 H), 1.06 (t, J = 7.2 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 167.4, 166.2, 157.9, 151.1, 140.2,
138.3, 132.9, 130.4, 129.8, 129.8, 128.2, 127.3, 122.0, 61.6, 61.0,
14.3, 13.7.
146 (10), 133 (6), 109 (12), 83 (4), 44 (30), 43 (5).
HRMS: m/z calcd for C12H11FN2O: 218.0855; found: 218.0842.
2-[3-(Trifluoromethyl)benzyl]pyrazine (3f)
According to GP, 2-(methylthio)pyrazine (2f; 126 mg, 1.00 mmol)
in THF (1 mL) was reacted with 3-(trifluoromethyl)benzylzinc
chloride (1f; 1.03 mL, 1.50 mmol, 1.45 M in THF), Pd(OAc)2 (5.6
mg, 2.5 mol%), and S-Phos (20.5 mg, 5.0 mol%). After 18 h at
25 °C, the reaction mixture was quenched with sat. aq Na2CO3 (10
mL), followed by extraction with EtOAc (3 × 20 mL). Purification
by flash chromatography (silica gel, pentane–Et2O, 3:7) afforded
the pyrazine 3f (163 mg, 68%) as a yellow oil.
MS (EI, 70 eV): m/z (%) = 299 (M+, 16), 270 (100), 254 (37), 242
(27), 227 (28), 208 (12), 198 (14), 182 (14), 155 (18), 127 (8), 91
(5).
HRMS: m/z calcd for C17H17NO4: 299.1158; found: 299.1155.
IR (Diamond-ATR, neat): 3059 (vw), 1474 (w), 1450 (w), 1404
(w), 1326 (s), 1230 (w), 1193 (m), 1160 (s), 1117 (vs), 1093 (m),
1073 (s), 1056 (m), 1018 (s), 918 (w), 878 (w), 825 (w), 797 (m),
768 (m), 744 (w), 701 (s), 658 cm–1 (m).
1H NMR (600 MHz, CDCl3): d = 8.51 (dd, J = 2.5, 1.24 Hz, 1 H),
8.48 (d, J = 1.2 Hz, 1 H), 8.44 (d, J = 2.5 Hz, 1 H), 7.53–7.39 (m, 4
H), 4.21 (s, 2 H).
13C NMR (150 MHz, CDCl3): d = 155.4, 144.6, 144.3, 142.7, 139.0,
132.4 (q, 4JC,F = 1.3 Hz), 131.0 (q, 2JC,F = 32.2 Hz), 129.2, 125.7 (q,
3JC,F = 3.9), 124.0 (q, 1JC,F = 272.4 Hz), 123.7 (q, 3JC,F = 3.9), 41.5.
Ethyl 3-(6,7-Dimethoxyquinazolin-4-yl)benzoate (4c)
According to GP 6,7-dimethoxy-4-(methylthio)quinazoline (2d;
236 mg, 1.00 mmol) in THF (1 mL) was reacted with 3-(ethoxycar-
bonyl)phenylzinc iodide (1g; 2.31 mL, 1.50 mmol, 0.65 M in THF),
Ni(acac)2 (6.4 mg, 2.5 mol%), and DPE-Phos (26.8 mg, 5.0 mol%).
After 18 h at 25 °C, the reaction mixture was quenched with sat. aq
Na2CO3 (25 mL), followed by extraction with EtOAc (3 × 25 mL).
Purification by flash chromatography (silica gel, pentane–EtOAc–
CH2Cl2, 1:1:2) afforded the quinazoline 4c (270 mg, 80%) as a
white solid; mp 174–175 °C.
MS (EI, 70 eV): m/z (%) = 239 (7), 238 (M+, 55), 237 (100), 217
IR (Diamond-ATR, neat): = 2920 (w), 2851 (w), 1730 (s), 1617
(w), 1569 (w), 1540 (m), 1501 (vs), 1464 (m), 1427 (s), 1371 (m),
1321 (m), 1302 (m), 1261 (s), 1230 (vs), 1214 (s), 1143 (m), 1122
(m), 1080 (m), 1030 (m), 1011 (m), 974 (w), 850 (m), 753 (m),
694 cm–1 (m).
1H NMR (600 MHz, CDCl3): d = 9.20 (s, 1 H), 8.46 (t, J = 1.8 Hz,
1 H), 8.24–8.21 (m, 1 H), 7.99–7.97 (m, 1 H), 7.65 (t, J = 7.8 Hz, 1
H), 7.43 (s, 1 H), 7.27 (s, 1 H), 4.40 (q, J = 7.0 Hz, 2 H), 4.08 (s, 3
H), 3.89 (s, 3 H), 1.38 (t, J = 7.1 Hz, 3 H).
(15), 168 (10), 85 (14), 71 (18), 57 (21), 55 (7), 43 (11).
HRMS: m/z calcd for C12H9F3N2: 238.0718; found: 238.0712.
4-(1,3-Benzothiazol-2-yl)-N,N-dimethylaniline (4a)
According to GP, 2-(methylthio)benzothiazole (2b; 3.63 g, 20.0
mmol) in THF (10 mL) was reacted with 4-(N,N-dimethylami-
no)phenylzinc iodide (1b; 34.9 mL, 30.0 mmol, 0.86 M in THF),
Ni(acac)2 (129 mg, 2.5 mol%), and DPE-Phos (539 mg, 5.0 mol%).
After 5 h at 25 °C, the reaction mixture was quenched with sat. aq
Na2CO3 (25 mL), followed by extraction with EtOAc (3 × 25 mL).
Purification by flash chromatography (silica gel, pentane–
Et2O, 8:2) afforded the pyridine 4a (4.30 g, 85%) as a light brown
solid; mp 173–175 °C.
13C NMR (150 MHz, CDCl3): d = 165.9, 164.0, 156.1, 153.2, 150.7,
148.9, 137.8, 133.7, 131.1, 130.8, 130.6, 129.0, 118.6, 106.8, 103.5,
61.3, 56.5, 56.1, 14.3.
MS (EI, 70 eV): m/z (%) = 338 (M+, 100), 323 (22), 309 (22), 277
IR (Diamond-ATR, neat): 1608 (vs), 1556 (m), 1514 (m), 1480 (s),
1454 (m), 1430 (s), 1368 (s), 1314 (m), 1228 (s), 1186 (s), 1126 (m),
1062 (m), 964 (m), 942 (m), 816 (vs), 800 (m), 750 (s), 718 (s), 688
cm–1 (m).
1H NMR (600 MHz, CDCl3): d = 8.00–7.93 (m, 3 H), 7.83 (d,
J = 7.39 Hz, 1 H) 7.46–7.40 (m, 1 H), 7.32–7.27 (m, 1 H), 6.75–
6.70 (m, 2 H), 3.02 (s, 6 H).
13C NMR (150 MHz, CDCl3): d = 168.7, 154.3, 152.1, 134.5, 128.8,
125.9, 124.1, 122.2, 121.4, 121.3, 111.6, 40.1.
MS (EI, 70 eV): m/z (%) = 256 (4), 255 (15), 254 (M+, 100), 253
(37), 239 (13), 238 (8), 237 (2), 210 (4), 127 (4), 126 (5).
(24), 265 (20), 249 (8), 221 (13), 192 (6), 147 (5), 84 (8).
HRMS: m/z calcd for C19H18N2O4: 338.1267; found: 338.1265.
4-(4-Methylpyrimidin-2-yl)benzonitrile (4d)
According to GP, 4-methyl-2-(methylthio)pyrimidine (2c; 140 mg,
1.00 mmol) in THF (1 mL) was reacted with 4-cyanophenylzinc io-
dide (1h; 2.31 mL, 1.50 mmol, 0.65 M in THF), Ni(acac)2 (6.4 mg,
2.5 mol%), and DPE-Phos (26.8 mg, 5.0 mol%). After 18 h at
25 °C, the reaction mixture was quenched with sat. aq Na2CO3
(25 mL), followed by extraction using EtOAc (3 × 25 mL). Purifi-
cation by flash chromatography (silica gel, pentane–Et2O–
EtOAc, 2:6:1) afforded the pyrimidine 4d (143 mg, 73%) as a white
solid; mp 191–193 °C.
HRMS: m/z calcd for C15H14N2S: 254.0878; found: 254.0876.
Synthesis 2010, No. 16, 2853–2858 © Thieme Stuttgart · New York

2858
A. Metzger et al.
PRACTICAL SYNTHETIC PROCEDURES
Acknowledgment
IR (Diamond-ATR, neat): 3047 (w), 2224 (w), 1678 (w), 1606 (w),
1583 (s), 1550 (s), 1378 (s), 1288 (m), 1254 (w), 1197 (w), 1108
(w), 1018 (w), 994 (w), 949 (w), 868 (m), 860 (m), 836 (vs), 789
(vs), 706 cm–1 (w).
1H NMR (300 MHz, CDCl3): d = 8.66 (d, J = 5.2 Hz, 1 H), 8.60–
8.52 (m, 2 H), 7.78–7.71 (m, 2 H), 7.11 (d, J = 5.6 Hz, 1 H), 2.59 (s,
3 H).
13C NMR (75 MHz, CDCl3): d = 167.7, 162.4, 156.9, 141.8, 132.3,
128.6, 119.5, 118.8, 113.8, 24.3.
MS (EI, 70 eV): m/z (%) = 195 (M+, 100), 180 (13), 128 (29), 101
(5), 67 (5).
We thank the DFG and the European Research Council (ERC) for
financial support. We thank Chemetall GmbH (Frankfurt) and
BASF SE (Ludwigshafen) for the generous gift of chemicals.
References
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de Meijere, A.; Diederich, F., Eds.; Wiley-VCH: Weinheim,
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HRMS: m/z calcd C12H9N3: 195.0796; found: 195.0796.
Ethyl 3-{[5-(Trifluoromethyl)pyridin-2-yl]methyl}benzoate
(4e)
According to GP, 2-(methylthio)-5-(trifluoromethyl)pyridine (2h;
193 mg, 1.00 mmol) in THF (1 mL) was reacted with 3-(ethoxycar-
bonyl)benzylzinc chloride (1i; 1.19 mL, 1.50 mmol, 1.26 M in
THF), Ni(acac)2 (6.4 mg, 2.5 mol%), and DPE-Phos (26.8 mg,
5.0 mol%). After 24 h at 25 °C, the reaction mixture was quenched
with sat. aq Na2CO3 (25 mL) followed by extraction with EtOAc
(3 × 25 mL). Purification by flash chromatography (silica gel, pen-
tane–Et2O, 9:1) afforded the pyridine 4e (230 mg, 74%) as a color-
less liquid.
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1447. (d) Wenkert, E.; Ferreira, T. W. J. Chem. Soc., Chem.
Commun. 1982, 840.
IR (Diamond-ATR, neat): 2984 (vw), 1715 (s), 1605 (m), 1574 (w),
1490 (w), 1445 (w), 1392 (w), 1368 (w), 1326 (vs), 1277 (s), 1192
(s), 1164 (m), 1123 (vs), 1105 (s), 1077 (vs), 1016 (s), 944 (w), 860
(w), 836 (w), 742 (s), 695 (m), 673 (w), 650 cm–1 (w).
1H NMR (300 MHz, CDCl3): d = 8.82–8.79 (m, 1 H), 7.97–7.89 (m,
2 H), 7.81 (dd, J = 8.1, 2.4 Hz, 1 H), 7.48–7.42 (m, 1 H), 7.38 (t,
J = 7.6 Hz, 1 H), 7.24 (d, J = 9.0 Hz, 1 H), 4.35 (q, J = 7.2 Hz, 2 H),
4.26 (s, 2 H), 1.37 (t, J = 7.2 Hz, 3 H).
(4) (a) Liebeskind, L. S.; Srogl, J. Org. Lett. 2002, 4, 979.
(b) Kusturin, C.; Liebeskind, L. S.; Rahman, H.; Sample, K.;
Schweitzer, B.; Srogl, J.; Neumann, W. L. Org. Lett. 2003,
5, 4349. (c) Prokopcova, H.; Kappe, C. O. J. Org. Chem.
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organostannanes, see: Egi, M.; Liebeskind, L. S. Org. Lett.
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4
13C NMR (75 MHz, CDCl3): d = 166.4, 164.3 (q, JC,F = 1.4 Hz),
3
3
146.3 (q, JC,F = 4.0 Hz), 138.6, 133.8 (q, JC,F = 3.4 Hz), 133.6,
2
131.0, 130.2, 128.8, 128.1, 124.6 (q, JC,F = 33.0 Hz), 123.6 (q,
1JC,F = 272.1 Hz), 122.8, 61.0, 44.3, 14.3.
(5) (a) Watanabe, T.; Miyaura, N.; Suzuki, A. Synlett 1992,
207. (b) Miyaura, N. Advances in Metal-Organic Chemistry,
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Org. React. 2001, 58, 417. (c) Organozinc Reagents;
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A.; Knochel, P. Angew. Chem. Int. Ed. 2006, 45, 6040.
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2000, 905. (b) Lee, K.; Counceller, C. M.; Stambuli, J. P.
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MS (EI, 70 eV): m/z (%) = 309 (M+, 41), 308 (100), 290 (11), 280
(93), 264 (44), 235 (86), 208 (16), 167 (32), 132 (13), 118 (11), 44
(21).
HRMS: m/z calcd for C16H14F3NO2: 309.0977; found: 309.0957.
2-(4-Methoxybenzyl)pyrazine (4f)
According to GP, 2-(methylthio)pyrazine (2f; 1.26 g, 10.0 mmol) in
THF (5 mL) was reacted with 4-methoxybenzylzinc chloride (1j;
20.8 mL, 15.0 mmol, 0.72 M in THF), Ni(acac)2 (64 mg,
2.5 mol%), and DPE-Phos (268 mg, 5.0 mol%). After 15 h at
25 °C, the reaction mixture was quenched with sat. aq Na2CO3
(250 mL), followed by extraction with EtOAc (3 × 250 mL). Puri-
fication by flash chromatography (silica gel, pentane–Et2O, 1:4) af-
forded the pyrazine 4f (1.69 g, 84%) as a yellow liquid.
IR (Diamond-ATR, neat): 3004 (w), 2956 (w), 2932 (w), 2908 (w),
2836 (w), 1610 (m), 1584 (w), 1510 (vs), 1472 (m), 1440 (w), 1400
(m), 1300 (m), 1246 (vs), 1176 (s), 1126 (m), 1104 (w), 1056 (m),
1032 (s), 1018 (s), 808 (s), 772 (m), 648 cm–1 (w).
1H NMR (300 MHz, CDCl3): d = 8.48 (dd, J = 2.5, 1.6 Hz, 1 H),
8.44 (d, J = 1.7 Hz, 1 H), 8.38 (d, J = 2.6 Hz, 1 H), 7.21–7.14 (m, 2
H), 6.87–6.81 (m, 2 H), 4.10 (s, 2 H), 3.76 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 158.4, 156.8, 144.6, 144.0, 142.2,
130.1, 130.0, 114.2, 55.2, 41.1.
MS (EI, 70 eV): m/z (%) = 200 (M+; 100), 185 (31), 157 (7), 121
(42), 77 (5).
(8) (a) Metzger, A.; Melzig, L.; Despotopoulou, C.; Knochel, P.
Org. Lett. 2009, 11, 4228. (b) Melzig, L.; Metzger, A.;
Knochel, P. J. Org. Chem. 2010, 75, 2131.
(9) (a) Charles, M. D.; Schultz, P.; Buchwald, S. L. Org. Lett.
2005, 7, 3965. (b) Anderson, K. W.; Tundel, R. E.; Ikawa,
T.; Altman, R. A.; Buchwald, S. L. Angew. Chem. Int. Ed.
2006, 45, 6523.
HRMS: m/z calcd for C12H12N2O: 200.0950; found: 200.0940.
Synthesis 2010, No. 16, 2853–2858 © Thieme Stuttgart · New York