Arylzinc species by microwave assisted Grignard formation-transmetallation sequence: Application in the Negishi coupling

Article abstract of DOI:10.1016/j.tet.2005.09.022

Arylmagnesium species can be efficiently generated from magnesium turnings and aryl chlorides or aryl bromides under dielectric heating conditions. Subsequent microwave assisted transmetallation using ZnCl₂-TMEDA afforded the corresponding arylzinc reagents. A sequential microwave assisted arylmagnesium formation-transmetallation-Negishi coupling protocol suitable for automated multiple parallel synthesis has been developed.

Full text of DOI:10.1016/j.tet.2005.09.022

Tetrahedron 61 (2005) 11168–11176
Arylzinc species by microwave assisted Grignard formation–
transmetallation sequence: application in the Negishi coupling
*
Ilga Mutule and Edgars Suna
Latvian Institute of Organic Synthesis, LV 1006 Riga, Latvia
Received 9 June 2005; revised 30 August 2005; accepted 8 September 2005
Available online 29 September 2005
Abstract—Arylmagnesium species can be efficiently generated from magnesium turnings and aryl chlorides or aryl bromides under
dielectric heating conditions. Subsequent microwave assisted transmetallation using ZnCl2–TMEDA afforded the corresponding arylzinc
reagents. A sequential microwave assisted arylmagnesium formation–transmetallation–Negishi coupling protocol suitable for automated
multiple parallel synthesis has been developed.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
under microwave conditions using readily available and
air-stable Zn–Cu couple.4 Unfortunately, our approach is
limited to the use of aryl iodides, as aryl bromides and
chlorides do not react with Zn–Cu couple. To expand the
scope of substrates in a microwave assisted synthesis, we
considered the use of a more reactive metal such as
magnesium. Transmetallation of the resulting organo-
magnesium reagent would afford organozinc species.
Herein, we report a convenient synthesis of arylzinc species
from aryl chlorides and bromides via a microwave assisted
Grignard generation5–transmetallation sequence.
During the last decade microwave dielectric heating has
developed into a convenient and widely used tool in organic
synthesis.1 Frequently observed acceleration of reaction
speed combined with the apparent ease of automation
renders the microwave methodology particularly useful in
the development of new drugs. The advantages of dielectric
heating in the Negishi C–C bond forming reaction
(a powerful means for construction of biaryl bond, which
is frequently found in a range of pharmaceuticals, natural
products and ligands) have already been demonstrated.2
However, the organozinc reagents for the desired Negishi
coupling have usually been prepared under conventional
conditions. Therefore, fast and operationally simple
microwave assisted arylzinc preparation procedure for the
subsequent Negishi cross-coupling is highly desirable,
especially for automated multiple parallel synthesis.
2. Microwave assisted generation of aryl magnesium
bromides
The formation of the Grignard reagents usually proceeds by
reaction of magnesium with the corresponding halide. The
success of the reaction depends critically on its initiation
and prior activation of magnesium surface usually is
necessary to start the reaction. Among various magnesium
activation methods, the most frequently employed are
overnight dry stirring in inert atmosphere,6 addition of
iodine or dibromoethane,7 chemical generation of activated
magnesium from Mg–anthracene complex8 as well as in situ
reduction of magnesium chloride using potassium.9
Notably, under microwave dielectric heating conditions,
Grignard species were readily formed from aryl bromides
without prior activation of magnesium.10 Thus, microwave
heating of bromobenzene and magnesium turnings11 in
THF12 at 80 8C for 10 min resulted in the formation of
characteristic metallic-gray solution of phenylmagnesium
bromide. Carbon dioxide was used as a quenching agent to
Recently, Kappe has demonstrated the microwave assisted
preparation of arylzinc species from Rieke zinc.3 The
methodology benefits from short reaction times and utilizes
aryl bromides along with aryl iodides as the starting
materials. However, the necessity to employ the highly
reactive Rieke zinc suspension hampers its use in automated
microwave systems, especially in those, equipped with
liquid handling tools. Moreover, aryl chlorides apparently
are unreactive under the reported conditions. As an
alternative, we reported the generation of arylzinc species
Keywords: Microwaves; Grignard reagents; Organozinc reagents; Trans-
metallation; Negishi coupling.
Corresponding author. Tel.:C371 755 32 37; fax: C371 755 31 42;
e-mail: edgars@osi.lv
*
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.09.022

I. Mutule, E. Suna / Tetrahedron 61 (2005) 11168–11176
Table 1. Microwave assisted preparation of arylmagnesium bromides
11169
Entry
1
Aryl halide
Time (min)
10
Temperature (8C)
Yield of ArCO2H 2 (%)a
80
88 (2a)
88 (2b)
1a
1b
2
3
20
20
80
80
71 (2c)
74 (2d)
1c
4
20
80
1d
5
6
7
20
15
30
80
83 (2e)
87 (2f)
84 (2g)
1e
1f
80
120
1g
1h
8
10
80
88 (2h)
a Reactions were carried out using 2.2 mmol of Mg turnings and 2.0 mmol of aryl bromide in dry THF (2.0 mL); isolated yields represent an average of two
runs.
establish yields of the formed Grignard reagent.13 After
extractive workup, benzoic acid was isolated in 88% yield
(Table 1, entry 1).
species. Furthermore, the Grignard formation suffered from
low reproducibility.
Table 1 illustrates the scope of the procedure. Generally, a
temperature of 60 8C was sufficient to initiate the exotherm
of the Grignard formation (see Fig. 1 for a typical
temperature profile at 60 8C). Upon initiation of the
exotherm, the temperature rose to 30 8C above the adjusted
60 8C and the microwave power was instantaneously cut-off
by the temperature control system.14 The subsequent
formation of Grignard reagent occurred without microwave
irradiation until the temperature decreased back to 60 8C,
whereupon it was maintained by the dielectric heating. As
seen from Figure 1, temperature control during the reaction
allows to estimate time, necessary to initiate the Grignard
reaction. Thus, the exotherm of Grignard formation started
already after ca. 80 s at 60 8C in the case of aryl bromide 1b,
while the less reactive substrate 1c required microwave
heating for ca. 240 s to initiate the reaction. Consequently,
reluctant electron-rich aryl bromides were employed to
demonstrate the advantages of dielectric heating. Thus,
Grignard reagents were readily formed from aryl bromides
1b–c possessing electron donating substituents (entries 2
and 3) after microwave heating for 10–20 min at 80 8C.15
Higher temperature and longer time was necessary in the
case of even less reactive 5-bromoindole 1g (entry 7).
Selective formation of 4-chloro-phenylmagnesium bromide
Concentration of the aryl bromide was found to be critical
and the best yields of phenylmagnesium bromide were
obtained using ca. 1 M solution of the starting bromide in
THF. The use of lower concentrations (0.25 M) required
elevated temperature (up to 160 8C) and prolonged time
(30 min) to bring about the formation of arylmagnesium
Figure 1. Temperature profiles for the Grignard formation from aryl
bromides 1b–c and 1e (see entries 2, 3, and 5, Table 1) in THF at 60 8C.

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I. Mutule, E. Suna / Tetrahedron 61 (2005) 11168–11176
substantially improve the absorption of microwave energy
by the non-polar solvent.17 Indeed, addition of 0.5 M THF
solution of MgBr218 to a 1 M solution of chlorobenzene 3a
in THF resulted in much faster heating rate compared to the
analogous process without the salt additive (see Fig. 2).19
Disappointingly, non-activated magnesium turnings did not
react with aryl chlorides even after 15 min at 180 8C
suggesting that activation of metal surface is necessary to
bring about the oxidative magnesiation of aryl chlorides.
Among various activation methods examined, the use of
1,2-dibromoethane (DBE) was the most advantageous. The
addition of DBE resulted not only in the activation of mag-
nesium surface,7 but also in the in situ formation of MgBr2
solution in THF. The presence of salt substantially improved
absorption of microwaves by the reaction media, thus
allowing to perform reactions at temperatures up to 200 8C.
Figure 2. Dielectric heating profiles for a 1 M solution of chlorobenzene 3a
in THF with and without added 0.5 M MgBr2 in THF.
(entry 8) was possible, as aryl chloride was completely
unreactive at 80 8C.
Aryl chlorides possessing electron donating substituents
(substrates, which traditionally are regarded as difficult
substrates for the direct oxidative addition to magnesium)20
where chosen to demonstrate the scope of the developed
procedure. Carbon dioxide was used as a quenching agent
and yields of isolated benzoic acids represented yields of
the formed Grignard reagent.13 As seen from Table 2,
arylmagnesium species were efficiently formed from
reluctant aryl chlorides (entries 1 and 2, Table 3) as well
as from thienyl chloride 3f (entry 4).21 Indolyl chlorides 3g
and 3i (entries 5 and 6) and aryl chloride 3c (entry 3)
required heating at 200 8C for 30 min to form the Grignard
species. The most important side reaction was formation of
biaryls.
3. Microwave assisted preparation of Grignard regents
from aryl chlorides
High temperatures (140–180 8C) were initially applied to
bring about the reaction of non-activated magnesium
turnings with aryl chlorides. Unfortunately, heating above
140 8C of a 1 M solution of chlorobenzene 3a in a relatively
non-polar THF as a solvent16 required prolonged appli-
cation of the maximum irradiation power (300 W). This
frequently resulted in the overheating of the microwave
equipment and subsequent cut-off of the microwave energy.
Meantime, the use of salt additives was shown to
Table 2. Microwave assisted preparation of arylmagnesium chlorides
Entry
1
Aryl chloride
Time (min)
15
Temperature (8C)
Yield of ArCO2H 2 (%)a
81 (2a)
180
3a
3b
2
3
15
30
180
200
70 (2b)
72 (2c)
3c
3f
4
5
15
30
180
200
82 (2f)
48 (2g)
3g
3i
6
30
200
76 (2i)
a Reactions were carried out in THF (2.0 mL) using 3.5 mmol of Mg turnings, 2.0 mmol of aryl chloride and 1.0 mmol of 1,2-dibromoethane as additive; yields
of isolated products represent an average of two runs.

I. Mutule, E. Suna / Tetrahedron 61 (2005) 11168–11176
11171
Table 3. Microwave assisted preparation of arylzinc reagents and the Negishi cross-coupling
Entry
1
Arylzinc source
Product
Solvent
THF
Conditions
5 min, rt
Yield (%)a
81
1b
7
8
2
THF/DMF 1:1
2 min, 80 8C
76
3
4
THF
THF
2 min, 80 8C
2 min, 120 8C
88
86
1c
9
1d
1e
10
5
6
THF/DMF 1:2
THF
10 min, 80 8C
2 min, 80 8C
82
73
11
12
1g
7
THF
3 min, 120 8C
83
13
14
8
9
THF/DMF 1:1
THF
2 min, 80 8C
30 min, 80 8C
68
83
1h
3b
15
7
10
11
THF
THF
5 min, rt
87
92
2 min, 120 8C
16
17
12
13
THF
THF
2 min, 120 8C
2 min, 80 8C
81
92
3c
3f
18
14
15
THF
THF
2 min, 120 8C
2 min, 80 8C
70
64
3g
3i
19
20
a Yields of isolated products were calculated based on cross-coupling partner—bromo-arene (0.7 mmol). 1.1 mL of arylzinc reagent (0.7–0.9 mmol) was
employed in the Negishi cross-coupling reaction.

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4. Transmetallation of arylmagnesium to arylzinc
species
solvent was found to be beneficial because in pure THF the
reaction did not go to completion.
With efficient protocol for arylmagnesium generation in
hand, the transmetallation to the arylzinc species was
addressed. In a model study, phenylmagnesium bromide 1b
was transmetallated to phenylzinc reagent 4b (Scheme 1).
Given that the Negishi cross-coupling reaction of arylzinc
species with bromoarenes could be performed highly
chemoselectively in the presence of an aldehyde moiety22
the transmetallation reaction mixture was treated with
4-bromobenzaldehyde 5 (1 equiv) and (Ph3P)2PdCl2
(3 mol%) at room temperature for 5 min. Yields of biphenyl
aldehyde 7 reflected the chemical outcome of the
transmetallation product 4, while the amount of the
remaining Grignard reagent could be determined based on
the yields of alcohol 6.23
6. Conclusions
In summary, we have shown that arylmagnesium species
can be efficiently generated directly from magnesium
turnings and aryl chlorides or aryl bromides under dielectric
heating conditions. Grignard species were readily formed
from aryl bromides without prior activation of magnesium.
Generation of arylmagnesium reagents from aryl chloride
required activation of magnesium surface by in situ addition
of dibromoethane. A convenient procedure for microwave-
assisted generation of arylzinc species from aryl bromides
and aryl chlorides via Grignard formation–transmetallation
sequence has been developed. The methodology comple-
ments previously reported approach for arylzinc generation
from aryl iodides and Zn–Cu couple in a microwave
environment.4 To demonstrate the suitability of the
developed methodology for parallel high-throughput
organic synthesis, a sequential arylzinc formation–Negishi
cross coupling protocol has been designed.
7. Experimental
7.1. General
Scheme 1. Model study of the transmetallation reaction.
24
Reaction of Grignard reagent with ZnCl2 resulted in the
Microwave heating was performed on a purpose-built Smith
Synthesizer by Personal Chemistry (Uppsala, Sweden) with
a monomode cavity and temperature control. Melting points
were obtained on an OptiMelt apparatus and are uncor-
complete transmetallation after dielectric heating at 80 8C
for 15 min. However, the separation of the resulting solution
of phenylzinc chloride 4 from bulk precipitate of inorganic
salts was difficult. Meanwhile, the use of ZnCl2–TMEDA
complex25 also brought about the quantitative formation of
arylzinc chloride after 15 min at 80 8C. In this case, the
phenylzinc reagent was obtained as a slightly cloudy
solution and therefore could be easily handled. Conse-
quently, all transmetallation reactions were carried out
using ZnCl2–TMEDA complex.
1
rected. H and 13C NMR spectra were observed on Varian
Mercury 200 spectrometer with tetramethylsilane as an
internal standard. Column chromatography was performed
with Acros silica gel, (0.06–0.2 mm). Reactions were
monitored by thin-layer chromatography on Merck
Kieselgel 60F254
.
7.2. General procedure for the generation of Grignard
reagents from aryl bromides
5. The Negishi cross-coupling
An oven dried Emryse MW process vial (2–5 mL)
equipped with a Teflon-coated stirring bar was charged
with magnesium turnings (Acros, 53.5 mg, 2.2 mmol) and
aryl bromide (if solid at room temperature, 2.0 mmol),
flushed with argon and closed using an aluminum open-top
seal with PTFE-faced septum. Dry THF (2 mL) and aryl
bromide (if liquid at room temperature, 2.0 mmol) were
introduced via a syringe and the reaction mixture was
microwave-irradiated for the appropriate time and tempera-
ture, affording intensely colored (usually metallic gray or
brown) solution of the Grignard reagent.
To demonstrate the suitability of the developed method-
ology for automated multiple parallel synthesis, the design
of a sequential microwave assisted arylmagnesium forma-
tion—transmetallation—Negishi coupling protocol was
carried out. The Negishi cross-coupling between arylzinc
reagent 4b and bromobenzaldehyde 5 readily occurred at
room temperature (see the transmetallation step above; see
also entries 1 and 10, Table 3).26 The cross-coupling with
other aryl bromides, however, required higher temperatures.
Thus, the formation of esters 9, 12, and 18 (entries 3, 6, 13,
and 15) was completed after heating at 80 8C for 2 min,
while biaryl nitriles 10, 16, 17 and 19 (entries 4, 11, 12, and
14) required microwave heating at 120 8C for 2 min. Aryl
chlorides did not react under the Negishi conditions
and 2-chloro-bromobenzene selectively cross-coupled via
bromide, affording 5-aryl indole 13 (entry 7). Formation of
indole-2-carboxylic ester required prolonged heating
(30 min) at 80 8C (entry 9). In case of bromo-ketones
(entries 2, 5, and 8), the use of THF–DMF mixture as
7.3. General procedure for preparation of Grignard
reagents from aryl chlorides
An oven dried Emryse MW process vial (2–5 mL) equipped
with a Teflon-coated stirring bar was charged with
magnesium turnings (85.1 mg, 3.5 mmol) and aryl chloride
(if solid at room temperature, 2.0 mmol), flushed with
argon and closed using an aluminum open-top seal with

I. Mutule, E. Suna / Tetrahedron 61 (2005) 11168–11176
11173
PTFE-faced septum. Dry THF (2 mL) and aryl chloride (if
liquid at room temperature, 2.0 mmol) were introduced via
syringe, followed by 1,2-dibromoethane (86 mL, 1.0 mmol).
The reaction mixture was microwave-irradiated for the
appropriate time and temperature, affording intensely
colored (usually metallic gray or brown) solution of the
Grignard reagent.
whereupon the arylzinc solution (1.1 mL) from above was
introduced via cannula. The reaction was stirred at room
temperature or heated by microwaves (see Table 3), then
diluted with EtOAc (5 mL) and filtered through a Celite
plug (2!2 cm) with an EtOAc rinse. After solvent removal
(rotary evaporator) the residue was purified by flash column
chromatography on silica gel.
40-Methoxy-biphenyl-4-carbaldehyde (7) was isolated via
the sulfite adduct.
7.4. General procedure for isolation of arylcarboxylic
acids
7.6.1. 40-Methoxy-biphenyl-4-carbaldehyde (7). EtOH
(0.5 mL) and saturated NaHSO3 solution (0.5 mL) was
added to the reaction mixture and after vigorous shaking
(vortex) for 5 min, the formed precipitate was filtered off
and washed with EtOH (5 mL). The wet solid was
suspended in 4 N HCl (20 mL) and EtOAc (30 mL) and
stirred until clear biphasic solution formed. Layers were
separated and acidic solution was washed with EtOAc (3!
15 mL). The combined organic extracts were washed with
saturated NaHCO3 solution, brine and dried (Na2SO4).
Filtration and solvent removal (aspirator) afforded aldehyde
8 (122 mg, 81%) as white crystals, mp 101–102 8C. (lit.
101.5–102 8C).28 Analytical TLC on silica gel, 9:1
petroleum ether/EtOAc, RfZ0.24; IR (Nujol, cmK1) 1688
Sealed Emryse MW process vial containing solution of
arylmagnesium halide was cooled to 1 8C (crushed ice) and
a stream of dry CO2 (generated from ‘dry ice’ and dried by
passing through concentrated sulfuric acid) was introduced
via cannula for 5 min. Then, 4 N HCl (1.0 mL) was added to
the resulting mixture (caution! intense evolution of
hydrogen!) and after the gas evolution was ceased, the
reaction mixture was poured into 20 mL of 1 N HCl and
extracted with MeOtBu (4!10 mL). Combined organic
extracts were washed with 1 N NaOH solution (3!10 mL)
and basic extracts were acidified by careful addition of
concentrated HCl to pHw1.27 After extraction with
MeOtBu (3!10 mL), washing with brine and drying
(Na2SO4), solvent was removed in vacuo (aspirator) to
afford crystalline residue. After additional drying in vacuo
(0.1 Torr) for 1 h, analytically pure product was obtained.
1
C]O; 200 MHz H NMR (CDCl3, ppm) d 10.04 (1H, s)
7.96–7.90 (2H, m) 7.74–7.69 (2H, m) 7.63–7.56 (2H, m)
7.05–6.97 (2H, m) 3.87 (3H, s); GC–MS m/z (% relative
intensity, ion): 212 (100, M) 197 (15) 169 (18) 152 (14) 139
(48) 115 (39).
7.5. Characterization data for representative carboxylic
acids
7.5.1. 1-Methyl-1H-indole-5-carboxylic acid (2g). Brown
crystals, mp 214–215 8C (decomp.) 200 MHz 1H NMR
(DMSO-d6, ppm) d 12.44 (1H, br s) 8.22 (1H, d, JZ1.4 Hz)
7.75 (1H, dd, JZ8.6, 1.4 Hz) 7.48 (1H, d, JZ8.6 Hz) 7.41
(1H, d, JZ3.0 Hz) 6.56 (1H, d, JZ3.0 Hz) 3.80 (3H, s).
7.6.2. 1-(40-Methoxy-biphenyl-4-yl)-ethanone (8).
Following general procedure, 1-bromo-4-methoxy-benzene
1b was converted into arylzinc reagent and cross-coupled
with 1-(4-bromo-phenyl)-ethanone. Purification of the
crude product by column chromatography (75 mL silica
gel, column i.d. 30 mm) using 10% EtOAc in petroleum
ether afforded 122 mg (76%) of white solid; analytical TLC
on silica gel, 1:9 EtOAc/petroleum ether, RfZ0.30. Pure
material was obtained by crystallization from EtOAc/
petroleum ether, mp 156–158 8C, colorless plates (lit.29
153.5–155 8C); IR (Nujol, cmK1) 1678 C]O; 200 MHz 1H
NMR (CDCl3, ppm) d 8.05–7.96 (2H, m) 7.69–7.53 (4H, m)
7.05–6.95 (2H, m) 3.86 (3H, s) 2.62 (3H, s); GC–MS m/z
(% relative intensity, ion): 226 (50, M) 211 (100, MKCH3)
183 (10) 168 (30) 152 (24) 140 (40) 139 (76).
7.5.2. 1-Methyl-1H-indole-6-carboxylic acid (2i). Yellow
solid, mp 189–190 8C (decomp.); 200 MHz 1H NMR
(CDCl3, ppm) d 12.20 (1H, br s) 7.90 (1H, dd, JZ8.4,
0.9 Hz) 7.68 (1H,d, JZ8.4 Hz) 7.25 (1H, d, JZ2.8 Hz) 6.55
(1H, dd, JZ2.8, 0.9 Hz) 3.89 (3H, s).
7.6. General procedure for transmetallation-Negishi
cross-coupling
An oven dried Emryse MW process vial (2–5 mL)
equipped with a Teflon-coated stirring bar was charged
with ZnCl2–TMEDA (518 mg, 2.05 mmol), flushed with
argon and closed using an aluminum open-top seal with
PTFE-faced septum. A solution of Grignard reagent
(prepared as described above) was added via cannula to
the ZnCl2–TMEDA and the resulting mixture was heated by
microwaves at 80 8C for 15 min yielding slightly cloudy
solution of arylzinc reagent.
7.6.3. 40-Dimethylamino-biphenyl-2-carboxylic acid
ethyl ester (9). Following general procedure, 4-bromo-
N,N-dimethylaminobenzene 1c was converted into arylzinc
reagent and cross-coupled with 2-bromo-benzoic acid ethyl
ester. Purification of the crude product by column
chromatography (150 mL silica gel, column i.d. 50 mm)
using CH2Cl2 afforded 165 mg (88%) of pale yellow liquid;
analytical TLC on silica gel, 1:9 EtOAc/petroleum ether,
RfZ0.30; IR (Nujol, cmK1) 1720 C]O; 200 MHz 1H NMR
(CDCl3, ppm) d 7.78–7.70 (1H, m) 7. 53–7. 18 (5H, m)
6.86–6.72 (2H, m) 4.18 (2H, q) 3.00 (6H, s) 1.12 (3H, t); 13C
NMR (50 MHz, CDCl3, ppm) d 169.7, 150.1, 142.5, 131.6,
131.2, 130.7, 129.7, 129.4, 126.4, 112.5, 61.0, 40.8, 14.2;
GC–MS m/z (% relative intensity, ion): 269 (100, M) 240
(40, MKC2H5) 224 (11) 180 (10) 152 (22).
An oven dried Emryse MW process vial (2–5 mL)
equipped with a Teflon-coated stirring bar was charged
with Pd(PPh3)2Cl2 (21 mg, 0.03 mmol), aryl bromide
(0.7 mmol) and solvent (1.0 mL; see Table 3 for the
appropriate solvent), flushed with argon and closed using
an aluminum open-top seal with PTFE-faced septum. The
contents of the vial were stirred intensely for 2 min

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7.6.4. 20,40,60-Trimethyl-biphenyl-2-carbonitrile (10).
Following general procedure, 2-bromo-1,3,5-trimethyl-
benzene 1d was converted into arylzinc reagent and cross-
coupled with 2-bromo-benzonitrile. Purification of the
crude product by column chromatography (100 mL silica
gel, column i.d. 30 mm) using gradient elution from 2%
EtOAc/petroleum ether to 10% EtOAc/petroleum ether
afforded 133 mg (86%) of solid material; analytical TLC on
silica gel, 1:9 EtOAc/petroleum ether, RfZ0.60. Pure
material was obtained by crystallization from EtOAc/
petroleum ether, mp 91–92 8C, colorless prisms; IR
Following general procedure, 5-bromo-1-methyl-1H-indole
1g was converted into arylzinc reagent and cross-coupled
with 1-bromo-2-chlorobenzene. Purification of the crude
product by column chromatography (100 mL silica gel,
column i.d. 35 mm) using gradient elution from 0.5%
CH2Cl2/petroleum ether to 25% CH2Cl2/petroleum ether
afforded 140 mg (83%) pale yellow solid; analytical TLC on
silica gel, 1:9 EtOAc/petroleum ether, RfZ0.48. Pure
material was obtained by crystallization from EtOAc/
petroleum ether, mp 141–143 8C, pale yellow pyramidal
1
crystals; 200 MHz H NMR (CDCl3, ppm) d 7.69 (1H, dd,
1
(CHCl3 thin film, cmK1) 2220 C^N; 200 MHz H NMR
JZ1.5, 0.8 Hz) 7.52–7.21 (6H, m) 7.10 (1H, d, JZ3.1 Hz)
6.54 (1H, d, JZ2.9 Hz) 3.84 (3H, s); 13C NMR (50 MHz,
CDCl3, ppm) d 142.0, 136.3, 133.2, 132.2, 131.0, 130.1,
129.7, 128.5, 128.2, 127.0, 123.6, 122.1, 108.9, 101.6, 33.2;
GC–MS m/z (% relative intensity, ion): 241 (100, M) 204
(14) 190 (16) 165 (19) 163 (14). Anal. Calcd for C15H12ClN:
C, 74.53; H, 5.00; N, 5.79. Found: C, 74.32; H, 4.84; N,
5.50.
(CDCl3, ppm) d 7.76 (1H, dd, JZ7.7, 1.4 Hz) 7.65 (1H, ddd,
JZ7.7, 7.7, 1.4 Hz) 7.45 (1H, ddd, JZ7.7, 7.7, 1.1 Hz) 7.28
(1H, dd, JZ7.7, 1.1 Hz, overlapped with CHCl3) 2.34 (s,
3H) 1.98 (s, 6H); 13C NMR (50 MHz, CDCl3, ppm) d 145.7,
138.3, 135.8, 135.1, 133.2, 133.1, 130.8, 128.7, 127.6,
118.1, 113.5, 21.4, 20.5; GC–MS m/z (% relative intensity,
ion): 221 (100, M) 220 (32) 206 (57, MKCH3) 190 (35) 179
(57). Anal. Calcd for C16H15N: C, 86.84; H, 6.83; N, 6.33.
Found: C, 86.86; H, 6.89; N, 6.27.
7.6.8. 1-(40-Chloro-biphenyl-4-yl)-ethanone (14).
Following general procedure, 1-bromo-4-chloro-benzene
1h was converted into arylzinc reagent and cross-coupled
with 1-(4-bromo-phenyl)ethanone. Purification of the crude
product by column chromatography (75 mL silica gel,
column i.d. 30 mm) using 4% EtOAc/petroleum ether
afforded 109 mg (68%) of solid material; analytical TLC
on silica gel, 1:9 EtOAc/petroleum ether, RfZ0.31. Pure
material was obtained by crystallization from EtOAc/
petroleum ether, mp 100–101 8C, colorless needles (lit.30
7.6.5. 1-(4-Naphthalen-1-yl-phenyl)-ethanone (11).
Following general procedure, 1-bromo-naphthalene 1e
was converted into arylzinc reagent and cross-coupled
with 1-(4-bromo-phenyl)-ethanone. Purification of the
crude product by column chromatography (75 mL silica
gel, column i.d. 30 mm) using gradient elution from 2%
EtOAc/petroleum ether to 4% EtOAc/petroleum ether
afforded 142 mg (82%) of solid material; analytical TLC
on silica gel, 1:9 EtOAc/petroleum ether, RfZ0.43. Pure
material was obtained by crystallization from EtOAc/
petroleum ether, mp 102–103 8C, colorless prisms; IR
1
102–103 8C); IR (Nujol, cmK1) 1678 C]O; 200 MHz H
NMR (CDCl3, ppm) d 8.07–7.99 (2H, m) 7.68–7.40 (6H, m)
2.64 (3H, s); GC–MS m/z (% relative intensity, ion): 230
(35, M) 215 (98, MKCH3) 152 (100).
1
(Nujol, cmK1) 1685 C]O; 200 MHz H NMR (CDCl3,
ppm) d 8.14–8.06 (2H, m) 7.96–7.81 (3H, m) 7.65–7.40
(6H, m) 2.69 (3H, s); 13C NMR (50 MHz, CDCl3, ppm) d
198.1, 146.0, 139.2, 136.2, 134.0, 131.4, 130.6, 128.7,
128.6, 127.2, 126.6, 126.2, 125.8, 125.6, 26.9; GC–MS m/z
(% relative intensity, ion): 246 (53, M), 231 (75, MKCH3)
203 (35) 202 (100) 201 (25) 200 (28) 176 (10) 150 (10).
Anal. Calcd for C18H14O: C, 87.78; H, 5.73. Found: C,
87.59; H, 5.69.
7.6.9. 5-(4-Chloro-phenyl)-1-methyl-1H-indole-2-carb-
oxylic acid ethyl ester (15). Following general procedure,
1-bromo-4-chloro-benzene 1h was converted into arylzinc
reagent and cross-coupled with 5-bromo-1-methyl-1H-
indole-2-carboxylic acid ethyl ester. Purification of the
crude product by column chromatography (100 mL silica
gel, column i.d. 35 mm) using gradient elution from 15%
CH2Cl2/petroleum ether to 30% CH2Cl2/petroleum ether
afforded 183 mg (83%) of solid material; analytical TLC on
silica gel, 1:9 EtOAc/petroleum ether, RfZ0.38. Pure
material was obtained by crystallization from EtOAc/
petroleum ether, mp 128–129 8C, colorless plates; IR
7.6.6. 2-(1-Methyl-1H-indol-5-yl)-benzoic acid ethyl
ester (12). Following general procedure, 5-bromo-1-
methyl-1H-indole 1g was converted into arylzinc reagent
and cross-coupled with 2-bromo-benzoic acid ethyl ester.
Purification of the crude product by column chromato-
graphy (100 mL silica gel, column i.d. 35 mm) using
gradient elution from 15% CH2Cl2/petroleum ether to
50% CH2Cl2/petroleum ether afforded 143 mg (73%) pale
yellow liquid; analytical TLC on silica gel, 1:9 EtOAc/
petroleum ether, RfZ0.23; IR (neat, cmK1) 1719 C]O;
200 MHz 1H NMR (CDCl3, ppm) d 7.81–7.75 (1H, m)
7.60–7.16 (6H, m) 7.09–7.06 (1H, m) 6.51–6.47 (1H, m)
4.08 (2H, q, JZ7.2 Hz) 3.82 (3H, s) 0.96 (3H, t, JZ7.2 Hz);
13C NMR (50 MHz, CDCl3, ppm) d 169.8, 143.6, 136.3,
132.8, 132.1, 131.4, 131.1, 129.6, 128.7, 126.7, 122.8,
120.8, 101.5, 109.0, 61.1, 33.2, 14.1; GC–MS m/z (%
relative intensity, ion): 279 (100, M) 251 (24, MKC2H4)
234 (68) 219 (23) 207 (65) 190 (36) 178 (19) 165 (75).
1
(CHCl3 thin film, cmK1) 1712 C]O; 200 MHz H NMR
(CDCl3, ppm) d 7.85–7.82 (1H, m) 7.61–7.32 (7H, m) 4.39
(2H, q, JZ7.0 Hz) 4.11 (3H, s) 1.42 (3H, t, JZ7.0 Hz); 13C
NMR (50 MHz, CDCl3, ppm) d 162.3, 140.5, 139.4, 132.94,
132.88, 129.1, 128.7, 126.5, 124.7, 120.8, 110.9, 110.5,
60.8, 32.1, 14.5; GC–MS m/z (% relative intensity, ion): 313
(100, M) 285 (87, MKC2H4) 268 (15) 241 (24) 204 (18) 199
(59) 190 (31) 163 (22). Anal. Calcd for C18H16ClNO2: C,
68.90; H, 5.14; N, 4.46. Found: C, 68.39; H, 4.94; N, 4.14.
7.6.10. 40-Methoxy-biphenyl-2-carbonitrile (16).
Following general procedure, 1-chloro-4-methoxybenzene
3b was converted into arylzinc reagent and cross-coupled
with 2-bromo-benzonitrile. Purification of the crude product
by column chromatography (75 mL silica gel, column i.d.
30 mm) using gradient elution from 2.5% EtOAc/petroleum
7.6.7. 5-(2-Chloro-phenyl)-1-methyl-1H-indole (13).

I. Mutule, E. Suna / Tetrahedron 61 (2005) 11168–11176
11175
ether to 10% EtOAc/petroleum ether yielded 134 mg (92%)
of solid material; analytical TLC on silica gel, 1:9 EtOAc/
petroleum ether, RfZ0.33. Pure material was obtained by
crystallization from EtOAc/petroleum ether, mp 83–84 8C,
colorless needles (lit.31 81–82 8C); IR (Nujol, cmK1) 2213
147.2, 137.0, 133.9, 132.9, 130.7, 130.1, 129.8, 128.9,
126.9, 122.7, 121.7, 119.7, 111.6, 109.7, 101.9, 30.1; GC–
MS m/z (% relative intensity, ion): 232 (100, M) 190 (17).
Anal. Calcd for C16H12N2: C, 82.73; H, 5.21; N, 12.06.
Found: C, 82.65; H, 5.04; N, 12.11.
1
C^N; 200 MHz H NMR (CDCl3, ppm) d 7.77–7.35 (6H,
m) 7.06–6.97 (2H, m) 3.86 (3H, s); GC–MS m/z (% relative
intensity, ion): 209 (83, M) 194 (25, MKCH3) 166 (100)
140 (93) 113 (34) 63 (37).
7.6.14. 2-(1-Methyl-1H-indol-6-yl)-benzoic acid ethyl
ester (20). Following general procedure, 6-chloro-1-
methyl-1H-indole 3f was converted into arylzinc reagent
and cross-coupled with 2-bromo-benzoic acid ethyl ester.
Purification of the crude product by column chromato-
graphy (80 mL silica gel, column i.d. 30 mm) using gradient
elution from 15% CH2Cl2/petroleum ether to 50% CH2Cl2/
petroleum ether yielded 126 mg (64%) of yellow oil;
analytical TLC on silica gel, 1:9 EtOAc/petroleum ether,
RfZ0.23; IR (CHCl3 film, cmK1) 1720 C]O; 200 MHz 1H
NMR (CDCl3, ppm) d 7.82–7.76 (1H, m) 7.65–7.34 (4H, m)
7.31–7.28 (1H, m) 7.11–7.04 (2H, m) 6.50 (1H, dd, JZ3.3,
0.7 Hz) 4.07 (2H, q, JZ7.0 Hz) 3.80 (3H, s) 0.92 (3H, t, JZ
7.0 Hz); 13C NMR (50 MHz, CDCl3, ppm) d 169.8, 143.5,
136.9, 135.2, 132.2, 131.2, 131.1, 129.62, 129.55, 127.9,
126.9, 120.8, 120.6, 109.2, 101.1, 61.2, 33.1, 13.8; GC–MS
m/z (% relative intensity, ion): 279 (100, M) 251 (35) 234
(37) 219 (26) 207 (41) 190 (26) 178 (15) 165 (35).
7.6.11. 40-Dimethylamino-biphenyl-2-carbonitrile (17).
Following general procedure, 4-chloro-N,N-dimethyl-
aminobenzene 3c was converted into arylzinc reagent and
cross-coupled with 2-bromo-benzonitrile. Purification of the
crude product by column chromatography (100 mL silica
gel, column i.d. 50 mm) using gradient elution from 2%
EtOAc/petroleum ether to 10% EtOAc/petroleum ether
afforded 90 mg (81%) brown solid; analytical TLC on silica
gel, 1:9 EtOAc/petroleum ether, RfZ0.33. Pure material
was obtained by crystallization from EtOAc/petroleum
ether, mp 106–107 8C, brownish parallelepiped crystals;
IR (CHCl3 thin film, cmK1) 2213 C^N; 200 MHz 1H NMR
(CDCl3, ppm) d 7.75–7.68 (1H, m) 7.64–7.45 (4H, m) 7.39–
7.29 (1H, m) 6.87–6.77 (2H, m) 3.02 (6H, s); 13C NMR
(150 MHz, CDCl3, ppm) d 150.3, 145.7, 133.5, 132.3,
129.29, 129.31, 129.31, 126.1, 125.6, 112.09, 112.10, 119.4,
110.9, 40.2; GC–MS m/z (% relative intensity, ion): 222
(100, M) 205 (15) 178 (18) 151 (19). Anal. Calcd for
C15H14N2: C, 81.05; H, 6.35; N, 12.60. Found: C, 81.00; H,
6.38; N, 12.73.
Acknowledgements
This work has been partly supported by the European Social
Fund within the National Programme ‘Support for the
carrying out doctoral study programm’s and post-doctoral
researches’ project ‘Support for the development of doctoral
studies at Riga Technical University’. The financial support
of the Latvian Science Council (Grants 05.1775 and
05.1782) is also acknowledged.
7.6.12. 2-Thiophen-2-yl-benzoic acid ethyl ester (18).
Following general procedure, 2-chloro-thiophene 3d was
converted into arylzinc reagent and cross-coupled with
2-bromo-benzoic acid ethyl ester. Purification of the crude
product by column chromatography (100 mL silica gel,
column i.d. 30 mm) using gradient elution from 2% EtOAc/
petroleum ether to 4% EtOAc/petroleum ether gave 149 mg
(92%) of colorless oil, analytical TLC on silica gel, 1:9
EtOAc/petroleum ether, RfZ0.55; IR (neat, cmK1) 1718
1
References and notes
C]O; 200 MHz H NMR (CDCl3, ppm) d 7.77–7.70 (1H,
m) 7.51–7.32 (4H, m) 7.08–7.00 (2H, m) 4.18 (2H, q, JZ
7.2 Hz) 1.13 (3H, t, JZ7.2 Hz); 13C NMR (50 MHz, CDCl3,
ppm) d 169.0, 142.4, 134.4, 132.5, 131.4, 131.1, 129.6,
128.0, 127.3, 126.5, 126.0, 61.5, 14.0; GC–MS m/z (%
relative intensity, ion): 232 (70, M) 187 (87) 160 (27) 115
(100).
1. (a) Microwaves in Organic Synthesis; Loupy, A., Ed.; Wiley-
VCH: Weinheim, 2002. (b) Kappe, C. O. Angew. Chem., Int.
Ed. 2004, 43, 6250.
¨
2. (a) Ohberg, L.; Westman, J. Synlett 2001, 1893. (b) Stanetty,
P.; Schnurch, M.; Mihovilovic, M. D. Synlett 2003, 1862.
3. Walla, P.; Kappe, C. O. Chem. Commun. 2004, 564.
4. Mutule, I.; Suna, E. Tetrahedron Lett. 2004, 45, 3909.
5. (a) For a preliminary report on microwave assisted generation
of arylmagnesium species see: Mutule, I.; Avotina, D.; Suna E.
Microwave Assisted Preparation of Grignard and Organozinc
Reagents. Presented at the 2nd International conference on
organic synthesis, BOS 2002, Vilnius, June 2002; Paper PO-
49. (b) A single precedent of the preparation of 4-methoxy-
phenylmagnesium bromide under microwave dielectric heat-
ing has been reported in Ref. 3. (c) After submission of the
manuscript, related work on microwave assisted generation of
Grignard reagents was published: Gold, H.; Larhed, M.;
Nilsson, P. Synlett 2005, 1596.
7.6.13. 2-(1-Methyl-1H-indol-5-yl)-benzonitrile (19).
Following general procedure, 5-chloro-1-methyl-1H-indole
3e was converted into arylzinc reagent and cross-coupled
with 2-bromo-benzonitrile. Purification of the crude product
by column chromatography (80 mL silica gel, column i.d.
35 mm) using gradient elution from 15% CH2Cl2/petroleum
ether to 50% CH2Cl2/petroleum ether afforded 113 mg
(70%) of brownish solid; analytical TLC on silica gel, 1:9
EtOAc/petroleum ether, RfZ0.20. Pure material was
obtained by crystallization from EtOAc/petroleum ether,
mp 106–107 8C, brownish parallelepiped crystals; IR
1
(CHCl3 thin film, cmK1) 2220 C^N; 200 MHz H NMR
(CDCl3, ppm) d 7.84–7.72 (2H, m) 7.67–7.54 (2H, m) 7.47–
7.34 (3H, m) 7.11 (1H, d, JZ3.1 Hz) 6.57 (1H, d, JZ
3.1 Hz) 3.83 (3H, s); 13C NMR (50 MHz, CDCl3, ppm) d
6. Baker, K.; Brown, J.; Hughes, N.; Skarnulis, A. J.; Sexton, A.
J. Org. Chem. 1991, 56, 698.
7. Nu¨tzel, K. Organo-magnesium Verbindungen In Houben-

11176
I. Mutule, E. Suna / Tetrahedron 61 (2005) 11168–11176
Weyl, Methoden der Organiche Chemie, Band 13/2a; Thieme:
Stuttgart, 1973; pp 47-527.
(1.0 M) was employed, precipitation of magnesium salts was
observed.
8. Aleandri, L. E.; Bogdanovic, B. The Magnesium Route to
Active Metals and Intermetallics. In Active Metals; Fu¨rstner,
A., Ed.; VCH: Weinheim, 1996; pp 299–338.
20. For relative rates of the formation of various arylmagnesium
species see: Rogers, H. R.; Rogers, R. J.; Mitchell, H. L.;
Whitesides, G. M. J. Am. Chem. Soc. 1980, 102, 231.
21. Dielectric heating at 180 8C developed 13–19 bar pressure
inside the Emryse microwave process vial. However, we
never observed any of over pressurization incidents (the
maximum pressure that could be employed in the system is
20 bar).
9. (a) See Ref. 7. (b) Lee, J.; Velarde-Ortiz, R.; Guijarro, A.;
Wurst, J. R.; Rieke, R. D. J. Org. Chem. 2000, 65, 5428.
10. Inert atmosphere and moisture free conditions, necessary for
the Grignard generation can be easily realized in a Emryse
microwave process vial closed with aluminum open-top seal
with PTFE-faced septum.
22. Okamoto, Y.; Yoshioka, K.; Yamana, T.; Mori, H.
J. Organomet. Chem. 1989, 369, 285.
11. Magnesium turnings were purchased from Acros. Initially, we
made certain that the microwave irradiation of magnesium in
organic solvents can be carried out safely. Thus, dielectric
heating of magnesium turnings at various temperatures was
performed in THF and in Et2O, which are a routinely used
medium for preparation of Grignard reagents. We were
pleased to find that temperature and pressure profiles of the
heating did not show any unusual behavior such as quick rise
of temperature or sudden change of pressure, demonstrating
that microwave irradiation of magnesium turnings under the
tested conditions is safe and reliable procedure.
23. Ca. 5% of alcohol 6 was formed when 4-bromobenzaldehyde 5
was reacted with arylzinc chloride 4b in the absence of Pd
catalyst after 5 min at room temperature (yields of alcohol 6
and biphenyl aldehyde 7 were determined by GC–MS assay).
On the other hand, none of the alcohol 6 was formed in the
presence of (Ph3P)2PdCl2, thus demonstrating the high
chemoselectivity of the Negishi coupling over the 1,2-
addition.
24. The solution of ZnCl2 in Et2O (1 M) (Aldrich) and 0.5 M
solution of ZnCl2 in THF (Aldrich) was employed.
25. Kjonaas, R. A.; Vawter, E. J. J. Org. Chem. 1986, 51, 3993.
26. Elevated temperature (120 8C for 5 min) was applied in a
previous work (see Ref. 4) to bring the Negishi cross-coupling
of various arylzinc iodides with 4-bromobenzaldehyde 5 to
completion. However, back then, arylzinc iodides were
generated directly from aryl iodides and Zn–Cu couple and
therefore did not contain inorganic salts. Herein, apparently,
the presence of Mg salts (from transmetallation step) in the
solution of arylzinc reagent facilitates the palladium catalyzed
cross-coupling with aryl bromides. In a control experiment,
phenylzinc iodide was prepared from iodobenzene and Zn–Cu
couple in the presence of MgCl2 (0.5 M solution in THF).
Subsequent Negishi coupling with 4-bromobenzaldehyde 5
was completed at room temperature after 5 min (GC–MS
assay). Further work is in progress to establish the role of Mg
salts in the cross-coupling reaction.
12. THF was distilled from sodium benzophenone ketyl under
argon prior to use.
13. Prepared from ‘dry ice’ and dried by passing through
concentrated sulfuric acid. Carbon dioxide has been frequently
used as trapping agent to determine yields of organometallic
species: see: Schlosser, M. In Organoalkali Chemistry;
Schlosser, A., Ed.; Organometallics in Synthesis: a Manual;
Wiley: Chichester, 2002; pp 1–353.
14. During several 100 experiments performed, the pressure never
exceeded 2 bar and none of over pressurization incidents were
observed (the maximum pressure that could be employed in
the system is 20 bar).
15. The use of 80 8C (vs 60 8C) resulted in higher reproducibility
of the Grignard formation.
16. Dielectric constant of THF: 7.5 (at 22 8C); dielectric constant
of chlorobenzene: 5.7 (at 22 8C); see: CRC Handbook of
Chemistry and Physics; Lide, D. R., Ed.; CRC, 2000;
pp 6–149.
27. In the case of 4-dimethylamino-benzoic acid 2c the combined
basic extracts were acidified with 1 M HCl to pHw4. 0.1 M
HCl was employed to acidify the basic extracts in the case of
indoles 2g and 2i.
17. Ionic liquids are among the most frequently employed
additives; see, for example: Leadbeater, N. E.; Torenius,
H. M. J. Org. Chem. 2002, 67, 3145.
28. Cymerman-Craig, J.; Loder, J. W. J. Chem. Soc. 1956, 100.
29. Zhu, L.; Duquette, J.; Zhang, M. J. Org. Chem. 2003, 68, 3729.
30. Mowry, D. T.; Renoll, M.; Huber, W. F. J. Am. Chem. Soc.
1946, 68, 1105.
18. Prepared by the reaction of excess magnesium with 1,2-
dibromoethane, followed by removal of unreacted metal, then
evaporation of solvent and, finally, drying of the solid residue
in vacuo (0.1 Torr).
31. Kim, K. S.; Qian, L.; Bird, J. E.; Dickinson, K. E. J.; Moreland,
S.; Schaeffer, T. R.; Waldron, T. L.; Delaney, C. L.; Weller,
H. N.; Miller, A. V. J. Med. Chem. 1993, 36, 2335.
19. The use of less concentrated MgBr2 solution (0.1 M) did not
improve the heating rate. If more concentrated MgBr2 solution