Improved negishi cross-coupling reactions of an organozinc reagent derived from l -aspartic acid with monohalopyridines

Article abstract of DOI:10.1002/jhet.1807

The Negishi cross-coupling reaction of an organozinc derivative prepared from protected l-aspartic acid with monohalopyridines was improved by employing a combination catalyst of Pd₂(dba)₃ and P(2-furyl) ₃ and removing an extra Zn from the organozinc reagent via centrifugation. The reactivity of halogenated pyridines (Cl, Br, I) with substituents at the C2, C3, and C4 positions of the pyridine ring was investigated, and it was found that the use of 4-iodopyridine as a substrate gave the best yield (90%) for the cross-coupling reaction.

Full text of DOI:10.1002/jhet.1807

January 2014 Improved Negishi Cross-Coupling Reactions of an Organozinc Reagent
Derived from L-Aspartic Acid with Monohalopyridines
269
*
Toyonobu Usuki, Hiroto Yanuma, Takahiro Hayashi, Haruka Yamada, Noriyuki Suzuki, and Yoshiro Masuyama
Department of Materials and Life Sciences, Faculty of Science and Technology, Sophia University, 7-1 Kioicho, Chiyoda-ku,
Tokyo 102-8554, Japan
*
E-mail: t-usuki@sophia.ac.jp
Received April 10, 2012
DOI 10.1002/jhet.1807
Published online 31 October 2013 00 Month 2013 in Wiley Online Library (wileyonlinelibrary.com).
4
3
X
4
2
NHBoc
CO2Bn
NHBoc
CO2Bn
3
2
N
IZn
Pd2(dba)3 (2.5 mol%)
P(2-furyl)3 (10 mol%)
rt, 3 h (X = Cl, Br, I)
N
The Negishi cross-coupling reaction of an organozinc derivative prepared from protected L-aspartic acid
with monohalopyridines was improved by employing a combination catalyst of Pd2(dba)3 and P(2-furyl)3
and removing an extra Zn from the organozinc reagent via centrifugation. The reactivity of halogenated
pyridines (Cl, Br, I) with substituents at the C2, C3, and C4 positions of the pyridine ring was investigated,
and it was found that the use of 4-iodopyridine as a substrate gave the best yield (90%) for the cross-coupling
reaction.
J. Heterocyclic Chem., 51, 269 (2014).
INTRODUCTION
via centrifugation. The effect of halogen substituents (Cl,
Br, I) at different positions (C2, C3, C4) of the pyridine ring
on the Negishi cross-coupling reaction was also investigated.
The Negishi cross-coupling reaction [1–3] of organozinc
reagents derived from amino acids with aryl halides using a
catalytic amount of palladium has been investigated for the
production of enantiomerically pure non-natural amino
acid derivatives [4] that can be used for the preparation
of numerous organic molecules, including biologically active
compounds. For example, the cross-coupling reaction between
organozinc reagents derived from serine and aryl halides
was reported by Jackson and co-workers to afford the
corresponding phenylalanine derivatives in moderate yields
[5–8]. Moreover, the palladium-catalyzed Negishi cross-
coupling reaction of serine derived organozinc reagents with
halopyridines was shown to afford azatyrosine derivatives
[9,10]. Studies of the cross-coupling of aspartic acid derived
organozinc reagents with halopyridines has, however, not
been clearly investigated to date.
Improvement of the cross-coupling reaction to achieve
C–C bond formation between L-aspartic acids and pyridines
would lead to a practical preparation method for naturally
occurring pyridinium amino acids such as the osteopo-
rosis biomarkers pyridinoline (1) and deoxypyridinoline (2)
[11,12] and the chronic obstructive pulmonary disease
(COPD) biomarkers desmosine (3) and isodesmosine (4)
[13–16], as illustrated in Scheme 1. Herein, we report the
palladium-catalyzed Negishi cross-coupling reaction of an
organozinc reagent derived from protected L-aspartic acid
with monohalopyridines and optimization of the reaction
conditions via separation of the extra insoluble Zn species
RESULTS AND DISCUSSION
For the study of the Negishi cross-coupling reaction,
benzyl 2-(S)-(tert-butoxycarbonylamino)-4-iodobutanoate
(5) [17] and 3-iodopyridine were chosen as the substrates.
The protected amino acid 5 was prepared from commercially
available 4-benzoxyl-(S)-3-(tert-butoxycarbonylamino)-4-
oxobutanoic acid in two steps. A combination of 2.5 mol%
Pd2(dba)3 [tris(dibenzylideneacetone)dipalladium(0)] and
10 mol% P(o-tol)3 [tri(o-tolyl)phosphine] (final concentra-
tion of 1 M) in N,N-dimethylformamide (DMF) at room
temperature [18] was used for the reaction between 5
and 3-iodopyridine. Zn dust was activated with 1,2-
dibromoethane and trimethylsilyl chloride (TMSCl) in
DMF. To the solution of activated Zn was then added a
DMF solution of 1.3 equimolar amounts of iodo amino acid
5. After monitoring the generation of the organozinc reagent
from 5 by TLC, a DMF solution of Pd2(dba)3, P(o-tol)3,
and one equimolar amount of 3-iodopyridine was added to
the solution of the freshly prepared organozinc reagent.
The reaction proceeded for 2 h to afford the corresponding
coupling product 7 in 48% yields (entry 1, Table 1). When
the reaction was carried out with the bidentate ligand
DPEphos (bis[2-(diphenylphosphino)phenyl]ether) for 15 h,
only a trace amount of 7 was obtained (entry 2, Table 1).
Use of triphenylarsine (AsPh3) and tri(2-furyl)phosphine
© 2013 HeteroCorporation

270
T. Usuki, H. Yanuma, T. Hayashi, H. Yamada, N. Suzuki, and Y. Masuyama
Vol 51
Scheme 1. Pyridinolines (1 and 2) and desmosines (3 and 4).
NH2
CO2H
OH
NH2
CO2H
OH
CO2H
CO2H
CO2H
CO2H
H2N
H2N
H2N
H2N
N
N
OH
pyridinoline (1)
deoxypyridinoline (2)
NH2
CO2H
NH2
CO2H
CO2H
CO2H
NH2
CO2H
NH2
CO2H
H2N
H2N
H2N
H2N
CO2H
N
CO2H
N
desmosine (3)
isodesmosine (4)
Table 1
Effect of ligands on the Negishi cross-coupling reaction with 5.
Entry
Ligand
Time (h)
Yield (%)
1
2
3
4
P(o-tol)3, 10 mol%
DPEphos, 5 mol%
AsPh3, 10 mol%
2
15
24
3
48
Trace
32
P(2-furyl)3, 10 mol%
67
(P(2-furyl)3), which are known as useful ligands in the
Stille reaction [19], gave the desired coupling product 7 in
32 and 67% yield, respectively (entries 3 and 4, Table 1). It
has been proposed that AsPh3 and P(2-furyl)3 enhance the
rate of the transmetalation step in the Stille reaction, which
is the rate-determining step in the catalytic cycle [19,20].
Thus, a combination of 2.5 mol% Pd2(dba)3 and 10mol%
P(2-furyl)3 in the Negishi cross-coupling reaction was found
to be an outstanding catalytic system for affording 7, which
was isolated as a non-racemic product as confirmed by optical
rotation analysis.
to the activation of Zn. Because the coupling conditions
described earlier were not reproducible, particularly for small
scale experiments, it was considered that 1,2-dibromoethane
and TMSCl residue from the activation of Zn might affect
the activity of the catalytic systems for the cross-coupling.
A filtration technique was considered to be unsuitable for
removal of any extra insoluble Zn and other activating
species from the organozinc reagent reaction mixture because
of high viscosity (concentration) of the reactant at small
scale. Therefore, separation by centrifugation using a micro-
tube seemed to be a promising method for overcoming
this issue. The advantages of separation by centrifuge are as
follows: (1) TMSCl can be easily removed from the activated
In order to improve the yield of the cross-coupling reac-
tion, the experimental procedure was modified with respect
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2014
Improved Negishi Cross-Coupling Reactions of an Organozinc Reagent Derived
from L-Aspartic Acid with Monohalopyridines
271
Table 2
Negishi cross-coupling reaction of 5 and monohalopyridines.
Entry
Position
X
Yield (%)a
1
2
3
4
5
6
7
8
9
2
3
4
2
3
4
2
3
4
Cl
Cl
Cl
Br
Br
Br
I
NR
NR
NR
44
Trace (33b)
23
72
78
90
I
I
aIsolated yields.
bReaction time was 15 h.
Zn; (2) the high concentration can be maintained, even for
small scale reactions; (3) the coupling reaction can be moni-
tored more clearly by TLC because removal of Zn leads to a
clear solution; and (4) side reactions caused by the extra Zn
and TMSCl residue can be prevented. A reproducible method
for the activation of Zn was achieved as follows: (1) DMF
and TMSCl are added to a 1.5 mL microtube (Eppendorf
type) containing Zn dust; (2) after the mixture is stirred
vigorously for 30 min at room temperature, the solution,
including TMSCl, is removed by syringe; (3) iodo amino
acid 5 in DMF is added to the activated Zn to form the
organozinc amino acid reagent Zn-5; (4) the Zn-5 solution
is centrifuged in order to enable isolation of the organozinc
amino acid reagent Zn-5 for the cross-coupling reaction.
Utilizing this method, the Negishi cross-coupling reaction
between 3-iodopyridine and 5 gave the desired product 6 in
much better yield (78%, entry 8, Table 2).
Utilizing the optimized conditions, the reactivity of
different halogenated pyridines with Cl, Br, and I substitu-
ents at the C2, C3, and C4 positions of the pyridine ring
was investigated (Table 2). The cross-coupling reactions
with monochloropyridines did not proceed to afford the
corresponding coupling products (entries 1–3), even if
the reaction time was prolonged. Reactions with 2- and
4-bromopyridine gave the products 6 and 8 in 44 and
23% yields, respectively (entries 4 and 6), whereas the
reaction with 3-bromopyridine for 3 h gave only a trace
amount of the coupling product 7 and for 15 h gave 7 in
a 33% yield. These results indicate that the reactivity
of 2- and 4-bromopyridines is much better than that of
3-bromopyridine in the Negishi reaction [8]. Finally, reac-
tions with 2-, 3-, and 4-iodopyridine gave the desired
products 6, 7, and 8 in 72, 78, and 90% yield, respectively
(entries 7–9). These results indicate that the reactivity of
halogen substituents on the pyridine ring is in the order
I > Br >> Cl, but no clear trends can be assumed regarding
the substituent position.
CONCLUSION
The combination of Pd2(dba)3 and P(2-furyl)3 was found
to be an excellent catalyst system for the Negishi cross-
coupling reaction of an organozinc reagent derived from
protected L-aspartic acid with monohalopyridines. The
reaction was improved by removing both the undesired
Zn (II) species and an extra Zn metal from the activated
organozinc reagent via centrifugation. On the basis of the
studies of the reactivity of different halogenated (Cl, Br,
Journal of Heterocyclic Chemistry
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T. Usuki, H. Yanuma, T. Hayashi, H. Yamada, N. Suzuki, and Y. Masuyama
Vol 51
2-(S)-(tert-butoxycarbonylamino)-4-iodobutanoate 5 (210 mg,
0.5 mmol) in dry DMF (100mL Â 2) was added to the solution of
activated zinc. The reaction mixture was heated to 35ꢀC and
followed by TLC. When insertion of zinc was confirmed by TLC,
the solution was cooled to room temperature. The time for the
insertion ranges from approximately 30 min to 3 h. Pd2(dba)3
(10.4 mg, 0.01mmol), ligand (0.04mmol), and 3-iodopyridine
(76.9 mg, 0.38 mmol) were then added to the solution of the
organozinc reagent. After stirring for 3 h at room temperature, the
reaction mixture was diluted with ethyl acetate (50 mL), washed
with brine (30 mL Â 3), dried over sodium sulfate and concentrated
under reduced pressure to give the crude product as oil. Purification
by silica gel column chromatography (hexane/ethyl acetate = 1:2)
afforded the pure benzyl 2-(S)-(tert-butoxycarbonylamino)-4-
(3-pyridyl)butanoate 7 as a yellow oil (91.8 mg, 0.25 mmol,
67%); Rf = 0.56 (hexane/ethyl acetate = 1:2); [a]2D1 À16.5 (c1.0,
MeOH); IR (neat, cmÀ1) 3351, 3227, 3032, 2976, 2933,
1710, 1499, 1455, 1366, 1249, 1165, 1026, 866, 752, 699,607,
496; 1H NMR (300 MHz, CDCl3) d 8.44 (1H, d, J = 4.5 Hz,
Py-H6), 8.37 (1H, s, Py-H2), 7.43 (1H, d, J = 7.8 Hz, Py-H4),
7.36 (5H, s, Bn), 7.19 (1H, dd, J = 7.8, 4.8 Hz, Py-H5), 5.21 (1H,
d, J = 12.3 Hz, Bn), 5.12 (1H, d, J = 12.0Hz, Bn), 4.40 (1H, d,
J = 5.1Hz, CH), 2.70–2.52 (2H, m, CH2), 2.20–2.09 (1H, m, CH),
1.99–1.87 (1H, m, CH), 1.47 (9H, s, tBu); 13C NMR (75MHz,
CDCl3) d 172.17, 149.22, 147.12, 140.11, 137.43, 135.30,
128.83, 128.76, 128.62, 124.06, 80.30, 67.41, 53.17, 34.12,
31.06, 28.78, 28.42; ESI–HRMS (m/z) calcd for C21H26O4N2Na
[M+ Na]+ 393.1790, found 393.1785.
Improved method. Zinc dust (200 mg, 3.0 mmol) was placed
in a nitrogen-purged 1.5 mL Eppendorf microtube. Dry DMF
(150 mL) and trimethylsilyl chloride (60.0mL, 0.47 mmol) were
added to the microtube, and the resulting mixture was stirred
vigorously for 30min at room temperature. After stirring, the
solution was removed by microsyringe. The remaining solid
was dried using a hot air gun at reduced pressure. The activated
zinc was then cooled to room temperature. A solution of benzyl
2-(S)-(tert-butoxycarbonylamino)-4-iodobutanoate 5 (210 mg,
0.5 mmol) in dry DMF (100 mL Â 2) was then added to the
activated zinc. The reaction mixture was then stirred at room
temperature. The insertion of zinc was monitored by TLC, with
the insertion time ranging from approximately 10 min to 1 h.
After completion of the insertion, the zinc solution was allowed
to settle using a centrifuge for 1 min at room temperature. The
organozinc solution was removed via a microsyringe and added
to a 10 mL flask containing Pd2(dba)3 (12.2 mg, 0.01 mmol),
P(2-furyl)3 (9.29 mg, 0.04mmol), and 3-iodopyridine (76.9 mg,
0.38 mmol), rinse with DMF (150 mL). After stirring for 3 h
at room temperature, the reaction mixture was diluted with
ethyl acetate (50 mL), washed with brine (30 mL Â 3), dried
over sodium sulfate, and concentrated under reduced pressure to
give the crude product as oil. Purification by silica gel column
chromatography (hexane/ethyl acetate = 1:2) afforded the pure
benzyl 2-(S)-(tert-butoxycarbonylamino)-4-(3-pyridyl)butanoate 7
as a yellow oil (107 mg, 0.29mmol, 78%).
I) pyridines at different substitution positions (C2, C3, C4)
on the pyridine ring, it was determined that 4-iodopyridine
gives the best yield (90%) in the cross-coupling. The opti-
mized Negishi reaction can be useful for the preparation of
important biomarkers 1–4, as well as biologically-related
molecules and several building blocks [21].
EXPERIMENTAL
General experimental procedures.
All reactions were
conducted under an atmosphere of nitrogen with magnetic stirring
in DMF, which was dried by distillation from magnesium sulfate
and stored over molecular sieves. All reagents were obtained from
commercial suppliers unless otherwise stated. Analytical TLC was
performed on Silica gel 60F254 plates produced by Merck
(Whitehouse Station, NJ). Visualization was accomplished with
UV light and phosphomolybdic acid followed by heating. Column
chromatography was performed with acidic or neutral Silica
gel 60 (spherical, 40–50 mm) produced by Kanto Chemical
Co. Ltd (Tokyo, Japan). Centrifugation was performed by
LMS Mini Centrifuge MCF-2360 (6,600 rpm). Benzyl 2-(S)-
(tert-butoxycarbonylamino)-4-iodobutanoate
5
was prepared
following the literature procedure [7] and was recrystallized
from pentane before use. Zinc dust was purchased from Wako
Pure Chemical Industries (Osaka, Japan). 4-Bromopyridine
hydrochloride and 4-chloropyridine hydrochloride were converted
to the corresponding free pyridines by mixing in an ice-cold 1 M
potassium hydroxide solution followed by extraction with cold
ether. The extracts were dried over magnesium sulfate in the
refrigerator and evaporated under reduced pressure to give the free
pyridines, which were used immediately [22].
Optical rotations were measured on a JASCO (Tokyo, Japan)
P-2200 digital polarimeter at the sodium lamp (l = 589 nm) D
T
line and are reported as follows: [a]D (c g/100 mL, solvent).
Infrared (IR) spectra were recorded on a JASCO FT-IR 4100
1
spectrometer and are reported in wavenumbers (cmÀ1). H and
13C NMR spectra were recorded on a JEOL JNM-EXC 300 spec-
trometer (300 MHz) and a JEOL (Tokyo, Japan) JNM-ECA 500
spectrometer (500 MHz) in deuterated solvents. 1H NMR data
are reported as follows: chemical shift (d, ppm), integration, mul-
tiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet, or
unresolved), coupling constants (J) in Hz, assignments. 13C NMR
data are reported in terms of chemical shift (d, ppm). ESI–HRMS
spectra were recorded on a JEOL JMS-T100LC instrument or on
a Thermo (MA, USA) Exactive spectrometer.
Benzyl 2-(S)-(tert-butoxycarbonylamino)-4-(3-pyridyl)
butanoate (7).
Benzyl 2-(S)-(tert-butoxycarbonylamino)-4-(2-pyridyl)
butanoate (6).
Initial method. Zinc dust (200 mg, 3.0 mmol) was placed in a
nitrogen-purged flask. Dry DMF (150mL) and 1,2-dibromoethane
(13 mL, 0.15mmol) were added to a flask, and the solution was
heated at 60ꢀC for 30min in an oil bath. The mixture was
allowed to cool to room temperature, and then trimethylsilyl
chloride (4.0 mL, 0.03mmol) was added. After the resulting
mixture was stirred vigorously for 30min, a solution of benzyl
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2014
Improved Negishi Cross-Coupling Reactions of an Organozinc Reagent Derived
from L-Aspartic Acid with Monohalopyridines
273
Zinc dust (200 mg, 3.0 mmol) was placed in a nitrogen-purged
1.5 mL Eppendorf microtube. Dry DMF (150 mL) and trimethylsilyl
chloride (60.0 mL, 0.47mmol) were added to the microtube, and
the resulting mixture was stirred vigorously for 30 min at room
temperature. After stirring, the solution was removed by micro-
syringe. The remaining solid was dried using a hot air gun at
reduced pressure. The activated zinc was cooled to room temper-
ature. A solution of benzyl 2-(S)-(tert-butoxycarbonylamino)-
4-iodobutanoate 5 (210 mg, 0.5 mmol) in dry DMF (100 mL Â 2)
was then added to the activated zinc. The reaction mixture was
stirred at room temperature. The insertion of zinc was monitored
by TLC, with the insertion time ranging from approximately
10min to 1 h. After stirring, the zinc solution was allowed to settle
by using a centrifuge for 1 min at room temperature. The organozinc
solution was removed via a microsyringe and added to a 10mL
flask containing Pd2(dba)3 (12.2 mg, 0.01 mmol), P(2-furyl)3
(9.29 mg, 0.04mmol), and 2-iodopyridine (38.8mL, 0.38mmol),
rinse with DMF (150 mL). After stirring for 3 h at room temperature,
the reaction mixture was diluted with ethyl acetate (50 mL), washed
with brine (30 mL Â 3), dried over sodium sulfate, and concentrated
under reduced pressure to give the crude product as oil. Purification
by silica gel column chromatography (hexane/ethyl acetate = 2:1)
afforded the pure benzyl 2-(S)-(tert-butoxycarbonylamino)-4-
(2-pyridyl)butanoate 6 as a yellow oil (100.9 mg, 0.47 mmol,
72%); Rf = 0.50 (hexane/ethyl acetate = 1:1); [a]2D1 À15.5 (c 0.1,
MeOH); IR (neat, cmÀ1) 3356, 2976, 1710, 1591, 1570, 1500,
1366, 1163, 1050, 865, 752, 699, 580, 499, 461; 1H NMR
(300MHz, CDCl3) d 8.52 (1H, d, J = 4.2 Hz, Py-H6), 7.61
(1H, dd, J = 6.9, 6.3 Hz, Py-H3), 7.35 (5H, d, J = 2.7 Hz, Bn),
7.15–7.11 (1H, m, Py-H4), 7.15–7.11 (1H, m, Py-H5), 5.39 (1H,
m, NH), 5.15 (2H, d, J = 2.1 Hz, Bn), 4.39 (1H, s, CH), 2.89–2.84
(2H, m, CH2), 2.31–2.26 (1H, m, CH), 2.16–2.11 (1H, m, CH),
1.43 (9H, s, tBu); 13C NMR (75 MHz, CDCl3) d 160.05, 155.13,
148.83, 136.09, 135.06, 128.16, 127.94, 127.85, 122.66, 120.92,
79.32, 66.57, 53.04, 33.58, 31.66, 29.28, 27.91; ESI–HRMS (m/z)
calcd for C21H26N2NaO4 [M+ Na]+ 393.1790, found 393.1791.
Benzyl 2-(S)-(tert-butoxycarbonylamino)-4-(4-pyridyl)
butanoate (8).
rinse with DMF (150mL). After stirring for 3 h at room temperature,
the reaction mixture was diluted with ethyl acetate (50 mL), washed
with brine (30 mLÂ 3), dried over sodium sulfate, and concentrated
under reduced pressure to give the crude product as oil. Purification
by silica gel column chromatography (hexane/ethyl acetate = 1:1)
afforded the pure benzyl 2-(S)-(tert-butoxycarbonylamino)-4-
(4-pyridyl)butanoate 8 as a yellow oil (124.2 mg, 0.34 mmol,
90%); Rf = 0.47 (hexane/ethyl acetate = 1:2); [a]2D1 À20.0 (c 0.1,
MeOH); IR (neat, cmÀ1) 3356, 2978, 1710, 1619, 1514, 1454,
1
1367, 1168, 1027, 914, 737, 699, 578, 499, 472, 419; H NMR
(300 MHz, CDCl3) d 8.61 (2H, d, J = 5.7 Hz, Py-H2,H6), 7.35
(5H, s, Bn), 7.20 (2H, d, J = 5.7 Hz, Py-H3,H4), 5.24–5.09 (2H,
dd, J = 12.3, 12.0Hz, Bn), 5.16 (1H, s, NH), 4.36 (1H, s, CH),
2.75–2.55 (2H, m, CH2), 2.20–2.08 (1H, m, CH), 1.99–1.87
(1H, m, CH), 1.43 (9H, s, tBu); 13C NMR (75MHz, CDCl3) d
154.96, 152.62, 148.67, 134.75, 128.36, 128.34, 128.23, 128.15,
124.45, 79.88, 66.98, 51.62, 32.64, 30.58, 27.93; ESI–HRMS (m/z)
calcd for C21H26N2NaO4 [M + Na]+ 393.1790, found 393.1776.
Acknowledgments. This work was supported by a Grant-in-Aid
for Young Scientists (B) from the Ministry of Education, Culture,
Sports, Science and Technology (MEXT) of Japan (KAKENHI
Grant Number 22710224), the Sophia University Collaborative
Research Grant, and the Japan Gasoline Company—Saneyoshi
(JGC-S) Scholarship Foundation. We thank Dr. Yong Y. Lin
(Columbia University) for suggestions.
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Zinc dust (200 mg, 3.0 mmol) was placed in a nitrogen-purged
1.5 mL Eppendorf microtube. Dry DMF (150 mL) and trimethylsi-
lyl chloride (60.0 mL, 0.47 mmol) were added to the microtube,
and the resulting mixture was stirred vigorously for 30 min at
room temperature. After stirring, the solution was removed by
microsyringe. The remaining solid was dried using a hot air gun
at reduced pressure. The activated zinc was cooled to room tem-
perature. A solution of benzyl 2-(S)-(tert-butoxycarbonylamino)-
4-iodobutanoate 5 (210 mg, 0.5 mmol) in dry DMF (100 mL Â 2)
was then added to the activated zinc. The reaction mixture was
stirred at room temperature. The insertion of zinc was monitored
by TLC, with insertion time ranging from approximately 10min
to 1 h. After stirring, the zinc solution was allowed to settle by
using a centrifuge for 1 min at room temperature. The organozinc
solution was removed via microsyringe and added to a 10mL
flask, containing Pd2(dba)3 (12.2 mg, 0.01mmol), P(2-furyl)3
(9.29 mg, 0.04mmol), and 4-iodopyridine (76.9mg, 0.38mmol),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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