Halogen–metal exchange on bromoheterocyclics with substituents containing an acidic proton via formation of a magnesium intermediate

Article abstract of DOI:10.3390/molecules22111952

A selective and practical bromine–metal exchange on bromoheterocyclics bearing substituents with an acidic proton under non-cryogenic conditions was developed by a simple modification of an existing protocol. Our protocol of using a combination of i-PrMgCl and n-BuLi has not only solved the problem of intermolecular quenching that often occurred when using alkyl lithium alone as the reagent for halogen–lithium exchange, but also offered a highly selective method for performing bromo–metal exchange on dibrominated arene compounds through chelation effect.

Full text of DOI:10.3390/molecules22111952

molecules
Article
Halogen–Metal Exchange on Bromoheterocyclics with
Substituents Containing an Acidic Proton via
Formation of a Magnesium Intermediate
Qingqiang Tian, Suqin Shang, Huajun Wang, Guoqiang Shi, Zhiyao Li and Jianyong Yuan *
Pharmacy College, Chongqing Medical University, Chongqing 400016, China; Tqingqiang@163.com (Q.T.);
ssqhcq@163.com (S.S.); Wanghuajun333@163.com (H.W.); 17790191007@163.com (G.S.);
18883850724@163.com (Z.L.)
* Correspondence: Yuanjianyong@cqmu.edu.cn; Tel./Fax: +86-23-6848-5161
Received: 18 October 2017; Accepted: 9 November 2017; Published: 11 November 2017
Abstract: A selective and practical bromine–metal exchange on bromoheterocyclics bearing
substituents with an acidic proton under non-cryogenic conditions was developed by a simple
modification of an existing protocol. Our protocol of using a combination of i-PrMgCl and n-BuLi
has not only solved the problem of intermolecular quenching that often occurred when using alkyl
lithium alone as the reagent for halogen–lithium exchange, but also offered a highly selective method
for performing bromo–metal exchange on dibrominated arene compounds through chelation effect.
Keywords: acidic proton; non-cryogenic; arene; bromine–metal exchange
1. Introduction
Substituted heterocyclics are an important class of heterocyclic building blocks that are routinely
used in the synthesis of medicinal and agrochemical products [1]. Functionalization of heterocyclics
via organometallic intermediates has been one of the most frequently used methods for the synthesis
of various heterocyclic derivatives. One of the strategies relies on the rapid bromine–lithium
exchange reaction on halogenated heterocyclics under cryogenic conditions at low temperature [2].
However, the reactivity and stability of the lithiated species under the reaction conditions usually
require cryogenic conditions to minimize undesired side-reactions, such as nucleophilic attack of the
heterocyclic ring by alkyl lithium (Scheme 1) [3–10]. The protocol reported by the literature basically
allows for the lithiation of bromo-substituted heterocycles in the presence of N–H and O–H acidic
protons such as indoles or phenols. Corresponding protocols are known. In these papers, as the authors
did more than two equivalents of the organo-lithium reagent (or another strong base such as KH) is
employed, and first deprotonation of the acidic protons takes place, followed by the lithiation [11–14].
Alternatively, the preparation of the Grinard reagent via halogen–magnesium exchange typically
uses i-PrMgCl. The subsequent quenching with various electrophiles has been proven to be a highly
useful method for the synthesis of heterocyclic derivatives [15
functional groups can tolerate the process of halogen–metal exchange, which considerably enhanced its
synthetic utility. However, for those substrates that bearing an acidic proton (Compound , Scheme 1),
–21]. In this method, the additional
1
i-PrMgCl is generally not reactive enough to affect Br–Mg exchange. Under these circumstances,
the use of more reactive alkyl lithium reagents only made limited success because of nucleophilic
attack on the pyridine ring by n-BuLi as well as the formation of corresponding protonated products
due to intermolecular quenching [22–25] (Br–Li exchange is usually fast enough to compete with the
removal of an acidic proton by n-BuLi).
Molecules 2017, 22, 1952; doi:10.3390/molecules22111952
www.mdpi.com/journal/molecules

Molecules 2017, 22, 1952
2 of 12
previous works
E+
E
X
R
R
R1MgX
R1MgLi
KH, tBuLi/n-BuLi
LITMP
X
Y
E+
or
or
(i-Pr)2MgaLiCl
R'
R'
R
R
+
N
E
E
X = I, Br, Cl
Y = C , N
R, R' = Alkyl, Aryl, Ester, Cyan, etc
N
X
X
Y
This work
E+
Br
E
R1
R1
A
H
A
H
X
i-PrMgCl
n-BuLi
X
or
or
-20-0
℃
E+
H2O
R1
E+
R1
X
E
X
Br
X = C , N
A = O, N
R1 = Alkyl; Aryl, Halogen etc
N
N
H
H
3
1
Scheme 1. Metal halogen exchange method.
Therefore, the development of new methodologies that can address these issues is highly desirable.
In this paper, we wish to report that halogen–metal exchange on heterocyclic substrates bearing an
acidic proton can be performed efficiently through a combined use of i-PrMgCl and n-BuLi under
essentially noncryogenic conditions and that high regioselectivity can be achieved on halogen–metal
exchange on substrate with two bromo groups via chelation effect.
2. Results and Discussion
We started with bromopyridine 1a that substituted with a Boc-protected amino group to explore
the best condition to execute the Br–Mg exchange in the presence of an acidic carbamate proton.
When Compound 1a was treated with one to three equivalents of i-PrMgCl at room temperature,
no expected Br–Mg exchange took place (Table 1, entries 1–3). In addition, we used three equivalents of
◦
i-PrMgCl, lowered the temperature to 0 C and increased the reaction time, with no expected exchange
results, resulting in a list of impurities (Table 1, entry 4). Subsequently, we used the more active lithium
reagent to treat Compound 1a with one to three equivalents of n-BuLi at low temperature and did
not find the desired target product to obtain unwanted polymers (Table 1, entries 5–7). In this case,
we considered the combination of i-PrMgCl and n-BuLi. First, we explored i-PrMgCl:n-BuLi = 1:1
equivalent and found no efficient exchange (Table 1, entry 8). Then, when we increased the amount
of i-PrMgCl to i-PrMgCl:n-◦BuLi = 1:2 equivalents, compound 1a was treated successively with one
equivalent of i-PrMgCl at 0 C and two equivalents of n-BuLi, gratifyingly a clean exchange took place
and subsequent quenching of the intermediate with DMF gave a 90% yield of the expected aldehyde
product 3a (Table 1, entry 9).
According to Knochel et al. [26], LiCl-mediated Br–Mg exchange reaction was used to prepare
functionalized aryl compounds from organic bromides. Then we guessed the role of lithium in the
system. We used inorganic lithium carbonate and lithium chloride instead of n-BuLi, and found no
target product formated (Table 1, entries 10 and 11). At the same time, we used p-bromophenol as
raw material, to further explore the role of inorganic lithium chloride in the system and found no
p-hydroxybenzaldehyde but the starting material (Table 1, entry 12). Therefore, n-BuLi plays a pivotal
role in the reaction.

Molecules 2017, 22, 1952
3 of 12
Table 1. Tert-butyl (5-formylpyridin-2-yl) carbamate of metalating reagents prepared from
2-(N-BOC-amino)-5-bromopyridine.
OHC
Br
metalating
conditions
DMF
BOC
BOC
N
NH
N
NH
3a
1a
Entry
Metalating Reagent
Reaction Conditions
Yield a of 3a (%)
1
2
3
4
5
i-PrMgCl (1.0 equiv.)
i-PrMgCl (2.0 equiv.)
i-PrMgCl (3.0 equiv.)
i-PrMgCl (3.0 equiv.)
n-BuLi (1.0 equiv.)
n-BuLi (2.0 equiv.)
n-BuLi (2.0 equiv.)
THF, rt, 24 h
THF, rt, 24 h
THF, rt, 24 h
Trace
Trace
Trace
Trace
Trace
Trace
Trace
Trace
90
◦
THF, 0 C, 36 h
◦
THF, −78 C, 24 h
◦
6
7
THF, −20 C, 0.5 h
◦
THF, −20 C, 0.5 h
◦
8 b
9 c
10
11
12 d
i-PrMgCl + n-BuLi (1.0:1.0 equiv.)
i-PrMgCl + n-BuLi (1.0:2.0 equiv.)
i-PrMgCl + Li2CO3 (1.0:2.0 equiv.)
i-PrMgCl + LiCl (1.0:2.0 equiv.)
i-PrMgCl + LiCl (1.0:2.0 equiv.)
THF, −20 C, 0.5 h
◦
THF, −20 C, 0.5 h
◦
THF, −20 C, 0.5 h
Trace
Trace
Trace e
◦
THF, −20 C, 0.5 h
◦
THF, −20 C, 0.5 h
a
b
Yields were determined by HPLC; reaction conditions: i-PrMgCl (1.0 equiv.), THF, at 0 ◦C, then n-BuLi
(2.0 equiv.) at
−
20 ◦C; c reaction conditions: i-PrMgCl (1.0 equiv.), THF, at 0 ◦C, then n-BuLi (2.0 equiv.) at
−
20 ◦C;
d
raw materials for bromophenol; e starting material only.
We examined the stability of the metalated species and found that the intermediate was stable in
THF at
20 ◦C, give 3a with a yield of 90%, even after aging for 0.5 h before treated with tert-butyl
−
(5-formylpyridin-2-yl) carbamate (Table 2).
Table 2. Stability of metalating reagents prepared from 2-(N-BOC-amino)-5-bromopyridine.
OHC
Br
*
Reaction conditions
aging time
DMF
BOC
BOC
N
NH
N
NH
3a
1a
*
i-PrMgCl (1.0 equiv); 0 ℃
then n-BuLi (2.0 equiv); -20 ℃
Aging Time (h)
Yield a
0.25
0.5
1
2
5
69
90
75
40
23
a
Yields were determined by HPLC analysis.
Compared with the typical Br–Li exchange with alkyl lithium which requires to be performed
◦
under cryogenic condition, the current reaction could be performed at about 0 C. It was found
that two equivalents of n-BuLi were necessary for the exchange to be completed, indicating that the
bromine–metal exchange was probably affected by the action of an “ate” complex (
formed from one equivalent of N-magnesium salt and two equivalents of n-BuLi [27
2
) (Scheme 2)
–
29]. Similarly,
following the same protocol, bromine–magnesium exchange could be performed successively on
other bromopyridines bearing an acidic carbamate proton, then quenching of the organometallic
intermediates with DMF and other electrophiles to afford a high yield of the corresponding products
(Table 3, entry 1).

Molecules 2017, 22, 1952
4 of 12
Br
A
Mg(n-Bu)2 Li
N
A = O, N
2
Scheme 2. Metal halogen exchange method.
The above-mentioned efficient method for performing halogen–metal exchange on substrates
bearing carbamate group(s) was established. Then, we sought to extend the same procedure to
bromopyridines bearing other phenolic hydroxyl groups. We obtained the same results for the selective
functionalization of the p-bromophenol substrate as those reported with the lithium trialkylmagnesiate
complex (ref. [30,31], 56% yield). Then, we turned our attention to the effect of the acetyl amino
substituent (Table 3, entry 9). The series proceeded here with the same trend as for the bromopyridines
bearing an acidic carbamate proton and resulted in moderate to good yields (94%) with high selectivity.
We examined the selectivity of Br–Mg exchange on a series of dibromo-substituted aromatic
hydrocarbon derivatives bearing an acidic functional group which would allow us to synthesize
aromatic hydrocarbon derivatives substituted with multiple functional groups. As summarized in
Table 3, when dibromo substrates 1e and 1o were treated with one equivalent of i-PrMgCl and two
equivalents of n-BuLi, only one of the bromo groups was exclusively exchanged. Subsequent reaction
of the metallated aromatic hydrocarbons with various electrophiles afforded trisubstituted aromatic
hydrocarbon derivatives 3e and 3o with high yield (Table 3, entries 5 and 15).
Table 3. Br–Mg (Li) exchange on bromopyridines bearing an acidic proton a.
Yield b, %
Entry
Substrate
Electrophile
Product
OHC
Br
O
O
N
N
O
N
N
H
O
1
DMF
90
H
1a
3a
COOH
Br
N
H
2
3
4
5
N
CO2
CO2
CO2
DMF
85
89
65
80
H
3b
1b
Br
COOH
N
N
H
H
3c
1c
Br
HOOC
N
H
N
H
3d
1d
Br
CHO
Br
Br
N
N
H
H
1e
1f
3e
H
H
O
N
O
N
Br
COOH
6
7
CO2
CO2
80
71
3f
Br
HOOC
N
N
N
H
N
H
3g
1g

Molecules 2017, 22, 1952
5 of 12
Table 3. Cont.
Yield b, %
Entry
Substrate
Electrophile
Product
Br
HO
CHO
HO
8
DMF
DMF
90
1h
3h
CHO
H COCHN
3
Br
H COCHN
3
9
94
89
1i
3i
H
N
H
N
Br
CHO
10
DMF
1j
NH
3j
NH
CHO
Br
11
12
13
DMF
DMF
CO2
91
85
93
N
N
3k
1k
NH
NH
N
Br
OHC
N
1l
3l
3m COOH
HO
N
HO
N
Br
1m
3m
1m
Br
HO
HOOC
14
CO2
CO2
79
80
N
HO
N
1n
3n
Br
Br
Br
HO
HOCC
HO
15
N
N
1o
3o
a
Reaction conditions: i-PrMgCl (1.0 equiv.), THF, 0 ◦C, then n-BuLi (2.0 equiv.)
−
20 ◦C; b yield of isolated product.
To further illustrate the efficient method for bromine–metal exchange on bromopyridines and
arenes bearing an acidic proton-containing substituent, we selected bromoindole and heteroaromatic
substrates that have active hydrogen sensitive moieties (Table 3), such as bromoindole (entries 3,
4 and 6), bromo benzimidazole (entry 7), bromopyrrole (entry 10), bromoimidazole (entries 11 and 12).
In a few cases (entries 4 and 7), the isolated yields were poor (e.g., <80%), which can be attributed to a
combination of steric and electronic factors or to the volatility of the product (entries 4 and 7).
Based on the above results and the published literature [32–35], we postulated a tentative
mechanism of halogen–metal exchange in Scheme 3. Initially, we used one equiv. of i-PrMgCl to remove
the active proton hydrogen from the aromatic hydrocarbon at 0 ◦C to form the organomagnesium
reagent (
the magnesium salt to form an “ate” complex and the rest of n-BuLi exchanged with the halogen to
form magnesium compound ( ). Next, one equiv. of an electrophilic reagent was coupled to the C–Li
bond (c). Finally, water was added to provide proton hydrogen to obtain the desired product (d).
a), and then added two equivs. of n-BuLi at
−
20 ◦C. A half of the n-BuLi combined with
b
Br
Br
Li
2equiv n -BuLi
MgCl
i-PrMgCl
H
A
A
A
Mg(n-Bu) Li
2
N
N
N
a
b
E
E
E
H O
2
A
Mg(n-Bu) Li
2
A
H
N
N
d
c
A = O ,N
Scheme 3. Metal halogen exchange method.

Molecules 2017, 22, 1952
6 of 12
3. Materials and Methods
General remarks: All reagents were obtained from Aladdin Reagent Shanghai Co., Ltd. (Shanghai,
China), Lagewell Technology Co., Ltd., Meyer Reagent Shanghai Co., Ltd., Macklin Reagent Shanghai
Co., Ltd., Chongqing Chuandong Chemical Co., Ltd. etc. without further purification unless otherwise
noted. High resolution mass spectra (South China Agricultural University, Guangzhou) were measured
on commercial instruments. NMR spectra were recorded on commercial instruments (Bruker company,
Karlsruhe, Germany) and operated at 600 MHz for 1H-NMR and 151 MHz for 13C-NMR. Chemical
shifts were reported in ppm from tetramethylsilane with the solvent resonance as the internal standard
((CD3)2SO,
tetramethylsilane with the solvent resonance as internal standard ((CD3)2SO,
spectra. Spectra are reported as follows: chemical shift ( ppm), multiplicity (s = singlet, d = doublet,
δ
= 2.50,
δ
= 3.33) in 1H-NMR spectra and chemical shifts were reported in ppm from the
= 39.5) in 13C-NMR
δ
δ
t = triplet, q = quartet, m = multiplet), coupling constants (Hz), integration and assignment.
(5-Formyl-pyridin-2-yl)-carbamic acid tert-butyl ester (3a): To a solution of (5-Bromo-pyridin-2-yl)-
carbamic acid tert-butyl ester (1.0 g, 3.7 mmol, 1.0 equiv.) in dry THF (12 mL) at 0 ◦C was added a
2 M solution of i-PrMgCl in THF (1.85 mL, 3.7 mmol, 1.0 equiv.) during 5 min. The clear solution was
stirred at that temperature for an additional 5 min, and a 2.5 M solution of n-BuLi in hexanes (3 mL,
7.5 mmol, 2.0 equiv.) was added dropwise during 5 min, while maintaining the temperature below
−
20 ◦C. The resulting mixture was stirred at that temperature for 0.5 h, dry DMF (0.27 g, 3.7 mmol,
1.0 equiv.) in dry THF (5 mL) was added dropwise during 10 min. The resulting mixture was warmed
◦
◦
20 C for 10 min,
to
the phases were separated and the water phase was extracted one additional time with ethyl acetate.
The resulting suspension was allowed to reach room temperature and fitered through a 0.5 1 cm
−
20 C in 0.5 h and quenched with water (6 mL). After stirring the mixture below
−
×
pad of silica gel eluted with 10 mL of ethyl acetate. The filtrate was concentrated and the residue was
purified by flash chromatography on silica gel (eluent: petroleum ether/ethyl acetate = 10:1) to afford
1
product 3a as white solid, 0.73 g (yield: 90%). H-NMR (600 MHz, DMSO)
δ 10.42 (s, 1H), 9.94 (s, 1H),
8.93–8.60 (m, 1H), 8.17 (dd, J = 8.8, 2.3 Hz, 1H), 7.99 (d, J = 8.8 Hz, 1H), 1.48 (s, 9H). 13C-NMR (151 MHz,
DMSO) δ 191.18, 157.08, 152.82, 152.40, 138.23, 127.30, 112.23, 80.97, 28.37.
1H-Indole-2-carboxylic acid (3b): To a solution of 2-Bromo-1H-indole (1.0 g, 5 mmol, 1.0 equiv.) in dry
◦
THF (20 mL) at 0 C was added a 2 M solution of i-PrMgCl in THF (2.5 mL, 5 mmol, 1.0 equiv.) during
5 min. The clear solution was stirred at that temperature for an additional 5 min, and a 2.5 M solution
of nBuLi in hexanes (4 mL, 10 mmol, 2.0 equiv.) was added dropwise during 5 min, while maintaining
◦
the temperature below
−
20 C. The resulting mixture was stirred at that temperature for 0.5 h, dry CO2
◦
◦
(0.22 g, 5 mmol, 1.0 equiv.) was added to
and quenched with water (6 mL). After stirring the mixture below
separated and the water phase was extracted one additional time with ethyl acetate. The resulting
suspension was allowed to reach room temperature and fitered through a 0.5 1 cm pad of silica
−
20 C. The resulting mixture was warmed to
−
20 C in 0.5 h
◦
−
20 C for 10 min, the phases were
×
gel eluted with 10 mL of ethyl acetate. The filtrate was concentrated and the residue was purified
by flash chromatography on silica gel (eluent: petroleum ether/ethyl acetate = 3:1) to afford product
3b as white solid, 0.7 g (yield: 85%), m.p.: 203–204 ◦C. 1H-NMR (600 MHz, DMSO)
δ
12.94 (s, 1H),
11.76 (s, 1H), 7.79–6.89 (m, 5H). 13C-NMR (151 MHz, DMSO)
122.40, 120.41, 112.95, 107.77.
δ 163.29, 137.71, 128.88, 127.34, 124.73,
1H-Indole-3-carboxylic acid (3c): To a solution of 3-Bromo-1H-indole (0.86 g, 4.4 mmol, 1.0 equiv.) in dry
◦
THF (20 mL) at 0 C was added a 2 M solution of i-PrMgCl in THF (2.2 mL, 4.4 mmol 1.0 equiv.) during
5 min. The clear solution was stirred at that temperature for an additional 5 min, and a 2.5 M solution of
n-BuLi in hexanes (3.5 mL, 8.8 mmol, 2.0 equiv.) was added dropwise during 5 min, while maintaining
◦
the temperature below
−
20 C. The resulting mixture was stirred at that temperature for 0.5 h, dry CO2
(0.2 g, 4.4 mmol, 1.0 equiv.) was added to
0.5 h and quenched with water (6 mL). After stirring the mixture below −20 ◦C for 10 min, the phases
−
20 ◦C. The resulting mixture was warmed to
−
20 ◦C in

Molecules 2017, 22, 1952
7 of 12
were separated and the water phase was extracted one additional time with ethyl acetate. The resulting
suspension was allowed to reach room temperature and fitered through a 0.5 1 cm pad of silica
×
gel eluted with 10 mL of ethyl acetate. The filtrate was concentrated and the residue was purified by
flash chromatography on silica gel (eluent: petroleum ether/ethyl acetate = 3:1) to afford product 3c
as off-white solid, 0.63 g (yield: 89%), m.p.: 193–196 ◦C. 1H-NMR (600 MHz, DMSO)
δ
11.82 (s, 1H),
166.43,
8.02 (t, J = 5.7 Hz, 2H), 7.47 (d, J = 7.6 Hz, 1H), 7.32–6.99 (m, 2H). 13C-NMR (151 MHz, DMSO)
δ
136.89, 132.71, 126.48, 122.58, 121.42, 121.05, 112.65, 107.87.
1H-Indole-5-carboxylic acid (3d): To a solution of 5-Bromo-1H-indole (0.86 g, 4.4 mmol, 1.0 equiv.) in dry
◦
THF (20 mL) at 0 C was added a 2 M solution of i-PrMgCl in THF (2.2 mL, 4.4 mmol, 1 equiv.) during
5 min. The clear solution was stirred at that temperature for an additional 5 min, and a 2.5 M solution of
n-BuLi in hexanes (3.5 mL, 8.8 mmol, 2.0 equiv.) was added dropwise during 5 min, while maintaining
◦
the temperature below
−
20 C. The resulting mixture was stirred at that temperature for 0.5 h, dry CO2
(0.2 g, 4.4 mmol, 1.0 equiv.) was added to −20 ◦C. The resulting mixture was warmed to
−
20 ◦C in
0.5 h and quenched with water (6 mL). After stirring the mixture below for 10 min, the phases were
separated and the water phase was extracted one additional time with ethyl acetate. The resulting
suspension was allowed to reach room temperature and fitered through a 0.5 × 1 cm pad of silica
gel eluted with 10 mL of ethyl acetate. The filtrate was concentrated and the residue was purified by
flash chromatography on silica gel (eluent: petroleum ether/ethyl acetate = 3:1) to afford product 3d
as off-white solid, 0.46 g (yield: 65%), m.p.: 210–214 ◦C. 1H-NMR (600 MHz, DMSO)
δ 12.39 (s, 1H),
11.46 (s, 1H), 8.25 (s, 1H), 7.72 (dd, J = 8.5, 1.5 Hz, 1H), 7.45 (dd, J = 8.4, 5.7 Hz, 2H), 6.57 (s, 1H).
13C-NMR (151 MHz, DMSO) δ 168.90, 138.80, 127.64, 127.35, 123.28, 122.67, 121.87, 111.57, 102.93.
5-Bromo-1H-indole-3-carbaldehyde (3e): To a solution of 3,5-dibromo-1H-indole (1.2 g, 4.4 mmol,
◦
1.0 equiv.) in dry THF (20 mL) at 0 C was added a 2 M solution of iPrMgCl in THF (2.2 mL,
4.4 mmol, 1.0 equiv.) during 5 min. The clear solution was stirred at that temperature for an additional
5 min, and a 2.5 M solution of n-BuLi in hexanes (3.5 mL, 8.8 mmol, 2.0 equiv.) was added dropwise
during 5 min, while maintaining the temperature below
that temperature for 0.5 h, dry DMF (0.32 g, 4.4 mmol, 1.0 equiv.) was added to
−
20 ◦C. The resulting mixture was stirred at
−
20 ◦C. The resulting
20 ◦C in 0.5 h and quenched with water (6 mL). After stirring the mixture
mixture was warmed to
−
◦
below
−
20 C for 10 min, the phases were separated and the water phase was extracted one additional
time with ethyl acetate. The resulting suspension was allowed to reach room temperature and fitered
through a 0.5 1 cm pad of silica gel eluted with 10 mL of ethyl acetate. The filtrate was concentrated
and the residue was purified by flash chromatography on silica gel (eluent: petroleum ether/ethyl
acetate = 3:1) to afford product 3e as yellow solid, 0.78 g (yield: 80%), m.p.: 192–194 C. 1H-NMR
×
◦
(600 MHz, DMSO)
δ
12.35 (s, 1H), 9.93 (s, 1H), 8.47–8.05 (m, 2H), 7.57–7.21 (m, 2H). 13C-NMR (151 MHz,
DMSO) δ 185.57, 139.67, 136.23, 126.49, 126.36, 123.39, 117.90, 115.27, 115.01.
5-Methoxy-1H-indole-2-carboxylic acid (3f): To a◦solution of 2-Bromo-5-methoxy-1H-indole (1.0 g,
4.4 mmol, 1.0 equiv.) in dry THF (20 mL) at 0 C was added a 2 M solution of i-PrMgCl in THF
(2.2 mL, 4.4 mmol, 1.0 equiv.) during 5 min. The clear solution was stirred at that temperature for an
additional 5 min, and a 2.5 M solution of n-BuLi in hexanes (3.5 mL, 8.8 mmol, 2.0 equiv.) was added
dropwise during 5 min, while maintaining the temperature below
stirred at that temperature for 0.5 h, dry CO2 (0.20 g, 1.0 equiv.) was added to
−
20 ◦C. The resulting mixture was
20 ◦C. The resulting
−
mixture was warmed to
−
20 ◦C in 0.5 h and quenched with water (6 mL). After stirring the mixture
below −20 ◦C for 10 min, the phases were separated and the water phase was extracted one additional
time with ethyl acetate. The resulting suspension was allowed to reach room temperature and fitered
through a 0.5
×
1 cm pad of silica gel eluted with 10 mL of ethyl acetate. The filtrate was concentrated
and the residue was purified by flash chromatography on silica gel (eluent: petroleum ether/ethyl
◦
1
acetate = 3:1) to afford product 3f as brown solid, 0.68 g (yield: 80%), m.p.: 199–201 C. H-NMR
(600 MHz, DMSO) 7.36 (d, J = 8.9 Hz, 1H), 7.06 (d, J = 23.6 Hz, 2H), 6.90 (d, J = 8.8 Hz, 1H), 3.73 (s, 3H)
13C-NMR (151 MHz, DMSO)
163.25, 154.31, 133.07, 129.10, 127.65, 116.28, 113.83, 107.47, 102.44, 55.61.
δ
.
δ

Molecules 2017, 22, 1952
8 of 12
1H-Benzoimidazole-5-carboxylic acid (3g):◦To a solution of 5-Bromo-1H-benzimidazole (0.87 g, 4.4 mmol,
1.0 equiv.) in dry THF (20 mL) at 0 C was added a 2 M solution of i-PrMgCl in THF (2.2 mL,
1 equiv.) during 5 min. The clear solution was stirred at that temperature for an additional 5 min,
and a 2.5 M solution of n-BuLi in hexanes (3.5 mL, 8.8 mmol, 2.0 equiv.) was added dropwise during
5 min, while maintaining the temperature below
temperature for 0.5 h, dry CO2 (0.20 g, 4.4mmol, 1.0 equiv.) was added to
−
20 ◦C. The resulting mixture was stirred at that
◦
−
20 C. The resulting
mixture was warmed to
−
20 ◦C in 0.5 h and quenched with water (6 mL). After stirring the mixture
◦
below
−
20 C for 10 min, the phases were separated and the water phase was extracted one additional
time with ethyl acetate. The resulting suspension was allowed to reach room temperature and fitered
through a 0.5 1 cm pad of silica gel eluted with 10 mL of ethyl acetate. The filtrate was concentrated
×
and the residue was purified by flash chromatography on silica gel (eluent:petroleum ether/ethyl
1
acetate = 3:1) to afford product 3g as brown solid, 0.5 g (yield: 71%). H-NMR (600 MHz, DMSO)
8.43 (s, 1H), 8.26 (s, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H). 13C-NMR (151 MHz, DMSO)
168.47, 144.83, 125.10, 123.74, 118.13, 115.12.
δ
δ
4-Hydroxy-benzaldehyde (3h): To a solution of 4-Bromo-phenol (1.5 g, 8.7 mmol, 1 equiv.) in dry THF
(25 mL) at 0 ◦C was added a 2 M solution of i-PrMgCl in THF (4.3 mL, 8.7 mmol, 1.0 equiv.) during
5 min. The clear solution was stirred at that temperature for an additional 5 min, and a 2.5 M solution of
n-BuLi in hexanes (7.0 mL, 17.4 mmol, 2.0 equiv.) was added dropwise during 5 min, while maintaining
◦
the temperature below
−
20 C. The resulting mixture was stirred at that temperature for 0.5 h, dry DMF
(0.63 g, 8.7 mmol, 1.0 equiv.) in dry THF (5 mL) was added dropwise during 10 min. The resulting
mixture was warmed to
−
20 ◦C in 0.5 h and quenched with water (6 mL). After stirring the mixture
◦
below
−
20 C for 10 min, the phases were separated and the water phase was extracted one additional
time with ethyl acetate. The resulting suspension was allowed to reach room temperature and fitered
through a 0.5 1 cm pad of silica gel eluted with 10 mL of ethyl acetate. The filtrate was concentrated
and the residue was purified by flash chromatography on silica gel (eluent:petroleum ether/ethyl
×
◦
1
acetate = 5:1) to afford product 3h as white solid, 0.94 g (yield: 90%), m.p.: 114–116 C. H-NMR
(600 MHz, DMSO)
δ
10.59 (s, 1H), 9.78 (s, 1H), 7.75 (d, J = 8.6 Hz, 2H), 6.93 (d, J = 8.6 Hz, 2H). 13C-NMR
(151 MHz, DMSO) δ 191.35, 191.33, 163.76, 132.53, 128.89, 116.29.
N-(4-Formyl-phenyl)-acetamide (3i): To a solution of 4-Bromo-phen N-(4-Formyl -phenyl)-acetamide
(1.5 g, 7.0 mmol, 1.0 equiv.) in dry THF (25 mL) at 0 ◦C was added a 2 M solution of iPrMgCl in THF
(3.5 mL, 7.0 mmol, 1.0 equiv.) during 5 min. The clear solution was stirred at that temperature for an
additional 5 min, and a 2.5 M solution of n-BuLi in hexanes (5.6 mL, 14.0 mmol, 2.0 equiv.) was added
dropwise during 5 min, while maintaining the temperature below
−
20 ◦C. The resulting mixture was
stirred at that temperature for 0.5 h, dry DMF (0.5 g, 1.0 equiv.) in dry THF (5 mL) was added dropwise
◦
during 10 min. The resulting mixture was warmed to
After stirring the mixture below
was extracted one additional time with ethyl acetate. The resulting suspension was allowed to reach
room temperature and fitered through a 0.5 1 cm pad of silica gel eluted with 10 mL of ethyl acetate.
−
20 C in 0.5 h and quenched with water (6 mL).
−
20 ◦C for 10 min, the phases were separated and the water phase
×
The filtrate was concentrated and the residue was purified by flash chromatography on silica gel
(eluent: petroleum ether/ethyl acetate = 10:1) to afford product 3i as white solid, 1.0 g (yield: 94%) ,
m.p.: 157–158 ◦C. 1H-NMR (600 MHz, DMSO)
δ 10.35 (s, 1H), 9.86 (s, 1H), 7.81 (dd, J = 32.9, 8.6 Hz,
4H), 2.10 (s, 3H). 13C-NMR (151 MHz, DMSO) δ 191.92, 169.55, 145.29, 131.56, 131.27, 119.01, 24.68.
1H-Pyrrole-2-carbaldehyde (3j): To a solution of 2-Bromo-1H-pyrrole (0.5 g, 3.4 mmol, 1.0 equiv.) in
dry THF (15 mL) at 0 ◦C was added a 2 M solution of i-PrMgCl in THF (1.7 mL, 3.4 mmol, 1.0 equiv.)
during 5 min. The clear solution was stirred at that temperature for an additional 5 min, and a
2.5 M solution of n-BuLi in hexanes (2.7 mL, 6.8 mmol, 2.0 equiv.) was added dropwise during
5 min, while maintaining the temperature below
−
20 ◦C. The resulting mixture was stirred at that
temperature for 0.5 h, dry DMF (0.25 g, 1.0 equiv.) in◦dry THF (5 mL) was added dropwise during
10 min. The resulting mixture was warmed to
−
20 C in 0.5 h and quenched with water (6 mL).

Molecules 2017, 22, 1952
9 of 12
After stirring the mixture below
−
20 ◦C for 10 min, the phases were separated and the water phase
was extracted one additional time with ethyl acetate. The resulting suspension was allowed to reach
room temperature and fitered through a 0.5 × 1 cm pad of silica gel eluted with 10 mL of ethyl acetate.
The filtrate was concentrated and the residue was purified by flash chromatography on silica gel
(
eluent:petroleum ether/ethyl acetate = 10:1) to afford product 3j as white solid, 0.29 g (yield: 89%) ,
m.p.: 42–44 ◦C. 1H-NMR (600 MHz, DMSO)
δ 12.19 (s, 1H), 11.69 (s, 1H), 7.04–6.85 (m, 1H), 6.72 (dd,
J = 4.2, 2.9 Hz, 1H), 6.12 (dd, J = 5.8, 2.4 Hz, 1H). 13C-NMR (151 MHz, DMSO)
δ 162.31, 123.82, 123.35,
115.11, 109.73.
1H-Imidazole-2-carbaldehyde◦(3k): To a solution of 2-bromo-1H-imidazole (0.65 g, 4.4 mmol, 1.0 equiv.)
in dry THF (20 mL) at 0 C was added a 2 M solution of i-PrMgCl in THF (2.2 mL, 4.4 mmol,
1.0 equiv.) during 5 min. The clear solution was stirred at that temperature for an additional
5 min, and a 2.5 M solution of n-BuLi in hexanes (3.5 mL, 8.8 mmol, 2.0 equiv.) was added
dropwise during 5 min, while maintaining the temperature below −20 ◦C. The resulting mixture
was stirred at that temperature for 0.5 h, dry DMF ◦(0.32 g, 4.4 mmol, 1.0 equiv.) was added to
20 C in 0.5 h and quenched with water (6 mL).
−20 ◦C. The resulting mixture was warmed to
−
After stirring the mixture below
−
20 ◦C for 10 min, the phases were separated and the water phase
was extracted one additional time with ethyl acetate. The resulting suspension was allowed to reach
room temperature and fitered through a 0.5 × 1cm pad of silica gel eluted with 10 mL of ethyl acetate.
The filtrate was concentrated and the residue was purified by flash chromatography on silica gel
(
eluent: petroleum ether/ethyl acetate = 10:1) to afford product 3k as pale yellow solid, 0.38 g (yield:
◦
91%), m.p.: 205–206 C. 1H-NMR (600 MHz, DMSO)
δ
13.60 (s, 1H), 9.64 (s, 1H), 7.42 (s, 2H). 13C-NMR
(151 MHz, DMSO) δ 181.66, 146.09.
1H-Imidazole-4-carbaldehyde (3l): To a solution of 4-bromo-1H-imidazole (0.65 g, 4.4 mmol, 1.0 equiv.) in
dry THF (20 mL) at 0 ◦C was added a 2 M solution of i-PrMgCl in THF (2.2 mL, 4.4 mmol, 1.0 equiv.)
during 5 min. The clear solution was stirred at that temperature for an additional 5 min, and a
2.5 M solution of n-BuLi in hexanes (3.5 mL, 8.8 mmol, 2.0 equiv.) was added dropwise during
5 min, while maintaining the temperature below
temperature for 0.5 h, dry DMF (0.32 g, 4.4 mmol, 1.0 equiv.) was added to
−
20 ◦C. The resulting mixture was stirred at that
20 ◦C. The resulting
20 ◦C in 0.5 h and quenched with water (6 mL). After stirring the mixture
−
mixture was warmed to
−
◦
below
−
20 C for 10 min, the phases were separated and the water phase was extracted one additional
time with ethyl acetate. The resulting suspension was allowed to reach room temperature and fitered
through a 0.5 1 cm pad of silica gel eluted with 10 mL of ethyl acetate. The filtrate was concentrated
and the residue was purified by flash chromatography on silica gel (eluent:petroleum ether/ethyl
acetate = 10:1) to afford product 3l as off-white solid, 0.36 g (yield: 85%), m.p.: 175–177 ◦C. 1H-NMR
×
(600 MHz, DMSO)
134.9, 129.5.
δ δ 184.46, 139.44,
9.74 (s, 1H), 7.99 (s, 1H), 7.94 (s, 1H). 13C-NMR (151 MHz, DMSO)
6-Hydroxy-pyridine-2-carboxylic acid (3m): To a solution of 2-bromo-6-hydroxypyridine (0.76 g, 4.4 mmol,
◦
1.0 equiv.) in dry THF (20 mL) at 0 C was added a 2 M solution of -PrMgCl in THF (2.2 mL,
4.4 mmol, 1.0 equiv.) during 5 min. The clear solution was stirred at that temperature for an
additional 5 min, and a 2.5 M solution of n-BuLi in hexanes (3.5 mL, 8.8 mmol, 2.0 equiv.) was
added dropwise during 5min, while maintaining the temperature below −20 ◦C. The resulting
mixture was stirred at that temperature for 0.5 h, dry CO2 (0.20 g, 1.0 equiv.) was added to
◦
−20 ◦C. The resulting mixture was warmed to
−
20 C in 0.5 h and quenched with water (6 mL).
After stirring the mixture below −20 ◦C for 10 min, the phases were separated and the water phase
was extracted one additional time with ethyl acetate. The resulting suspension was allowed to reach
room temperature and fitered through a mbox0.5
acetate. The filtrate was concentrated and the residue was purified by flash chromatography on silica
×
1 cm pad of silica gel eluted with 10 mL of ethyl
gel (eluent: petroleum ether/ethyl acetate = 10:1) to afford product 3m as off-white solid, 0.56 g (yield:

Molecules 2017, 22, 1952
10 of 12
◦
93%) , m.p.: 275–277 C. 1H-NMR (600 MHz, DMSO)
δ
7.56 (dd, J = 8.9, 7.0 Hz, 1H), 6.97 (d, J = 6.8 Hz
,
1H), 6.65 (d, J = 9.0 Hz, 1H). 13C-NMR (151 MHz, DMSO)
δ
163.28, 162.67, 140.51, 137.97, 123.88, 110.42.
2-Hydroxy-nicotinic acid (3n): To a solution of 3-bromo-2-hydroxypyridine (0.76 g, 4.4 mmol, 1.0 equiv.)
◦
in dry THF (20 mL) at 0 C was added a 2 M solution of i-PrMgCl in THF (2.2 mL, 4.4 mmol, 1.0 equiv.)
during 5 min. The clear solution was stirred at that temperature for an additional 5 min, and a
2.5 M solution of n-BuLi in hexanes (3.5 mL, 8◦.8 mmol, 2.0 equiv.) was added dropwise during 5 min,
while maintaining the temperature below
−
20 C. The resulting mixture was stirred at that temperature
for 0.5 h, dry CO2 (0.20 g, 1.0 equiv.) was added to
−
20 ◦C. The resulting mixture was warmed to
−20 ◦C in 0.5 h and quenched with water (6 mL). After stirring the mixture below
−
20 ◦C for 10 min,
the phases were separated and the water phase was extracted one additional time with ethyl acetate.
The resulting suspension was allowed to reach room temperature and fitered through a 0.5 × 1 cm
pad of silica gel eluted with 10 mL of ethyl acetate. The filtrate was concentrated and the residue was
purified by flash chromatography on silica gel (eluent: petroleum ether/ethyl acetate = 10:1) to afford
product 3n as off-white solid, 0.48 g (yield: 79%), m.p.: 255–257 ◦C. 1H-NMR (600 MHz, DMSO)
δ
14.76 (s, 1H), 13.38 (s, 1H), 8.38 (dd, J = 7.2, 2.0 Hz, 1H), 7.95 (dd, J = 6.3, 2.0 Hz, 1H), 6.68 (t, J = 6.7 Hz,
1H). 13C-NMR (151 MHz, DMSO) δ 165.46, 165.04, 146.61, 141.95, 117.12, 109.09.
5-Bromo-3-hydroxyethynyl-pyridin-2-ol (3o): To a solution of 3,5-dibromo-2-hydroxypyridine (1.1 g,
◦
4.4 mmol, 1.0 equiv.) in dry THF (20 mL) at 0 C was added a 2 M solution of i-PrMgCl in THF (2.2 mL,
4.4 mmol, 1.0 equiv.) during 5 min. The clear solution was stirred at that temperature for an additional
5 min, and a 2.5 M solution of n-BuLi in hexanes (3.5 mL, 8.8 mmol, 2.0 equiv.) was added dropwise
during 5 min, while maintaining the temperature below
that temperature for 0.5 h, dry CO2 (0.20 g, 4.4 mmol, 1.0 equiv.) was added to
−
20 ◦C. The resulting mixture was stirred at
−
20 ◦C. The resulting
20 ◦C in 0.5 h and quenched with water (6 mL). After stirring the mixture
mixture was warmed to
−
◦
below
−
20 C for 10 min, the phases were separated and the water phase was extracted one additional
time with ethyl acetate. The resulting suspension was allowed to reach room temperature and fitered
through a 0.5 1 cm pad of silica gel eluted with 10 mL of ethyl acetate. The filtrate was concentrated
and the residue was purified by flash chromatography on silica gel (eluent: petroleum ether/ethyl
acetate = 10:1) to afford product 3o as Off-white solid, 1.0 g (yield: 80%), m.p.: 245–247 ◦C. 1H-NMR
×
(600 MHz, DMSO)
δ
13.82 (s, 2H), 8.31 (d, J = 2.8 Hz, 1H), 8.23 (d, J = 2.8 Hz, 1H). 13C-NMR (151 MHz,
DMSO) δ 164.43, 163.72, 147.95, 142.51, 118.49, 99.96.
Experimental procedures and analytical data of all compounds (1H-and 13C-NMR), copy of the
1H, 13C and data are available in the Supplementary Materials.
4. Conclusions
In summary, we have developed an efficient method for performing bromine–metal exchange
process under non-cryogenic conditions on bromopyridines and arenes bearing an acidic
proton-containing substituent. The use of a combination of i-PrMgCl and n-BuLi in this method
has solved the problem of intermolecular quenching that is often encountered when using alkyl
lithium. Moreover, the method is particularly suitable for aryl bromides of poor reactivity.
Supplementary Materials: The following are available online, general procedure for Halogen-metal exchange
reaction and 1H and 13C NMR spectra of all products.
Acknowledgments: We are grateful for the generous financial support by the conversion of outstanding
achievements in colleges and universities in Chongqing of China (KJZH14204).
Author Contributions: Guoqiang Shi and Jianyong Yuan conceived and designed the experiments;
Qingqiang Tian performed the experiments; Qingqiang Tian and Suqin Shang analyzed the data; Huajun Wang
and Zhiyao Li contributed reagents/materials/analysis tools; Qingqiang Tian wrote the paper.
Conflicts of Interest: The authors declare no conflicts of interest.

Molecules 2017, 22, 1952
11 of 12
References
1.
2.
Scriven, E. Pyridines: From Lab to Production; Elsevier Ltd.: Amsterdam, The Netherlands, 2013.
Schlosser, M.; Ginanneschi, A.; Leroux, F. In Search of Simplicity and Flexibility: A Rational Access to Twelve
Fluoroindolecarboxylic Acids. Eur. J. Org. Chem. 2006, 13, 2956–2969. [CrossRef]
3.
4.
Knochel, P.; Dohle, W.; Gommermann, N.; Kneisel, F.F.; Kopp, F.; Korn, T.; Sapountzis, I.; Vu, V.A.
Highly Functionalized Organomagnesium Reagents Prepared Through Halogen—Metal Exchange.
Angew. Chem. Int. Ed. 2003, 42, 4302–4320. [CrossRef] [PubMed]
Satoshi, K.; Atsushi, A.; Takehiko, I.; Toshiaki, M.; Nobuyoshi, Y. Bromine–magnesium exchange of
5-bromo-2-picoline via an organomagnesium complex nBu2iPrMgLi: A new preparation methodology
of functionalized picolines under noncryogenic conditions. Tetrahedron Lett. 2006, 47, 1877–1879.
Abarbri, M.; Dehmel, F.; Knochel, P. Bromine-magnesium-exchange as a general tool for the preparation of
polyfunctional aryl and heteroaryl magnesium-reagents. Tetrahedron Lett. 1999, 40, 7449–7453. [CrossRef]
Hui, X.; Schmid, F.; Frank, X.; Figadère, B. Novel and highly regioselective synthesis of unsymmetrical
2,3-disubstituted quinoxalines. Heterocycles 2007, 72, 353–361.
5.
6.
7.
Skillinghaug, B.; Rydfjord, J.; Odell, L.R. Synthesis of sodium aryl sulfinates from aryl bromides employing
1,4-diazabicyclo[2.2.2]octane bis(sulfur dioxide) adduct (DABSO) as a bench-stable, gas-free alternative to
SO2. Tetrahedron Lett. 2016, 57, 533–536. [CrossRef]
8.
9.
Yang, Y. Expedient Synthesis of Quinazoline Analogues through Direct Nucleophilic Arylation/Alkylation
of 2-Chloroquinazoline. Synthesis 2016, 48, 2255–2262. [CrossRef]
Gross, S.; Heuser, S.; Ammer, C.; Heckmann, G.; Bach, T. 2,4-Disubstituted Thiazoles by Regioselective
Cross-Coupling or Bromine–Magnesium Exchange Reactions of 2,4-Dibromothiazole. Synthesis 2011, 2,
199–206. [CrossRef]
10. Fritzsche, R.; Seidel, F.; Rueffer, T.; Buschbeck, R.; Jakob, A.; Freitag, H.; Zahn, D.R.T.; Lang, H.; Mehring, M.
New organosilanes based on N-methylpyrrole–Synthesis, structure and characterization. J. Organomet. Chem.
2014, 755, 86–92. [CrossRef]
11. Kong, W.; Fu, C.; Ma, S. General Au-Catalyzed Benzannulation Towards Naturally Occurring Carbazole
Alkaloids from Methoxypropadiene. Chem. Eur. J. 2011, 17, 13134–13137. [CrossRef] [PubMed]
12. Tois, J.; Koskinen, A. Solid-phase lithiation of 5-carboxyindoles. Tetrahedron Lett. 2003, 44, 2093–2095.
[CrossRef]
13. Qiu, Y.; Ma, D.; Fu, C.; Ma, S. An efficient Au-catalyzed synthesis of isomukonidine, clausine L, mukonidine,
glycosinine, mukonal, and clausine V from propadienyl methyl ether. Org. Biomol. Chem. 2013, 11, 1666–1671.
[CrossRef] [PubMed]
14. Ragan, J.A.; Jones, P.B.; Meltz, C.N.; Teixeira, J.J., Jr. Process for the preparation of isonicotinic acid derivatives.
Synthesis 2002, 4, 483–486. [CrossRef]
15. Trecourt, F.; Breton, G.; Bonnet, V.; Mongin, F.; Marsais, F.; Queguiner, G. Pyridylmagnesium chlorides from
bromo and dibromopyridines by bromine magnesium exchange: A convenient access to functionalized
pyridines. Tetrahedron Lett. 1999, 40, 4339–4342. [CrossRef]
16. Dohle, W.; Staubitz, A.; Knochel, P. Mild Synthesis of Polyfunctional Benzimidazoles and Indoles by the
Reduction of Functionalized Nitroarenes with Phenylmagnesium Chloride. Chem. Eur. J. 2003, 9, 5323–5331.
[CrossRef] [PubMed]
17. Bergauer, M.; Gmeiner, P. Diethoxymethyl Protected Pyrroles: Synthesis and Regioselective Transformations.
Synthesis 2001, 15, 2281–2288. [CrossRef]
18. Kromann, H.; Slok, A.F.; Johansen, N.T.; Krogsgaard-Larsen, P. A convenient synthesis of 4-substituted
3-ethoxy-5-methylisoxazoles by palladium-catalyzed coupling reactions. Tetrahedron 2001, 57, 2195–2201.
[CrossRef]
19. Smith, A.B., III; Minbiole, K.P.; Verhoest, P.R.; Schelhaas, M. Total Synthesis of (+)-Phorboxazole A Exploiting
the Petasis−Ferrier Rearrangement. J. Am. Chem. Soc. 2001, 123, 10942–10953. [CrossRef] [PubMed]
20. Abarbri, M.; Knochel, P. Preparation and Reactions of Magnesiated Uracil Derivatives. Synlett 1999
,
1577–1588. [CrossRef]
21. Jaramillo, C.; Carretero, C.J.; de Diego, E.J.; del Prado, M.; Hamdouchi, C.; Roldán, L.J.; Sánchez-Martínez, C.
Regioselective synthesis of 3,6-disubstituted-2-aminoimidazo[1,2-a]pyridines. Tetrahedron Lett. 2002, 43,
9051–9054. [CrossRef]

Molecules 2017, 22, 1952
12 of 12
22. Beak, P.; Musick, T.J.; Chen, C. Does Formal Intramolecular Transfer of an Acidic Deuterium to a Site
of Halogen-Lithium Exchange Show That Lithium-Halogen Exchange Is Faster than Loss of the Acidic
Deuterium? Evidence in Favor of an Alternative Mechanism. J. Am. Chem. Soc. 1988, 110, 3538–3542.
[CrossRef]
23. Parham, W.E.; Bradsher, C.K. Aromatic Organolithium Reagents Bearing Electrophilic Groups.
Preparation by Halogen-Lithium Exchange. Acc. Chem. Res. 1982, 15, 300–305. [CrossRef]
24. Bailey, W.F.; Patricia, J. The mechanism of the lithium—halogen Interchange reaction: A review of the
literature. J. Organomet. Chem. 1988, 352, 1–46. [CrossRef]
25. Barluenga, J. Preparation and some applications of functionalized organo-lithium compounds in organic
synthesis. Pure Appl. Chem. 1990, 62, 595–604. [CrossRef]
26. Arkady, K.; Knochel, P. A LiCl-Mediated Br/Mg Exchange Reaction for the Preparation of Functionalized Aryl-
and Heteroarylmagnesium Compounds from Organic Bromides. Angew. Chem. Int. Ed. 2004, 3333–3336.
27. Inoue, A.; Kitagawa, K.; Shinokubo, H.; Oshima, K. Selective halogen-magnesium exchange reaction via
organomagnesium ate complex. J. Org. Chem. 2001, 66, 4333–4339. [CrossRef] [PubMed]
28. Kitagawa, K.; Inoue, A.; Shinokubo, H.; Oshima, K. Halogen–Magnesium Exchange via Trialkylmagnesates
for the Preparation of Aryl- and Alkenylmagnesium Reagents. Angew. Chem. Int. Ed. 2000, 39, 2481–2483.
[CrossRef]
29. Iida, T.; Wada, T.; Tomimoto, K.; Mase, T. Tributylmagnesium ate complex-mediated novel bromine–
magnesium exchange reaction for selective monosubstitution of dibromoarenes. Tetrahedron Lett. 2001
42, 4841–4844. [CrossRef]
,
30. Fabrice, G.; Ruedi, H.; Hans, H.; Wolfgang, M.; Frank, S.; Manuela, S.W. A practical non-cryogenic process
for the selective functionalization of bromoaryls. Tetrahedron Lett. 2008, 49, 5024–5027.
31. Kato, S.; Nonoyama, N.; Tomimoto, K.; Mase, T. Non-cryogenic metalation of aryl bromides bearing proton
donating groups: formation of a stable magnesio-intermediate. Tetrahedron Lett. 2002, 43, 7315–7317.
[CrossRef]
32. Malpass, D.B.; Eastham, J.F. Preparation of organometallic complexes by reduction of magnesium alkyls
with alkali metals. J. Org. Chem. 1973, 38, 3718–3723. [CrossRef]
33. Ashby, E.C.; Chao, L.C.; Laemmle, J. Stereoselective organometallic alkylation reactions. III. Ate complex
addition to cyclic and bicyclic ketones. J. Org. Chem. 1974, 39, 3258–3263. [CrossRef]
34. Wakefield, B.J.; Laschat, S. Organomagnesium Methods in Organic Synthesis; Academic Press: London, UK,
1996; pp. 21–71.
35. Comins, D.L.; Higuchi, K. Synthesis of the Benzo-fused Indolizidine Alkaloid Mimics. Beilstein J. Org. Chem.
2007, 3, 42. [CrossRef] [PubMed]
Sample Availability: Samples of the compounds are not available from the authors.
©
2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).