“Snapshot” Trapping of Multiple Transient Azolyllithiums in Batch

Article abstract of DOI:10.1002/chem.202101256

Recent developments in flow microreactor technology have allowed the use of transient organolithium compounds that cannot be realized in a batch reactor. However, trapping the transient aryllithiums in a “halogen dance” is still challenging. Herein is reported the trapping of such short-lived azolyllithiums in a batch reactor by developing a finely tuned in situ zincation using zinc halide diamine complexes. The reaction rate is controlled by the appropriate choice of diamine ligand. The reaction is operationally simple and can be performed at 0 °C with high reproducibility on a multigram scale. This method was applicable to a wide range of brominated azoles allowing deprotonative functionalization, which was used for the concise divergent syntheses of both constitutional isomers of biologically active azoles.

Full text of DOI:10.1002/chem.202101256

Accepted Article
Accepted Article
Title: “Snapshot” Trapping of Multiple Transient Azolyllithiums in Batch
Authors: Kengo Inoue, Yuxuan Feng, Atsunori Mori, and Kentaro
Okano
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of the final Version of Record (VoR). This work is currently citable by
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To be cited as: Chem. Eur. J. 10.1002/chem.202101256
Link to VoR: https://doi.org/10.1002/chem.202101256
01/2020

10.1002/chem.202101256
Chemistry - A European Journal
RESEARCH ARTICLE
“Snapshot” Trapping of Multiple Transient Azolyllithiums in
Batch
Kengo Inoue,[a] Yuxuan Feng,[a] Atsunori Mori,[a,b] and Kentaro Okano*[a]
[a]
K. Inoue, Y. Feng, Prof. Dr. A. Mori, and Prof. Dr. K. Okano
Department of Chemical Science and Engineering, Kobe University
1-1 Rokkodai, Nada, Kobe 657-8501 (Japan)
E-mail: okano@harbor.kobe-u.ac.jp
[b]
Prof. Dr. A. Mori
Research Center for Membrane and Film Technology, Kobe University
1-1 Rokkodai, Nada, Kobe 657-8501 (Japan)
Supporting information for this article is given via a link at the end of the document.
Abstract: Recent developments in flow microreactor technology
have allowed the use of transient organolithium compounds that
cannot be realized in a batch reactor. However, trapping of the
transient aryllithiums in a “halogen dance” is still challenging. We
report trapping of such short-lived azolyllithiums in a batch reactor by
developing a finely tuned in situ zincation using zinc halide diamine
complexes, whose reaction rate is controlled by the appropriate
choice of the diamine ligand. The reaction is operationally simple
and can be performed at 0 °C with high reproducibility on a multi-
a) Transition metal-catalyzed C–H arylation (Nomura)
Pd(OAc)2, PPh3
CuI, Cs2CO3
N
N
+
PhI
H
H
Ph
Ph
S
S
DMF, 140 °C, 47 h
66%
b) Deprotozincation with zinc amide base/electrophilic trap (Knochel)
CuCN·2LiCl
Br
Br
(TMP)2Zn·2MgCl2·2LiCl
THF, 25 °C then
then
N
N
O
gram scale. This method was applicable to
a wide range of
benzoyl chloride
25 °C, 15 min
H
Br
Br
S
S
brominated azoles allowing for deprotonative functionalization, which
was used for the concise divergent syntheses of both constitutional
isomers of biologically active azoles.
Ph
84%
c) In situ transmetalation with ZnCl2·TMEDA and LiTMP/electrophilic trap (Mongin)
ZnCl2·TMEDA (1.0 Equiv)
LiTMP (3.0 Equiv)
I2
N
N
H
I
THF, RT, 2 h then
S
S
67%
Introduction
d) This work: selective in situ trapping of multiple azolyllithiums in the halogen dance
Halogen Dance
Multiply substituted azoles are one of the most common
structural motifs in pharmaceuticals, agrochemicals, and
functional organic materials.[1] Their physical properties depend
on the functional groups and their substitution patterns.[2]
Regioselective functionalization of an azole ring is still required[3]
as a complementary method to the established cyclization
strategy.[4] Azoles are categorized as electron-deficient aromatic
rings; however, the azole nitrogen acts as a base, which limits
the range of functional groups able to be installed by
electrophilic aromatic substitution.[5] Recently developed flow
chemistry can generate organolithium species by halogen–
lithium exchange rather than deprotolithiation,[6] which requires
the corresponding halogenated arene as the substrate.
In this context, a transition metal-catalyzed C–H arylation of
thiazole has been developed (Scheme 1a).[7,8] Halogen atoms
such as a bromo group can be easily introduced onto azoles,
and then converted through a halogen–metal exchange, cross
coupling reaction, and SNAr reaction. Knochel reported
deprotozincation of the dibromothiazole with a zinc amide base
with the bromo groups intact (Scheme 1b).[9,10] The generated
organozinc species was used for benzoylation with copper
cyanide. Instead of using the zinc amide base, in situ
H
Li
Br
LDA
N
N
N
complex mixture
w/o ZnCl2·diamine
THF
0 °C
Br
Br
Br
Br
Li
Br
Br
S
S
S
S
S
+ ZnCl2·diamine
Selective In Situ
Transmetalation
N
N
Zn
Cl
N
N
ClZn
Br
Zn
Cl
N
N
Cl
Cl
Br
Br
ClZn
ZnCl2·TMEDA
ZnCl2·TMPDA
Scheme 1. Synthetic methods for functionalized azoles.
promoted halogen dance.[12] This reaction has been used for
synthesizing multiply brominated heteroaromatic compounds;
however, several azoles have been reported to deteriorate by
ring opening reaction after deprotolithiation.[13] Furthermore, only
the thermodynamically most stable organolithiums can be used
in the halogen dance.[14,15] Herein, we present the first examples
of selective in situ trapping of transient thiazolyllithiums in a
halogen dance, which led to a complex mixture at 0 °C in the
absence of a zinc chloride diamine complex (Scheme 1d). This
method provides each constitutional isomer simply by changing
the diamine ligand and can be applied to other brominated
azoles.
transmetalation of benzothiazole was achieved with
a
combination of LiTMP (lithium 2,2,6,6-tetramethylpiperidide) and
ZnCl2·TMEDA by Mongin and co-workers (Scheme 1c).[11]
Subsequent iodination provided 2-iodobenzothiazole.
Recently, our laboratory reported the functionalization of
bromothiophenes, bromofurans, and bromopyrroles via a base-
Results and Discussion
1
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10.1002/chem.202101256
Chemistry - A European Journal
RESEARCH ARTICLE
byproduct. [h] The reaction was performed using 7.5 mmol of 2,5-
dibromothiazole (1).
First, we began with the deprotolithiation of 2,5-
dibromothiazole (1) with LDA (lithium diisopropylamide) to obtain
a fully substituted thiazole. Treatment of 2,5-dibromothiazole
with LDA at 0 °C and subsequent addition of iodine provided a
complex mixture without any iodinated thiazoles (Eq 1). This
result implies that the thiazolyllithium intermediate decomposes
at 0 °C.
N
N
N
N
N
N
Zn
Cl
Zn
Cl
Zn
Cl
Cl
Cl
Cl
ZnCl2·TMEDA
ZnCl2·TMCDA
ZnCl2·TEEDA
LDA
I2
H
(1.5 Equiv)
(2.0 Equiv)
N
complex mixture
(1)
Br
Br
THF
0 °C, 30 min
then
0 °C, 1 h
S
N
N
Zn
Cl
N
N
Zn
Cl
N
N
Zn
Cl
O
O
1
Cl
Cl
Cl
ZnCl2·BuMeEDA
ZnCl2·TMPDA
ZnCl2·DMP
We then explored a suitable ZnX2·diamine to prevent the
decomposition of the transient thiazolyllithium by in situ zincation.
The efficacy of the ZnX2·diamine was evaluated by subsequent
Figure 1. Structures of zinc halide diamine complexes.
iodination (Table 1). Following the report by Knochel,[16]
a
mixture of 2,5-dibromothiazole (1) and ZnCl2 in THF was treated
with LDA and iodine to afford a mixture of 4-iodothiazole 2a and
5-iodothiazole 2b in 13% and 57% yields, respectively (entry 1).
Because this mixture proved very difficult to separate by column
chromatography, the yields were determined by a quantitative
13C NMR spectroscopy.[17] Structures of both products 2a and 2b
were identified by X-ray crystallography using the pure
compounds that were obtained under the optimal conditions
described later.[18] We next examined a variety of zinc halide
diamine complexes (Figure 1).[19] The use of ZnCl2·TMEDA[20]
resulted in the exclusive formation of 2a in 89% isolated yield
(entry 2). This result indicates transmetalation is slower with
ZnCl2, compared to ZnCl2·TMEDA. In contrast, ZnBr2·TMEDA
and ZnI2·TMEDA provided 2b as the major product (entries 3
and 4).
These results indicate that the rate of transmetalation with
ZnCl2·TMEDA was much faster than that with ZnBr2·TMEDA or
ZnI2·TMEDA. We next investigated a suitable diamine ligand for
the selective formation of 2b. ZnCl2·TMCDA bearing trans-1,2-
bis(dimethylamino)cyclohexane provided 2a and 2b in 44% and
30% yields, respectively (entry 5). ZnCl2·TEEDA, with four ethyl
groups on the two nitrogen atoms, provided a better product
ratio (entry 6), which suggests that the larger alkyl group
reduced the rate of the transmetalation. ZnCl2·BuMeEDA, with a
sterically more demanding ethylene diamine group, improved
the yield of 2b, albeit with 12% of the undesired isomer 2a (entry
7). After intensive optimization, the newly prepared
ZnCl2·TMPDA, where the dimethylamino groups are tethered
with
a propylene unit, proved effective for the exclusive
formation of 5-iodothiazole 2b in 72% yield (entry 8). When both
dimethylamino groups were replaced with the morpholino groups,
the undesired isomer 2a was observed (entry 9). ZnBr2·TMPDA
was also effective for the selective preparation of 2b, albeit in
lower yield than that with ZnCl2·TMPDA (entry 10). ZnI2·TMPDA
provided a comparable yield of 2b; however, isomer 2a (5%)
and another inseparable byproduct (<10%) were also observed
(entry 11). The optimal conditions were robust and were
performed on a gram scale to provide compounds 2a or 2b
exclusively.
LDA
(1.5 Equiv)
I2
H
I
Br
(2.0 Equiv)
N
N
N
+
Br
Br
Br
Br
I
Br
THF
0 °C, 30 min
then
0 °C, 1 h
S
S
S
1
2a
2b
+ ZnX2·diamine
(1.2 Equiv)
Table 1. Effects of ZnX2·diamine complexes on the in situ zincation of
thiazolyllithiums[a]
Entry
ZnX2·diamine
2a [%][b]
2b [%][b]
These results indicate that the rate of the in situ
transmetalation can be controlled by choosing an appropriate
diamine ligand (Scheme 2). The initially generated
thiazolyllithium 3a was selectively trapped with ZnCl2·TMEDA to
yield the corresponding organozinc reagent 4a, which was
treated with iodine to give thiazolyl iodide 2a. On the basis of the
experimental results, bulkier substituents on the nitrogen or
homologation of the alkyl tether between the two nitrogen atoms
led to a slower transmetalation rate. Transmetalation with
ZnCl2·TMPDA was sufficiently sluggish to trap thiazolyllithium 3b
which was generated after a halogen dance, leading to the
formation of organozinc reagent 4b. Although, the different
relative reaction rates of the halogen dance and in situ
transmetalation is a plausible explanation for the observed
outcomes of the reaction, some uncertainty remains. Thus,
relative transmetalation rates of thiazolyllithiums 3a and 3b
should be considered, if both thiazolyllithiums 3a and 3b exist.
This result does not exclude the possibility that transmetalation
of 3b with ZnCl2·TMPDA is faster than that of 3a; however, this
complex can selectively trap the azolyllithiums after the halogen
1[c]
2
ZnCl2
13
57
[e]
ZnCl2·TMEDA
ZnBr2·TMEDA
ZnI2·TMEDA
ZnCl2·TMCDA
ZnCl2·TEEDA
ZnCl2·BuMeEDA
ZnCl2·TMPDA
ZnCl2·DMP
89[d] (91[d,f]
)
–
3
23
4
61
4[g]
5
65
44
13
12
30
6
54
7
71
[e]
8
–
72[d] (87[d,h]
)
9
16
69
39
78
[e]
10
ZnBr2·TMPDA
ZnI2·TMPDA
–
11[g]
5
[a] Reaction conditions: 2,5-dibromothiazole (1) (1.0 equiv, 0.30 mmol),
ZnX2·diamine (1.2 equiv, 0.36 mmol), THF (3.0 mL), then LDA (1.5 equiv, 0.45
mmol), 0 °C, 30 min, then I2 (2.0 equiv, 0.60 mmol), 0 °C, 1 h. [b] The yield
was determined by a quantitative 13C NMR technique. [c] Recovery of 3% of
1. [d] Isolated yield. [e] Not observed in the 13C NMR spectrum of the crude
product. [f] The reaction was performed using 10 mmol of 2,5-dibromothiazole
(1). [g] The products involved a minute amount (<10%) of an inseparable
2
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10.1002/chem.202101256
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RESEARCH ARTICLE
dance, which is described later. This means that a zinc halide
diamine complex with a slower transmetalation rate is preferred
to trap the thiazolyllithium 3b. Preformed i-Pr2NZnCl·TMEDA
from LDA and ZnCl2·TMEDA led to the formation of trace
amount (<10%) of thiazoles 2a and 2b with 59% recovery of 1.
Similarly, preformed i-Pr2NZnCl·TMPDA from LDA and
ZnCl2·TMPDA did not provide thiazoles 2a and 2b with 62%
recovery of 1. These control experiments exclude the possibility
that thiazolylzinc species 4a undergoes the halogen dance to
afford 4b.
effective for mono-brominated azoles, providing each
constitutional isomer after iodination (Table 3).[22] Mono-
brominated azoles 7–10 were subjected to LDA in the presence
of ZnCl2·TMEDA, providing organozinc reagents from the initially
LDA
(1.5 Equiv)
H
I
Br
Br
Br
N
N
N
N
+
+
Br
Br
Br
Br
I
Br
I
THF
N
N
N
N
–78 °C, 30 min
then
Me
Me
Me
Me
I2 (2.0 Equiv)
–78 °C, 1 h
5
6a
6b
6c
+ ZnCl2·diamine
(1.2 Equiv)
Halogen Dance
Table 2. Effects of ZnCl2·diamine complexes on the in situ zincation of
H
Li
Br
LDA
imidazolyllithiums[a]
complex mixture
w/o ZnX2·diamine
N
N
N
THF
0 °C
Br
Br
Br
Br
Li
Br
6a [%][b]
6b [%][b]
6c [%][b]
S
S
S
Entry
ZnCl2·diamine
1
3a
3b
+ ZnX2·diamine
1[c]
2
ZnCl2
17
2
3
In Situ Transmetalation
ZnX2·diamine
ZnCl2·TMEDA
ZnCl2·TMEDA
ZnCl2·TMCDA
30
37
16
I
XZn
Br
Br
I2
3[d]
4
49 (58[e]
)
4
–
[f]
I2
N
N
N
N
[f]
–
50 (59[e], 64[e,g]
)
24
Br
Br
Br
Br XZn
Br
I
Br
S
S
S
S
[f]
5
6
7
ZnCl2·TEEDA
ZnCl2·TMPDA
none
–
49
38
18
36
2a
4a
4b
2b
[f]
–
49
Scheme 2. Rationale for the selective trapping of transient thiazolyllithiums.
[f]
–
73 (67[e]
)
[a] Reaction conditions: 2,5-dibromo-1-methyl-1H-imidazole (5) (1.0 equiv,
0.30 mmol), ZnCl2·diamine (1.2 equiv, 0.36 mmol), THF (3.0 mL), then LDA
(1.5 equiv, 0.45 mmol), –78 °C, 30 min, then I2 (2.0 equiv, 0.60 mmol), –
The findings from the reaction of dibromothiazole 1 were
also applicable for trapping the three resulting imidazolyllithiums
from the halogen dance of metalated dibromoimidazole 5 (Table
2). The structures of the products were identified by X-ray
crystallography.[21] The initially generated organolithium
intermediate was selectively trapped by ZnCl2·TMEDA at 0 °C to
provide 6a after iodination, whereas ZnCl2 led to a significant
reduction in yield (entries 1–3). Among the ZnCl2·diamine
complexes tested, ZnCl2·TMCDA provided compound 6b in the
highest isolated yield (64%; entries 3–6). In the absence of a
ZnCl2·diamine, lithiated bromoimidazole 5 underwent a halogen
dance twice to provide the thermodynamically most stable
organolithium, which was treated with iodine to provide 6c in
67% isolated yield (entry 7), displaying different properties to
dibromothiazole 1.
78 °C,
1
h. [b] The yield was determined by 1H NMR with 1,1,2,2-
tetrachloroethane as an internal standard. [c] Recovery of 51% of 5. [d] The
reaction was performed at 0 °C. [e] Isolated yield. [f] Not observed in the
crude product. [g] The reaction was performed using 1.0 mmol of 2,5-dibromo-
1-methyl-1H-imidazole (5).
generated organolithiums (entries 1, 3, 5, and 7). In contrast, the
azolyllithium species generated through the halogen dance were
selectively transmetalated with ZnCl2·TMPDA to provide the
corresponding azolylzinc species, simply by changing the
diamine ligand (entries 2, 4, and 6). In the case of the halogen
dance of bromoimidazole 10, ZnCl2·TMPDA also provided 14a,
probably due to a slow halogen dance. Compound 14b was
obtained in 80% yield without the zinc halide diamine complex
(entry 8).
In addition to dibromothiazole 1 and dibromoimidazole 5, the
combination of LDA and ZnCl2·TMEDA/ZnCl2·TMPDA was
Table 3. Selective trapping of multiple azolyllithiums by in situ transmetalation with ZnCl2·TMEDA or ZnCl2·TMPDA followed by iodination[a]
LDA
(1.5 Equiv)
I2
( )n
(2.0 Equiv)
N
N
Zn
Cl
bromoazole
+
product
THF
0 °C, 30 min
then
0 °C, 1 h
Cl
ZnCl2·TMEDA (n = 1) or
ZnCl2·TMPDA (n = 2)
Entry
1
Bromoazole
ZnCl2·diamine
ZnCl2·TMEDA
Product / Yield [%][b]
Entry
5
Bromoazole
ZnCl2·diamine
ZnCl2·TMEDA
Product / Yield [%][b]
I
I
N
N
N
N
Br
Ph
O
Br
S
Ph
Ph
Br
Ph
Br
Ph
O
S
9
7
13a 85%
11a 91%
2
ZnCl2·TMPDA
6[c]
N
ZnCl2·TMPDA
Br
Br
N
N
N
Br
Ph
O
Br
S
I
Ph
O
I
Ph
S
9
7
13b 91%
11b 91%
3
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10.1002/chem.202101256
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RESEARCH ARTICLE
3
N
ZnCl2·TMEDA
I
7[c]
N
ZnCl2·TMEDA
N
N
Br
Br
OMe
OMe
Br
Br
I
Br
S
N
N
Br
OMe
S
8
Me
Me
12a 83%
10
14a 71%
4[c]
N
ZnCl2·TMPDA
8[c]
N
none
N
Br
N
Br
I
S
N
N
I
OMe
S
8
Me
Me
12b 78%
10
14b 80%
[a] Reaction conditions: bromoazole (1.0 equiv, 0.30 mmol), ZnCl2·diamine (1.2 equiv, 0.36 mmol), THF (3.0 mL), then LDA (1.5 equiv, 0.45 mmol), 0 °C, 30 min,
then I2 (2.0 equiv, 0.60 mmol), 0 °C, 1 h. [b] Isolated yield. [c] Reaction temperature: –78 °C.
Table 4. Selective trapping of multiple azolyllithiums by in situ transmetalation with ZnCl2·TMEDA or ZnCl2·TMPDA followed by electrophilic trapping[a]
LDA
(1.5 Equiv)
E+
( )n
(1.1–3.0 Equiv)
N
N
Zn
Cl
bromoazole
+
product
THF
0 °C, 30 min
then
Temp
Cl
ZnCl2·TMEDA (n = 1) or
ZnCl2·TMPDA (n = 2)
Entry
1
Bromoazole
ZnCl2·diamine
Product / Yield [%][b]
Entry
5
Bromoazole
ZnCl2·diamine
E+, Temp
Product / Yield [%][b]
E+, Temp
ZnCl2·TMEDA
N
ZnCl2·TMEDA
N
PhS
N
Br
Br
OMe
Br
Br
Br
N
S
S
Phth–SPh
7 mol% Cu(OAc)2
RT
Br
OMe
I
CuCN·2LiCl
RT
S
8
Br
Br
1
S
17a 47%
15a 87%
2
3
ZnCl2·TMPDA
6[c]
N
ZnCl2·TMPDA
Br
Br
N
N
N
OMe
Br
S
S
Phth–SPh
5 mol% Cu(OAc)2
RT
PhS
OMe
Br
I
CuCN·2LiCl
RT
S
S
8
1
15b 65%
17b 27%
ZnCl2·TMEDA
7[c]
ZnCl2·TMEDA
N
MeO
N
N
HO
Ar
Br
Ph
Br
Br
N
S
N
MeO
CHO
Me
Me
7
N
I
MeO
10
18a 32%
Br
Ph
3 mol% Pd2(dba)3
11 mol% P(C6H5CF3)3
60 °C
S
nBuMgCl, 0 °C
16a 65%
8[c]
None
Br
N
4
ZnCl2·TMPDA
N
N
N
OH
Br
Ph
Br
Br
S
N
N
MeO
CHO
Ph
S
Ar
Me
Me
18b 45%
7
MeO
16b 78%
I
MeO
10
3 mol% Pd2(dba)3
–78 °C
11 mol% P(C6H5CF3)3
60 °C
[a] Reaction conditions: bromoazole (1.0 equiv, 0.30 mmol), ZnCl2·diamine (1.2 equiv, 0.36 mmol), THF (3.0 mL), then LDA (1.5 equiv, 0.45 mmol), 0 °C, 30 min,
then E+ (1.1–3.0 equiv). [b] Isolated yield. [c] Reaction temperature: –78 °C. Phth = phthalimide.
The scope of this reaction was investigated using a range of
other electrophiles (Table 4). In the case of 2,5-dibromothiazole
(1), both organozinc reagents were smoothly converted into the
corresponding allylated products 15a and 15b through
transmetalation with CuCN·2LiCl[23] (entries 1 and 2). Neither
15a nor 15b was obtained at all in the absence of CuCN·2LiCl.
ZnCl2·TMPDA instead of ZnCl2·TMEDA (entry 4). Copper-
catalyzed thiolation[25] proceeded to afford compounds 17a and
17b in moderate yields (entries 5 and 6). The organozinc
reagent generated from bromoimidazole 10 and ZnCl2·TMEDA
was not reactive toward p-anisaldehyde. Addition of
2
equivalents of nBuMgCl[26] to the resulting organozinc proved
effective for the nucleophilic addition to the aldehyde. During the
reaction, a halogen dance was not observed to give adduct 18a
as the sole product with 40% recovery of imidazole 10 (entry 7).
The other isomer (18b) was synthesized by reacting p-
anisaldehyde to the corresponding imidazolyllithium species
(entry 8).
The thiazolylzinc reagent from bromothiazole
7
and
ZnCl2·TMEDA was kinetically stable and did not undergo a
halogen dance, even at 60 °C, compared with the corresponding
organolithium, and was transformed into arylated thiazole 16a by
Negishi coupling in 65% yield[24] (entry 3). In contrast, its
constitutional isomer 16b was obtained in 78% by using
4
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RESEARCH ARTICLE
The established method was applied to the divergent
syntheses of biologically active azoles in a stereoselective
manner (Scheme 3). Bromothiazole 7 was treated with the
combination of LDA and ZnCl2·TMEDA to form organozinc 19a,
which underwent Negishi coupling to give arylated thiazole 20a
with the bromo group intact. Subsequent palladium-catalyzed
installation of the acetate moiety and acidic removal of the tert-
butyl group provided the anti-inflammatory fentiazac[1f,27] (21a).
Its constitutional isomer 21b was also synthesized through the
same route using ZnCl2·TMPDA.[28] This method was applicable
to the stereocontrolled syntheses of multiply arylated oxazoles.
The use of ZnCl2·TMEDA or ZnCl2·TMPDA was effective for the
selective generation of organozinc species 22a and 22b from a
single starting material, brominated oxazole 9. Subsequent
Negishi coupling in the presence of 5 mol% Pd(PPh3)4 smoothly
afforded the corresponding products 23a and 23b in 67% and
80% yields, respectively.[29] The remaining bromo group was
converted to
a 4-methanesulfonylphenyl group by Suzuki–
Miyaura coupling[30] to provide cyclooxygenase-2 inhibitor 24a[31]
and its constitutional isomer 24b in a stereocontrolled manner.
Compared with conventional methods such as selective
arylation of multiple halogen or pseudohalogen groups,[32] this
method provides two constitutional isomers via the selective in
situ transmetalation. Furthermore, this method is superior from
the perspective of atom economy.[33]
Cl
N
N
tBuO2C
ZnBr
Cl
Cl
Zn
Cl
I
1) Pd2(dba)3 (2.5 mmol%)
DavePhos (10 mol%)
THF, reflux, 3 h
Cl
LDA
(1.5 Equiv)
Pd2(dba)3 (2.5 mol%)
P(C6H5CF3)3 (10 mol%)
ClZn
ZnCl2·TMEDA
N
N
N
HO2C
Br
Ph
Br
Ph
Ph
THF
0 °C, 30 min
reflux, 3.5 h, 61%
2) TFA, CH2Cl2, RT
81% (2 steps)
S
S
S
19a
20a
Fentiazac (21a)
N
(antiinflammatory)
Cl
Br
Ph
tBuO2C
ZnBr
S
I
7
1) Pd2(dba)3 (5 mmol%)
XPhos (20 mol%)
THF, reflux, 1 h
Br
HO2C
LDA
(1.5 Equiv)
Pd2(dba)3 (2.5 mol%)
P(C6H5CF3)3 (10 mol%)
Br
N
N
N
N
N
Zn
Cl
Ph
Ph
S
S
ClZn
Ph
THF
0 °C, 30 min
reflux, 3 h, 83%
2) TFA, CH2Cl2, RT
52% (2 steps)
S
Cl
Cl
Cl
19b
20b
Fentiazac isomer (21b)
ZnCl2·TMPDA
B(OH)2
F
N
N
F
F
Zn
Cl
MeO2S
I
Cl
LDA
(1.5 Equiv)
Pd(PPh3)4 (5 mol%)
Cs2CO3
ClZn
ZnCl2·TMEDA
Pd(PPh3)4 (5 mol%)
reflux, 24 h, 67%
N
N
N
Br
Ph
Br
Ph
Ph
O
THF
0 °C, 30 min
DMF/H2O (4:1)
110 °C, 3 h, 86%
O
O
MeO2S
22a
23a
24a
N
(cyclooxygenase-2 inhibitor)
B(OH)2
F
Br
Ph
MeO2S
O
MeO2S
I
9
LDA
(1.5 Equiv)
Pd(PPh3)4 (5 mol%)
Cs2CO3
Br
Br
Pd(PPh3)4 (5 mol%)
reflux, 24 h, 80%
N
N
N
N
N
Zn
Cl
ClZn
Ph
Ph
Ph
O
THF
–78 °C, 30 min
DMF/H2O (4:1)
110 °C, 5 h, 82%
O
O
Cl
F
F
22b
23b
24b
ZnCl2·TMPDA
Scheme 3. Divergent syntheses of biologically active azoles.
exist but have not been exploited synthetically until now. The
development of additional functionalization methods involving
this class of amine ligands and trapping principles will be
reported in due course.
Conclusion
In summary, we have developed a divergent synthesis of
multiply substituted azoles using selective trapping of multiple
azolyllithiums via a halogen dance. The appropriate choice of
diamine ligand provides the desired azolylzinc for the
stereoselective synthesis. The protocol is robust, and the Acknowledgements
transformations can be performed using the combination of
commercially available LDA and bench-stable zinc halide
diamine complexes. In addition, these reactions can be
performed in a batch reactor at 0 °C with high reproducibility and
can be used for the synthesis of pharmaceutically important
heteroaromatic compounds. The reaction not only enables direct
functionalization of brominated heteroarenes while leaving the
bromo group untouched; it also provides regioisomers from their
transient organolithium species, which have been thought to
This work was financially supported by JSPS KAKENHI Grant
Numbers JP16K05774 in Scientific Research (C), JP19H02717
in Scientific Research (B), JP16H01153 and JP18H04413 in the
Middle Molecular Strategy, and The Kyoto Technoscience
Center Research Fellowship. This work was performed under
the Cooperative Research Program of “Network Joint Research
Center for Materials and Devices. We thank Professor Shigeki
Mori (Ehime University) and Ms. Rimi Konishi (Ehime University)
5
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10.1002/chem.202101256
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RESEARCH ARTICLE
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[9]
Keywords: Carbanions • Halogen dance • Heteroarenes • In situ
transmetalation • Zinc
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7
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RESEARCH ARTICLE
Entry for the Table of Contents
Halogen Dance
H
Li
Br
Br
LDA
N
N
N
complex mixture
w/o ZnCl2·diamine
THF
0 °C
Br
Br
Br
Li
Br
S
S
S
Selective
In Situ
Transmetalation
+ ZnCl2·diamine
N
Zn
Cl Cl
N
N
Zn
Cl Cl
N
ClZn
Br
N
N
Br
Br
ClZn
Br
ZnCl2·TMEDA
ZnCl2·TMPDA
S
S
√ Selective trapping of multiple transient heteroaryllithiums
√ Operationally simple and highly reproducible reaction
√ Synthetic use of hitherto unexplored carbanions
√ Scope: thiazole, oxazole, and imidazole
“Snapshot” trapping of multiple transient azolyllithiums via a halogen dance is realized in a batch reactor. This method allows
selective generation of isomeric azolylzinc species from a single starting material using newly synthesized bench-stable zinc halide
diamine complexes, leading to the divergent and stereoselective synthesis of functionalized azoles.
8
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