Magnesium Bisamide-Mediated Halogen Dance of Bromothiophenes

Article abstract of DOI:10.1021/acs.orglett.8b00566

A magnesium bisamide-mediated halogen dance of bromothiophenes is described. The thienylmagnesium species generated in situ is more stable than the corresponding thienyllithium species, which was applied to trap the transient anion species with several electrophiles, such as allyl iodide, phenyl isocyanate, and tributylstannyl chloride. The utility of the magnesium bisamide-mediated halogen dance is useful in the concise synthesis of a medicinally advantageous compound via a one-pot, ester-directed halogen dance/Negishi cross coupling.

Full text of DOI:10.1021/acs.orglett.8b00566

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Magnesium Bisamide-Mediated Halogen Dance of Bromothiophenes
Yoshiki Yamane, Kazuhiro Sunahara, Kentaro Okano,* and Atsunori Mori
Department of Chemical Science and Engineering, Kobe University, 1-1 Rokkodai, Nada, Kobe 657-8501, Japan
*
S Supporting Information
ABSTRACT: A magnesium bisamide-mediated halogen dance of
bromothiophenes is described. The thienylmagnesium species
generated in situ is more stable than the corresponding
thienyllithium species, which was applied to trap the transient
anion species with several electrophiles, such as allyl iodide, phenyl
isocyanate, and tributylstannyl chloride. The utility of the magnesium
bisamide-mediated halogen dance is useful in the concise synthesis of
a medicinally advantageous compound via a one-pot, ester-directed
halogen dance/Negishi cross coupling.
a
n 1951, the treatment of 2-bromothiophene with sodium
acetylide in liquid ammonia was reported to lead to the1
Table 1. Exploration of Bases in the Halogen Dance
I
formation of a mixture of di-, tri-, and tetrabromothiophene.
The base-induced halogen migration has been referred to as
2
halogen scrambling, halogen isomerization, or halogen dance.
The reaction mechanism by which this occurs was elucidated to
be sequential deprotonation and halogen−metal exchange3,
which gives a thienyl anion species bearing a halogen atom.
From the viewpoint of synthetic chemistry, the halogen dance
reaction allows the formation of two chemical bonds in one
pot, which in turn reduces the number of reaction pots needed
for this particular transformation when compared with
conventional stepwise introduction of functional groups. In
addition, the halogen dance reaction enables facile access to
aromatic/heteroaromatic halides whose substitution pattern is
often difficult to achieve via general synthetic methods, such as
electrophilic aromatic substitution. Despite this attractive
synthetic potential, the scope of this substrate has not been
investigated in detail probably because of difficulties in
controlling the reactivity of the transient thienyllithium species.
Recently, our research group published the first one-pot
halogen dance/Negishi coupling for rapid access to multiple4
arylated thiophenes and furans in a regiocontrolled manner.
During the course of the investigation, transmetalation of the
transient organolithium species to organozinc species proved
essential for smooth transformation. We also noticed that either
alkyllithium or lithium amides were employed as bases in
halogen dance reactions. Herein, we report the magnesium
amide-mediated halogen dance of bromothiophenes and several
examples that cannot be performed with lithium amides. The
mild reaction conditions also allow for ester-directed 1,3-
migration of a bromo group. The applicability of this method is
demonstrated by the concise synthesis of a key intermediate for
an inhibitor of HCV NS5B polymerase through a one-pot ester-
directed halogen dance/Negishi cross coupling.
b
b
entry
base
LiTMP
temp (°C)
time
1
(%) 2a (%)
1
2
3
4
−78
rt
5 min
24 h
3 h
−c
68
40
63
36
TMPMgCl·LiCl
15
−c
−c
Mg(TMP) ·2LiCl
rt
2
Mg(Ni-Pr ) ·2LiCl
rt
3 h
2
2
a
Reaction conditions: 2,5-dibromothiophene (1) (0.50 mmol), base
(0.60 mmol, 1.2 equiv), THF, then H O. The yield was determined
by H NMR of the crude material using 1,1,2,2-tetrachloroethane as an
b
2
1
c
internal standard. Not observed.
5
LiTMP at −78 °C. The reaction was quenched with water to
give 2,4-dibromothiophene (2a) in 68% H NMR yield (entry
1
1). The starting material 1 was not consumed with Knochel−
6
Hauser base (TMPMgCl·LiCl, TMP = 2,2,6,6-tetramethylpi-
peridide), even after the experiment was performed at room
7
temperature for 24 h (entry 2). Mg(TMP)
·2LiCl proved to
be effective for the completion of the reaction (entry 3).
Structurally similar Mg(Ni-Pr ) ·2LiCl led to the formation
of 2a in a lower yield (entry 4). In the magnesium amide-
mediated halogen dance, we identified 2-bromothiophene
(<10%) as an intermediate among several byproducts, which
has not been reported in lithium amide-promoted reactions.
2
7
c,8
2 2
Having found that Mg(TMP) ·2LiCl facilitated the halogen
2
dance of 2,5-dibromothiophene (1), we subsequently inves-
tigated the scope of dibromothiophenes and electrophiles in the
said reactions (Table 2). First, upon treatment of 2,5-
dibromothiophene (1) with Mg(TMP) ·2LiCl at room
temperature for 3 h, the generated anion species were trapped
using several electrophiles. The reaction was quenched with
2
First, related amide bases were investigated using 2,5-
dibromothiophene (1) as a substrate (Table 1). According to
previous reports, the halogen dance of 1 was performed with
Received: February 15, 2018
2
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00566
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 2. Scope and Limitations of the Halogen Dance
Table 3. Selective Trapping of Two Thienyl Anion Species
from 2,3-Dibromothiophene
a
b
b
entry
temp (°C)
time
6
(%)
2d (%)
1
2
3
4
rt
rt
0
3 h
28
3
39
39
10
−e
12 h
3 min
−c
71
d
0
59
a
Reaction conditions: dibromothiophene 5 (0.50 mmol), Mg(TMP)2·
2
LiCl (0.60 mmol, 1.2 equiv), THF, then allyl iodide (1.0 mmol, 2.0
b
c
equiv). NMR yield using 1,2-diiodoethane as an internal standard. A
mixture of dibromothiophene 5 and allyl iodide was added to the
d
e
1
magnesium amide at 0 °C. Isolated yield. Not observed in H NMR
of the crude material.
Scheme 1. Plausible Reaction Pathway of Halogen Dance
a
Reaction conditions: dibromothiophene (0.50 mmol), Mg(TMP) ·
2
+
2
LiCl (0.60 mmol, 1.2 equiv), THF, rt, 3 h, then E (1.0 mmol, 2.0
b
c
1
equiv). Isolated yield. The yield was determined by H NMR of the
crude material using 1,1,2,2-tetrachloroethane as an internal standard.
d
e
Electrophile: 2.4 equiv. Reaction time: 12 h (for the halogen dance).
f
1
The yield was determined by H NMR of the crude material using
1
,2-diiodoethane as an internal standard.
water to give 2,4-dibromothiophene (2a) in 63% yield.
Treatment with benzaldehyde provided the desired alcohol
2
b in 51% yield. Trapping the resultant anion species with ethyl
chloroformate gave compound 2c in 42% yield. An allyl group
was also introduced using allyl iodide to provide the
corresponding product 2d in 50% yield. Halogen dance of
dibromothiophene 3 smoothly occurred to give 3,4-dibromo-
thiophenes 4a and 4b in moderate yields. Next, we examined
thienylmagnesium species 7 should be a transient carbanion,
which when allylated, provides thiophene 6. Prolonged reaction
times or elevated reaction temperatures allowed the formation
of the thermodynamically favored thienylmagnesium species 8
through halogen−magnesium exchange of transient thienyl-
magnesium 9 and tribromothiophene 10, thus giving allylated
thiophene 2d.
2
,3-dibromothiophene (5), which gave the same substitution
pattern as the above example using 2,5-dibromothiophene (1).
Compared with 2,5-dibromothiophene (1), prolonged reaction
time (12 h) was necessary for the halogen dance of 2,3-
dibromothiophene (5) to provide the corresponding products
2
a and 2d.
Notably, only one example of the termination of the halogen
dance of 2,3-dibromothiophene (5) has been reported using
Selective trapping of two thienyl anion species from 2,3-
1
0
dibromothiophene (5) was achieved by using the magnesium
amide (Table 3). The halogen dance of 5 provided a mixture of
allylated dibromothiophenes 6 and 2d in 28% and 39% yields,
respectively (entry 1). A prolonged reaction time (12 h)
resulted in the formation of 2d as a major product (entry 2).
flow metalation with LiTMP in the presence of LaCl ·2LiCl.
3
We then investigated the trapping of the transient thienyl anion
9
species with a batch system using Mg(TMP) ·2LiCl because
2
the intermolecular halogen−magnesium exchange is much
slower than halogen−lithium exchange (Scheme 2). Instead of
On the other hand, treatment of 6 with Mg(TMP) ·2LiCl at 0
Mg(TMP) ·2LiCl, a mixture of 2,3-dibromothiophene (5) and
2
2
°
C for 3 min followed by allyl iodide provided 6 as a major
isomer (entry 3). Addition of a mixture of allyl iodide and 5 to
allyl iodide was treated with LiTMP to give 2,4-dibromothio-
phene (2a) as a major product with none of the corresponding
Mg(TMP) ·2LiCl led to exclusive formation of 6 in 59%
allylated thiophene 6. In addition, n-Bu SnCl smoothly reacted
2
3
isolated yield (entry 4). These findings indicate that the
magnesium amide-mediated halogen dance could be used to
provide each regioisomer simply by controlling reaction
conditions.
to give the corresponding product 11 in 93% yield. Similarly,
phenyl isocyanate was successfully trapped to provide amide 12
in 42% yield after generation of the initial thienyl anion species
7, whereas in situ trapping caused the reaction of magnesium
amide and phenyl isocyanate to give the corresponding urea,
resulting in recovery of the starting 2,3-dibromothiophene (5).
The transient thienylmagnesium species 7 could be trans-
In the case of 2,3-dibromothiophene (5), the initial
deprotonation was expected to be faster than the subsequent
halogen−magnesium exchange (Scheme 1). Thus, the
B
DOI: 10.1021/acs.orglett.8b00566
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Trapping of the Transient Thienylmagnesium
Species
in the first deprotonation step (Scheme 3). The proton
adjacent to the ester group is thought to be preferably
Scheme 3. Plausible Reaction Pathway for an Ester-Directed
1,3-Halogen Dance
abstracted to generate anion species 16, which is also supported
by Eaton and Knochel’s reports that utilized magnesium amides
13
for deprotonation/functionalization reactions. The resultant
thienylmagnesium species 16 then reacts with the starting
bromothiophene 14 to generate thienylmagnesium species 17
and dibromothiophene 18, which in turn undergo halogen−
magnesium exchange to regenerate bromothiophene 14 with
production of the thermodynamically stable thienylmagnesium
species 19. This is trapped using an electrophile to give 15’.
The resultant thienylmagnesium species 19 proved effective
for the synthesis of functionalized thiophenes (Scheme 4). The
metalated to organozinc species without halogen dance, which
underwent Negishi coupling to provide arylated thiophene 13
in 76% yield. In situ trapping of the thienyl magnesium species
11
9
with ZnCl resulted in the reduction of the yield of 13.
2
During the course of the investigation of the scope of the
reaction, we found that bromothiophene 14, which bears an
ester group, underwent halogen dance through an unusual 1,3-
migration of the bromo group (Table 4). After treatment of 14
Scheme 4. Synthesis of Functionalized Thiophenes
a
Table 4. Ester-Directed 1,3-Halogen Dance
b
b
b
b
entry
base
LiTMP
14 (%) 14′ (%)
15 (%)
15′ (%)
c
e
1
6
12
<1
2
−d
<1
5 (66 )
52
30
55
2
3
TMPMgCl·LiCl
15
,
ef
Mg(TMP) ·2LiCl
14 (68 )
2
a
Reaction conditions: bromothiophene 14 (0.50 mmol), base (0.60
b
mmol, 1.2 equiv), THF, 0 °C, 30 min, then D O. NMR yield using
1
performed at −78 °C for 5 min. Not observed. The reaction was
quenched with H O. Isolated yield.
2
c
,1,2,2-tetrachloroethane as an internal standard. Halogen dance was
d e
f
established conditions were suitable for introducing an allyl
group to give the corresponding product 20 in 51% yield,
whereas LiTMP facilitated the halogen dance but gave a
complex mixture of unidentified products. Halogen dance of
bromothiophene 14 was successfully applied for the concise
synthesis of a key intermediate for an inhibitor of HCV NS5B
2
with LiTMP at −78 °C for 5 min, the reaction was quenched
with D O to provide 15′ and 15 in 52% and 5% yields,
2
respectively (entry 1). Switching the base to TMPMgCl·LiCl
led to the formation of 15′ and 15 in 30% and 15% yields with
14a
polymerase, ultimately leading to the prevention of Hepatitis
1
4b
14c
12% recovery of the starting material 14 (entry 2). In this case,
C virus infection /flavivirus infection.
The resultant
none of deuterated 14′ was observed, which indicates that, once
generated, the initial anion species immediately undergoes
subsequent halogen−magnesium exchange. The combined
NMR yield of 15 and 15′ improved up to 69% when the
thienylmagnesium species 19 was transmetalated using the
15
ZnCl ·TMEDA complex to generate thienylzinc species 21,
2
16
and subsequent Negishi coupling provided the arylated
compound 22 in 57% yield in one pot.
12
reaction was conducted using Mg(TMP) ·2LiCl (entry 3).
In summary, we have demonstrated a magnesium bisamide-
promoted halogen dance of bromothiophenes. The reaction
rate was much slower than that of a lithium amide-mediated
2
The regiochemistry of the novel 1,3-halogen dance can be
rationalized by invoking the directing effect of the ester group
C
DOI: 10.1021/acs.orglett.8b00566
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
halogen dance. The magnesium bisamide-induced deprotona-
tion of 2,3-dibromothiophene incorporated the trapping of the
transient thienyl anion species by several electrophiles to
provide dibrominated thiophene derivatives with different
substitution pattern. An ester group was tolerated during the
halogen dance reaction and facilitated the novel 1,3-migration
of the bromo group. The method can be applied for the
synthesis of the medicinally important compound.
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ASSOCIATED CONTENT
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Experimental procedure, compound characterization
1
13
data, and H and C NMR spectra for all new
compounds (PDF)
(
9b
bromothiophene with TMPMgCl·LiCl at room temperature
followed by CBr . (b) Janssen, C. G. M.; Macco, A. A.; Buck, H.
4
AUTHOR INFORMATION
Corresponding Author
E-mail: okano@harbor.kobe-u.ac.jp.
M.; Godefroi, E. F. Recl. Trav. Chim. Pays-Bas 1979, 98, 448.
■
*
(10) Becker, M. R.; Knochel, P. Angew. Chem., Int. Ed. 2015, 54,
1
2501.
(11) Kobayashi, K.; Sugie, A.; Takahashi, M.; Masui, K.; Mori, A. Org.
Lett. 2005, 7, 5083.
ORCID
(
12) D O (99.8% D) was purchased and used as received. Compared
2
Kentaro Okano: 0000-0003-2029-8505
Notes
to LiTMP, substantial amounts of 15 were generated when
TMPMgCl·LiCl or Mg(TMP) ·2LiCl was used as a base. These
2
results indicate that equilibrium between the thermodynamically
favored α-magnesiothiophene 19 and 15 exists in the presence of
TMPH, generated in the deprotonation step.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
(13) Dong, Z.; Clososki, G. C.; Wunderlich, S. H.; Unsinn, A.; Li, J.;
■
Knochel, P. Chem. - Eur. J. 2009, 15, 457. Eaton and Knochel also
reported deprotonation of an aromatic proton adjacent to an ester
group (ref 7a−c).
This work was financially supported by JSPS KAKENHI Grant
Nos. JP16K05774 in Scientific Research (C), JP16H01153 in
the Middle Molecular Strategy, Creation of Innovation Centers
for Advanced Interdisciplinary Research Areas (Innovative
Bioproduction Kobe), and Kawanishi Memorial ShinMaywa
Education Foundation. This work was performed under the
Cooperative Research Program of “Network Joint Research
Center for Materials and Devices”. We thank Dr. Takashi Niwa
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V. J. P.; Hang, J. Q.; Le Pogam, S.; Reuter, D.; Tavares, G. A. Bioorg.
Med. Chem. Lett. 2010, 20, 4614. (b) Barnes, D.; Cohen, S. L.; Fu, J.;
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WO2012006055A2, 2012.
(
The “Compass to Healthy Life” Research Complex program,
RIKEN) for mass spectrometric analyses.
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DOI: 10.1021/acs.orglett.8b00566
Org. Lett. XXXX, XXX, XXX−XXX