Arylation of aryllithiums with: S-arylphenothiazinium ions for biaryl synthesis

Article abstract of DOI:10.1039/d0cc05830k

Aryllithiums are one of the most common and important aryl nucleophiles; nevertheless, methods for arylation of aryllithums to produce biaryls have been limited. Herein, we report arylation of aryllithiums with S-arylphenothiazinium ions through selective

Full text of DOI:10.1039/d0cc05830k

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Arylation of aryllithiums with S-arylphenothiazinium ions for
biaryl synthesis
a
a
b
b
Tatsuya Morofuji,* Tatsuki Yoshida, Ryosuke Tsutsumi, Masahiro Yamanaka and Naokazu
Kano*
Received 00th January 20xx,
Accepted 00th January 20xx
a
DOI: 10.1039/x0xx00000x
Aryllithiums are one of the most common and important aryl use electron-poor heteroaromatic rings such as pyridine, azole,
nucleophiles; nevertheless, methods for arylation of aryllithums to or quinoline as coupling partner, which promote desired ligand
7
i,8
produce biaryls have been limited. Herein, we report arylation of coupling.
In contrast, the selective synthesis of
aryllithiums with S-arylphenothiazinium ions through selective unsymmetrical biphenyl derivatives from sulfonium salts and
ligand coupling of intermediary sulfuranes. Various unsymmetrical aryl metals is a long-standing problem.
biaryls could be obtained without transition-metal catalysis.
Herein, we report that S-arylphenothiazinium ions can solve
the problem and be used as versatile arylation reagents for
Aryllithiums are one of the most common and important aryl
nucleophiles in organic chemistry. Aryllithiums are known to
react with various electrophiles, such as alkyl halides, carbonyl
aryllithiums. The reaction of aryllithiums
1
with S-
arylphenothiazinium ions selectively afforded the
2
corresponding biaryls 3 and phenothiazine (Figure 1c). In
contrast to the transition-metal-catalyzed approach, bromo-
1
compounds, chlorosilanes and trimethoxyborane. However,
methods for arylation of aryllithums to produce biaryls are very
limited. Arylation of aryllithiums based on nucleophilic aromatic
2
3
substitution or nucleophilic attack to aryne was reported, but
there were few options regarding the applicable substrates.
Although a few palladium-catalyzed methods have been
4
reported, development of electrophilic arylation reagents that
react with aryllithiums in the absence of transition metals is a
5
simple but challenging problem (Figure 1a).
In sulfur chemistry, the ligand coupling of
4
tetraarylsulfuranes (IUPAC nomenclature: tetraaryl- -
6
sulfanes) has been reported. Reaction of triarylsulfoniums with
arylmetal reagents including aryllithiums affords the
tetraarylsulfurane intermediate, which decomposes to the
corresponding biaryls and diaryl sulfides without transition-
7
metal catalysis (Figure 1b). However, these processes have
very limited applications because the selectivity of the resulting
products depends on aromatic substituents on the sulfur
atom.7 One of the reasons why control of the selectivity of the
ligand coupling is difficult is that conformation of sulfurane is
b,f
7
a
not fixed through Berry’s pseudorotation.
To obtain
unsymmetrical biaryls, previous ligand coupling was limited to
a. Department of Chemistry, Faculty of Science, Gakushuin University, 1-5-1 Mejiro,
Toshima-ku, Tokyo 171-8588, Japan.
b.
Department of Chemistry, Faculty of Science, Rikkyo University, 3-34-1 Nishi-
Ikebukuro, Toshima-ku, Tokyo 171-8501, Japan.
Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: Experimental procedures,
DFT calculations, and NMR data. See DOI: 10.1039/x0xx00000x
Figure 1. Arylation of aryllithiums. (a) Our blueprint: development of arylation
reagents for aryllithiums. (b) Previous work: Reactivity of sulfurane and its
limitation for the synthesis of biaryl. (c) This work: S-arylphenothiazinium ions
used as electrophilic arylation reagents for synthesizing unsymmetrical biaryls.
†
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and iodo-substituted biaryls, which are attractive synthetic of biaryl. The specificity of S-phenylphenothiazinium was
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DOI: 10.1039/D0CC05830K
intermediates, could be synthesized using the present method. examined by theoretical calculations, as described later.
A computational study was performed to reveal the reaction
mechanism of this sulfurane-mediated biaryl-formation.
The scope of the arylation of aryllithiums using S-
arylphenothiazinium 2 investigated in the present study is
First, we examined the reaction of some cyclic sulfonium shown in Scheme 1. To perform desymmetrizative mono-
ions9 with phenyllithium (Table 1). Reaction of S- arylation of inexpensive 1,4-dibromobenzene, it was lithiated
phenylphenothiazinium hexafluorophosphate (2a) with with n-BuLi and reacted with various S-arylphenothiaziniums
phenyllithium (1a) in THF at –78 °C and 23 °C afforded biphenyl successively to obtain the desired bromo-substituted biaryls
(3a) and N-methylphenothiazine (4) in good yields (entry 1). (3b–3g) in good yields. Significantly, the reaction of S-(4-
When the amount of 1a used was reduced, the conversion of 2a bromophenyl)phenothiazinium with aryllithiums bearing a
decreased (entry 2). In contrast, the reaction of S- bromo-substituent also afforded mono-arylated products
phenylphenoxathiinium 5 with phenyllithium (1a) afforded a bearing two bromo groups, 3h, 3i, and 3j. Other halogen-
mixture of biphenyl (3a), phenoxathiin (6), and ring-opening substituted biaryls could also be synthesized by the present
product 7a (entry 3). As previously reported, the reaction of S- method (3k–3o). The resulting bromo- or iodo-substituted
phenylthianthrenium 8 with phenyllithium (1a) under the same biaryls are synthetically attractive intermediates for further
conditions afforded biphenyl (3a) in only 8% yield, while derivatization by transition-metal-catalyzed cross-coupling
dibenzothiophene (9) (55%), diphenyl sulfide (10) (51%), and reactions. It should be noted that bromo- or iodo-substituted
ring-opening product 7b (31%) were obtained in higher yields biaryls have never been synthesized by Murahashi coupling
1
0
(
entry
4).
It
was
also
reported
that
S- because C–C bond formation takes place at the halogen-
4
phenyldibenzothiophenium (11) afforded ring-opening product substituted position. Furthermore, various unsymmetrical
c in a quantitative yield (entry 5). It should be noted that ring biaryls were synthesized using the present method (3p–3z).
1
1
7
opening product and N-methylcarbazole were not observed by Reactions using p-chlorophenyllithium produced the desired
1
H NMR analysis when 2a was used. These results suggest that products in good yields (3p–3r), whereas the use of aryllithiums
the phenothiazine moiety is essential for successful formation bearing a methylchalcogeno group slightly decreased the yields
of the product (3s, 3t). Notably, the reaction efficiently
Table 1. Reaction of phenyllithium (1a) with sulfonium salts.
produced 3p on the gram scale. Ortho- or meta-methyl-
substituted aryllithium was applicable to the present reaction
system (3u, 3v). Reactions of -extended aryllithiums with S-
arylphenothiaziniums also afforded the corresponding
unsymmetrical biaryls in good yields (3w–3z).
To gain insight into the selective formation of
unsymmetrical biaryls from the S-arylphenothiazinium ions,
density functional theory (DFT) calculations were conducted at
the B3LYP/6-311G+(d,p) level. Possible reaction pathways of
entry
1
sulfonium
products
3
phenyllithium(THF) (1a) with S-phenylphenothiazinium (2a) via
2
a
3a 91%a
3a 61%a
4 97%a
4 60%a
the corresponding sulfurane were explored. The relative free
energy profiles of the formation of biphenyl (path A), ring-
opening reaction (path B), and formation of diphenyl sulfide
2b
3
2a
(
path C) from tetracoordinated sulfuranes are summarized in
Figure 3a. Three types of sulfurane intermediates (IM A, IM B,
and IM C) afforded the corresponding transition states (TS A, TS
B, and TS C). Each sulfurane intermediate has a different
pseudo-trigonal bipyramidal structure and similar free energy.
Interconversion between IM A, IM B, and IM C occurs easily
through pseudorotation. Therefore, the selectivity of the
reaction products is determined by the TS, not by the relative
stability of IM. TS A is energetically more stable than TS B and
TS C, which is in good agreement with the experimental results,
as described in Table 1.
5
3a 38%a
6 31%a
7a 62%c
7
a
4
8
3a 8%a
9 55%c 10 51%c
7b 31%c
5d
DFT calculations using S-phenylphenoxathiinium (4), S-
phenylthianthrenium (6), or S-phenyldibenzothiophenium (7)
instead of 2a indicated that biphenyl formation was not
energetically preferred to ring opening-reaction and formation
of diphenyl sulfide when 4, 6, or 7 was used (see SI for details).
These computational results are consistent with the
experimental results. To understand the major factor in the
preference of path A for S-phenylphenothiazinium ion, we
1
1
7c quant.
Phenyllithium (1a) (0.6 mol) was added to sulfonium salt (0.2 mmol) in THF (5
mL) at –78 °C. The reaction mixture was stirred at –78 °C for 30 min and 23 °C
for 1 h. Determined by H NMR spectroscopy. 0.4 mmol of 1a was used.
a
1
b
c
d
Isolated yield. Result from ref 11.
2
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relatively close structure to TS A. This indicates that biphenyl
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formation from the S-arylphenothiazinium ion (path A) requires
a smaller structural distortion with a lower energy loss than that
from other sulfonium ions. Such a structural difference is due to

-electron donation by the lone pair on the nitrogen atom,
which would strengthen and shorten apical C–S bond II (Figure
c). In general, when one apical bond is strengthened, the other
3
1
2
apical bond becomes weaker and longer. Therefore, apical
bond I in IM A is longer than that in others. This structural
difference of IM A can be favorable for biaryl formation from
phenyllithium (1a) and S-phenylphenothiazinium ion 2a.
In summary, we developed S-arylphenothiazinium ions as
efficient arylation reagents for aryllithiums. The reaction can
provide various unsymmetrical biaryls without transition-metal
catalysis. Notably, transformable halogen substituents such as
bromo- and iodo-groups are tolerated. The resulting halogen-
substituted biaryls are attractive synthetic intermediates. This
result contrasts sharply with that obtained through palladium-
catalyzed Murahashi coupling. In contrast to other similar
sulfonium salts, S-arylphenothiazinium ions are specifically
suitable for biaryl synthesis through selective ligand coupling of
a sulfurane intermediate, which is consistent with theoretical
calculations. We are currently developing new transition-metal-
free arylation reactions using S-arylphenothiazinium ions; the
results will be presented in due course.
This research was partially supported by the MEXT-
supported program for the Strategic Research Foundation at
Private Universities, and the Society of Iodine Science. DFT
calculations were performed using Research Center for
Computational Science, Okazaki, Japan.
Conflicts of interest
There are no conflicts to declare.
Notes and references
1
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Scheme 1. Scope of cross-coupling of aryllithiums and S-arylphenothiazinium ions
a
for synthesizing biaryls. S-Arylphenothiazinium 2 (0.2 mmol) was added to a
solution of aryllithium 1 (0.6 mmol) in THF (5 mL) at –78 °C. The reaction mixture
a
was stirred at –78 °C for 30 min and 23 °C for 1 h. See SI for details. Isolated yield.
b
The reaction was performed on a gram scale.
compared the structural differences between IM A and TS A
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respectively, than those in IM D, IM G, and IM J. IM A has a
5
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Figure 3. DFT calculations of reaction of phenyllithium (1a) and S-phenylphenothiazinium ion (2a) at the B3LYP/6-311G+(d,p) level. (a) Relative free energy
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for the structural difference in sulfurane IM A.
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