Three-component coupling based on flash chemistry. Carbolithiation of benzyne with functionalized aryllithiums followed by reactions with electrophiles

Article abstract of DOI:10.1021/ja5071762

A flow microreactor method for three-component coupling of benzyne was developed based on flash chemistry. o-Bromophenyllithium generated from 1-bromo-2-iodobenzene and a functionalized aryllithium generated from the corresponding aryl halide were mixed at -70 °C. In the subsequent reactor o-bromophenyllithium is decomposed to generate benzyne without affecting the functionalized aryllithium at -30 °C, and carbolithiation of benzyne with the aryllithium took place spontaneously. The resulting functionalized biaryllithium was reacted with an electrophile in the subsequent reactor to give the corresponding three-component coupling product. The precise optimization of reaction conditions using the temperature-residence time mapping is responsible for the success of the present transformation. The present method has been successfully applied to the synthesis of boscalid.

Full text of DOI:10.1021/ja5071762

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Communication
Three-Component Coupling Based on Flash Chemistry.
Carbolithiation of Benzyne with Functionalized
Aryllithiums Followed by Reactions with Electrophiles
Aiichiro Nagaki, Daisuke Ichinari, and Jun-ichi Yoshida
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja5071762 • Publication Date (Web): 14 Aug 2014
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Three-Component Coupling Based on Flash Chemistry.
Carbolithiation of Benzyne with Functionalized Aryllithiums
Followed by Reactions with Electrophiles
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Aiichiro Nagaki, Daisuke Ichinari, and Jun-ichi Yoshida*
Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University,
Nishikyo-ku, Kyoto 615-8510, Japan.
RECEIVED DATE (automatically inserted by publisher); yoshida@sbchem.kyoto-u.ac.jp
cyano and nitro groups giving three-component coupling products
bearing such functionalities.
ABSTRACT:
A flow microreactor method for three-
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component coupling of benzyne was developed based on
flash chemistry. o-Bromophenyllithium generated from 1-
bromo-2-iodobenzene and
a
functionalized aryllithium
generated from the corresponding aryl halide were mixed at
o
–70 C. In the subsequent reactor o-bromophenyllithium is
decomposed to generate benzyne without affecting the
o
functionalized aryllithium at –30 C, and carbolithiation of
benzyne with the aryllithium took place spontaneously. The
resulting functionalized biaryllithium was reacted with an
electrophile in the subsequent reactor to give the
corresponding three-component coupling product. The
precise optimization of reaction conditions using the
temperature – residence time mapping is responsible for the
success of the present transformation. The present method
has been successfully applied to the synthesis of boscalid.
Figure 1. Carbolithiation of benzyne with aryllithiums.
Consecutive three-component coupling with subsequently added
electrophiles.
Arynes including benzyne are highly reactive intermediates,
and extensive studies on their synthetic applications have been
reported so far.1,2 In particular, carbometalation of benzyne serves
as
a powerful method for constructing organic structures
containing an o-disubstituted benzene ring.3 Although it is well
known that o-halophenyllithiums serve as good precursors of
benzyne, it is difficult to use them for carbolithiation because
various organolithium species are generated simultaneously,
which compete with each other.
Schlosser reported
a
smart way of controlling the
carbolithiation of benzyne by adding an o-dihalobenzene to an
aryllithium. The reaction proceeds by a chain mechanism.4,5
Benzyne generated from o-halophenyllithium reacts with an
Figure 2. An integrated flow microreactor system for the three-
component coupling of benzyne, functionalized aryllithiums, and
electrophiles. T-shaped micromixers: M1, M2, M3 and M4,
microtube reactors: R1, R2, R3 and R4.
aryllithium to give
a
biaryllithium, which undergoes
halogen/lithium exchange with o-dihalobenzene to give a biaryl
halide as a product regenerating o-halophenyllithium. However,
the method suffers from the limitation of the substrates because of
the requirement of delicate balance of the reactivity of
organolithium intermediates (vide infra, Scheme 1).
If the biaryllithiums formed by carbolithiation could be used
for reactions with various electrophiles at will, the carbolithiation
method should serve as powerful and straightforward tansition
metal-free three-component synthesis of ortho-disubstituted
benzenes. Such transformations, however, seem to be very
difficult or impossible in batch because of short lifetimes of the
intermediates.
Flash chemistry6 solves the problem. We report here
carbolithiation of benzyne generated from an o-halophenyllithium
with aryllithiums followed by reactions of the resulting
biaryllithiums with subsequently added electrophiles using an
integrated flow microreactor system7,8,9 (Figure 1). It should be
emphasized that the present flash method enables the use of short-
lived aryllithiums bearing electrophilic functional groups such as
We envisaged that space integration of reactions10 using the
integrated flow microreactor system shown in Figure 2 enables
the present transformation involving multiple short-lived reactive
intermediates.11 An o-halophenyllithium and an aryllithium are
generated by halogen/lithium exchange in M1/R1 and M2/R2,
respectively. They are mixed in M3. In R3, the o-
halophenyllithium is selectively decomposed to generate benzyne
without affecting the aryllithium, which adds to benzyne
spontaneously. The resulting biaryllithium is allowed to react with
an electrophile in M4 and R4 to give the corresponding three-
component coupling product. To achieve these transformations in
a harmonious way, the residence time and the temperature for
each step should be precisely controlled.
First, we optimized the conditions for generating and
accumulating o-halophenyllithiums from o-dihalobenzenes using
a flow microreactor system12 shown in Figure 3. The reactions of
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1,2-dibromobenzene,
1-bromo-2-iodobenzene,
and
1,2-
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diiodobenzene were carried with varying the temperature (T1) and
the residence time in R1 (tR1), and o-halophenyllitiums were
trapped with benzaldehyde. The yields of the products are plotted
against T1 and tR1 as contour maps with scattered overlays (Figure
4). In the case of 1,2-dibromobenzene using BuLi as a lithiating
agent, the yields at short residence times are low, because
bromine/lithium exchange is not so fast. The yield increases with
an increase in the residence time, and then decreases because of
the decomposition to generate benzyne. In the case of 1-bromo-2-
iodobenzene using PhLi as a lithiating agent, the yields at short
residence times are high because iodine/lithium exchange is faster.
At longer residence times the decomposition to benzyne takes
place. In the case of 1,2-diiodobenzene using PhLi as a lithiating
agent, the yields at short residence times are high, but the yield
decrease very quickly with an increase in the residence time,
presumably because o-iodophenylithium is less stable than o-
bromophenyllithium. Based on these results, we chose to generate
o-bromophenyllithium as a precursor of benzyne from 1-bromo-2-
iodobenzene. In this case the highest yield (93%) was obtained at
–70 oC with the residence time of 0.16 s, and therefore these
conditions were used for the subsequent studies. Also, it should be
noted that the temperature-residence time maps in Figure 4 give
crucial information about the conditions for benzyne generation.
(a)
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(b)
(c)
Figure 3. A flow microreactor system for generation and
accumulation of o-halophenyllithiums. T-shaped micromixers:
M1 and M2, microtube reactors: R1 and R2.
Next, we examined the generations of benzyne from o-
bromophenyllithium in the presence of p-chlorophenyllithium
using an integrated flow microreactor system (Figure 2). The
carbolithiation of benzyne with p-chlorophenyllithium followed
by the reaction with added electrophiles should take place. Thus,
1-bromo-2-iodobenzene was reacted with PhLi (T1 = –70 oC, tR1
=
0.22 s) at M1 and R1 to give o-bromophenyllithium, which is
stable at this temperature within 1 s as indicated in Fig 4b. 1-
Bromo-4-chlorobenzene was reacted with n-BuLi (T2 = 0 oC, tR1
=
Figure 4. Temperature (T1) - residence time (tR1) maps for the
halogen/Li exchange reaction of (a) 1,2-dibromobenzene with n-
BuLi, (b) 1-bromo-2-iodobenzene with PhLi and (c) 1,2-
diiodobenzene with PhLi followed by reaction with benzaldehyde
in the flow microreactor.
0.31 s)13 at M2 and R2 to generate p-chlorophenyllithium, and the
resulting solution was cooled to –70 oC (T1). The two
o
organolithium species were mixed at M3 at –70 C (T1), and the
o
mixture was warmed to –30 C (T3) in R3 (tR3 = 2.69 s) (See the
Supporting Information for details). Because o-bromo-
phenyllithium decomposes completely at –50 oC within 2.4 s
(Figure 4b), such decomposition should take place very quickly at
Various
electrophiles
such
as
methyl
trifluoromethanesulfonate,
trimethylsilyl
trifluoromethane-
o
sulfonate, phenyl isocyanate, benzaldehyde, tributyltin chloride,
diethyl oxalate, and methyl formate were effective (Table 1).
Notably, selective reaction of biaryllithiums with diethyl oxalate
using a flow microreactor was achieved to obtain -keto esters
with high selectivity by virtue of fast 1 : 1 micromixing.14
Moderate yields for these reactions seem to be attributed to
inevitable competitive reactions of benzyne with other
–30 C to generate benzyne. In contrast, p-chlorophenyllithium,
which is generated at 0 oC, should be stable at –30 oC. Thus, flash
generated benzyne reacted with p-chlorophenyllithium in R3 to
give the corresponding biaryllithium, which was transferred to
M4, where an electrophile was added. The reaction in R4 (T4 (=
T3) = –30 oC, tR4 = 1.06 s) gave the final three-component
coupling products.
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organolithium species that should be present in the reaction
mixture, such as o-bromophenyllithium and biaryllithiums.
formation of a mixture of desired 2-bromo-4’-chlorobiphenyl and
undesired 2,2‘-dibromobiphenyl at –25 C (Scheme 1). At lower
temperatures such –50 oC, the yield of the desired product slightly
o
Table 1. Three-component coupling of benzyne, aryllithiums, and
increased, but
a
significant amount of undesired 4-
electrophiles using the integrated flow microreactor system.a
chlorobromobenzene was also obtained. In the present flash
method, however, desired 2-bromo-4’-chlorobiphenyl was
obtained selectively in a good yield (Table 1).
electrophile
product
yield
(%)
73
MeOTf b
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Scheme 1
TMSOTf b
PhCNO b
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PhCHOb
Bu3SnClb
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In addition to p-chlorophenyllithium, various aryllithiums
bearing electrophilic functional groups16 can be used for the
present three-component coupling. For example, o-, m-, and p-
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cyanophenyllithiums generated at –20 − –30 oC using BuLi (tR2
=
b
(CO2Et)2
0.16 − 0.31 s),17 and p-nitrophenyllithium generated at –30 oC
using PhLi (tR2 = 0.31 s)18 were successfully used in this
transformation. Benzyne were generated without affecting such
functionalized aryllithiums. The carbolithiation followed by the
subsequent reactions with electrophiles gave the three-component
coupling products. Such transformations are very difficult or
HCO2Me b
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b
I2
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impossible to achieve using conventional batch reactors.
Heteroaryllithiums such as 2-pyridyllithium (T2 = –30 C, tR2
2.36 s) and 2-thiophenyllithium (T2 = –30 C, tR2 = 0.31 s)19 can
also be used for the three-component coupling, because they are
also stable at –30 oC within a second or so.
To demonstrate the utility of the present flash method, we
examined the application to the synthesis of boscalid,20,21 an
important fungicide, which belongs to the class of succinate
dehydrogenase inhibitors. Benzyne generation from o-
bromophenyllithium and the carbolithiation with 4-
chlorophenyllithium followed by the reaction with tosyl azide
gave 4’-chloro-2-azidobiphenyl in 60% yield (Figure 5).
Reduction with NaBH4 followed by the reaction with 2-
chloronicotinoyl chloride gave boscalid in 88% yield (53%
overall yield from 1-bromo-2-iodobenzene).
o
=
b
o
CBr4
b
C2Cl6
NFSI b,c
MeOTf d
MeOTf d
e
–
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MeOTf f
MeI g
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MeOTf d
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a The reactions were usually carried out with 0.6 mmol/min of 1-bromo-
o
o
2-iodobenzene. b R'Li = BuLi, tR2 = 0.31 s, T2 = 0 C, c T3 = –50 C, d
R'Li = BuLi, tR2 = 0.31 s, T2 = –30 oC, e R'Li = BuLi, tR2 = 0.16 s, T2 = –
20 oC, f R'Li = PhLi, tR2 = 1.18 s, T2 = –70 oC, g R'Li = BuLi, tR2 = 2.36 s,
T2 = –30 oC
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Halogenating agents such as tetrabromomethane, iodine,
hexachloroethane and N-fluorobenzenesulfonimide (NFSI) were
also effective as electrophiles, and the corresponding biaryl
halides were obtained.15 It should be noted that similar products
were difficult to obtain selectively by the chain reaction via in situ
halogen transfer. For example, the reaction of p-chlorobenzene
and o-dibromobenzene in a batch macro reactor led to the
Figure 5. Synthesis of boscalid.
In conclusion, flash chemistry using integrated flow
microreactor systems enabled three-component coupling of
benzyne generated from o-bromophenyllithium, functionalized
aryllithiums, and electrophiles. The precise control of the reaction
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Y.; Takahashi, T. Angew. Chem. Int. Ed. 2014, 53, 851. (l) Nagaki, A.;
conditions based on the relative stability of the organolithium
species that are involved in the benzyne formation and the
carbolithiation is responsible for the success of the transformation.
Further work is in progress to explore the full scope of this useful
three-component coupling and its applications in organic
synthesis.
Takahashi, Y.; Yoshida, J. Chem. Eur. J. 2014, in press.
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Acknowledgment. This work was partially supported by the
Grant-in-Aid for Scientific Research (S) (no. 26220804) and
Scientific Research (B) (no. 26288049).
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