Continuous-flow synthesis of trimethylsilylphenyl perfluorosulfonate benzyne precursors

Article abstract of DOI:10.1021/ol500959e

2-(Trimethylsilyl)phenyl perfluorosulfonated aryne precursors may now be accessed using flow chemistry, enabling the fast preparation of pure compounds with no requirement for low temperature lithiation or column chromatography. The process has been adapted to novel nonaflate precursors, utilizing the cheaper and more user-friendly nonaflyl fluoride reagent. The resultant nonaflates are shown to successfully participate in a range of aryne reaction classes.

Full text of DOI:10.1021/ol500959e

Letter
pubs.acs.org/OrgLett
Continuous-Flow Synthesis of Trimethylsilylphenyl
Perfluorosulfonate Benzyne Precursors
Boris Michel and Michael F. Greaney*
School of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, U.K.
S
* Supporting Information
ABSTRACT: 2-(Trimethylsilyl)phenyl perfluorosulfonated
aryne precursors may now be accessed using flow chemistry,
enabling the fast preparation of pure compounds with no
requirement for low temperature lithiation or column
chromatography. The process has been adapted to novel
nonaflate precursors, utilizing the cheaper and more user-
friendly nonaflyl fluoride reagent. The resultant nonaflates are
shown to successfully participate in a range of aryne reaction
classes.
he introduction of 2-(trimethylsilyl)phenyl triflates, 1, as
Scheme 1. Benzyne Generation from 2-Trimethylsilylphenyl
T
benzyne precursors that function under mild conditions
Triflates
has led to a resurgence in aryne chemistry.1 Triggered by
fluoride at room temperature or above, these precursors have
dramatically expanded the range of reactions possible using the
strained triple bond.2 Transformations that were previously
restricted in scope (e.g., aryne σ-insertion processes) or
unknown (e.g., transition-metal-catalyzed aryne chemistry)
with classical precursors have now grown into powerful
methods for arene and heteroarene synthesis. These new
reactions have powered applications in natural product
synthesis, materials science, and polymer synthesis.3
The accessibility of precursors 1 is central to the viability of
the aryne field. The parent triflate 1a is commercially available,4
whereas analogues generally must be synthesized. The synthesis
of 1 is usually achieved through a variant of Kobayashi’s initially
reported method,1 which uses a retro-Brook rearrangement of a
2-(trimethylsilyloxy)phenyl halide as the key step (Scheme 1).
́
In a particularly step-efficient modification, Guitian and co-
workers replaced the sodium in refluxing toluene protocol with
a low temperature lithiation, using n-BuLi at −100 °C in THF.5
The phenoxide arising from retro-Brook rearrangement may
then be trapped with triflic anhydride (Tf2O) in situ.6 Despite
the step efficiency, the route suffers the drawback of cryogenic
conditions (−100 °C) limiting both applicability and scalability
of the chemistry. In our experience, both the lithiation and the
trifluoromethylsulfonation step produce a number of side
products that can be difficult to remove from the product. In
addition, small amounts of triflic acid generated by the
degradation of triflic anhydride can enable cationic polymer-
ization of the THF reaction solvent, further complicating
purification.
heat transport. By utilizing flow chemistry’s precise temperature
and mixing control, it was hoped that the problematic side
reactions of the n-BuLi-initiated retro-Brook step could be
addressed, eliminating the requirement for tedious column
chromatography.8 Furthermore, flow processing segregates
toxic, corrosive, sensitive, or otherwise obnoxious chemicals
(e.g., n-BuLi and Tf2O) from the operator,9 which require the
utmost care and (often cumbersome) process management to
Our continued interest in aryne chemistry7 motivated us to
address the limitations in the synthesis of these starting
materials through the application of continuous flow chemistry.
The obvious advantages of microscale processing are the
enhanced surface-to-volume ratio, leading to excellent mass and
Received: April 1, 2014
© XXXX American Chemical Society
A
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Letter
use under batch conditions. Optimization of this delicate
reaction followed by further in-line reactions10 was expected to
be rapid and cost-effective due to the innate repeatability and
small scale of flow systems.11 A final advantage of a continuous
system is the facile scaling up/out of the system by simply
running the optimized reaction for longer; thereby removing
synthetic bottlenecks and enabling the important process of
discovery to take over.
Scheme 2. Continuous Flow Synthesis of 2-
Trimethylsilylphenols
a
We set out to develop a usable process that would not
require any significant investment in sophisticated microscale
reactor equipment. We addressed the key retro-Brook step first,
using the syringe-pump flow scheme set out in Figure 1. This
a
Reaction conditions: 1 mmol of (2-bromophenoxy)trimethylsilane
(1.0 M in Et2O) and 1.2 mmol of n-BuLi (1.6 M in hexane) were
loaded into syringes and diluted to 10 mL with the appropriate
solvents. The reaction was carried out in a setup as displayed in Figure
b
1. Substrate dissolved in THF; n-BuLi diluted with ether.
Figure 1. Schematic for continuous flow retro-Brook rearrangement.
The linking together of multistep processes is a key
advantage of flow and could be exemplified by the further
reaction of the retro-Brook phenolates with Tf2O under
controlled flow conditions (Scheme 3). We added Tf2O in
Et2O to the phenolate stream via a PTFE Y-junction and then
allowed reaction in a 0.12 mL residence element for 7.8 s. All
reaction system was assembled using cheap and readily available
flangeless fittings, PTFE microtubing and Y- or T-unions. We
chose TMS capped phenols (6) as the starting point for
continuous flow synthesis as their batch synthesis via HMDS
treatment of phenols is extremely facile, requiring simple
heating and subsequent evaporation. We were pleased to find
that initial attempts at flow retro-Brook rearrangement of 6
were successful, with a reaction temperature of −78 °C in THF
affording usable yields of the phenol 7a. There were problems
with reproducibility, however, as the flow rate was impacted by
degradation of n-BuLi to gaseous butane in THF while in a
syringe pump at room temperature. A solvent change to diethyl
ether, in which n-BuLi is more stable, removed this issue, but
the lower polarity and coordination behavior of Et2O slowed
the reaction down significantly at −78 °C. We solved this
problem by conducting the flow lithiation at room temperature,
a process that would not be feasible in batch, affording 7a in
92% yield as a pure compound following filtration through a
pad of silica and concentration. The method proved general for
a range of substrates, yielding the product phenols (7a−e) in
excellent yields (Scheme 2). We were interested in extending
the method to substrates containing two halogens (6f and 6g),
as the bromine atom in the final aryne precursors would
represent a useful directing group and point of further
functionalization. Initial application of our optimized flow
conditions to these substrates led to selectivity problems;
lithiation of (2,6-dibromo)phenoxytrimethylsilane in Et2O at
temperatures between 0 or 25 °C led to additional lithiation of
the second halide atom and thus to side products that required
time-consuming column chromatography to remove. Lowering
the temperature to −78 °C gave no reaction at all in Et2O, but
was productive in THF. By loading the substrate in THF and n-
BuLi in Et2O we could circumvent the issue of n-BuLi
degradation while still maintaining the activating properties of
THF upon mixing the two solutions at −78 °C. The reactions
then proceeded to completion, producing pure 7f (76% yield)
and 7g (75% yield).
Scheme 3. Flow Diagram and Substrate Scope for
Continuous Flow Synthesis of 2-Trimethylsilylaryl
a
Trifluoromethylsulfonates
a
For multihalogenated species an exact equivalent of n-butyllithium
has to be used to suppress successive lithium halide exchange.
b
Containing a small amount <5% of an impurity.
B
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Organic Letters
Letter
substrates that underwent retro-Brook rearrangement success-
fully were converted to the homologous Kobayashi type
benzyne precursors in excellent yields, following filtration
over a pad of silica to remove inorganic side products and
concentration (Scheme 3). To test the scalability of the process,
we prepared 2.7 g of 1a from bromophenol 6a in 30 min. The
product was homogeneous and required no chromatographic
purification (see the Supporting Information).
Scheme 4. Flow Diagram and Substrate Scope for
Continuous Flow Synthesis of 2-Trimethylsilyl
Nonafluorobutylsulfonates
Having established a flow synthesis of 2-trimethylsilyphenyl
triflate aryne precursors, we then turned our attention to the
triflate nucleofuge. The expense of triflic anhydride, relative to
other activating groups, severely restricts its use on scale.4 In
addition, its high reactivity makes it difficult to store and handle
in the research laboratory, being subject to rapid hydrolytic
degradation and incompatibility with common solvents such as
THF. The nonaflate group represents an attractive alternative,
being cheaper4 and far more stable in terms of its precursor
reagent 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonyl fluoride
(NfF). Aryl nonaflates12 share similar reactivity to triflates as
leaving groups, but are more resistant to hydrolysis. Critically,
the nonaflate leaving group is non-nucleophilic−a key require-
ment for any functional group displaced in a benzyne-
generating reaction.
Preparing nonaflate aryne precursors presents an obvious
problem, however, in that the fluoride generated from
treatment of phenols 7 with NfF could generate benzyne,
degrading the precursor as soon as it is formed. This potential
in situ reactivity has been harnessed by Akai and co-workers,
who treated 2-trimethylsilylphenols with NfF/Cs2CO3 in
MeCN in the presence of furans.13 The nonaflates formed in
situ underwent fluoride-triggered aryne formation and Diels−
Alder reaction, affording adducts in good yield. This approach
is necessarily restricted to aryne transformations tolerant of the
electrophilic NfF reagent and (strongly) nucleophilic phenolate
component present in the reaction. We speculated that our flow
synthesis could be adapted to the successful synthesis and
isolation of nonaflate aryne precursors, if the displaced fluoride
could be held as a tight ion-pair (e.g., LiF in Et2O) while
remaining in solution such that the flow apparatus would not
block.
would likely require temperatures higher than our solvent
choice can permit in the flow apparatus.
To verify that the pure nonaflates (8) can effectively act as
general aryne precursors, we tested them in the transformations
shown in Scheme 5. We were pleased to observe successful
reaction in 4 + 2 cycloaddition,14 Pd-catalyzed triphenylene
synthesis,15 amide insertion,16 benzyne Fisher-indole synthe-
sis,7c and β-keto ester insertion.17 All reactions gave good to
excellent yields that are comparable with those reported in the
literature for the analogous triflates. The reactions demonstrate
Scheme 5. Nonaflate Precursors in Aryne Transformations
Initial observations on the flow nonaflate process established
that the lithium phenolate arising from retro-Brook rearrange-
ment of 6 in Et2O would not react with NfF directly. No
reaction was observed at all on substituting NfF for Tf2O under
the previously successful flow conditions. An optimization
study (see the Supporting Information) established that amine
bases could promote the reaction, with the key observation
being that the nonaflation responded to nucleophilic catalysis.
We developed the flow process shown in Scheme 4, where a
THF solution of excess triethylamine containing 4-pyrrolidi-
nopyridine (3 mol %) was mixed with the stream of retro-
Brook product 7 in ether. A second mixing of NfF in THF was
fed into a residence element held at 55 °C for the longer time
of 3.75 min.
This process gave an excellent 90% yield of nonaflate 8a in
97% purity after simple filtration through a silica plug and was
scaled to produce 20 mmol of 8a in 1 h. The flow process was
applied to the synthesis of nonaflates 8a−e, affording the novel
aryne precursors in excellent yields and purities. A limitation
was observed when using the dibromo-substituted systems that
had been previously observed to react sluggishly with Tf2O
(Scheme 1, 7f and 7g). Nonaflation failed in these cases and
C
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Letter
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TBAT and CsF fluoride sources, transition-metal catalysis, and
MeCN, THF, and toluene reaction solvents.
In conclusion, we have devised a novel continuous flow
process for the synthesis of 2-(trimethylsilyl)phenyl triflate and
nonaflate aryne precursors in excellent yields and purities. The
flow preparation processes are scalable on a concentration
range from 0.1 to 1 M and thus output 2−20 mmol of fine
product per hour without further purification. We have used the
cheaper and more stable reagent NfF to prepare a range of
nonaflate aryne precursors in flow, and demonstrated their
effectiveness in a range of aryne chemistries. Further
applications of these reagents and processes in arene synthesis
will be reported in due course.
(4) Current prices: 2-(trimethylsilyl)phenyl triflate, 1a. $167 per 5 g;
triflic anhydride, $348 per 100 g; nonaflyl fluoride, $225 per 100 g (all
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́ ́
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ASSOCIATED CONTENT
* Supporting Information
Experimental procedures, characterization data, and copies of
spectroscopic data. This material is available free of charge via
the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
■
(8) Recent examples of flow lithiation: (a) Newby, J. A.; Huck, L.;
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Butters, C.; Guthrie, D.; Ley, S. V. Org. Process Res. Dev. 2013, 17,
1192−1208. (c) Nagaki, A.; Matsuo, C.; Kim, S.; Saito, K.; Miyazaki,
A.; Yoshida, J.-i. Angew. Chem., Int. Ed. 2012, 51, 3245−3248. (d) Shu,
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(e) Nagaki, A.; Moriwaki, Y.; Yoshida, J.-i. Chem. Commun. 2012, 48,
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*E-mail: michael.greaney@manchester.ac.uk.
Author Contributions
The manuscript was written through contributions of both
authors.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the EPSRC for funding (Leadership Fellowship to
MFG). Dr. Christopher Smith (University of Manchester) is
thanked for helpful discussions.
(9) Baumann, M.; Baxendale, I. R.; Ley, S. V.; Nikbin, N.; Smith, C.
D.; Tierney, J. P. Org. Biomol. Chem. 2008, 6, 1577−1586.
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