Robust Buchwald-Hartwig amination enabled by ball-milling

Article abstract of DOI:10.1039/c8ob01781f

An operationally simple mechanochemical method for the Pd catalysed Buchwald-Hartwig amination of arylhalides with secondary amines has been developed using a Pd PEPPSI catalyst system. The system is demonstrated on 30 substrates and applied in the context of a target synthesis. Furthermore, the performance of the reaction under aerobic conditions has been probed under traditional solution and mechanochemical conditions, the observations are discussed herein.

Full text of DOI:10.1039/c8ob01781f

Organic &
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Robust Buchwald–Hartwig amination enabled by
ball-milling†
Cite this: DOI: 10.1039/c8ob01781f
Qun Cao, William I. Nicholson, Andrew C. Jones and Duncan L. Browne
*
Received 24th July 2018,
Accepted 3rd September 2018
DOI: 10.1039/c8ob01781f
rsc.li/obc
Table 1 Optimisation
reaction
of
mechanochemical
Buchwald–Hartwig
An operationally simple mechanochemical method for the Pd cata-
lysed Buchwald–Hartwig amination of arylhalides with secondary
amines has been developed using a Pd PEPPSI catalyst system. The
system is demonstrated on 30 substrates and applied in the
context of a target synthesis. Furthermore, the performance of the
reaction under aerobic conditions has been probed under tra-
ditional solution and mechanochemical conditions, the obser-
vations are discussed herein.
Introduction
The C–N bond is ubiquitous in functional materials, includ-
ing; pharmaceuticals, agrochemicals, flavours, fragrances and
dyes. The Buchwald–Hartwig reaction offers a highly versatile
catalytic method to forge aryl C–N bonds and is regularly used
in the discovery of new compounds.1 Since its inception the
development of the Buchwald–Hartwig reaction has focused
on increasing the range of amenable substrates through the
design of privileged ligands and pre-catalysts.2 Some of the
most studied systems involve phosphine or NHC ligand classes
and collectively have led to a catalytic toolkit capable of deliver-
ing very broad substrate scopes at low catalyst loadings.1,2
Nonetheless, for several of these systems a potential drawback
is the sensitivity of the reaction to aerobic conditions which
can lead to variability in reaction outcome. Improvements on
this front have been made by Organ and co-workers with the
discovery and development of the PEPPSI series of catalysts
which feature both an imidazolium based NHC ligand and a
‘throw away’ pyridine component to afford an easy to handle
pre-catalyst that renders
reaction.3
a highly active catalyst in the
School of Chemistry, Cardiff University, Main Building, Park Place,
Cardiff CF10 3EQ, UK. E-mail: dlbrowne@cardiff.ac.uk
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c8ob01781f
a Yield determined by 1H NMR using mesitylene as internal standard,
numbers in parentheses represent isolated yields.
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Recently, ball milling and other automated mechanochem-
ical techniques have been explored as a means to conduct
solvent-minimised reactions, with several recent examples
demonstrating additional opportunities to synthetic chemists,
such as, decreased reaction times, increased selectivity or
differing reaction outcomes over solution results.4 Indeed
several palladium mediated processes have been explored
through ball-milling.5 It is also known that solid-state syn-
thesis by ball-milling can enable (water and/or oxygen) sensi-
tive reactions to be more reliably carried-out.6 This is particu-
larly attractive, not only from the view-point of increased repro-
ducibility but also from the stance of reduced effort and
resource required for solvent drying and purification and pro-
vision of inert atmospheres during weighing of materials and
running the reaction. Thus, we set out to explore the mechano-
chemical Buchwald–Hartwig reaction to see what the unison
of these two processes could offer, our observations are
reported herein.7
Results and discussion
Our studies commenced by evaluating the model coupling of
chlorobenzene (1) with morpholine (2) under mixer mill con-
ditions using Pd-PEPPSI-iPent as catalyst (2 mol% loading)
and potassium tert-butoxide as base.8 All materials were
weighed and then added directly to the milling jar under an
air atmosphere, i.e. no precaution was taken, the jars were
then milled at 30 Hz for 3 hours. Under these conditions the
cross-coupled product (3) was afforded in 56% yield (1H NMR,
Scheme 1 Aryl halide scope of mechanochemical Buchwald–Hartwig
reaction. Reaction conditions: Arylhalide (1 mmol), amine (1.2 mmol),
Pd-PEPPSI-iPENT (1 mol%), tBuOK (2 mmol), sand (0.338 g), 15 mL Jar,
1 × 12 g stainless steel ball, 3 h under air in mixer mill. Isolated yields
reported.
Table 1, entry 1). With this result in hand we explored refine- ered method can be dependant on the form, density and hard-
ment of the parameters to further optimise the reaction ness of the input materials – within the substrate scope pre-
outcome and commenced with the addition of grinding agents sented here the morpholine is a liquid and amongst the aryl
to improve the flowability and mixing of the reaction mixture.9 halide coupling partners explored were both solid and liquid
For this purpose addition of silica gel, Celite, sodium chloride reagents.
or sand (Table 1, entries 2–7), to the reaction mixture was
With respect to the reaction scope of the secondary amine
explored; 3 mass equivalents of sand provided a clear improve- component 14 partners were successfully coupled, demonstrat-
ment, affording compound 3 in 75% isolated yield. Screening ing that the reaction is not only limited to the privileged mor-
a small range of catalysts at 1 mol% loading (Table 1, entries pholine. Other highly nucleophilic cyclic amines led to good
8–11) demonstrated that the Pd-PEPPSI-iPent was optimal for to excellent yields from 91% for the optimised substrate mor-
this process, with an intriguing improvement in yield observed pholine to 60% for N-Boc protected piperazine (Scheme 2,
at this reduced loading (91% isolated yield, Table 1, entry 9). compounds 3 and 27). Acyclic secondary amines also partici-
Further experiments explored the species of base, equivalents pated in this reaction affording the resulting cross-coupled
of base and reaction time, with no further improvements products in good to very good yields. For the benzyl acyclic
observed (Table 1, entries 12–19). With optimal conditions examples, the more sterically hindered N-isopropyl amine
identified (Table 1, entry 9), application to a small range of afforded essentially the same yield as the N-methyl variant
15 aryl halides was investigated, initially this lead to the verifi- (Scheme 2, compounds 23 & 24).
cation that these conditions were applicable to aryl chlorides,
It should be noted that the presently reported conditions
bromides and iodides but also heteroaromatic, electron rich were not successfully applied to primary amine coupling reac-
and electron poor substrates, although in the latter case, a tions, attempted cross coupling of aniline or octylamine with
simple SNAr mechanism could achieve the same targeted pro- morpholine 3 afforded the corresponding product in less than
ducts (Scheme 1). In each case the reaction was conducted 5% GC yield. Nonetheless with a proven applicability to a
under an air atmosphere and afforded the products in moder- small range of both coupling partners the synthesis of a
ate to excellent yield (31–91% isolated yields, Scheme 1). pharmaceutical (API) was targeted using the mechanochemical
Exploring an applicable substrate scope under mechanochem- Buchwald–Hartwig coupling. Treatment of thio-ether (29)
ical conditions is important as the robustness of any discov- under the optimised reaction conditions with N-Boc piperazine
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Scheme 2 Amine scope of mechanochemical Buchwald–Hartwig
reaction. Reaction conditions: Chlorobenzene (1 mmol), amine
(1.2 mmol), Pd-PEPPSI-iPENT (1 mol%), tBuOK (2 mmol), sand (0.338 g),
15 mL Jar, 1 × 12 g stainless steel ball, 3 h under air in mixer mill.
Isolated yields reported.
afforded the resultant protected vortioxetine (30) in 69% yield
(A, Scheme 3). Notably, this reaction was conducted without
any precaution for air or moisture sensitivity. Intrigued by the
apparent robustness of the discovered reaction process we
explored the reaction parameters at 0.2 mol% catalyst loading;
at this catalyst loading a good yield of the desired product was
obtained within eight hours (B, Scheme 3). Furthermore, the
apparent robustness of these reaction parameters was checked
by comparison of the same conditions applied to reactions
conducted in solvent and the presence of air, i.e. where careful
preparation of the solvent was omitted (C, Scheme 3).
Common solvents for the Buchwald–Hartwig amination reac-
tion were chosen for this experiment, including THF, 1,4-
dioxane and toluene. In the event, it can be seen that in the
absence of any precaution, THF preforms the best, affording
the cross-coupled product in 37% yield. It can be seen from
the data that the solvent based reaction stalls by the two hour
point, potentially through catalyst deactivation, indeed such
sensitivity has been reported by Organ and co-workers.10 With
these experimental observations we can hypothesise about
where such reaction performance may derive. If we crudely
consider the overall effectiveness of the reaction being a reflec-
tion of the effective rate of the desired product formation (K1)
versus the effective rate of catalyst degradation (K2), then
clearly in the case of milling, where the reaction is faster than
in solution, the differences between K1 and K2 are greater rela-
Scheme 3 (A) Synthesis of Vortioxetine featuring the mechanochem-
ical Buchwald–Hartwig reaction. (B) reduced catalyst loading for the
mechanochemical Buchwald–Hartwig amination. (C) robustness of
these conditions under solvent based and solvent-free conditions. aYield
was determined by GC using mesitylene as internal standard. bIsolated
yield.
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tive to solution (empirically shown in C, Scheme 3). This obser-
vation could be due to the rate of the desired reaction being
faster under milling conditions, or, because the rate of catalyst
degradation is slower, indeed, milling could afford a pathway
whereby deactivated catalyst is transformed back into active
catalyst by mechanical activation.10 Regarding air and moist-
ure sensitivity, it should be noted that mechanochemical
milling jars are not hermetically sealed, but, air ingress is
likely to be greatly reduced, thus if the reaction system is able
to generate it’s own anaerobic conditions within the milling-
jar then disruption of those conditions is likely to be slow in
comparison to a solution based reaction, such considerations
could help prevent catalyst deactivation and contribute
towards the observed behaviour.
Notes and references
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Conclusion
Herein we report an operationally simple mechanochemical
method to carry out a solvent-less Buchwald–Hartwig amin-
ation reaction of secondary amines. The reported method is
robust and can be achieved without special precaution to pre-
clude air or water from the reaction system. The method has
been applied to 30 different substrates including both liquid
and solid components and was successfully incorporated into
the synthesis of the antidepressant API Vortioxetine. The
potential for mechanical activation to offer benefits to catalytic
reactions has been briefly described.
Notes
Information about the data underpinning the results pre-
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Conflicts of interest
There are no conflicts to declare.
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Acknowledgements
D. L. B. is grateful to the EPSRC for a First Grant (D. L. B. &
Q. C. EP/P002951/1), the EPSRC U.K. National Mass
Spectrometry Facility at Swansea University and the School of
Chemistry at Cardiff University for generous support. We
thank the Cardiff Catalysis Institute for providing access to the
GC equipment used in this study and in particularly the expert
technical support from Dr Greg Shaw.
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