Communication
doi.org/10.1002/chem.202101617
Chemistry—A European Journal
Sodium Butylated Hydroxytoluene: A Functional Group
Tolerant, Eco-Friendly Base for Solvent-Free, Pd-Catalysed
Amination
A major contributor to E-Factor is organic solvent and
Abstract:
NaBHT
(sodium
2,6-di-tert-butyl-4-meth-
chemists have primarily looked to reduce the waste produced
from reaction solvent by trying to adapt processes to tolerate
water as the solvent,[1,4] or to avoid reaction solvent all together
by performing the transformation solvent free.[1,5] If all reaction
components, including products and byproducts, are liquids,
then neat transformations are somewhat more straightforward
because the reaction components all serve the role as solvent
for each other. Conversely, if one or more of the reaction
components are solids, instead of forming a homogeneous
solution, the reaction takes on a paste-like consistency making
uniform distribution of the reaction components difficult. This is
especially challenging for reactions that are performed catalyti-
cally, in particular when the use of as little catalyst as possible is
desired to enhance process efficiency and ‘greeness’.
ylphenolate), a strong, but hindered and lipophilic base, has
been effectively paired with similarly lipophilic, high-
reactivity Pd-NHC (N-heterocyclic carbene) catalysts to
produce an ideal combination for performing solvent-free
(melt) cross-coupling amination. The mild nucleophilicity of
NaBHT, coupled with the anti-oxidant properties of its
conjugate acid byproduct, BHT means the process seems to
have no functional group incompatibilities. Highly effective
coupling of base-sensitive and redox-active functional
groups was observed in all cases with only 0.1–0.2 mol
percent catalyst. Comparisons using the standard base for
this reaction, KOtBu, led to poor couplings or complete
degradation in most applications – only NaBHT works.
Not only does the insolubility of the catalyst negatively
impact reactivity in melts, poorly soluble, critical additives, such
as bases and salts,[6] also inhibit conversion. In amination, the
base is essential to generate the metal amide that is necessary
to undergo reductive elimination and complete the catalytic
cycle; base strength (pKb) and solubility are key in this respect.
Very strong bases like tert-butoxide are very effective at
deprotonating the metal-ammonium complex and have shown
useful in melts to overcome insolubility.[7] However, such
conditions are aggressive and base-sensitive functional groups
such as carbonyls, esters, nitriles, etc. typically do not survive
such conditions.[6d,8] Further, substrates and products that are
redox active also have had limited success under amination in
general, let alone in melt applications.[9] Even electrophiles
stable against tert-butoxide often show CÀ O coupling
products[8a,c,10]
To address all of the above-mentioned concerns, we have
examined the use of NaBHT (butylated hydroxytoluene sodium
salt, sodium 2,6-di-tert-butyl-4-methylphenolate) as the base.
The structure is quite lipophilic and greasy improving its
solubility and allowing it to diffuse more readily through the
paste. The corresponding acid has a pKa around ~11.3, so
NaBHT is sufficiently basic to deprotonate any Pd-amine
complex, while the bulk surrounding the phenoxy centre will
mitigate aggressive behaviour toward sensitive functionality.
Finally, BHT, the byproduct of amination, is the most widely
used antioxidant and a potent radical scavenger and this could
further broaden the scope of this transformation.[11]
As all businesses struggle to achieve a zero-carbon footprint,
the fine-chemical manufacturing sector faces unique challenges.
Commodity chemical companies such as those in the
petrochemical[1] and polymer sectors,[2] are actually quite
efficient in terms of atom-economy and produce relatively little
waste. Conversely, companies that conduct traditional organic
synthesis, such as those in the agrichemical, pharmaceutical,
and electronics sectors, produce waste that dwarfs the actual
quantity of the final target. This can be evaluated in a number
of ways, but one of the most common metrics used is the
process ‘E-Factor’ (Environmental Factor),[1] which is a ratio of
the mass of waste produced relative to the desired product.
This number is shockingly high for fine chemical and pharma-
ceutical manufacturing, often surpassing a value of 100 for
many processes.[1,3]
[a] Dr. V. Semeniuchenko, Prof. M. G. Organ
Centre for Catalysis Research and Innovation (CCRI)
Department of Chemistry and Biomolecular Sciences
University of Ottawa
Ottawa,Ontario K1N6N5 (Canada)
E-mail: organ@uottawa.ca
[b] Dr. W. M. Braje
AbbVie Deutschland GmbH & Co. KG
Neuroscience Discovery Research
Knollstrasse, 67061
The catalysts that we chose to explore in this melt chemistry
were bulky Pd-HNC (N-heterocyclic carbene) pre-catalysts (Fig-
ure 1) as they possess the right balance of high intrinsic
reactivity[6a,8a,c,12] to help offset the heterogeneity of the melt
Ludwigshafen (Germany)
Supporting information for this article is available on the WWW under
Chem. Eur. J. 2021, 27, 1–6
1
© 2021 Wiley-VCH GmbH
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