N-Heterocyclic Carbene Acyl Anion Organocatalysis by Ball-Milling

Article abstract of DOI:10.1002/cssc.201902346

The ability to conduct N-heterocyclic carbene-catalysed acyl anion chemistry under ball-milling conditions is reported for the first time. This process has been exemplified through applications to intermolecular-benzoin, intramolecular-benzoin, intermolecular-Stetter and intramolecular-Stetter reactions including asymmetric examples and demonstrates that this mode of mechanistically complex organocatalytic reaction can operate under solvent-minimised conditions.

Full text of DOI:10.1002/cssc.201902346

DOI: 10.1002/cssc.201902346
Communications
N-Heterocyclic Carbene Acyl Anion Organocatalysis by
Ball-Milling
William I. Nicholson, Alex C. Seastram, Saqib A. Iqbal, Benjamin G. Reed-Berendt,
Louis C. Morrill,* and Duncan L. Browne*[a]
The ability to conduct N-heterocyclic carbene-catalysed acyl
anion chemistry under ball-milling conditions is reported for
the first time. This process has been exemplified through appli-
cations to intermolecular-benzoin, intramolecular-benzoin, in-
termolecular-Stetter and intramolecular-Stetter reactions in-
cluding asymmetric examples and demonstrates that this
mode of mechanistically complex organocatalytic reaction can
operate under solvent-minimised conditions.
vironment.[4] As part of this process the field has recently been
moving towards assessing the possibility of running complex
catalytic reactions and enantioselective processes under milling
conditions.[5]
The area of organocatalysis is one such area where the pro-
posed reaction pathways require several discrete steps and
enantioselectivity rests on the organisation of complex transi-
tion states. Of the many areas of organocatalysis (some of
which are shown in Figure 1A), only secondary amine systems
have been well studied under milling conditions, with pioneer-
ing contributions from Bolm and co-workers.[6] It has been es-
tablished that several reaction manifolds accessible by secon-
dary amine organocatalysis in solution can also operate under
milling conditions.[7] Given the wealth of transformations and
activation modes we were intrigued by the prospect of con-
ducting nucleophilic heterocyclic carbene (NHC) catalysis
under milling conditions. NHC organocatalysis has been rapidly
Mechanochemistry is characterised by the input of mechanical
energy into chemical bonds to initiate reactivity of those
bonds.[1] Chemical reactions brought about by ball-milling con-
stitute an area of mechanochemistry. That a reaction takes
place under ball-milling conditions does, however, not necessa-
rily mean that the process is mechanically driven. Indeed, ball-
milling reactions also typically feature solvent-free or solvent-
minimised, high-concentration and occasionally high-instanta-
neous/bulk-temperature conditions. Many of these factors are
inextricably linked and may never be fully delineated. Nonethe-
less, the fields of mechanochemistry and ball-milling, in combi-
nation with reactive extrusion, are capable of delivering a
more sustainable approach to some aspects of chemical syn-
thesis and chemical manufacturing.[2] Given the complex inter-
related nature of parameters, one approach to gain a better in-
sight into these techniques is through attrition, that is, gaining
many experimental data points and building a picture of un-
derstanding as a whole. In recent years the community in this
area has been building towards this vision.[3] In several instan-
ces there have emerged trends and conceptual frameworks,
and in others there is simply a translation to a solvent-mini-
mised process. However, perhaps the most exciting aspect of
this approach is the increased opportunity for serendipitous
discoveries by exploring this unchartered chemical reactor en-
[a] W. I. Nicholson, A. C. Seastram, S. A. Iqbal, B. G. Reed-Berendt,
Dr. L. C. Morrill, Dr. D. L. Browne
Cardiff Catalysis Institute, School of Chemistry,
Cardiff University
Park Place, Cardiff, CF10 3AT (United Kingdom)
E-mail: morrilllc@cardiff.ac.uk
dlbrowne@cardiff.ac.uk
Supporting Information and the ORCID identification number(s) for the
author(s) of this article can be found under:
https://doi.org/10.1002/cssc.201902346.
ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.
This is an open access article under the terms of the Creative Commons
Attribution License, which permits use, distribution and reproduction in
any medium, provided the original work is properly cited.
Figure 1. (a) Some areas of organocatalysis; (b) example activation modes of
NHC catalysis; (c) this work: NHC acyl anion organocatalysis under ball-mill-
ing conditions.
ChemSusChem 2019, 12, 1 – 6
1
ꢀ 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
These are not the final page numbers! ÞÞ

Communications
established as a key area for catalyst-mediated synthesis, with
many activation modes established for a wide range of sub-
strates (Figure 1B).[8] The first established activation mode of
acyl anions stemmed from the pioneering work of Breslow on
thiamine-catalysed reactions and has led to numerous exam-
ples across a range of carbonyl functional groups.[9] These in-
clude benzoin, Stetter and hydroacylation reactions, with dem-
onstration of homo-, cross-, inter- and intramolecular exam-
ples. Herein we report the first results of combining this NHC
activation mode with ball-milling (Figure 1C).[10]
Our initial investigations commenced with the intermolecu-
lar homo-benzoin reaction of 4-chlorobenzaldehyde under
planetary milling conditions. A range of ten NHC precatalysts
based on thiazolium, imidazolium and triazolium heterocycles
were screened, along with five bases [K3PO4, K2CO3, Cs2CO3,
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and Et3N] and three
grinding auxiliaries.[11] Pleasingly, it was found that the penta-
fluorophenyl bearing triazolium tetrafluoroborate NHC precata-
lyst 8 was the most effective at 10 mol% loading.
Combining the 4-chlorobenzaldehyde with the precatalyst,
Cs2CO3, sand (as a grinding auxiliary) and grinding in a planeta-
ry mill at 300 rpm for 15 min furnished the homo-benzoin
product 11 in 72% isolated yield (Scheme 1, conditions A).
However, extending these conditions to a small range of sub-
strates did not return positive outcomes in every case. The lit-
erature concerning NHC-catalysed benzoin reactions demon-
strates that several of the reaction steps can be equilibrium
processes, in which the reversibility of individual steps is highly
dependent on the catalyst and substrate combinations.[12] We
hypothesised that the presence of liquids/solvents may help to
stabilise or drive reactions forward, and, in the solid state, crys-
tal lattice enthalpies may also play a critical role in determining
the position of equilibrium for reactions featuring solid prod-
ucts and/or starting materials (notably, 4-chlorobenzaldehyde
is a solid, and other benzaldehyde derivatives are liquids). With
this in mind, we screened the addition of 100 mL of several
LAG (Liquid-Assisted Grinding) materials, including EtOAc, tet-
rahydrofuran (THF), dichloromethane (DCM), hexafluoroisopro-
panol (HFIP), isopropanol (IPA), EtOH, dimethylformamide
(DMF), MeCN, dimethylacetamide (DMA) and dimethyl sulfox-
ide (DMSO). It was found that addition of IPA was optimal and
permitted 76% isolated yield of 14 (in the case of benzalde-
hyde) and 63% yield of 12 (in the case of 4-tolaldehyde). With
these conditions in hand, a total of six aldehydes were then as-
sessed under “no LAG” and “IPA LAG” (100 mL) conditions
(Scheme 1, inter-benzoin). It appears that milling with LAG
gives the most robust conditions, that is, those that permit the
greatest chances of success under this milling protocol. As
common in many solvent-based approaches, it too was found
that the reaction is highly dependent on the purity of the alde-
hyde introduced into the reaction; trace carboxylic acid ap-
pears to have a disproportionately negative effect on the out-
come of the reaction. Pleasingly, the “no LAG” conditions
could also be directly applied to the intra-cross-benzoin reac-
tion of tethered ketone–aldehyde substrates to yield a-hy-
droxychromanone products in good yields (Scheme 1, intra-
benzoin). With confirmation in hand of carbene generation
Scheme 1. NHC-catalysed benzoin reaction under milling conditions.
and its engagement in catalysis through acyl anion activation,
our attention turned to demonstrating this reactivity also in
the case of the Stetter reaction. Application of previously opti-
mised conditions A to a model inter-Stetter reaction featuring
4-chlorobenzaldehyde and chalcone did not return favourable
yields of the desired product. However, conditions A (5 mol%
precatalyst) were applicable to a range of intramolecular Stet-
ter reactions to furnish the corresponding chromanones and
3-oxo-2,3-dihydrobenzofurans in good-to-excellent yields
(Scheme 2, intra-Stetter 6,6 and intra-Stetter 6,5). Indeed, fur-
ther reaction screening was required to deliver the intermolec-
ular Stetter reaction under milling conditions. Again, screening
a range of precatalysts, bases, grinding auxiliaries, LAGs and
&
ChemSusChem 2019, 12, 1 – 6
www.chemsuschem.org
2
ꢀ 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Communications
forded moderate-to-good yields in all nine cases. Attention
was then turned to exploring if enantioselectivity could be im-
parted to this reaction manifold under milling conditions. Con-
ditions A were chosen to be explored, and the pentafluoro-
phenyl bearing triazolium pre-NHC 8 was switched for the priv-
ileged aminoindane-based triazolium pre-NHC 33, reported by
Kerr and Rovis.[13] Three of the reaction modes were explored,
including intra-benzoin, inter-benzoin and both the 6,6- and
6,5-intra-Stetter reactions. All experiments were run with
10 mol% catalyst loading, and preliminary results show that it
is indeed possible to transmit enantioselectivity under these
conditions (Scheme 3). For the intra-benzoin reaction, it was
found that addition of IPA as LAG permitted the reaction to
return increased yield and slightly increased enantiomeric
excess (24% yield, 72% ee without LAG vs. 52% yield and 82%
ee with LAG). The 6,6-intra-molecular Stetter reaction returned
the highest ee of 92% (with an isolated yield of 96%).
Despite these results, some of the ee values are lower than
those reported under solution conditions, perhaps pointing to-
wards poorer temperature control of the milled process.[5k]
However, these are complex reactions, and clearly the balance
of all reaction parameters requires significant fine-tuning to de-
liver optimal conditions for maximum enantioselectivity, and
this would have to be compared directly with a fully optimized
solution protocol. Thus, the conclusion proposed here is that
imparting enantioselectivity of NHC-catalysed reactions under
ball-milling is possible and can deliver excellent results, al-
though how these compare directly against solution-phase
conditions is not yet clear. Nonetheless, it is particularly nota-
ble that carbenes can be used catalytically in complex reaction
pathways and also impart stereocontrol in the absence of sol-
vent and under milling conditions.
In summary, ball-milling has been used as a technique to
conduct NHC catalysis for the first time. A range of catalysts,
bases and grinding auxiliaries have been screened to reach
general conditions for the acyl anion activation mode, which
has been demonstrated in four application areas: intermolecu-
lar-benzoin, intramolecular-benzoin, intermolecular-Stetter and
intramolecular-Stetter. Notably, these reactions are run without
precaution to obscure air and moisture from the reaction
vessel, and in general this works well, although, in some in-
stances, increased catalyst loadings compared to solvent-based
techniques are used. Notably, among all catalysts screened,
perhaps the simplest and longest-known thiazolium pre-NHC 1
is the most optimal catalyst for the intermolecular Stetter reac-
tion under ball-milling conditions. Finally, it has been demon-
strated that several of the reaction modes can also be ren-
dered asymmetric under milling conditions.
Scheme 2. NHC-catalysed Stetter reaction under milling conditions.
milling speeds delivered optimal results. We were pleased to
find that the archetypal thiazolium catalysts were highly effec-
tive under these conditions with K3PO4 serving as base (and
likely the grinding auxiliary). Thiazolium pre-NHC 1 was opti-
mal and afforded conditions B (Scheme 2), requiring 3 h milling
at 700 rpm. With these conditions in hand, a sample of nine in-
termolecular Stetter reactions was explored. A combination of
three aldehydes with three different chalcone derivatives af-
Experimental Section
Information about the data that underpins the results presented in
this article, including how to access them, can be found in the Car-
diff University data catalogue at http://doi.org/10.17035/
d.2019.0087455694. Further experimental details can be found in
the Supporting Information·
ChemSusChem 2019, 12, 1 – 6
www.chemsuschem.org
3
ꢀ 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
These are not the final page numbers! ÞÞ

Communications
Conflict of interest
The authors declare no conflict of interest
Keywords: acyl anion · ball milling · mechanochemistry · N-
heterocyclic carbenes · organocatalysis
[1] For the IUPAC Gold Book definition of mechanochemistry see: https://
goldbook.iupac.org/terms/view/MT07141 or https://doi.org/10.1351/
goldbook.MT07141.
[2] For selected reviews in the area of mechanochemistry see: a) J. L.
Howard, Q. Cao, D. L. Browne, Chem. Sci. 2018, 9, 3080–3094; b) J. An-
ˇˇ ´
dersen, J. Mack, Green Chem. 2018, 20, 1435–1443; c) J.-L. Do, T. Friscic,
ACS Cent. Sci. 2017, 3, 13–19; d) J. G. Hernꢁndez, C. Bolm, J. Org. Chem.
2017, 82, 4007–4019; e) T.-X. Mꢂtro, J. Martinez, F. Lamaty, ACS Sustain-
able Chem. Eng. 2017, 5, 9599–9602; f) D. Tan, F. Garcꢃa, Chem. Soc. Rev.
2019, 48, 2274–2292; g) N. Willis-Fox, E. Rognin, T. A. Aljohani, R. Daly,
Chem 2018, 4, 2499–2537; h) M. J. MuÇoz-Batista, D. Rodriguez-Padron,
A. R. Puente-Santiago, R. Luque, ACS Sustainable Chem. Eng. 2018, 6,
9530–9544; i) J. C. Robertson, M. L. Coote, A. C. Bissember, Nat. Chem.
Rev. 2019, 3, 290–304.
[3] For some recent publications in the area of mechanochemistry see:
a) K. L. Denlinger, L. Ortiz-Trankina, P. Carr, K. Benson, D. C. Waddell, J.
Mack, Beilstein J. Org. Chem. 2018, 14, 688–696; b) L. Appy, A. Depaix,
X. Bantreil, F. Lamaty, S. Peyrottes, B. Roy, Chem. Eur. J. 2019, 25, 2477–
2481; c) M. Ferguson, M. S. Moyano, G. A. Tribello, D. E. Crawford, E. M.
Bringa, S. L. James, J. Kohanoff, M. G. D. Pꢄpolo, Chem. Sci. 2019, 10,
2924–2929; d) K. J. Ardila-Fierro, D. E. Crawford, A. Kçrner, S. L. James,
C. Bolm, J. G. Hernꢁndez, Green Chem. 2018, 20, 1262–1269; e) Y.
Yeboue, B. Gallard, N. Le Moigne, M. Jean, F. Lamaty, J. Martinez, T.-X.
Mꢂtro, ACS Sustainable Chem. Eng. 2018, 6, 16001–16004; f) K. J. Ardila-
Fierro, C. Bolm, J. G. Hernꢁndez, Angew. Chem. Int. Ed. 2019, 58, 12945–
12949; Angew. Chem. 2019, 131, 13079–13083; g) K. J. Ardila-Fierro, A.
Pich, M. Spehr, J. G. Hernꢁndez, C. Bolm, Beilstein J. Org. Chem. 2019, 15,
811–817; h) Q. Cao, R. T. Stark, I. A. Fallis, D. L. Browne, ChemSusChem
2019, 12, 2554–2557; i) A. Porcheddu, F. Delogu, L. De Luca, E. Colacino,
ACS Sustainable Chem. Eng. 2019, 7, 12044–12051; j) Z.-Z. Gu, F.-C. Guo,
P. Zhang, Y.-J. Qin, Z.-X. Guo, Tetrahedron Lett. 2019, 60, 1687–1690;
k) K. Kubota, R. Takahashi, H. Ito, Chem. Sci. 2019, 10, 5837–5842.
[4] We have been benefactors of serendipitous observations under ball-
milling conditions in the following publications: a) J. L. Howard, M. C.
Brand, D. L. Browne, Angew. Chem. Int. Ed. 2018, 57, 16104–16108;
Angew. Chem. 2018, 130, 16336–16340; b) J. L. Howard, Y. Sagatov, L.
Repusseau, C. Schotten, D. L. Browne, Green Chem. 2017, 19, 2798–
2802.
[5] For some recent examples of catalytic and/or enantioselective process-
es under ball-milling conditions see: a) Q. Cao, J. L. Howard, E. Wheatley,
D. L. Browne, Angew. Chem. Int. Ed. 2018, 57, 11339–11343; Angew.
Chem. 2018, 130, 11509–11513; b) Q. Cao, W. I. Nicholson, A. C. Jones,
D. L. Browne, Org. Biomol. Chem. 2019, 17, 1722–1726; c) J. Yu, Z. Li, K.
Jia, Z. Jiang, M. Liu, W. Su, Tetrahedron 2013, 54, 2006–2009; d) Z. Li, Z.
Jiang, W. Su, Green Chem. 2015, 17, 2330–2334; e) Y. Wang, H. Wang, Y.
Jiang, C. Zhang, J. Shao, D. Xu, Green Chem. 2017, 19, 1674–1677; f) P.
Staleva, J. G. Hernꢁndez, C. Bolm, Chem. Eur. J. 2019, 25, 9202–9205;
g) Y. Pang, T. Ishiyama, K. Kubota, H. Ito, Chem. Eur. J. 2019, 25, 4654–
4659; h) Z. A. Ignatiuk, M. J. Janicki, R. W. Gꢄra, K. Koniecznym, R. Ko-
walczyk, Adv. Synth. Catal. 2019, 361, 1108–1116; i) K. Kubota, T. Seo, K.
Koide, Y. Hasegawa, H. Ito, Nat. Commun. 2019, 10, 111; j) J. Andersen, J.
Brunemann, J. Mack, React. Chem. Eng. 2019, 4, 1229–1236; k) J. Ander-
sen, J. Mack, Angew. Chem. Int. Ed. 2018, 57, 13062–13065; Angew.
Chem. 2018, 130, 13246–13249; l) C. G. Avila-Ortiza, M. Pꢂrez-Venegasa,
J. Vargas-Caporalia, E. Juaristi, Tetrahedron Lett. 2019, 60, 1749–1757.
[6] For the seminal work of secondary amine organocatalysis under ball-
milling conditions see: B. Rodrꢃguez, T. Rantanen, C. Bolm, Angew.
Chem. Int. Ed. 2006, 45, 6924–6926; Angew. Chem. 2006, 118, 7078–
7080.
Scheme 3. Overview of asymmetric NHC-mediated acyl anion chemistry
under milling conditions.
Acknowledgements
The authors are grateful to Cardiff University School of Chemistry
for generous support and the EPSRC for a partially funded PhD
studentship (via a DTG to B.G.R.-B., EP/M507842/1). We thank the
EPSRC UK National Mass Spectrometry Facility at Swansea Uni-
versity for mass spectrometry measurements.
[7] For papers concerning secondary amine organocatalysis under milling
conditions see: a) G. Guillena, M. del. Carmen Hita, C. Nꢁjera, S. F. Viꢄ-
&
ChemSusChem 2019, 12, 1 – 6
www.chemsuschem.org
4
ꢀ 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Communications
zquez, Tetrahedron: Asymmetry 2007, 18, 2300–2304; b) A. Bruckmann,
A. Krebs, C. Bolm, Green Chem. 2008, 10, 1131–1141; c) G. Guillena, M.
del Carmen Hita, C. Nꢁjera, S. F. Viꢄzquez, J. Org. Chem. 2008, 73, 5933–
5943; d) J. G. Hernꢁndez, E. Juaristi, J. Org. Chem. 2011, 76, 1464–1467;
e) J. G. Hernꢁndez, E. Juaristi, Tetrahedron 2011, 67, 6953–6959; f) J. G.
Hernꢁndez, V. Garcꢃa-Lꢄpez, E. Juaristi, Tetrahedron 2012, 68, 92–97;
g) P. Chauhan, S. S. Chimni, Asian J. Org. Chem. 2012, 1, 138–141; h) E.
Bugaut, F. Glorius, Chem. Soc. Rev. 2012, 41, 3511–3522; f) J. Douglas, G.
Churchill, A. D. Smith, Synthesis 2012, 44, 2295–2309; g) D. M. Flanigan,
F. Romanov-Michailidis, N. A. White, T. Rovis, Chem. Rev. 2015, 115,
9307–9387; h) R. S. Menon, A. T. Biju, V. Nair, Chem. Soc. Rev. 2015, 44,
5040–5052.
[9] R. Breslow, J. Am. Chem. Soc. 1958, 80, 3719–3726.
[10] Ema et al. have reported acyl anion NHC organocatalysis under solvent-
free conditions (stirring materials neat in a reaction tube): T. Ema, Y.
Nanjo, S. Shiratori, Y. Terao, R. Kimura, Org. Lett. 2016, 18, 5764–5767.
[11] For further details see the Supporting Information.
[12] J. Mahatthananchai, J. W. Bode, Chem. Sci. 2012, 3, 192–197.
[13] M. S. Kerr, T. Rovis, J. Am. Chem. Soc. 2004, 126, 8876–8877.
ˇ
ˇ
ˇ
Veverkovꢁ, V. Polꢁckovꢁ, L. Liptꢁkovꢁ, E. Kꢁzmerovꢁ, M. Meciarovꢁ, S.
ˇ
Toma, R. Sebesta, ChemCatChem 2012, 4, 1013–1018; i) J. G. Hernꢁndez,
E. Juaristi, Chem. Commun. 2012, 48, 5396–5409; j) P. Chauhan, S. S.
Chimni, Beilstein J. Org. Chem. 2012, 8, 2132–2141.
[8] For reviews on NHC organocatalysis see: a) D. Enders, O. Niemeier, A.
Henseler, Chem. Rev. 2007, 107, 5606–5655; b) N. Marion, S. Dꢃez-Gon-
zꢁlez, S. P. Nolan, Angew. Chem. Int. Ed. 2007, 46, 2988–3000; Angew.
Chem. 2007, 119, 3046–3058; c) J. Read de Alaniz, T. Rovis, Synlett 2009,
1189–1207; d) V. Nair, R. S. Menon, A. T. Biju, C. R. Sinu, C. R. R. R. Paul,
A. Jose, V. Sreekumar, Chem. Soc. Rev. 2011, 40, 5336–5346; e) X.
Manuscript received: August 27, 2019
Version of record online: && &&, 0000
ChemSusChem 2019, 12, 1 – 6
www.chemsuschem.org
5
ꢀ 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
These are not the final page numbers! ÞÞ

COMMUNICATIONS
W. I. Nicholson, A. C. Seastram, S. A. Iqbal,
B. G. Reed-Berendt, L. C. Morrill,*
D. L. Browne*
&& – &&
N-Heterocyclic Carbene Acyl Anion
Organocatalysis by Ball-Milling
Having a ball: The ability to conduct
mechanistically complex N-heterocyclic
carbene-catalysed acyl anion chemistry
under ball-milling conditions is reported
for the first time. This process is exem-
plified through applications to intermo-
lecular-benzoin, intramolecular-benzoin,
intermolecular-Stetter and intramolecu-
lar-Stetter reactions including asymmet-
ric examples.
&
ChemSusChem 2019, 12, 1 – 6
www.chemsuschem.org
6
ꢀ 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!