"Greener" Friedel-Crafts acylations: A metal- and halogen-free methodology

Article abstract of DOI:10.1021/ol200482s

Chemical equations presented. The utility of methanesulfonic anhydride for promoting the Friedel-Crafts acylation reaction of aryl and alkyl carboxylic acids is disclosed. This reagent allows the preparation of aryl ketones in good yield with minimal waste containing no metallic or halogenated components, clearly differentiating it from other available methodologies.

Full text of DOI:10.1021/ol200482s

ORGANIC
LETTERS
2011
Vol. 13, No. 9
2232–2235
“Greener” FriedelÀCrafts Acylations: A
Metal- and Halogen-Free Methodology
Mark C. Wilkinson†,*
API Chemistry & Analysis, Product Development, GlaxoSmithKline, Gunnels Wood
Road, Stevenage, Hertfordshire SG1 2NY, U.K.
Mark.C.Wilkinson@hotmail.co.uk
Received February 22, 2011
ABSTRACT
The utility of methanesulfonic anhydride for promoting the FriedelÀCrafts acylation reaction of aryl and alkyl carboxylic acids is disclosed. This
reagent allows the preparation of aryl ketones in good yield with minimal waste containing no metallic or halogenated components, clearly
differentiating it from other available methodologies.
Recently the desire for “greener” or “sustainable” meth-
odology for bond forming steps fundamental to the fine
chemical and pharmaceutical industries has significantly
increased.
One example of such a fundamental transformation is the
FriedelÀCrafts acylation reaction. There has and continues
to be a tremendous amount of research in this field. The
union of a carboxylic acid with an aromatic component
promoted by a single substoichiometric catalyst would be
the ideal solution. While progress has been made,1 and not
to overlook exciting developments in heterogeneous cata-
lysis (perhaps best suited for bulk fine chemicals),2,3 there is
still a requirement for improved methods suitable for the
batch manufacture of pharmaceuticals. This is reflected in
the ACS Green Chemistry Institute Pharmaceutical Round-
table highlighting a desire for improved methodologies in
the area, especially for unactivated systems.4 A disappoint-
ingly high proportion of the prior work focuses on electron-
rich aromatic systems (e.g., anisole) on which FriedelÀ
Crafts acylations are relatively easy to promote and may
also rely on a large excess of the aromatic nucleophile. For
the synthesis of the complex aromatic motifs typical in the
pharmaceutical industry, mass efficient reactions on more
electron deficient systems are essential.
We now wish to report our development of a metal- and
halogen-free FriedelÀCrafts acylation methodology with
minimal waste streams, albeit still currently relying on a
stoichiometric reagent. Reactions are possible with chlor-
obenzene, the archetypical electron-poor FriedelÀCrafts
substrate, and generallyrequire just2 equiv of the aromatic
nucleophile with no further solvent.
† Future address: Centec International, The Science Park, Brooks Lane,
Middlewich, Cheshire, CW10 0JG.
(1) Selected references: (a) Effenberger, F.; Sohn, E.; Epple, G. Chem.
ꢀ
Ber. 1983, 116, 1195. (b) Desmurs, J. R.; Labrouillere, M.; Le Roux, C.;
Gaspard, H.; Laporterie, A.; Dubac, J. Tetrahedron Lett. 1997, 38, 8871.
(c) Smyth, T. P.; Corby, B. W. Org. Process Res. Dev. 1997, 1, 264. (d)
Kobayashi, S.; Matsuo, J.-I.; Odashima, K. Synlett 2000, 403. (e) Olah,
G. A.; Hwang, J. P.; Surya Prakash, G. K. Tetrahedron 2000, 56, 7199. (f)
Frost, C. G.; Hartley, J. P.; Griffin, D. Tetrahedron Lett. 2002, 43, 4789.
(g) Surya Prakash, G. K.; Yan, P.; Torok, B.; Bucsi, I.; Tanaka, M.;
Olah, G. A. Catal. Lett. 2003, 85, 1. (h) Sharghi, H.; Sarvari, M. H.
J. Org. Chem. 2004, 69, 6953. (i) Matsushita, Y.-I.; Sugamoto, K.;
Matsui, T. Tetrahedron Lett. 2004, 45, 4723. (j) Earle, M. J.; Hakala, U.;
McAuley, B. J.; Nieuwenhuyzen, M.; Ramani, A.; Seddon, K. R. Chem.
Commun. 2004, 1368. (k) Cai, C.; Yi, W.-B. J. Fluorine Chem. 2005, 126,
1191. (l) Garlyauskayte, R. Y.; Posternak, A. G.; Yagupolskii, L. M.
Tetrahedron Lett. 2009, 50, 446.
Defining what truly constitutes a “green” methodology
is difficult, but the guiding principles for this work have
(2) Metivier, P. In Fine Chemicals through Heterogeneous Catalysis;
Sheldon, R. A., Van Bekkum, H., Eds.; Wiley-VCH: Weinheim, 2001, 161.
(3) Selected references: (a) Olah, G. A.; Malhotra, R.; Narabg, S. C.;
Olah, J. A. Synthesis 1978, 672. (b) Zhou, D.-Q.; Zhang, Y.-H.; Huang,
M.-Y.; Jiang, Y.-Y. Polm. Adv. Technol. 2003, 14, 360. (c) Jin, T.-S.;
Yang, M.-N.; Feng, G.-L.; Li, T.-S. Synth. Commun. 2004, 34, 479. (d)
Gawande, M. B.; Deshpande, S. S.; Sonavane, S. U.; Jayaram, R. V.
J. Mol. Catal. A: Chem. 2005, 151. (e) Ghatpande, S.; Mahajan, S. Indian
J. Chem., Sect. B 2005, 44, 188.
(4) Constable, D. J. C.; Dunn, P. J.; Hayler, J. D.; Humphrey, G. R.;
Leazer, J. L.; Russell, J.; Linderman, R. J.; Lorenz, K.; Manley, J.;
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411.
r
10.1021/ol200482s
Published on Web 03/25/2011
2011 American Chemical Society

been waste minimization (atom economy) and generation
of benign waste streams.
Table 1. FriedelÀCrafts Acylations Promoted by Methanesul-
We have previously examined the utility of trifluoroa-
cetic anhydride (TFAA) mediated FriedelÀCrafts acyla-
tion methodology for the preparation of pharmaceutical
intermediates.5 While this methodology was useful, it
suffered from three drawbacks: (1) The fluorinated waste
streams were difficult to process for disposal. (2) The
reaction appeared limited to activated aromatics (at least
as electron rich as toluene). (3) The mass of waste asso-
ciated with stoichiometric reagents.
fonic Anhydride (MSAA)
We began to consider how to improve this methodology.
We reasoned a stronger acid than TFA may extend the
reaction to less activated aromatics. Thus we sought a strong
acid, with a low molecular weight, and preferably not halo-
genated to aid waste treatment. This logic led us to methane-
sulfonic acid (MSA) and the corresponding methanesulfonic
anhydride (MSAA). MSA is attractive from a sustainability
point of view as it can be derived from biomass and as such is
not reliant on petrochemical sources. It can also be biode-
graded and suitable industrial processes have already been
disclosed,6 which would be a significant benefit for waste
steam processing. We believe the use of MSAA for FriedelÀ
Crafts reactions to be novel, although intermolecular acyla-
tions with Eaton’s reagent (P2O5/MSA) have been reported
previously.7 Similar reactions promoted by graphite,8 or
alumina,9 using MSA as solvent have also been detailed.
We began by screening conditions similar to those we
had used previously with TFAA. We were delighted to
observe excellent reactivity. Even more gratifyingly, this
reactivity was preserved in the absence of an additional
catalyst. Presumably the methanesulfonic acid generated
by the reaction of the MSAA with the substrate acid is a
sufficiently strong acid to catalyse the subsequent reaction
of the mixed anhydride. A similar observation has been
made in trichloroacetic anhydride promoted intramolecu-
lar FriedelÀCrafts acylations.10 The ability of this metho-
dology to deliver aryl ketones is illustrated in Table 1.
Steric hindrance presented little difficulty, with the pre-
paration of a tetra-ortho substituted benzophenone (entry 1).
Pleasingly, a methyl ester was successfully carried through the
reaction sequence (entry 4). Diaryl ethanones could also be
prepared (entry 5). Reactivity was preserved with chlorinated
aromatics (entrys 6À9), although the yields were reduced
with these more challenging substrates. Also, additional
MSAA was charged later in the reaction (entries 7À9) as
competing formation of a methyl aryl sulfone derived from
a Determined by NMR. b Determined by HPLC. c At 3 h 30, a further
30 mol % of MSAA was charged. d 1.8 equiv of MSAA used, and at 23 h,
a further 40 mol % of MSAA was charged. e 2 mol % of In(OTf)3 and 1.5
equiv of MSAA were used. At 5 h, a further 35 mol % of MSAA was
charged.
(5) Wilkinson, M. C.; Saez, F.; Hon, W. L. Synlett 2006, 1063.
(6) Boyle, R.; Venkataramani, E. S. PCT Int. Appl. WO 9521135
(CAN 123:207938), 1995.
(7) (a) Li, J. J.; Mitchell, L. H.; Dow, R. L. Biorg. Med. Chem. Lett.
2010, 20, 306. (b) Wu, Z.; Guo, W.; Lian, G.; Yu, B. J. Org. Chem. 2010,
75, 5725. (c) Gruber, J. M.; Seemayer, R. US5962743 (CAN
131:243065), 1999. (d) Kelly, T. R.; Ghoshal, M. J. Am. Chem. Soc.
1985, 107, 3879. (e) Eck, G.; Julia, M.; Pfeiffer, B.; Rolando, C.
Tetrahedron Lett. 1985, 26, 4723. (f) Stott, P. E.; Bradshaw, J. S.; Parish,
W. W.; Copper, J. W. J. Org. Chem. 1980, 45, 4716.
(8) (a) Sharghi, H.; Hosseini-Sarvari, M.; Eskandari, R. Synthesis
2006, 2047. (b) Sharghi, H.; Hosseini-Sarvari, M. Synthesis 2004, 2165.
(9) Sharghi, H.; Kaboudon, B. J. Chem. Res., Synop. 1998, 628.
(10) Andrews, B.; Bullock, K.; Condon, S.; Corona, J.; Davis, R.;
Grimes, J.; Hazelwood, A.; Tabet, E. Synth. Commun. 2009, 39, 2664.
the aromatic nucleophile was observed. The reaction time for
chlorobenzene was rather long (32 h, entry 8) but could be
significantly reduced with the use of 2 mol % of indium
triflate.1f The use of a metal catalyst rather undermines the
aim of this work but may be beneficial if reaction time is an
issue. Reactions with nitrated aromatics were not successful.
The reactions depicted in Table 1 required only 2 equiv
of aromatic nucleophile. However, it was also demonstrated
Org. Lett., Vol. 13, No. 9, 2011
2233

that even less aromatic component may be used.
4-Fluorobenzoic acid (1.0 equiv) was reacted with toluene
(1.3 equiv) and methanesulfonic anhydride (1.3 equiv),
and then the product crystallized directly from the reac-
tion mixture with n-PrOH/H2O. This minimization of the
reagents correspondingly minimized waste, with only 50 g
of waste for every 10 g of product produced (Scheme 1).
Various metrics have been developed to compare the
efficiency of chemical process, with this result corre-
sponding to an E (environmental) factor of 411 or a mass
intensity of 5 (mass productivity of 20%).12,13 This is a
pleasing result for a (albeit single stage) chemical process.
Table 2. MSAA-Promoted FriedelÀCrafts Reactions Benefit-
ing from Co-solvent
Scheme 1. FriedelÀCrafts Acylation with Minimal Waste
a 1 volume = 1 mL per 1 g of limiting reagent. b DCB = 1,2-
dichlorobenzene.
Despite one of the guiding principles of this work being
waste reduction by eliminating unnecessary solvent, some
reactions did benefit from the introduction of small
amounts of a cosolvent (Table 2). Alkyl acids gave the
desired products successfully but appeared to undergo
further reaction and decomposition. This was mitigated
by reduction of excess aromatic component and introduc-
tion of cosolvent (entry 1). Benzene was a successful aro-
matic nucleophile in this methodology, but the reactions
The utility of this methodology for the synthesis of
pharmaceutical intermediates has been demonstrated.
Thediarylethanone15wasanintermediateinthesynthesis
of COX-2 inhibitor GW406381X, which has potential
therapeutic applications to chronic inflammatory pain.14
Using the MSAA methodology it was prepared as shown
in good yield with minmal waste (Scheme 2).
Scheme 2. Synthesis of Phenyl Benzyl Ketone Intermediate to GW406381X
were slow because of its low boiling point. The introduction
of a higher boiling cosolvent enabled higher reaction tem-
peratures, with corresponding quicker reactions and higher
isolated yields. Because of the high reactivity of anisole in
FriedelÀCrafts acylations, aryl ketones such as 13 produced
by acylation of this solvent were observed to undergo
further reaction and side product formation. This undesired
over-reaction was much reduced by the introduction of a
diluting cosolvent (entry 3).
In conclusion, we report a novel methodology for
FriedelÀCrafts acylation reactions, which allows the pre-
paration of various aryl ketones with minimal waste contain-
ing no halogenated or metallic components, clearly differentiat-
ing it from other methodologies. The reactions proceed on
the parent carboxylic acids via 1.3 equiv of a activating agent
(methanesulfonic anhydride) and as little as 1.3 equiv of an
aromaric nucleophile, with in general no additional solvent.
All products (with the exeption of low melting 12) were
isolated by crystallization from the reaction mixture giving
an efficient one-pot process suitable for further scale up.
(11) Sheldon, R. A. Chem. Commun. 2008, 3352.
(12) Constable, D. J. C.; Curzons, A. D.; Cunningham, V. L. Green
Chem. 2002, 4, 521.
(14) Whitehead, A. J.; Ward, R. A.; Jones, M. F. Tetrahedron Lett.
2007, 48, 911.
(13) Mass productivity = 100 ÷ (mass intensity).
2234
Org. Lett., Vol. 13, No. 9, 2011

Acknowledgment. Andrew Hazelwood is acknowl-
edged for invaluable discussions. Lee Boulton, Marco
Smith, Simon Watson, and Ben Bardsley (all GSK,
Stevenage) are acknowledged for analytical support.
Supporting Information Available. Experimental de-
tails and characterization of all compounds. This material
is available free of charge via the Internet at http://pubs.
acs.org.
Org. Lett., Vol. 13, No. 9, 2011
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