A convenient one-pot synthesis of boroxoles from diboronic acid

Article abstract of DOI:10.1016/j.tetlet.2017.08.011

The preparation of the boroxole motif traditionally relies on a 3-step process and the use of n-butyl lithium that can limit substrate scope. Herein during our exploration toward novel RORγ inhibitors, we identified a convenient one-pot preparation of the motif in good yields with good substrate scope.

Full text of DOI:10.1016/j.tetlet.2017.08.011

Accepted Manuscript
A convenient one-pot synthesis of boroxoles from diboronic acid
Guillaume Lafitte, Kana Kunihiro, Céline Bonneaud, Bénédicte Dréan,
Frédéric Gaigne, Véronique Parnet, Romain Pierre, Catherine Raffin, Rodolphe
Vatinel, Jean-François Fournier, Branislav Musicki, Gilles Ouvry, Claire Bouix-
Peter, Loic Tomas, Craig S. Harris
PII:
S0040-4039(17)31000-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.08.011
TETL 49201
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
28 June 2017
1 August 2017
5 August 2017
Please cite this article as: Lafitte, G., Kunihiro, K., Bonneaud, C., Dréan, B., Gaigne, F., Parnet, V., Pierre, R.,
Raffin, C., Vatinel, R., Fournier, J-F., Musicki, B., Ouvry, G., Bouix-Peter, C., Tomas, L., Harris, C.S., A convenient
one-pot synthesis of boroxoles from diboronic acid, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/
j.tetlet.2017.08.011
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A convenient one-pot synthesis of boroxoles using
diboronic acid
Guillaume Lafitte, Kana Kunihiro, Céline Bonneaud, Bénédicte Dréan, Frédéric Gaigne, Véronique Parnet, Romain Pierre,
Catherine Raffin, Rodolphe Vatinel, Jean-François Fournier, Branislav Musicki, Gilles Ouvry, Claire Bouix-Peter, Loic
Tomas, Craig S. Harris

Tetrahedron Letters
1
TETRAHEDRON
LETTERS
Pergamon
A convenient one-pot synthesis of boroxoles from diboronic acid
Guillaume Lafitte, Kana Kunihiro, Céline Bonneaud, Bénédicte Dréan, Frédéric Gaigne, Véronique
Parnet, Romain Pierre, Catherine Raffin, Rodolphe Vatinel, Jean-François Fournier, Branislav Musicki,
Gilles Ouvry, Claire Bouix-Peter, Loic Tomas,* Craig S. Harris*
Nestlé Skin Health R&D, 2400 Route de Colles, 06410 Biot, France
Abstract— The preparation of the boroxole motif traditionally relies on a 3-step process and the use of n-butyl lithium that can limit
substrate scope. Herein during our exploration toward novel RORγ inhibitors, we identified a convenient one-pot preparation of the motif
in good yields with good substrate scope. © 2017 Elsevier Science. All rights reserved
Psoriasis is a chronic inflammatory disease involving marked immunological changes that affects 2%-3% of the Caucasian
population and is characterised by thick, red and scaly lesions.1 IL-17-targeting biologics have been successful in reducing
the disease burden of psoriasis patients with moderate-to-severe disease.2 The Retinoid-related Orphan Receptor γt (RORγt),
a subfamily of nuclear hormone receptors, is known as the master regulator of IL-17 family cytokines. Therefore, inhibition
of the RORγt receptor represents an interesting opportunity for the treatment of psoriasis.
Bis-aryl sulfonamides have been described by multiple groups as potent RORγt modulators.3 Our internal research program
extensively explored bicyclic heteroaromatic sulfonamides.4,5 As part of this approach boroxole 1 was envisaged as a possible
interesting target molecule (Figure 1). Boroxoles6 have recently risen to fame in dermatology with the approval of
Crisaborole for the topical treatment of atopic dermatitis.7
Figure 1. Targeted boroxole 1
Retrosynthetic analysis of 1 drove us to consider an ambitious and direct approach starting from commercially-available 3,4-
dibromobenzenesulfonyl chloride (7) and 4-ethyl-N-isobutylaniline (6), easily prepared through reductive amination of 4-
ethylaniline. From inspection of the literature,8 Singh et al reported an excellent yield and selectivity at C-4 for a Sonagashira
coupling using 1,2-dibromo-4-nitrobenzene as the substrate. Given the fact the C-4-bromine atom of sulfonamide 5 is also
directly activated by the sulfonamide group, we anticipated that we should be able differentiate between them to afford
Sonagahira product 4 using commercially-available, 4-ethynyltetrahydro-2H-pyran. We anticipated that the hydration step of
4 as high risk as there were very few clear examples of Markovnikov hydration selectivity of alkynes separated by aromatic
moieties and secondary alkyl groups.9-11 However, given the fact 4 was prepared very quickly in just three steps and the
wealth of options to evaluate9-11 we were certain we could find conditions that would provide 3 in sufficient yield. Finally,
after reduction to afford 2, we anticipated that using the 4-step literature protocol involving protection of the alcohol,
borylation using trimethoxyborane after lithium halogen exchange, deprotection and cyclocondensation to the boroxole under
acid catalysis would afford 1 (Scheme 1).12
———
* Craig Harris. Tel.: +33 (0)4 93 95 7042; fax: +33 (0)4 93 95 7071; e-mail: craig.harris@galderma.com
Keywords: Diboronic acid, boroxole formation; one-pot

2
Tetrahedron Letters
Scheme 1. Retrosynthetic analysis of 1
Sulfonamide 5 was easily prepared in 70% yield from 7 and 6. The Sonagashira coupling of 5 was surprisingly very
inefficient and not as selective as we anticipated. However, we managed to isolate sufficient 4 to progress the reaction.
During the evaluation of the hydration step, we came across several issues. Under Bronsted acid-catalysed conditions, we
principally obtained the desired regiochemistry but the competing Fries rearrangement product dominated the reaction profile
affording 9 as the only product.13 To overcome this issue, we tried several conditions and found that the combination of 1,3-
10
bis(2,6-diisopropylphenyl-imidazol-2-ylidene)gold(I) chloride and silver hexafluoroantimoniate afforded 3 albeit in very
poor yield and selectivity. Finally, our attempts to convert 3 to desired target 1 following the closest literature process
failed.12
Scheme 2. First route for the preparation of 1. Reagents and conditions: a) Pyridine, THF, r.t., 19 h (quant.); b) 4-
Ethynyltetrahydro-2H-pyran, CuI, Pd(PPh3)2Cl2, DMF, 60°C, 1 h, 34% (4), 8% (8); c) Sulfuric acid, dioxane, 100 °C, 65%; d)
IPrAuCl, AgSbF6, 1,4-dioxane, H2O, 120 °C, 3 h, 41%; e) NaBH4, THF, MeOH, 0 °C, 1 h, 60%; f) MOM-Cl, DIPEA, THF,
67%; g) n-Bu-Li, B(OMe)3, THF -78 °C-r.t., 0% (f) 6N HCl, r.t., 16 h
To avoid the Fries’ product, we decided to prepare the imidazole sulfonamide 10, with the knowledge that if we had
difficulty to displace the imidazole with 6,14 we could activate the imidazole group by methylation for the coupling reaction
downstream.15 To our surprise, the selectivity of the Sonagashira step was greatly improved from 34% to 72% of 11. We
opted to trial directly the gold catalyzed conditions10 and obtained desired ketone 13 as the sulfonic acid in excellent
conversion, albeit in 59:41 ratio in favour of the undesired isomer 14. In situ activation of the sulfonic acid was achieved
using the Vilsmeier reagent16 followed by coupling with aniline 8 and reduction to afford 2 in poor overall yield. With 2 in
hand, we decided to see if we could apply Molander’s borylation conditions using dibronic acid and second generation
Buchwald catalyst17 anticipating that if transformation to the boronic acid takes place we could expect in situ cyclisation to

Tetrahedron Letters
3
desired boroxole 1. To our delight, the reaction proceeded as expected affording an excellent conversion to 1 in a non-
optimised yield of 32% (Scheme 2).
Scheme 2. Adapted route for the preparation of 1. Reagents and conditions: a) Imidazole, Et3N, DCM, r.t., 19 h, quant.; b) 4-
Ethynyltetrahydro-2H-pyrane, CuI, Pd(PPh3)2Cl2, DMF, 60 °C, 1 h, 72% (11) 5% (12); c) IPrAuCl, AgSbF6, 1,4-dioxane,
H2O, 120 °C, 3 h, 41%; (d) Vilsmeier salt, Et3N, DCM, r.t., 1 h, followed by 4-ethyl-N-isobutylaniline (8), pyridine, 100°C,
microwave, 15 min., 28%; e) NaBH4, THF, MeOH, 0 °C, 1 h, 55%); f) Tetrahydroxydiboron, XPhos Pd G2, XPhos KOAc,
EtOH, 80 °C, 1 h, 32%
With this knowledge in hand, we decided to explore substrate scope of the one-pot borylation-cyclocondensation step. While
the authors acknowledge a recent process using B2pin2 was reported by Huang et al,18 we anticipated that the use of diboronic
acid directly is much more atom economic and should avoid contamination of boroxole products with pinacol. Both bromides
and iodides were equally good substrates for this process (Table 1, entries 1 and 2). Increasing steric hindrance at the
benzylic position with one, two methyl groups or a cyclopropyl group was also afforded boroxole product with acceptable to
good yields (Table 1, entries 4, 6 and 7). Unfortunately, going from aryl-bromide to aryl-chloride gave lower yield despite the
utilization of XPhos Pd G2 catalyst (Table 1, entry 4 v 5). Six and seven membered boroxoles were also isolated albeit in
moderate yield using this convenient one-pot approach (entries 7-8).
Table 1. One pot synthesis of boroxoles using diboronic acid
Isolated Yield
Entry
Aryl halide
(%)
1
2
3
59
69
35
57
32
4
5
OH
Cl

4
Tetrahedron Letters
6
7
8
9
42
51
37
45
In conclusion, during our exploration to prepare and test boroxole 1 for RORγ activity, we successfully employed diboronic
acid to the convenient and functional group tolerant one pot borylation-cyclocondensation reaction18 to prepare a range of
novel boroxoles in moderate to good yield. Work in ongoing in the laboratory to enlarge substrate scope.
Supplementary data
Full experimental procedures and supporting LCMS, 1H-NMR characterisation data are available for a selection of
compounds described in this letter is available at no extra charge via the on-line version.
References and notes
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Brusq, J. M.; Birault, V.; Viviani, F.; Hofland, H.; Jetten, A.M.; Cote-Sierra, J. PLoS ONE 2016, 11, 1-18.
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2014; (g) Fauber, B. P.; Rene, O.; Burton, B.; Everett, C.; Gobbi, A.; Hawkins, J.; Johnson, A. R.; Liimatta, M.;
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23 Jun. 2016.
5. Full account of the medicinal chemistry including SAR and SPR will be published elsewhere shortly.
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8738-8744; c) Gunasekera, D. S.; Gerold, D. J.; Aalderks, N. S.; Chandra, J. S.; Maanu, C. A.; Kiprof, P.;
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.

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Tetrahedron Letters
An efficient one-pot process to prepare
•
•
•
boroxoles directly from diboronic acid is
disclosed
This mild process avoids the necessity of
carrying out a halogen-lithium exchange
under cryogenic conditions
A diverse range of boroxoles were prepared
in acceptable yield with good substrate scope