Improved preparation of 1,3-Bis(2,6-di-iso-propylphenyl)imidazolium tetrafluoroborate

Article abstract of DOI:10.1080/00397911.2013.768671

A convenient, high-yielding, multi-hundred-gram preparation of 1,3-bis(2,6-di-iso-propylphenyl)imidazolium tetrafluoroborate is described. The preparation of this salt has significant advantages over the chloride as it eliminates potential bis(chloromethy

Full text of DOI:10.1080/00397911.2013.768671

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Improved Preparation of 1,3-Bis(2,6-
di-iso-propylphenyl)imidazolium
Tetrafluoroborate
Andrew J. Briggs a
a Chemical Development , Roche Palo Alto LLC , Palo Alto ,
California , USA
Accepted author version posted online: 09 Aug 2013.Published
online: 05 Sep 2013.
To cite this article: Andrew J. Briggs (2013) Improved Preparation of 1,3-Bis(2,6-di-iso-
propylphenyl)imidazolium Tetrafluoroborate, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 43:24, 3258-3261, DOI:
10.1080/00397911.2013.768671
To link to this article: http://dx.doi.org/10.1080/00397911.2013.768671
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Synthetic Communications1, 43: 3258–3261, 2013
Copyright # Roche TCRC, Inc.
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2013.768671
IMPROVED PREPARATION OF 1,3-BIS(2,6-DI-ISO-
PROPYLPHENYL)IMIDAZOLIUM
TETRAFLUOROBORATE
Andrew J. Briggs
Chemical Development, Roche Palo Alto LLC, Palo Alto, California, USA
GRAPHICAL ABSTRACT
Abstract A convenient, high-yielding, multi-hundred-gram preparation of 1,3-bis(2,6-di-iso-
propylphenyl)imidazolium tetrafluoroborate is described. The preparation of this salt has
significant advantages over the chloride as it eliminates potential bis(chloromethyl) ether
formation. The improved conditions provided the tetrafluoroborate salt in 61% overall yield
in two steps from 2,6-di-iso-propylaniline.
Keywords N-Heterocycle carbene; IPr-HBF4; ligand preparation
INTRODUCTION
N-Heterocycle carbenes are commonly used as highly active ligands in a variety
of different metal-catalyzed coupling reactions.[1] Published syntheses of 1,3-bis(2,6-
di-iso-propylphenyl)imidazolium chloride (IPr-HCl, 1, Scheme 1) often suffered
from poor yields, particularly in the ring-formation step,[2] until the publication of
Nolan’s improved procedure.[3] In the patent he reports a 70% yield for this step,
using hydrogen chloride gas and paraformaldehyde in ethyl acetate to convert the
glyoxaldiimine 4 to the imidazolium salt. The combination of hydrogen chloride
gas and paraformaldehyde has been reported to form bis(chloromethyl) ether,[4]
a
known potent human carcinogen,[5] which was considered undesirable for large-scale
preparation. The tetrafluoroborate salt 2 has been prepared not only from chloride
1[6] but also directly from 4 using tetrafluoroboric acid.[7] In the latter preparation
glyoxaldiimine 4 and paraformaldehyde were heated in tetrahydrofuran (THF)
and then treated with tetrafluoroboric acid diethyl ether complex to give 2 in 38%
isolated yield.
Received January 8, 2013.
Address correspondence to Andrew J. Briggs, Process Research and Synthesis, Hoffman–La
Roche, 340 Kingsland Street, Nutley, NJ 07110, USA. E-mail: andrew.briggs@roche.com
3258

IMPROVED PREPARATION OF IPr-HBF4
3259
Scheme 1. IPr salts.
RESULTS AND DISCUSSION
The need to prepare multi-hundred-gram quantities of the IPr ligand for use in
a pilot plant-scale Buchwald–Hartwig coupling reaction resulted in development of
an optimized procedure (Scheme 2).
The preparation of glyoxaldiimine 4 has been reported in the literature using 3
and 40% aqueous glyoxal in ethanol in 78% yield.[2a,3] The yield of these previously
described procedures was increased to 90% by using a slight excess of glyoxal (0.52
equiv.), an extended reaction time, and increased concentration. A similar yield was
recently reported using methanol as the solvent.[6] n-Propanol was also investigated
and gave a lower yield, consistent with this trend in solvent polarity.
Conversion of 4 to 2 with tetrafluoroboric acid diethyl ether complex was
screened in a range of solvents including toluene, THF, dibutyl ether, CH2Cl2,
dimethoxyethane, cyclohexane, and ethyl acetate. Diethoxymethane, s-trioxane,
and paraformaldehyde were investigated for the one carbon unit. Of the solvents,
the best results were obtained in ethyl acetate. For the one carbon unit, diethoxy-
methane gave a salt of superior color and in greater yield than either s-trioxane or par-
aformaldehyde. In the final procedure a solution of diethoxymethane in ethyl acetate
was first treated with tetrafluoroboric acid diethyl ether complex at 0 ꢀC, followed by
addition of an ethyl acetate solution of 4. After warming to room temperature, iso-
lation provided analytically pure 2 in 68% yield.
Even though significant counterion effects have been observed in other
systems,[6,8] 2 performed equally well as 1 in the downstream amination chemistry.
The Buchwald–Hartwig chemistry, after scale-up in 22-L glass, was ultimately
carried out on a 7-kg scale in the pilot plant.
Scheme 2. Preparation of 2.

3260
A. J. BRIGGS
CONCLUSION
An improved two-step process for the preparation of IPr-HBF4 was developed
with an overall yield of 61% from commercially available 2,6-di-iso-propylaniline.
The simple and efficient procedures were demonstrated at a multi-hundred-gram
scale.
EXPERIMENTAL
N,N’-Bis(2,6-di-iso-propylphenyl)glyoxaldiimine (4)[9]
Glyoxal (199 g of a 40% aqueous solution, 1.37 mol) was added to a solution of
2,6-di-iso-propylaniline (470 g, 2.65 mol) in ethanol (1.25 L) followed by 4 drops of
formic acid. The mixture was stirred at 18–23 ꢀC for 65 h. The product was collected
by filtration, washed with ca. ꢁ10 ꢀC methanol (2 ꢂ 250 mL), and dried under
vacuum at ꢃ65 ꢀC to give 2 (447.1 g, 90%) as a yellow solid. Mp 107–108 ꢀC;
1H NMR (CDCl3): d 8.10 (s, 2H), 7.12–7.23 (m, 6H), 2.94 (septet, J ¼ 6.8 Hz, 4H),
1.21 (d, J ¼ 6.8 Hz, 24H).
1,3-Bis(2,6-di-iso-propylphenyl)imidazolium tetrafluoroborate (2)[10]
Tetrafluoroboric acid diethyl ether complex (198 mL, 234 g, 1.44 mol) was
added to a solution of diethoxymethane (157 mL, 1.25 mol) in ethyl acetate
(950 mL) at 0–2 ꢀC. A solution of glyoxaldiimine 4 (359 g, 0.95 mol) in ethyl acetate
(1.9 L) was added over 1 h, keeping the temperature at 0–2 ꢀC. The mixture was
allowed to slowly warm to room temperature overnight. The product was collected
by filtration, washed with ethyl acetate (450 mL, in portions), and dried under
1
vacuum at ꢃ65 ꢀC to give 2 (306.9 g, 68%) as a white solid. Mp > 300 ꢀC; H NMR
(DMSO-d6): d 10.15 (t, J ¼ 1.5 Hz, 1H), 8.54 (d, J ¼ 1.5 Hz, 2H), 7.69 (t, J ¼ 7.4 Hz,
2H), 7.53 (d, J ¼ 7.4 Hz, 4H), 2.36 (septet, J ¼ 6.8 Hz, 4H), 1.27 (d, J ¼ 6.8 Hz,
12H), 1.17 (d, J ¼ 6.8 Hz, 12H); 13C NMR (DMSO-d6): d 145.2, 139.6, 132.2,
130.4, 126.6, 125.0, 29.0, 24.4, 23.5. Anal. calcd. for C27H37N2BF4: C, 68.07; H,
7.83; N, 5.88. Found: C, 68.32; H, 7.67; N, 6.07.
ACKNOWLEDGMENT
I thank M. Okabe for valuable input during the preparation of the manuscript.
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1. For a recent review, see Fortman, G. C.; Nolan, S. P. Chem. Soc. Rev. 2011, 40,
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Sep. 19, 2006; Chem. Abstr. 145, 356776.
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IMPROVED PREPARATION OF IPr-HBF4
3261
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