Synthesis of acyltrifluoroborates

Article abstract of DOI:10.1021/ol300668m

Acylboranes are among the most elusive boron-containing organic functional groups, a fact that has impeded development of new reactions employing them as substrates. A new synthesis of acyltrifluoroborates from benzotriazole (Bt)-based N,O-acetals has bee

Full text of DOI:10.1021/ol300668m

ORGANIC
LETTERS
2012
Vol. 14, No. 8
2138–2141
Synthesis of Acyltrifluoroborates
Aaron M. Dumas and Jeffrey W. Bode*
Laboratorium fu€r Organische Chemie, Department of Chemistry and Applied
Biosciences, Swiss Federal Institute of Technology (ETH) Zu€rich, Wolfgang Pauli
Strasse 10, 8093 Zurich, Switzerland
bode@org.chem.ethz.ch
Received March 16, 2012
ABSTRACT
Acylboranes are among the most elusive boron-containing organic functional groups, a fact that has impeded development of new reactions
employing them as substrates. A new synthesis of acyltrifluoroborates from benzotriazole (Bt)-based N,O-acetals has been developed. Two other
routes provide acyltrifluoroborates containing alcohols, aldehydes, and carbamates. The ketone-like reactivity of the acyltrifluoroborate
functional group is demonstrated, and the first X-ray structure of an acyltrifluoroborate is reported.
The current practice of synthetic organic chemistry relies
heavily on the use of general, predictable coupling reac-
tions of functionalized building blocks. Boronic acids and
their derivatives are perhaps the most successful class of
prefunctionalized reagents, as they are both amenable to a
wide range of transformations and generally stable toward
a variety of reaction conditionsand unprotectedfunctional
groups. This has led to a large and ever growing number of
commercially available boronic acids and their derivatives
as well as creative new reactions that employ them as
substrates.1 Besides the common aryl and alkenylboronic
acids, recent work has provided routes to previously
inaccessible derivatives including those containing enan-
tioenriched alkyl,2 heteroaryl,3 alkynyl,4 and R-amino and
R-alkoxy functional groups.5
(1) Hall, D. G., Ed. Boronic Acids: Preparation and Applications in
Organic Synthesis, Medicine and Materials, 2nd ed.; WILEY-VCH:
Weinheim, 2011.
(2) For recent examples of their synthesis, see: (a) Lee, J. C. H.;
McDonald, R.; Hall, D. G. Nat. Chem. 2011, 3, 894–899. (b) Bagutski,
V.; Elford, T. G.; Aggarwal, V. K. Angew. Chem., Int. Ed. 2011, 50,
Figure 1. (a) Known acylboranes. (b) Previous synthesis of an
acyltrifluoroborate.
€
1080–1083. (c) Schiffner, J. A.; Muther, K.; Oestreich, M. Angew.
Chem., Int. Ed. 2010, 49, 1194–1196. (d) Kliman, L. T.; Mlynarski,
S. N.; Morken, J. P. J. Am. Chem. Soc. 2009, 131, 13210–13211. For
stereoretentive cross-couplings, see: (e) Imao, D.; Glasspoole, B. W.;
Laberge, V. S.; Crudden, C. M. J. Am. Chem. Soc. 2009, 131, 5024–5025.
(f) Taylor, B. L. H.; Jarvo, E. R. J. Org. Chem. 2011, 76, 7573–7576.
(3) For solutions to the instability of 2-pyridyl boronic acid deriva-
tives in cross-coupling reactions, see: (a) Billingsley, K. L.; Buchwald,
S. L. Angew. Chem., Int. Ed. 2008, 47, 4695–4698. (b) Knapp, D. M.;
Gillis, E. P.; Burke, M. D. J. Am. Chem. Soc. 2009, 131, 6961–6963. (c)
Dick, G. R.; Woerly, E. M.; Burke, M. D. Angew. Chem., Int. Ed. 2012,
51, 2667–2672.
In contrast, acylboronic acids are currently considered
esoteric compounds that are difficult to prepare, and only
five derivatives have been reported.6 Nozaki prepared the
amino-stabilized acylborane 1 in 2007 by nucleophilic
^
7
addition of an anionic boron reagent, and Lacote,
(4) For syntheses of ethynyl boronic acid derivatives, see: (a) Struble,
J. R.; Lee, S. J.; Burke, M. D. Tetrahedron 2010, 66, 4710–4718. (b)
Yamamoto, Y.; Hattori, K.; Ishii, J.-i.; Nishiyama, H. Tetrahedron
2006, 62, 4294–4305.
(5) (a) Beenen, M. A.; An, C.; Ellman, J. A. J. Am. Chem. Soc. 2008,
130, 6910–6911. (b) Laitar, D. S.; Tsui, E. Y.; Sadighi, J. P. J. Am. Chem.
Soc. 2006, 128, 11036ꢀ11037. (c) Molander, G. A.; Sandrock, D. L. Org.
Lett. 2007, 9, 1597–1600.
r
10.1021/ol300668m
Published on Web 04/04/2012
2012 American Chemical Society

Curran, and co-workers reportedNHC-stabilized acylbor-
ane 2 in 2010 (Figure 1a).8 Recently, Molander described
the synthesis of a single acyltrifluoroborate, 3, by hydro-
lysis/fluorination of an intermediate R-borylvinyl ether
(Figure 1b), but was not able to extend this route to other
examples.9 The lack of access to acylboronic acid derivatives
has impeded a thorough investigation of their chemistry.
Prompted by our finding that 3 undergoes rapid and
clean amide-forming ligations with O-Bz hydroxylamines
in water,10 we have identified new approaches to the
synthesis of acyltrifluoroborates. This work primarily
takes advantage of Katritzky’s benzotriazole-based N,O-
acetals as acyl-anion equivalents.12,15 By combining this
chemistry with in situ formation of the acyltrifluoroborate
from the intermediate boronate ester, we have prepared a
dozen new examples. Two other approaches were used to
prepare acyltrifluoroborates bearing amine, alcohol, and
aldehyde functional groups. These synthetic routes make
acyltrifluoroborates available as starting materials for the
amide-forming ligation and for further explorations of
their properties and chemical reactivity.
At the outset, we considered that an ideal starting
material for acyltrifluoroborates would be an acyl-anion
equivalent that was easily prepared, readily deprotonated,
and which regenerated the carbonyl under mild conditions,
preferably with the aqueous acid of the boron fluorination
step.11 Based on these criteria, the benzotriazole-ethoxy N,
O-acetals 4 developed by Katritzky were selected as pos-
sible precursors to benzoyltrifluoroborates.12 These N,O-
acetals are prepared directly from the corresponding alde-
hydes, lithiated rapidly at ꢀ78 °C, and hydrolyzed by a
mild acid. They have also been used to prepare acylsilanes,
demonstrating their suitability to form unconventional
carbonyl-containing molecules.13
used as the limiting reagent to avoid the formation of trace
amounts of BuBF3K that were difficult to separate from
the desired product. It was also crucial to trap with
B(OMe)3 rather than B(Oi-Pr)3 as the latter led only to the
formation of decomposed products, presumably from
inefficient quenching of the relatively unstable benzyl anion.
Substituted benzoyltrifluoroborates 5bꢀ5f were prepared
according to the same procedure. Of the N,O-acetals used,
only the 2-methoxyphenyl group proved problematic, as
no trifluoroborate wasobserved in that reaction. Although
the overall yields were modest, they were acceptable con-
sidering that the synthesis comprises a three-step, one-pot
sequence as well as the isolation of the potassium trifluor-
oborate salt without any chromatography.14 Further, the
scale was sufficiently large that a single reaction produced
>300 mg of each example, providing ample material for
further studies.
Having demonstrated thatBt-acetalscould serveasacyl-
anion equivalents leading to acyltrifluoroborates, we
wished to also prepare non-benzoyl products. Katritzky
had previously shown that replacing ethoxy with phenoxy
allowed lithiation of alkyl-substituted N,O-acetals such
as 7.15 Furthermore, 7 can be prepared from the readily
available benzotriazole derivative 6, which would then be
the common precursor to acyltrifluoroborates if the phe-
noxy-acetal could be hydrolyzed effectively in aqueous
KHF2. This was indeed the case, and a variety of new
acyltrifluoroborates were prepared by the two-step meth-
od outlined in Scheme 2.
The first lithiation/alkylation reaction was performed
with both both primary benzyl and alkyl as well as sec-
ondary benzyl bromides as electrophiles and gave 7aꢀf in
73ꢀ85% yield. Although one-pot sequential double lithia-
tion/alkylation sequences for disubstitution of 6 have been
(6) (a) A titanium organometallic complex containing a carbonyl
tris(pentafluorophenyl)borate has been isolated; see: Hair, G. S.; Jones,
R. A.; Cowley, A. H.; Lynch, V. Organometallics 2000, 20, 177–181. (b)
A phosphineꢀborane complex similar to 2 has been prepared; see:
Imamoto, T.; Hikosaka, T. J. Org. Chem. 1994, 59, 6753–6759. We
thank a referee for pointing us to this reference.
Scheme 1. Benzoyltrifluoroborates from N,O-Acetals 4aꢀf
(7) (a) Yamashita, M.; Suzuki, Y.; Segawa, Y.; Nozaki, K. J. Am.
Chem. Soc. 2007, 129, 9570–9571. (b) Segawa, Y.; Suzuki, Y.; Yamashita,
M.; Nozaki, K. J. Am. Chem. Soc. 2008, 130, 16069–16079.
ꢀ
(8) Monot, J.; Solovyev, A.; Bonin-Dubarle, H.; Derat, E.; Curran,
^
D. P.; Robert, M.; Fensterbank, L.; Malacria, M.; Lacote, E. Angew.
Chem., Int. Ed. 2010, 49, 9166–9169.
(9) (a) Molander, G. A.; Raushel, J.; Ellis, N. M. J. Org. Chem. 2010,
75, 4304–4306. (b) Ellis, N. M., PhD thesis, University of Pennsylvania,
Philadelphia, USA, 2009.
(10) Dumas, A. M.; Molander, G. A.; Bode, J. W. Angew. Chem., Int.
Ed., in press (DOI: 10.1002/anie.201201077).
(11) Lithiated dithianes have been trapped with B(OMe)3 and con-
verted to the corresponding trifluoroborates with aqueous KHF2;
however their conversion into acyltrifluoroborates has not been re-
ported. See: Vieira, A. S.; Fiorante, P. F.; Zukerman-Schpector, J.;
Alves, D.; Botteselle, G. V.; Stefani, H. A. Tetrahedron 2008, 64, 7234–
7241.
(12) Katritzky, A. R.; Lang, H.; Wang, Z.; Zhang, Z.; Song, H.
J. Org. Chem. 1995, 60, 7619–7624.
(13) Katritzky, A. R.; Wang, Z.; Lang, H. Organometallics 1996, 15,
486–490.
(14) One-pot syntheses of aryltrifluoroborates commonly give yields
of ∼50ꢀ60%. For examples, see Schemes 11 and 12 in Darses, S.; Genet,
J.-P. Chem. Rev. 2007, 108, 288–325.
(15) Katritzky, A. R.; Lang, H.; Wang, Z.; Lie, Z. J. Org. Chem. 1996,
61, 7551–7557.
We found that quenching the anion of 4a with B(OMe)3
followed by the addition of aqueous KHF2 gave benzoyl-
trifluoroborate 5a in 45% yield (Scheme 1). n-BuLi was
Org. Lett., Vol. 14, No. 8, 2012
2139

direct preparation of the vinyl boronic esters by Ir-cata-
lyzed CꢀH functionalization will provide another entry
into the requisite starting materials.18
Scheme 2. Synthesis of Acyltrifluoroborates 8aꢀf
Scheme 4. Synthesis of N-Protected δ-Amino Acyltrifluorobo-
rates
Another route to functionalized acyltrifluoroborates
was achieved from cyclic carbamates 12aꢀb, which were
easily prepared from the corresponding vinyl triflates by
Pd-catalyzed cross-coupling with B2pin2.19 Treatment of
an acetone solution of the vinyl boronate with aqueous
KHF2 gave acyltrifluoroborates 13aꢀb in 54% and 39%
yield, respectively (Scheme 4).
The first structure determination of an acyltrifluorobo-
rate was obtained by X-ray analysis of a single crystal of 5c
(Figure 2), grown by vapor diffusion of hexane into a
described, preparation of acyltrifluoroborates was infea-
sible with this approach as they were difficult to isolate
from the accumulated byproducts. However, starting from
pure 7, one-pot deprotonation/borylation and fluorination/
hydrolysis gave acyltrifluoroborates 8aꢀf in yields similar
to those obtained from N,O-acetals 4. Phenylacetyltrifluor-
oborates 8aꢀb are similar to the example previously pre-
pared by Molander,9a however derived from a route that is
more amenable to product diversity. Non-benzylic exam-
ples could also be prepared, including those with aromatic
(8d) and alkenyl (8e) groups. Terminal alkyl chloride 8f was
formed equally well, despite some competitive cyclization
during the lithiation/borylation stage of the reaction.
During our attempts to develop a general synthesis of
structurally diverse acyltrifluoroborates, we also explored
several other routes to specific substrates. Cyclic vinyl
boronic esters proved particularly valuable for the pre-
paration of acyltrifluoroborates bearing functional groups
(Scheme 3). Cyclic vinyl ethers are known to be easily
lithiated to give relatively stable anions, which could be
trapped with electrophilic boron reagents.16 Starting from
2,3-dihydropyran 9a, a one-pot sequence of deprotona-
tion, borylation, and treatment with aqueous KHF2 gave
acyltrifluoroborate 10.
˚
solution of 5c in acetone. The CdO bond length of 1.24 A
suggested that the carbonyl was ketone-like; the IR fre-
quency of 1636 cmꢀ1 was lower than that of a typical
ketone or aldehyde, but close to that reported for other
acylboranes such as 1, 2, and 3.7ꢀ9
Figure 2. X-ray crystal structure of acyltrifluorobate 5c.
Similarly, the reaction of ethoxy-substituted dihydro-
pyran 9b gave acyltrifluoroborate 11 by spontaneous loss
of ethanol during the hydrolysis step.17 It is likely that
Somewhat to our surprise, the acyltrifluoroborates
maintained typical carbonyl reactivity and behaved in
(16) Boeckman, R. K., Jr.; Bruza, K. J. Tetrahedron 1981, 37, 3997–
4006.
Scheme 3. Acyltrifluoroborates from Cyclic Vinyl Ethers
(17) For the use of Schlosser’s base to deprotonate alkoxydihydro-
pyrans, see: Yu, C.-M.; Jung, W.-H.; Choi, H.-S.; Lee, J.; Lee, J.-K.
Tetrahedron Lett. 1995, 36, 8255–8258.
(18) (a) Kikuchi, T.; Takagi, J.; Isou, H.; Ishiyama, T.; Miyaura, N.
Chem.;Asian. J. 2008, 3, 2082–2090. (b) Kikuchi, T.; Takagi, J.;
Ishiyama, T.; Miyaura, N. Chem. Lett. 2008, 37, 664–665.
(19) Occhiato, E. G.; Lo Galbo, F.; Guarna, A. J. Org. Chem. 2005,
70, 7324–7330.
(20) (a) Larock, R. C. Comprehensive Organic Transformations, 2nd
ed.; WILEY-VCH: Weinheim, 1999. (b) Otera, J. Modern Carbonyl Chem-
istry; WILEY-VCH: Weinheim, 2000.
(21) For the preparation of a boryloxime in a carborane, see: Herzog,
A.; Knobler, C. B.; Hawthorne, M. F. Angew. Chem., Int. Ed. 1998, 37,
1552–1556.
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Org. Lett., Vol. 14, No. 8, 2012

many case like ketones or aldehydes (Scheme 5).20 Hydro-
genolysis of the Cbz group in 13a with H2 and Pd/C did not
affect the trifluoroborate moiety and revealed the primary
amine, which underwent immediate cyclization to give
imine 14 in quantitative yield (Scheme 5a). Similarly, tri-
fluoroborate 3 condensed with hydroxylamine 15 to form
nitrone 16 as a single isomer in 86% yield (Scheme 5b).21
The configuration was determined by an X-ray crystal
structure (Scheme 5c); the Z arrangement is presumably
preferred in order to maximize the distance between the two
anionic centers. In preliminary studies, this nitrone was
reluctant to undergo either [3 þ 2] dipolar cycloadditions
or amide formation as we had initially expected by analogy
to the chemistry of R-ketoacids.22,23
Scheme 5. Reactions of Acyltrifluoroborates
Our results establish acyltrifluoroborates as a new, read-
ily accessible carbonyl-based functional group. From a
practical standpoint, they were prepared on a useful labo-
ratory scale, are air and water stable, and can be stored for
at least a year in a refrigerator. Current efforts are aimed at
discovering new methods for the preparation of more
elaborately functionalized examples. We have shown that
they possess a reactivity typical of carbonyls, such as imine
and nitrone formation and, in separate work,10 that they
undergo remarkably rapid and clean amide-forming liga-
tions with O-Bz hydroxylamines. Having taken steps to-
ward making the acylborane functional group more than a
rare curiousity, we hope that they will be exploited for the
development of new methods that take advantage of their
unique properties and reactivity.
Acknowledgment. This work was support by ETH
€
Zurich and ETH Research Grant ETH-12 11-1. We are
grateful to Dr. Bernd Schweizer (ETH Zurich) and Mi-
€
€
chael Lopar (ETH Zurich) for the acquisition of X-ray
structures.
Supporting Information Available. Experimental de-
tails. This material is available free of charge via the
Internet at http://pubs.acs.org.
(22) Bode, J. W.; Fox, R. M.; Baucom, K. D. Angew. Chem., Int. Ed.
2006, 45, 1248–1252.
(23) Pusterla, I.; Bode, J. W. Angew. Chem., Int. Ed. 2012, 51, 513–516.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 8, 2012
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