A reagent for the one-step preparation of potassium acyltrifluoroborates (KATs) from aryl- and heteroarylhalides

Article abstract of DOI:10.1002/anie.201403931

Potassium acyltrifluoroborates (KATs) are fascinating functional groups whose further exploration is limited by poor synthetic access. Documented herein is the design and synthesis of a new reagent for their one-step preparation from aryl- and heteroarylhalides. The reagent is a stable, soluble zwitterion prepared by S-alkylation of a novel thioformamide trifluoroboronate. The KATs are prepared by adding one equivalent of nBuLi to a mixture of the aryl halide and the reagent at -78 C. This protocol is suitable for the preparation of KATs containing pyridines, esters, nitro groups, and halides.

Full text of DOI:10.1002/anie.201403931

Angewandte
Chemie
DOI: 10.1002/anie.201403931
Acyltrifluoroborate Reagents
Hot Paper
A Reagent for the One-Step Preparation of Potassium
Acyltrifluoroborates (KATs) from Aryl- and Heteroarylhalides**
˝
Gꢀbor Eros, Yo Kushida, and Jeffrey W. Bode*
Dedicated to Professor Keisuke Suzuki on the occasion of his 60th birthday
Abstract: Potassium acyltrifluoroborates (KATs) are fascinat-
ing functional groups whose further exploration is limited by
poor synthetic access. Documented herein is the design and
synthesis of a new reagent for their one-step preparation from
aryl- and heteroarylhalides. The reagent is a stable, soluble
zwitterion prepared by S-alkylation of a novel thioformamide
trifluoroboronate. The KATs are prepared by adding one
equivalent of nBuLi to a mixture of the aryl halide and the
reagent at À788C. This protocol is suitable for the preparation
of KATs containing pyridines, esters, nitro groups, and halides.
KATs (Scheme 1). Importantly, this method avoids the need
for KHF2 and is well suited for the preparation of heteroaryl
KATs. It also introduces a new class of stable, soluble
electrophilic trifluoroborate reagents which will be useful for
other applications.
P
otassium acyltrifluoroborates (KATs) are fascinating func-
tional groups that undergo rapid amide-forming ligations with
hydroxylamines.[1] Although acylboron compounds have been
long considered to be esoteric, unstable constructs,[2] we have
found KATs to be easily handled solids that are stable to air
and water. The further exploration of their chemistry and the
use of their remarkably fast ligations[3] are currently ham-
pered by poor synthetic access to these compounds. Molander
et al. reported the first example in 2010 by lithiation of
a methoxy vinyl ether, subsequent trapping with B(OiPr)3,
and treatment of the resulting vinylboron with KHF2.[4] We
documented a synthesis from benzotriazole acetals, suitable
for preparing KATs, bearing simple aromatic and aliphatic
side chains.[5] Unfortunately, the reaction conditions and
workup (KHF2) precluded the synthesis of many substrates,
including those containing basic nitrogen atoms, esters, and
even many aryl halides. KATs can be easily formed from acyl
MIDA (MIDA = N-methyliminodiacetic acid) boronates,[6]
which were recently prepared by Yudin and co-workers
through a multistep synthesis.[7]
Scheme 1. One-step synthesis of acyltrifluoroborates.
At the outset of our studies, we sought to identify
a reagent for the one-step conversion of organolithium
reagents, which are commercially available or readily pre-
pared under a variety of reaction conditions,[8] into acyltri-
fluoroborates. Furthermore, we hoped to incorporate the
trifluoroborate moiety into the electrophilic reagent, with the
aim of avoiding etching conditions[9] typically required for
constructing it from boronic acids or esters. These consid-
erations led us to the reagent designs shown in Scheme 2.
Potassium trifluorocyanoborate (2) is a known compound
and readily prepared in one step from boron trifluoride
diethyl etherate and potassium cyanide.[10] All attempts to add
phenyl lithium to this reagent gave no identifiable products.
We turned instead to formyl amide derivatives, which were
previously unknown structures. Although lithiation of for-
mamides is well known,[11] we were unable to trap the
formamide anions with any electrophilic boron sources. In
contrast, N,N-dimethyl thioformamide could be lithiated12
and trapped with B(OMe)3, which following treatment with
KHF2 gave the thioamide derivative 4. Treatment of this
In this report we document a novel reagent for the one-
step synthesis of KATs from aryl halides that is suitable for
preparing a broad range of aromatic and heteroaromatic
˝
[*] Dr. G. Eros, Y. Kushida, Prof. Dr. J. W. Bode
Laboratorium fꢀr Organische Chemie
Department of Chemistry and Applied Bioscience
ETH Zꢀrich, 8093 Zꢀrich (Switzerland)
E-mail: bode@org.chem.ethz.ch
Homepage: http://www.bode.ethz.ch
[13]
[**] This work was supported by ETH Zꢀrich. G.E. is grateful to Novartis
for a postdoctoral fellowship. Y.K. thanks JSPS for a Fellowship for
Young Japanese Scientist. We thank Pavol Ondrisek, Leonardo
Nannini, and Sizhou Liu for their contributions to this project. We
are grateful to Dr. Nils Trapp (ETH Zꢀrich) and Dr. Bernd Schweizer
(ETH Zꢀrich) for the acquisition of X-ray structures.
compound with a mixture of KHF2 and NaNO2 afforded
the formamide derivative 3.
Unfortunately, the reagents 3 and 4 also proved unsuitable
as electrophilic traps[14] for aryl lithiums. No addition products
could be observed, an outcome we attributed largely to the
poor solubility of the reagents at low temperature. Reasoning
that formation of an internal zwitterionic salt would improve
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201403931.
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eventually found was best achieved with aqueous HF[16] rather
than KHF2. The use of B(OEt)3 in place of B(OMe)3 gave
a more stable intermediate and resulted in higher overall
yields. These improvements made possible the preparation of
4 on a greater than 10 gram scale. Furthermore, the unpuri-
fied thioamide could be telescoped into the alkylation
reaction to prepare 6 without isolation of the intermediate
and without purification other than washing and filtration.
The structure of 4 and its S-methyl derivative 5 were
established by X-ray crystallography (Figure 1).
Scheme 2. Candidate reagents for introduction of acyltrifluoroborates.
THF=tetrahydrofuran.
the solubility, we prepared reagents 5–7 by alkylation of 4
with the corresponding alkyliodides. The S-alkylations pro-
ceeded smoothly to give the imidates as stable compounds
which were highly soluble in typical organic solvents.[15] We
were pleased to find that phenyl lithium added smoothly to all
three reagents, and after a suitable workup gave the
corresponding KAT in good yield.
Figure 1. ORTEP drawings of 4 (left; counterion is not shown) and 5
(right). Thermal ellipsoids shown at 50% probability. CCDC 993821
and 993816 contain the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
We selected the crystalline S-ethyl derivative 6 for further
development. The S-propyl compound was an oil and the S-
methyl compound was less soluble. Although the alkylation of
4 with EtI to give 6 proceeded smoothly, the preparation of 4
was plagued by low yields and poor reproducibility, partic-
ularly on larger scale. An extensive optimization study of the
lithiation and trapping of N,N-dimethylthioformamide is
summarized in Table 1. As noted by Seebach and co-work-
ers,[12] maintaining the internal temperature of the lithiation
below À1008C proved to be critical for the success of the
reaction. Furthermore, breakdown of the resulting tetrahe-
dral intermediate was also an important parameter, which we
With a scalable synthesis of 6 established, we prepared
aromatic KATs from the corresponding aryl halides (Table 2).
After exploring several different protocols we found that
lithium–halogen exchange with nBuLi at À788C in the
presence of 6 proved to be the most general and highest
yielding procedure. The in situ generated aryl lithium adds to
6 to give a tetrahedral intermediate, which can be observed by
1H NMR analysis of the reaction. Decomposition of this
intermediate to the KAT was best accomplished by the
addition of aqueous KF to the reaction mixture at À788C.
Like all organotrifluoroborates,[18] the ionic nature of KATs
necessitates a good workup procedure. In our case, this was
easily accomplished by addition of CH2Cl2 to precipitate the
KAT, which was filtered and dissolved in acetone for isolation
in good yield and purity. This protocol tolerated aryl halides,
esters, nitro groups, and nitriles in the substrates.
Table 1: Optimized synthesis of the reagent 6.[a]
The in situ generation and trapping of the aryl lithium
could be smoothly extended to the synthesis of heteroaro-
matic KATs (Table 3), allowing the preparation of pyridine-
derived KATs and their substituted variants. In a few cases,
a small amount of 3, formed by the decomposition of
unreacted 6 during the reaction workup, is observed as
a side product and can be difficult to completely remove from
the desired product. This side product, however, does not
participate in ligations with hydroxylamines.
In summary, we have developed a novel reagent suitable
for the synthesis of potassium acyltrifluoroborates (KATs)
from aryl- and heteroarylhalides. This protocol considerably
expands the range of acyl boron compounds that can be
prepared, opening an avenue for the further exploration and
utilization of their unique chemistry. This work also introdu-
Entry
B(OR)3
FÀ source
T [8C][b]
Yield [%][c]
4
1
2
3
4
5
B(OMe)3
B(OMe)3
B(OEt)3
PinB(iOPr)
B(OEt)3
KHF2 (aq)
HF (aq)
HF (aq)
HF (aq)
HF (aq)
À110
À110
À110
À110
À78
15
40
80
90[d]
3
[a] All reactions were performed on a 16.8 mmol scale in THF (0.34m).
LDA was prepared at À788C with subsequent addition of B(OR)3 and by
N,N-dimethyl thioformamide at the indicated temperature. After 85 min,
9 equiv KHF2 (aq) or 6 equiv HF (aq) were added as fluoride sources at
À788C. [b] The dry ice/acetone bath was cooled to À1108C with liquid
N2. [c] Yield of isolated product. [d] The product was contaminated with
pinacol. LDA=lithium diisopropylamide.
2
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Table 2: Synthesis of aryl KATs with 6.[a]
Table 3: Synthesis of heteroaromatic KATs with 6.[a]
Entry
Substrate
Product
Yield [%][b]
60[c]
1
9a
9b
9c
9d
9e
Entry
1
Substrate
Product
Yield [%][b]
74
2
3
4
5
70[c,d]
8a
8b
81
66
2
79
69
3
4
5
8c
8d
8e
71
48
59
6
7
9 f
95
90
9g
8
9
9h
9i
77
35
6
7
8 f
89
86
8g
10
11
12
9j
9k
9l
30
89
65
8
9
8h
8i
86
44
[a] All reactions were performed on a 1.08 mmol scale in THF (0.54m) by
addition of nBuLi to a mixture of the arylhalide and 6. [b] Yield of isolated
product.
13
9m
64
ces several new classes of boronates, including thioforma-
mide, formamide, and imidate derivatives. These stable, easily
handled compounds are likely to possess unexplored chemical
and physical properties.
[a] All reactions were performed on a 1.08 mmol scale in THF (0.54m).
[b] Yield of isolated product. [c] This KAT was insoluble in acetone and
the yield was determined by NMR spectroscopy. Further isolation steps
were required. [d] Toluene was used as the solvent.[17]
heterogeneous mixture and the solution was stirred and filtered. The
solids were washed three times with CH2Cl2 (the THF and CH2Cl2
filtrate contained the residual aryl halide and reagent 6). The
remaining filter cake (product and inorganic salts) was washed
multiple times with acetone (2–50 mL) until the resulting filtrate was
colorless (note: the solution containing product is yellow). Acetone
was removed under reduced pressure and the product (8 or 9) was
obtained as a white or yellow solid.
Experimental Section
In a flame-dried, 10 mL round-bottom flask under an atmosphere of
dry N2, reagent 6 (0.200 g, 1.08 mmol, 1.00 equiv) and an arylhalide
(1.08 mmol, 1.00 equiv) were dissolved in THF (2 mL) and cooled to
À788C in a dry ice/acetone bath. n-Butyllithium (1.6m in hexane,
675 mL, 1.08 mmol, 1.00 equiv) was added dropwise over 30 min by
syringe pump. One hour after the end of n-butyllithium addition,
acetone (80 mL, 1.08 mmol, 1.00 equiv) was added to quench the
residual n-butyllithium, and 10 min later 0.5 mL aqueous KF solution
(6.5m, 3.24 mmol, 3.00 equiv) was added. The flask was removed from
the bath and stirred for one hour. CH2Cl2 (2 mL) was added to this
Received: April 2, 2014
Published online: && &&, &&&&
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Keywords: arenes · boron · lithiation · synthetic methods ·
zwitterions
.
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Acyltrifluoroborate Reagents
Bring it on! The challenge of forming acyl
boranes by trapping acyl anion equiva-
lents is avoided by the design and devel-
opment of an electrophilic source of the
acyltrifluoroborate group. This novel
reagent makes possible the one-step
transformation of aryl and heteroaryl
halides into the corresponding potassium
acyltrifluoroborates via organolithium
intermediates.
˝
G. Eros, Y. Kushida,
J. W. Bode*
&&&& — &&&&
A Reagent for the One-Step Preparation
of Potassium Acyltrifluoroborates (KATs)
from Aryl- and Heteroarylhalides
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers!