Organocatalytic Synthesis of α-Trifluoromethyl Allylboronic Acids by Enantioselective 1,2-Borotropic Migration

Article abstract of DOI:10.1021/jacs.0c09923

Chiral α-substituted allylboronic acids were synthesized by asymmetric homologation of alkenylboronic acids using CF3/TMS-diazomethanes in the presence of BINOL catalyst and ethanol. The chiral α-substituted allylboronic acids were reacted with aldehydes or oxidized to alcohols in situ with a high degree of chirality transfer. The oxygen-sensitive allylboronic acids can be purified via their isolated diaminonaphthalene (DanH)-protected derivatives. The highly reactive purified allylboronic acids reacted in a self-catalyzed reaction at room temperature with ketones, imines, and indoles to give congested trifluoromethylated homoallylic alcohols/amines with up to three contiguous stereocenters.

Full text of DOI:10.1021/jacs.0c09923

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Organocatalytic Synthesis of α‑Trifluoromethyl Allylboronic Acids
by Enantioselective 1,2-Borotropic Migration
Sybrand J. T. Jonker,§ Ramasamy Jayarajan,§ Tautvydas Kireilis, Marie Deliaval, Lars Eriksson,
́
́
́
and Kalman J. Szabo*
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ABSTRACT: Chiral α-substituted allylboronic acids were synthesized by asymmetric homologation of alkenylboronic acids using
CF3/TMS-diazomethanes in the presence of BINOL catalyst and ethanol. The chiral α-substituted allylboronic acids were reacted
with aldehydes or oxidized to alcohols in situ with a high degree of chirality transfer. The oxygen-sensitive allylboronic acids can be
purified via their isolated diaminonaphthalene (DanH)-protected derivatives. The highly reactive purified allylboronic acids reacted
in a self-catalyzed reaction at room temperature with ketones, imines, and indoles to give congested trifluoromethylated homoallylic
alcohols/amines with up to three contiguous stereocenters.
hiral allylboronic acids1 are ideal reagents for asymmetric
synthesis because of their high reactivity in self-catalyzed
allylboration reactions that occur with high stereochemical
fidelity. However, the synthesis of chiral allylboronic acids has been
an unmet challenge in organic synthesis. Our experience with Pd-
catalyzed synthesis of (achiral) allylboronic acids2 (Figure 1a)
and conclusions based on related mechanistic studies3
suggested that a metal-free approach would be rewarding for
effective control of the stereoselectivity. We hypothesized that
the synthesis of chiral allylboronic acids may be devised by
using an organocatalytic homologation strategy. The first
methods for asymmetric homologation of organoboron
compounds were reported by the Matteson group.4,5 Aggarwal
and co-workers6 applied a useful lithiation−borylation method
(Figure 1b) for the synthesis of chiral allyl-Bpin species,7
including an example of an α-trifluoromethyl allylboronate
derivative.8 This method is based on stoichiometric formation
of chiral lithium carbenoid intermediates, and therefore, it is
not suitable for the direct synthesis of allylboronic acids. The
Ley9−11 and Wang12 groups (Figure 1c) reported a
homologation method based on diazo carbenoid reagents.
This method was suitable for the synthesis of (achiral)
allylboronic acids, which were used in one-pot allylbora-
tions9,11 or converted to their Bpin derivatives.12 A similar
approach was employed by Molander and co-workers (Figure
1c) for the synthesis of benzylboronic acids from trifluor-
omethyl diazomethane.13,14 Arnold and co-workers presented a
method for the synthesis of chiral α-CF3 alkyl- and
benzylboron compounds by directed evolution of en-
zymes.15,16 Fluorinated organoboronates are useful reagents
for selective synthesis of organofluorines.13−21 The CF3 motif
very often occurs22−24 in pharmaceuticals and agrochemical
products (Figure 1d).25−29
C
Here we present a new methodology for the synthesis of
chiral α-CF3 allylboronic acids (Figure 1e). Our concept
(Figure 2) is based on reacting alkenylboroxine 2, trifluor-
Received: September 16, 2020
Figure 1. Synthesis of organoboronates and boronic acids as well as
examples of bioactive molecules with a CF3 group.
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A

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Table 1. Optimal Conditions for Synthesis of α-CF3
a
Allylboronic Acids
a
Boroxine 2a (0.033 mmol, equivalent to 0.1 mmol of the boronic
acid), 3 (0.3 mmol), 4 (0.02 mmol, 20 mol %), and ethanol (0.2
mmol) were reacted in DCM (0.8 mL) for 48 h at 40 °C, and then
Figure 2. Concept of catalytic asymmetric homologation with 1,2-
borotropic migration.
b
DanH (0.15 mmol) was added. Yields of 5a determined by 19F NMR
c
d
spectroscopy. Isolated yields. A complex reaction mixture was
obtained.
omethyl diazomethane 3, catalytic amounts of BINOL
(4),30−36 and stoichiometric amounts of EtOH. Alkenylbor-
oxine 2 readily reacts with diazo compound 3.9−11 However,
this reaction results in racemic product, such as rac-1-OR. The
racemic background reaction can be avoided by addition of
EtOH to the reaction mixture, which forms unreactive
alkylboronic esters 2-OEt, which are weaker Lewis acids37
than the corresponding boroxines 2.30,31 Because of the
dynamic covalent bonding38 ability of boron, BINOL 4
undergoes transesterification with 2-OEt to form chiral alkenyl
boronate A. Exchange of the alkyl group to an aromatic moiety
leads to a substantial increase in the Lewis acidity of boron,37
and therefore, A and 3 form ate complex B in the
stereoinduction step of the process (see Figure S3). Then
the alkenyl group undergoes stereoselective 1,2-migration10,39
to afford C. Subsequently, ethanolysis of C gives product 1-
OEt.
can be rationalized by the racemic background reaction (2 + 3
→ rac-1-OR in Figure 2). The complex reaction mixture is a
consequence of the poor stability of 1 and its boroxine in the
absence of EtOH. Simple aliphatic alcohols esterify the boronic
acids/boroxines and thus protect them from decomposition
under the reaction conditions of the borylation (Figure
1a).2,32,41 When both EtOH and the BINOL catalyst were
omitted (entry 10), a complex reaction mixture was obtained
again. Without molecular sieves (entry 11), the yield was poor,
probably because the slow formation of chiral alkenyl-BINOL-
type intermediate A (Figure 2). At room temperature,
changing dichloromethane (DCM) to toluene leads to
lowering the yield and a slight decrease of the ee (entries
12−13).
The optimal conditions for the homologation involved using
2a with an excess of 3, 20 mol % 4 and 2 equiv of EtOH
(Table 1, entry 1). The oxygen-sensitive allylboronic ester 1a-
OEt was protected with diaminonaphthalene (DanH)40 to give
5a with 98% ee in 69% yield. When the reaction was repeated
with 10 mol % catalyst 4, the yield was substantially lowered
(12%), but the enantioselectivity was practically unchanged
(96% ee) (entry 2). Replacement of iodo-BINOL 4 with
bromo-BINOL (entry 3) led to decreases in the yield (9%)
and the enantioselectivity (88% ee). Interestingly, increasing
the loading of bromo-BINOL (entry 4) to 30 mol % led to a
high yield (73%) and selectivity (94% ee). When bulky γ-
substituents were employed in the BINOL catalyst (entry 5),
both the yield and selectivity strongly declined. Application of
the parent BINOL as the catalyst gave a low yield (4%) and
relatively low selectivity (72% ee). When a commercially
available alkenylboronic acid was used as the substrate (entry
7), the reaction proceeded in poor yield (18%) but with
excellent selectivity (97% ee). When EtOH was replaced by
iPrOH (entry 8), the yield dropped (44%) but the selectivity
was still high (96% ee). In the absence of EtOH (entry 9), a
complex reaction mixture was obtained, from which 5a was
isolated in 4% yield with 47% ee. The poor enantioselectivity
Under the optimal conditions, alkyl-substituted alkenylbor-
onic acids 2a−c reacted readily to give the corresponding α-
CF3 allylboronic acid esters 1(a-c)-OEt and Bdan derivatives
5a−c (Figure 3a). Aryl-substituted alkenylboronic acids (2d−
g) reacted somewhat slower than the aliphatic ones. Cinnamyl
derivative 5d was formed in 54% yield (93% ee) when 20 mol
% catalyst was used. However, with 20 mol % catalyst, 5e
formed only in 26% yield (89% ee). Therefore, the catalyst
loading was increased to 30 mol % to obtain acceptable yields
of 5e−g (50−70%). The absolute configuration of crystalline
5e was determined to be S by X-ray diffraction. On the basis of
the structural similarities of the substrates and the reaction
conditions, we assumed that the absolute configuration of the
other species (5a−d, 5f, and 5g) was the same. The reactions
can be easily scaled up. For example, the synthesis of 5a on 1
and 2 mmol scales occurred with 98 and 96% ee in 78 and 68%
yield, respectively.
The transient allylboron compounds 1-OEt reacted with
aldehyde 6a in situ (Figure 1b). The enantioselectivity for the
formation of 7a−d varied between 90 and 98% ee. In addition,
only one of the four possible diastereomers was formed in each
case. We did not detect any Z isomer of 7a−e in the crude
product of the reaction. Usually, α-substituted allylboron
B
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yields are in the range of 41−60% based on alkenylboronic
acid monomers after a two-step process. Another useful
reaction is the stereoselective in situ oxidation of the chiral
allylboron compounds to the corresponding α-CF3 allylic
alcohols 8a−c (Figure 3c), which were obtained in 50−78%
yield with 90−99% ee. The corresponding trifluoroethanol
motif49,50 occurs for example in antitumor agent Z28 and the
monoamine oxidase inhibitor befloxatone (Figure 1d).29
The asymmetric homologation concept can also be extended
to the synthesis of chiral α-silyl allylboronic acids, such as 1h-
OEt (Figure 3d). In this reaction, 3 was replaced with TMS-
diazomethane. Dan protection of 1h-OEt failed, and therefore,
we isolated pinane derivative 9. The homologation affording 9
proceeded with high selectivity (99:1 d.r., corresponding to
98% ee for 1h-OEt) in 51% yield. In situ allylboration of 6a
gave homoallylic alcohol 10 with high selectivity.
We were able to obtain purified oxygen-sensitive allylboronic
acids such as 1a and 1d by hydrolysis of the corresponding
isolated Dan-protected products (5a and 5d) (Table 2). The
increased reactivity of the purified products unleashed the
outstanding synthetic potential of chiral allylboronic acids. As
we reported previously, in the presence of molecular sieves (or
other drying agents), pure allylboronic acids form very reactive
allylboroxines.2,30,31,37 Purified 1a in the presence of molecular
sieves reacted with 6a in just 10 min to afford 7a (Table 2,
entry 1). Notably, the enantioselectivities with purified and in
situ-formed 1a were identical. This was also confirmed by the
reaction of cinnamyl analogue 1d with 6a (entry 2).
Allylboration of 6b with in situ-generated 1a-OEt failed to
give 7f (Figure 3b). However, purified 1a in the presence of
molecular sieves gave 1a-boroxine (see the Supporting
Information), which reacted with 6b to afford 7f (entry 3)
with excellent selectivity (98% ee) in 67% yield. The
purification (1a-OEt → 5a → 1a sequence) is essential to
obtain 7f, as demonstrated by a control experiment (entry 4).
When 2 equiv of EtOH was added to 1a prior to addition of
6b, formation of 7f was not observed. Likewise, 1a-Bpin did
not react with 6b under the reaction conditions applied for 1a
(entry 5). Aliphatic ketones (6c−e) also reacted smoothly with
allylboronic acids. Cyclohexanones 6c and 6d gave the
corresponding products 7g and 7h with 91−97% ee in 50−
72% yield (entries 6 and 7). The reaction of racemic methyl
cyclohexanone 6d with 1d is spectacular, as in this reaction the
major enantiomer (97% ee) 7h was formed with three
contiguous stereocenters in a single reaction step. Acyclic
aliphatic ketone 6e reacted in high yield (72%) but with only
82% ee, affording densely functionalized tertiary homoallyl
alcohol 7i. The synthetic utility of purified chiral allylboronic
acids was further demonstrated by allylboration of in-
doles11,31,51,52 6f and 6g with 1d to afford 7j and 7k with
high selectivities (entries 9 and 10). From skatole 6g, the E-
alkenyl-CF3 product 7k with three adjacent stereocenters was
formed with 89% ee. Isoquinoline derivative31,53 6h reacted
with purified 1d to afford 7m with 93% ee in 54% yield.
Allylboration of 6i54,55 with 1a gave α-amino acid derivative 7n
with 98% ee in 72% yield.
Figure 3. Synthesis and applications of chiral α-substituted
a
b
c
allylboronic acids. 1 mmol scale. 2 mmol scale. 30 mol % 4 was
d
e
used. At 30 °C. 6b (0.15 mmol) was used.
compounds with bulky protecting groups (e.g., pinacol or 9-
BBN) react with poor E/Z selectivity in allylboration
reactions.42,43
These selectivity issues can often be solved by application of
additives, but in the presented processes, poor E/Z selectivity
was avoided by the small size of the B(OEt)2 group. Notably,
small molecules with alkenyl-CF3 motifs44−48 are very
important drugs, such as in anticancer agents,25 pesticides,26
and herbicides27 (Figure 1d). Formation of 7e from 1f
proceeded with 75% ee. The relatively low enantioselectivity is
a consequence of the fact that 1f-OEt is formed with lower
selectivity (86% ee, 5f) than other allylboronic acids. The
In summary, we have presented a new methodology for the
catalytic synthesis of chiral α-CF3 or α-SiMe3 allylboronic acids
using stabilized diazomethane derivatives. The basic concept of
stereoselective 1,2-borotropic migration can certainly be
extended to nonstabilized diazoalkanes as well by solving the
issues of electrophilic side reactions (e.g., protonation of the
diazoalkanes) competing with the formation of the ate complex
C
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Table 2. Showcase for Application of Purified α-CF3
Allylboronic Acids in Stereoselective Synthesis
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c09923.
■
a
sı
Materials and methods, characterization data, and NMR
spectra (PDF)
Crystallographic data for 5e (CIF)
AUTHOR INFORMATION
Corresponding Author
■
́
́
́
Kalman J. Szabo − Department of Organic Chemistry,
Arrhenius Laboratory, Stockholm University, SE-106 91
Stockholm, Sweden; orcid.org/0000-0002-9349-7137;
Email: kalman.j.szabo@su.se
Authors
Sybrand J. T. Jonker − Department of Organic Chemistry,
Arrhenius Laboratory, Stockholm University, SE-106 91
Stockholm, Sweden; orcid.org/0000-0002-5402-8418
Ramasamy Jayarajan − Department of Organic Chemistry,
Arrhenius Laboratory, Stockholm University, SE-106 91
Stockholm, Sweden; orcid.org/0000-0002-1848-1434
Tautvydas Kireilis − Department of Organic Chemistry,
Arrhenius Laboratory, Stockholm University, SE-106 91
Stockholm, Sweden
Marie Deliaval − Department of Organic Chemistry, Arrhenius
Laboratory, Stockholm University, SE-106 91 Stockholm,
Sweden; orcid.org/0000-0003-1396-2818
Lars Eriksson − Department of Materials and Environmental
Chemistry, Arrhenius Laboratory, Stockholm University, SE-
106 91 Stockholm, Sweden
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c09923
Author Contributions
§S.J.T.J. and R.J. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the Knut and Alice Wallenberg Foundation
(2018.0066) and the Swedish Research Council (2017-04235)
for financial support. A postdoctoral fellowship for R.J. from
the Wenner-Gren Foundation (UPD2019-0149) is gratefully
acknowledged. We thank Dr. D. Wang for performing some
preliminary experiments.
a
Unless otherwise stated, 5 (0.1 mmol) was hydrolyzed with 3 N
H2SO4 in DME, and then 1 was extracted with toluene under Ar.
b
c
Isolated yields. 1H NMR spectra of 1a and 1d are given in the
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■
Supporting Information. Using 2 equiv of EtOH without molecular
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