Synthesis and applications of α-trifluoromethylated alkylboron compounds

Article abstract of DOI:10.1002/anie.201308036

RBF₃K is a chemist's BFF: A metal-free synthetic route to unprecedented organoboron compounds bearing an α-trifluoromethyl substituent, employing a variety of trifluoroborate (RBF₃K) starting materials, is reported. These substrates represent the first isolated α-trifluoromethylated alkylboron building blocks, and these reagents lead to a variety of useful bench-stable, synthetic intermediates. Pin=pinacol. Copyright

Full text of DOI:10.1002/anie.201308036

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Chemie
DOI: 10.1002/anie.201308036
Synthetic Methods
Hot Paper
Synthesis and Applications of a-Trifluoromethylated Alkylboron
Compounds**
O. Andreea Argintaru, DaWeon Ryu, Ioana Aron, and Gary A. Molander*
The importance of incorporating fluorinated subunits into
organic molecules is well established in the pharmaceutical,
agrochemical, and materials industries.[1,2] Developing meth-
ods of incorporating such fluorinated moieties into organic
substrates in a safe, selective, and facile manner, therefore,
has been an area of great interest.[3] Among the various
fluorinated moieties, the strongly electron-withdrawing tri-
fluoromethyl group (CF3) has garnered much attention
because of the profound properties it can effect upon being
implanted within a molecule.[4] However, most of the
synthetic efforts have been focused on introducing CF3 into
functionalized arenes.[5]
By contrast, general methods for the incorporation of CF3
into alkyl systems are less well developed,[6–8] yet increasingly
more important in terms of structural diversity and expanding
chemical space.[9] b-Trifluoroethyl carbanion synthons repre-
sent an attractive set of reagents for the installation of
fluorinated substructures within the realm of alkyl building
blocks. However, owing to a strong driving force for the
alcohol cannot function as a bench-stable trifluoroethyl anion
or trifluoroethyl radical precursor, and the versatility of the
organoboron compounds in further functionalization (e.g.,
[13]
À
C C bond formation by metal-catalyzed cross-coupling or
radical reactions,[14] rhodium-catalyzed 1,2-additions,[15] ami-
nation,[16] etc.) is lost.
Herein, we report the synthesis of diverse libraries of
indefinitely bench-stable trifluoromethylated building blocks,
which can be further diversified through versatile organo-
boron transformations. This chemistry has the potential to
improve the existing paradigm for the introduction of CF3 at
sp3 centers, a reaction which is limited mostly to CF3-based
reagents such as Me3SiCF3 that minimally enhance molecular
complexity. Our strategy was to utilize trifluoroethylidene in
conjunction with tricoordinate organoborons to generate
unprecedented a-trifluoromethylated organoborons through
an established a-transfer mechanism (Scheme 1).
À
formation of metal–fluorine (M F) bonds, the propensity for
À
b-fluoride elimination of M F moieties is high [Eq. (1)], and
thus the chemistry of b-trifluoroethyl carbanion synthons is
astonishingly limited and underdeveloped.[10]
Scheme 1. a-Transfer mechanism.
The synthesis of 2,2,2-trifluorodiazoethane (CF3CHN2)
from the corresponding ammonium salt was first described in
the 1940s and was reported on a scale as large as 100–
200 mmol.[17] However, CF3CHN2 was not used extensively in
organic synthesis until the Carreiraꢀs group developed
a method to generate the material and react it in situ with
other organic compounds. As demonstrated by Carreira,
CF3CHN2 has a similar reactivity profile to that of ethyl
diazoacetate.[18] The reactivity of CF3CHN2 toward organo-
boron compounds, however, has never been explored,
although several organoborons have been shown to react
with ethyl diazoacetate and other a-diazocarbonyl com-
pounds to give a-arylated, a-vinylated, or a-alkylated car-
bonyl compounds after protodeboronation.[19] Unlike the
reactions of organoborons with diazocompounds such as ethyl
Although Brown, Ramachandran, and co-workers have
previously generated a-trifluoromethylated organoboranes
through a hydroboration route,[11] these intermediates were
never isolated but rather simply oxidized in situ.[12] With the
boron oxidized to the corresponding alcohol, the considerable
synthetic value of the trifluoroethyl subunit in subsequent
transformations is diminished. Unlike the organoborons, the
[*] O. A. Argintaru, D. Ryu, I. Aron, Prof. G. A. Molander
Roy and Diana Vagelos Laboratories, Department of Chemistry
University of Pennsylvania
diazoacetate, where an enol boronate is formed,[19] the B C
À
231 South 34th Street, Philadelphia, PA 19104-6323 (USA)
E-mail: gmolandr@sas.upenn.edu
bond in the present process was expected to remain intact
after reaction with CF3CHN2, thus giving rise to unprece-
dented organoboron compounds bearing an a-trifluoro-
methyl substituent.
[**] We thank Frontier Scientific for boronic acids and potassium
organotrifluoroborates. Financial support has been provided by the
NIH (NIGMS R01 GM035249). Dr. Rakesh Kohli (University of
Pennsylvania) is acknowledged for obtaining HRMS data. J.-B. Coty
(University of Pennsylvania) is acknowledged for repeating the
experiment using p-methoxyphenyltrifluoroborate (2 f) and running
the experiment using p-trifluoromethylphenyltrifluoroborate (2h).
By using the method reported by Carreira and co-
workers,[18] stock solutions of CF3CHN2 in several organic
solvents (heptanes, toluene, dichloromethane, and chloro-
benzene) at varying concentrations (0.1–1m) were prepared in
75–90% yield. With these stock solutions of CF3CHN2 in
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201308036.
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hand, their reactivity with various boron species was inves-
tigated. Initial attempts were made with commercially
available aryl pinacol boronates. No reactivity was observed
with these substrates, and the starting materials were fully
recovered. The lack of reactivity may be explained by the low
Lewis acidity of boronate esters.[20] With boronic acids,
reactivity was observed in various solvents and at different
temperatures. After optimization of the reaction conditions,
the desired a-trifluoromethylated organoborons were
detected in good yields by 1H NMR spectroscopy after
quenching the reaction mixtures with pinacol (Table 1).
alternative to boronic acids because of their precise stoichio-
metry and excellent stability across all classes of substrates
(alkyl, alkenyl, alkynyl, aryl, and heteroaryls). Vedejs et al.[22a]
and Kim and Matteson[22b] have shown that potassium
organotrifluoroborates can be converted into dihaloboranes
(RBX2, X = F or Cl) upon treatment with TMSCl or SiCl4.
After screening a variety of silicon sources, solvents, and
temperatures, the use of CH2Cl2 at room temperature or
toluene at 408C, with TMSCl or p-tolylSiCl3 as a fluorophile
proved optimal (Table 2). CH2Cl2 and toluene often provided
similar results, but the conversion in toluene was slower than
that in CH2Cl2 at room temperature. Therefore, a slight
increase in temperature for the toluene reactions (408C) was
necessary to achieve high conversions. During the optimiza-
tion, it was observed that all reagents could be added at once,
which obviated the step of preforming RBX2 prior to the
addition of the diazo solutions and facilitated the experimen-
tal setup.
To avoid the oxidation problem mentioned in reference to
Table 1, the crude reaction mixture was quenched with KHF2,
and the desired products were purified in good to excellent
yields as tetracoordinate potassium trifluoroborates. The
substrate scope of the transformation is extremely broad,
and the purification only requires hot acetone extraction and
recrystallization, thus avoiding the use of column chromatog-
raphy. Primary and secondary alkyl trifluoroborates reacted
in high yields (2a–c). Because of the importance of allylic and
propargylic organoborons in organic synthesis,[23] our atten-
tion was then focused toward alkenyl and alkynyl potassium
trifluoroborates as starting materials. These two classes of
substrates smoothly underwent the reaction with 2,2,2-
trifluorodiazoethane, thus leading to novel allylic and prop-
argylic a-trifluoromethylated trifluoroborates which are
indefinitely stable on the bench top (2d,e). No borotropic
shift was observed when an alkenyltrifluoroborate was used,
and no allenylboron was detected when starting with alky-
nyltrifluoroborate. The reaction of various aryltrifluorobo-
rates was then investigated, and the desired a-trifluorome-
thylated benzylic products were obtained in good to excellent
yields in all cases. Various functional groups such as ethers
(2 f), nitriles (2i), halides (2j), and olefins (2k) were tolerated
under the reaction conditions, and both electron-donating and
-withdrawing groups could be present on the aryltrifluorobo-
rates without affecting the yields. Important heterocyclic
systems such as indole (2n), thiophene (2o), and furan (2p)
were also successfully converted.
Table 1: Reactions of 2,2,2-trifluorodiazoethane with boronic acids.
Substrate
Product
Yield [%][a]
73(38)[b]
1a
81
85
73
[a] Yields determined by 1H NMR analysis of the crude reaction mixture.
[b] Yield of isolated product. Pin=pinacol.
Although the yields of the desired products in the crude
reaction mixtures were good, in most cases (especially when
using electron-poor boronic acids) the a-trifluoromethylated
pinacol boronates were prone to oxidation during purification
using silica gel chromatography. In certain cases, simple
exposure to air at room temperature led to the corresponding
alcohols, and the yields of the isolated products suffered
drastically. Conversion of the a-trifluoromethylated, tricoor-
dinate boronic acids to the more stable tetracoordinate
potassium organotrifluoroborates by quenching the crude
reaction mixture with KHF2 led to mixtures, and the desired
products could not be isolated in high yields after successive
recrystallizations.
In addition to the aforementioned purification problems,
the use of boronic acids as limiting reagents in the reaction
with 2,2,2-trifluorodiazoethane became rapidly unappealing
for other reasons. Along with the well-known instability of
some classes of boronic acids when exposed to air even at low
temperatures,[21] their equilibrium with cyclic boroxines also
leads to an uncertain stoichiometry. Furthermore, boronic
acids and boroxines were reported to have different Lewis
acidities and consequently different reactivity rates toward
the diazo compounds.[19b]
All these classes of a-trifluoromethylated products iso-
lated as trifluoroborates have been kept on the bench for over
six months without any sign of decomposition. These
trifluoroborates represent the first indefinitely stable a-
trifluoromethylated alkylborons.
To demonstrate the potential value of the a-trifluorome-
thylated organoborons in synthesis, preliminary studies for
the functionalization of the carbon–boron bond were per-
formed. Reactions were carried out in situ on the a-
trifluoromethylated, tricoordinate organoboron species. Oxi-
dation was performed by quenching the crude reaction
mixture with pinacol, and subsequent treatment with
NaOH/H2O2 [Eq. (2)]. This method is complementary to
The use of potassium organotrifluoroborates (RBF3K) as
starting materials was envisioned as a more favorable
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Table 2: Substrate scope of potassium organotrifluoroborates.
the synthesis of a-trifluoromethyl alcohols from
aldehydes and the expensive Ruppert–Prakash
reagent[24] or the reduction of trifluoromethyl
ketones, which have limited commercial avail-
ability.[25]
Substrate
Product
Solvent [Si]
Yield
[%][a]
Methods to prepare benzylic a-trifluoro-
methyl bromides involve multistep syntheses,
and require the isolation of the a-trifluorome-
thylated alcohol intermediates and subsequent
treatment with stoichiometric amounts of NBS
and triphenylphosphite, thus leading to low to
moderate overall yields.[25a,26] In a one pot
procedure, starting from the commercially avail-
able potassium p-methoxyphenyltrifluorobo-
rate, the a-trifluoromethyl benzyl bromide 3b
was prepared in 51% yield without any further
optimization (Table 3). Interestingly, when alke-
nyltrifluoroborates were used as starting mate-
rials, rearrangement occurred to provide the
secondary allylic bromide and chloride in
a regio- and stereodefined manner (3c and
3d). To our best knowledge, this class of
trifluoromethylated secondary allyl halides has
never been reported. Previous literature reports
only describe isolated multistep syntheses of
a few primary trifluoromethylated allyl bro-
mides and chlorides, along with their potential
applications in organic transformations (SN2,
addition to carbonyls).[27]
2a CH2Cl2 TMSCl 71
2b toluene TMSCl 80
2c toluene TMSCl 78
p-tolyl-
2d CH2Cl2
78
SiCl3
2e CH2Cl2 TMSCl 92
p-tolyl-
SiCl3
2 f CH2Cl2
71(67)[b]
2g CH2Cl2 TMSCl 72
p-tolyl-
SiCl3
2h toluene
83
Protodeboronation of the crude a-trifluoro-
methylated pinacol boronate was smoothly
achieved using the reaction conditions reported
by Aggarwal and co-workers [Eq. (3)].[28] Unlike
any existing procedures,[29] this transformation
provides an approach to metal-free trifluoroe-
thylation of a variety of organic substructures.
Thus, in addition to avoiding the transition-
metal waste, the substrate scope of the trifluor-
oborate starting materials is very broad (as
shown in Table 2), thus potentially allowing the
introduction of CF3CH2 on primary and secon-
dary alkyls, alkenyls, alkynyls, aryls, and hetero-
aryls by the same general experimental proce-
dure.
2i CH2Cl2 TMSCl 70
p-tolyl-
SiCl3
2j CH2Cl2
71
2k CH2Cl2 TMSCl 89
p-tolyl-
SiCl3
2l CH2Cl2
65
b-Fluoride elimination is a major unresolved
problem when a trifluoromethyl group and
a metal are situated on the same C(sp3). For an
2m CH2Cl2 TMSCl 88
2n CH2Cl2 TMSCl 90
a-trifluoromethylated
organolithium
or
Grignard reagent, b-fluoride elimination occurs
instantaneously unless strongly electron-with-
drawing groups are introduced to stabilize the
trifluoroethyl anions at very low tempera-
tures.[10] The a-trifluoromethylated dihalobor-
anes reported herein could be heated to 408C
under Ar without any sign of b-fluoride elimi-
nation. However, it was observed that a con-
trolled elimination could be induced by increas-
ing the temperature to 758C, wherein b-fluoride
elimination occurred to form substituted 1,1-
2o CH2Cl2 TMSCl 72
2p toluene TMSCl 86
[a] Yield of the isolated product. [b] Reaction performed on a 10 mmol scale.
TMS=trimethylsilyl.
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Table 3: Halogenation of a-trifluoromethyl organoborons.
Substrate
Product
Yield
[%][a]
ally simple and effective, but it can also be carried out without
resorting to metal mediation. Numerous carbon–carbon and
carbon–heteroatom bond-forming transformations appear to
be feasible with these reagents, employing well-known
reactivity patterns of organoborons. These reagents thus
represent potentially powerful building blocks for selective
incorporation of the CF3 unit at sp3-carbon centers in complex
molecules.
3b
51
3c
3d
60
61
[a] Yield of the isolated product. NBS=N-bromosuccinimide, NCS=N-
chlorosuccinimide.
Experimental Section
Potassium organotrifluoroborate (1 mmol) was added to a 20 mL
Biotage microwave vial equipped with a stir bar. The vial was sealed
and purged with argon three times. The solution of 2,2,2-trifluor-
odiazoethane in CH2Cl2 (ca. 0.5m, 4 mL) or toluene (ca. 0.5m, 4 mL)
was added under Ar, then freshly distilled Me3SiCl (120 mg,
1.1 mmol) or p-tolylSiCl3 (248 mg, 1.1 mmol) was added, and the
reaction was stirred at room temperature (in CH2Cl2) or 408C (in
toluene) overnight. The pressure was vented under Ar pressure. The
reaction was cooled to 08C, then a saturated solution of KHF2 (1 mL,
4.5m in H2O) was added dropwise under Ar. Acetone (3 mL) was
added to increase the solubility and improve the stirring of the
reaction. The reaction was allowed to warm to RT and stirred for an
additional 30 min under argon. The solvent was evaporated from the
crude reaction mixture, and the product was extracted into dry
acetone to eliminate the inorganic salts. The acetone was evaporated
and the desired product was recrystallized from the crude mixture.
difluoro-1,3-butadienes[30] (3 f). Although this transformation
can be applied to aryl trifluoroborates to synthesize difluor-
ostyrenes, higher yield and selectivity were obtained with an
alkenyl trifluoroborate under these conditions [Eq. (4)].
Received: September 12, 2013
Published online: && &&, &&&&
Keywords: boron · diazo compounds · silanes ·
.
synthetic methods · trifluoromethylation
Finally, to highlight another advantage of retaining the
boron intact after the trifluorodiazoethane insertion, a reac-
tion with a second diazo compound was performed. When
ethyl diazoacetate (EDA) was added in situ to the a-
trifluoromethylated dihaloborane, the double diazo insertion
product was obtained in an overall (unoptimized) yield of
43%. After the insertion of EDA, the resulting boron enolate
is rapidly protonated, thus leading directly to the observed
ester.[19] It is important to note that this approach represents
a complementary method to access the same class of
molecules that are obtained by the addition of the Ruppert–
Prakash reagent to a,b-unsaturated esters [Eq. (5)],[31] with
the potential to provide access to greater structural diversity
as well: the range of organoboron precursors available far
exceeds that of the requisite a,b-unsaturated carbonyl
substrates required for the conjugate addition reaction of
the Ruppert reagent.
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Angew. Chem. Int. Ed. 2013, 52, 1 – 6
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
Synthetic Methods
O. A. Argintaru, D. Ryu, I. Aron,
G. A. Molander*
&&&& — &&&&
Synthesis and Applications of a-
Trifluoromethylated Alkylboron
Compounds
RBF3K is a chemist’s BFF: A metal-free
synthetic route to unprecedented orga-
noboron compounds bearing an a-tri-
fluoromethyl substituent, employing
a variety of trifluoroborate (RBF3K) start-
ing materials, is reported. These sub-
strates represent the first isolated a-
trifluoromethylated alkylboron building
blocks, and these reagents lead to a vari-
ety of useful bench-stable, synthetic
intermediates. Pin=pinacol.
6
www.angewandte.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
These are not the final page numbers!