Facile synthesis of highly functionalized ethyltrifluoroborates

Article abstract of DOI:10.1021/jo800760f

(Formula Presented) Organotrifluoroborates are generating increased interest because of their ease of preparation and purification and indefinite shelf life. Herein we report the preparation of organotrifluoroborates bearing functional groups that can be manipulated at different stages of the synthetic route, exploiting the inertness of their carbon - boron bonds. The alkylation of 2,2-dicyanoethyltrifluoroborate with a variety of electrophiles and of (EWG)₂CH₂ with potassium iodomethyltrifluoroborate resulted in di- and trisubstituted ethyltrifluoroborates in good to excellent yields.

Full text of DOI:10.1021/jo800760f

in the Suzuki-Miyaura cross-coupling,2 as well as in the
preparation of secondary amines3 and alkyl iodides.4
Facile Synthesis of Highly Functionalized
Ethyltrifluoroborates
Despite the advantages and increasing applicability of alkyl-
trifluoroborates, to date they are normally prepared by three
general methods: (i) from commercially available boronic acids
or boronate esters,5 (ii) by transmetalation of organolithium or
Grignard reagents,6 and (iii) by hydroboration of alkenes.7 For
that reason, access to more highly elaborated or unique
organotrifluoroborates is an area of synthetic interest. Recently,
we described a new method for the preparation of a wide range
of organotrifluoroborates, including potassium 2,2-dicyanoeth-
yltrifluoroborate (2), by direct nucleophilic substitution of
potassium iodomethyltrifluoroborate (1).8 Few alkylborons have
been elaborated by nucleophilic reactions at ancillary electro-
philic functional groups. Herein, we expand the functional
diversity of organotrifluoroborates by preparing both di- and
trisubstituted ethyltrifluoroborates using just such a strategy.
The gram scale synthesis of the starting potassium 2,2-
dicyanoethyltrifluoroborate (2) was achieved in 92% yield (eq
1). Malononitrile (3 equiv) was deprotonated with sodium
hydride (3 equiv), followed by the addition of potassium
iodomethyltrifluoroborate (1 equiv).8 After completion, the
reaction was quenched with potassium hydrogen fluoride to
ensure counterion homogeneity, and the product was purified
by precipitation from acetone-ether.9
Gary A. Molander,*,† Wilma Febo-Ayala,† and
Montserrat Ortega-Guerra†,‡
Roy and Diana Vagelos Laboratories, Department of
Chemistry, UniVersity of PennsylVania,
Philadelphia, PennsylVania, 19104-6323
gmolandr@sas.upenn.edu
ReceiVed April 4, 2008
Organotrifluoroborates are generating increased interest
because of their ease of preparation and purification and
indefinite shelf life. Herein we report the preparation of
organotrifluoroborates bearing functional groups that can be
manipulated at different stages of the synthetic route,
exploiting the inertness of their carbon-boron bonds. The
alkylation of 2,2-dicyanoethyltrifluoroborate with a variety
of electrophiles and of (EWG)2CH2 with potassium iodo-
methyltrifluoroborate resulted in di- and trisubstituted ethyl-
trifluoroborates in good to excellent yields.
With 2 in hand we investigated suitable reaction conditions
for its subsequent alkylation. Initially, sodium hydride was used
as the base, and the highly reactive iodomethane was utilized
as the electrophile. The first solvent tested was THF, which
resulted in either no reaction or complex reaction mixtures at
longer reaction times. Hexamethylphosphoramide (HMPA) was
added to facilitate solubilization of the anion, resulting in a 64%
yield of the desired product. To avoid the use of toxic HMPA,
more polar solvents (4:1 THF-DMF, DMSO, and DMF) were
tested. After reacting for 4 h, all of these protocols resulted in
higher yields of the desired product, with the best yields obtained
Tricoordinate boronic acids are sensitive to bases, nucleo-
philes, and oxidants owing to their acidic protons and vacant
p-orbital. Consequently, they cannot be carried through synthetic
steps involving these reagents. This has limited the preparation
of functionalized boronic acids under basic or nucleophilic
conditions. The increased stability of boronate esters allows them
to survive functionalization under some, but not all, of these
conditions.
Organotrifluoroborates have emerged as a versatile alternative
to boronic acids and boronate esters. They are tetracoordinate
boron salts prepared from the addition of inexpensive KHF2 to
organoboron intermediates.1 The absence of an empty p-orbital
makes them mechanistically inert to many reagents utilized in
organic synthesis, allowing their installation early on in a
synthetic sequence. Potassium organotrifluoroborates are crystal-
line solids that are air- and moisture-stable and easy to handle
and can be stored indefinitely without special precautions.
Although aryl-, vinyl-, and allyltrifluoroborates find use in a
variety of applications,1 alkyltrifluoroborates remain relatively
unexplored, with a few notable applications, including their use
(2) (a) Molander, G. A.; Ito, T. Org. Lett. 2001, 3, 393–396. (b) Molander,
G. A.; Yun, C.-S.; Ribagorda, M.; Biolatto, B. J. Org. Chem. 2003, 68, 5534–
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775. (d) Molander, G. A.; Ribagorda, M. J. Am. Chem. Soc. 2003, 125, 11148–
11149.
(3) Matteson, D. S.; Kim, G. Y. Org. Lett. 2002, 4, 2153–2155.
(4) Kabalka, G. W.; Mereddy, A. R. Tetrahedron Lett. 2004, 45, 343–345.
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J. Org. Chem. 1995, 60, 3020–3027. (b) Vedejs, E.; Fields, S. C.; Hayashi, R.;
Hitchcock, S. R.; Powell, D. R.; Schrimpf, M. R. J. Am. Chem. Soc. 1999, 121,
2460–2470.
(6) Matteson, D. S. Tetrahedron 1989, 45, 1859–1885.
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1311–1316. (b) Burgess, K.; Ohlmeyer, M. J. Chem. ReV. 1991, 91, 1179–1191.
(c) Pereira, S.; Srebnik, M. J. Am. Chem. Soc. 1996, 118, 909–910. (d) Kabalka,
G. W.; Narayana, C.; Reddy, N. K. Synth. Commun. 1994, 24, 1019–1023. (e)
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† University of Pennsylvania.
‡ Departamento de Qu´ımica Orga´nica, Universidad Auto´noma de Madrid,
Ciudad Universitaria de Cantoblanco, 28049 Madrid.
(1) (a) Darses, S.; Geneˆt, J.-P. Chem. ReV. 2008, 108, 288–325. (b) Molander,
G. A.; Ellis, N. Acc. Chem. Res. 2007, 40, 275–286. (c) Stefani, H. A.; Cella,
R.; Vieira, A. S. Tetrahedron 2007, 63, 3623–3658. (d) Molander, G. A.;
Figueroa, R. Aldrichimica Acta 2005, 38, 49–56.
(8) Molander, G. A.; Ham, J. Org. Lett. 2006, 8, 2031–2034.
(9) Alternatively, 2 can be prepared from pinacol iodomethylboronate (6);
see Supporting Information for experimental details.
6000 J. Org. Chem. 2008, 73, 6000–6002
10.1021/jo800760f CCC: $40.75 2008 American Chemical Society
Published on Web 06/28/2008

TABLE 1. Alkylation of Potassium 1,2-Dicyanoethyltrifluoroborate (2)a
Unfortunately, attempts to substitute 1 directly with nucleo-
philes derived from substrates such as 5a under the conditions
described in eq 1 were unsuccessful. The use of different bases
(KH, NaOH, KOH, K2CO3) and solvents (DMSO, CH3CN) or
phase transfer catalysts did not give any product. The reaction
conditions described in eq 1 along with a higher temperature
(80 °C) and longer reaction time (3 d) in DMF yielded some
product along with decomposition of materials as indicated by
1H NMR. The attenuated electrophilic character of the iodom-
ethyltrifluoroborate represents a challenge when highly enoliz-
able or bulkier nucleophiles were employed.
An alternative route was explored starting from the pinacol
iodomethylboronate (6),10 which reacts by an entirely different
mechanism than the iodomethyltrifluoroborate. Thus, whereas
the organotrifluoroborates appear to react by a direct SN2
reaction on the halide, the pinacolboronates react by initial
complexation of the nucleophile at the boron, generating an
intermediate “ate” complex. This is followed by an R-transfer
process in which the nucleophile migrates, displacing the halide
intramolecularly. Reaction of 6 with various stabilized anions
followed by the addition of KHF2 thus afforded the desired
organotrifluoroborates in good yields (Table 2). Only an
equimolar amount of base, electrophile, and nucleophile was
required to afford the product. A significant advantage of the
organotrifluoroborate products over that of the corresponding
boronates is the easy purification of the former products via
acetone-ether precipitation. In contrast, the boronate esters are
usually purified by distillation at high temperatures.11
In summary, the high-yielding synthesis of functionalized
ethyl trifluoroborates has been described, including the 1 g
synthesis of 2. The scope and limitations in the alkylation of 2
were further described, demonstrating the manipulation and
stability advantages of organotrifluoroborates over boronic acids
and boronate esters. Studies are underway to optimize the
Suzuki-Miyaura cross-coupling reaction conditions for these
materials.
Experimental Section
Potassium 2,2-Dicyanoethyltrifluoroborate (2). The title com-
pound was prepared according to the literature procedure8 from
potassium iodomethyltrifluoroborate (1) (1.00 g, 4.0 mmol), and
the malononitrile anion [generated by treatment of malononitrile
(800.6 mg of a 99% purity reagent, 12.0 mmol) with NaH (484.5
mg of a 60% dispersion in oil, 12.0 mmol)], affording 765 mg (92%
yield) of the title compound as a pink solid whose spectroscopic
data agree with those reported in the literature.8
General Experimental Procedure for the Alkylation of
Potassium 2,2-Dicyanoethyltrifluoroborate. Preparation of
Potassium 2,2-Dicyanobutyltrifluoroborate (4b). To a solution
of potassium 2,2-dicyanoethyltrifluoroborate (2) (100 mg, 0.53
mmol) in 500 µL of DMF were sequentially added NaH (25 mg of
a 60% dispersion in mineral oil, 0.64 mmol) and iodoethane (127
µL, 1.59 mmol). The resulting suspension was stirred at 25 °C until
the reaction was complete (4.5 h) as indicated by 19F NMR. The
reaction was then quenched with 1 N KHF2 (0.5 mL). The solvents
were removed under high vacuum, the solid was redissolved in
HPLC grade acetone (5 mL), and the insoluble salts were filtered
off. After concentration, the resulting solid was redissolved in the
minimum quantity of HPLC grade acetone (1 mL) and precipitated
by adding Et2O (3 mL). After decantation, the resulting solid was
a Reaction conditions: substrate (1 equiv), NaH (1.2 equiv),
electrophile (3 equiv). b Reaction conditions: substrate (1 equiv), NaH
(1.1 equiv), electrophile (1.1 equiv).
using DMF. Three equivalents of the electrophile were needed;
use of 1 or 2 equiv gave lower yields. This set of conditions
gave product 4a in 82% yield after purification (Table 1), and
the method was extended to other electrophiles with the results
outlined in Table 1.
All of the products were obtained in good to excellent yields.
Of note, we find no evidence for formation of the allenyl product
upon using the propargyl bromide (3g) as an electrophile in
the reaction (entry 7). Some electrophiles were ineffective in
the substitution reactions. For example, only 2 was recovered
when benzyl bromoacetate, 2-bromoacetophenone, and bro-
momethyl benzyl ether were used as the electrophiles.
(10) Smoum, R.; Rubinstein, A.; Srebnik, M. Bioorg. Chem. 2003, 31, 464–
474.
(11) Kinder, D. H.; Ames, M. M. J. Org. Chem. 1987, 52, 2452–2454.
J. Org. Chem. Vol. 73, No. 15, 2008 6001

TABLE 2. Preparation of Di- and Trisubstituted Ethyltrifluoroboratesa
11B NMR (128.4 MHz, DMSO-d6) δ: 1.91 (q, J ) 52.5 Hz). IR
(neat): 2937, 2250, 1683, 1463, 1269, 1024, 926, 770, 483 cm-1
.
HRMS (m/z): calcd for C6H7BF3N2, 175.0654 [M - K]+, found
175.0654.
General Experimental Procedure for the Alkylation with Pin-
acol Iodomethylboronate. Preparation of Potassium Methyl 2-Cy-
ano-3-(trifluoroborato) Propanoate (7b). A flame-dried round-
bottom flask with a stir bar was charged with 95% NaH dispersion
in mineral oil (14 mg, 0.54 mmol) followed by anhydrous THF
(1.7 mL). The flask was cooled to 0 °C, and methyl cyanoacetate
(53.4 mg, 0.54 mmol) was added dropwise via syringe. The reaction
was slowly warmed to 25 °C and stirred under N2 for 2 h. Next,
the pinacol iodomethylboronate (141.8 mg, 0.53 mmol) was added
dropwise and stirred at 25 °C until the reaction was complete as
indicated by 11B NMR (12 h). The reaction was quenched with ∼1
mL of H2O and extracted using Et2O (∼3 mL). The organic layer
was washed with H2O (2 × 2 mL) and brine (1 × 2 mL). The
product was dried (MgSO4), filtered, and concentrated. (Note: in
one instance the aqueous workup was not performed, and the yield
of the product was unaffected.) The crude product was redissolved
in 5.25:1 MeOH-H2O (1.35 mL) followed by the addition of KHF2
(124.2 mg, 1.59 mmol). The reaction was stirred at 25 °C until
completion as indicated by 11B NMR (4 h). The solvent was then
removed under high vacuum and the material redissolved in HPLC
grade acetone (10 mL). The insoluble salts were filtered off, and
the filtrate was concentrated. The crude product was redissolved
in the minimum amount of HPLC grade acetone (2 mL) necessary
and precipitated by adding Et2O (6 mL). The solid was collected
via decantation to give a light yellow solid (88.4 mg, 76% yield).
1
Mp ) 100-105 °C. H NMR (500 MHz, acetone-d6) δ: 3.69 (s,
3H), 3.44 (t, J ) 7.5 Hz, 1H), 0.77 (d, J ) 34.5 Hz, 2H). 13C
NMR (125.8 MHz, acetone-d6) δ: 171.1, 120.7, 53.1, 34.9. 19F NMR
(470.8 MHz, acetone-d6) δ: -142.32 (s). 11B NMR (128.4 MHz,
acetone-d6) δ: 4.35 (s). IR (neat): 2958, 2254, 1740, 1439, 1259,
1036 cm-1. HRMS (m/z): calcd for C5H6BF3NO2, 180.0444 [M -
K+], found 180.0422.
Acknowledgment. The authors wish to thank Mr. Adam
Brown (University of Pennsylvania) for his contribution to the
project. Dr. Rakesh Kohli (University of Pennsylvania) is
acknowledged for obtaining high-resolution mass spectra of the
new compounds. This work was supported by the NIH
(GM35249) and the Spanish Ministerio de Educacio´n y Ciencia
FPU grant.
a Reaction conditions: nucleophile (1 equiv), NaH (1 equiv), elec-
trophile (1 equiv).
Supporting Information Available: Experimental proce-
dures, spectral characterization, and copies of 1H, 13C, 11B, and
19F spectra for all compounds prepared by the method described.
This material is available free of charge via the Internet at
http://pubs.acs.org.
pulverized using a mortar and pestle and washed with Et2O (3 mL)
to give a white solid (111 mg, 98% yield). Mp > 250 °C. 1H NMR
(500 MHz, DMSO-d6) δ: 1.94 (q, J ) 7.3 Hz, 2H), 1.07 (t, J )
7.3 Hz, 3H), 0.76 (br s, 2H). 13C NMR (125.8 MHz, DMSO-d6) δ:
118.5 (2C), 31.6, 9.9. 19F NMR (470.8 MHz, DMSO-d6) δ: -135.2.
JO800760F
6002 J. Org. Chem. Vol. 73, No. 15, 2008