Preparation of potassium alkoxymethyltrifluoroborates and their cross-coupling with aryl chlorides

Article abstract of DOI:10.1021/ol800532p

(Chemical Equation Presented) A wide variety of alkoxymethyltrifluoroborate substrates were prepared via S_N2 displacement of potassium bromomethyltrifluoroborate with various alkoxides in excellent yields. These alkoxymethyltrifluoroborates were effectively cross-coupled with several aryl chlorides. This method provides a unique dissonant disconnect that allows greater flexibility in the design of new and improved synthetic pathways.

Full text of DOI:10.1021/ol800532p

ORGANIC
LETTERS
2008
Vol. 10, No. 11
2135-2138
Preparation of Potassium
Alkoxymethyltrifluoroborates and Their
Cross-Coupling with Aryl Chlorides
Gary A. Molander* and Belgin Canturk
Roy and Diana Vagelos Laboratories, Department of Chemistry, UniVersity of
PennsylVania, Philadelphia PennsylVania 19104-6323
gmolandr@sas.upenn.edu
Received March 8, 2008
ABSTRACT
A wide variety of alkoxymethyltrifluoroborate substrates were prepared via SN2 displacement of potassium bromomethyltrifluoroborate with
various alkoxides in excellent yields. These alkoxymethyltrifluoroborates were effectively cross-coupled with several aryl chlorides. This method
provides a unique dissonant disconnect that allows greater flexibility in the design of new and improved synthetic pathways.
Ethers are prevalent in natural products and compounds of
pharmacological interest. Ethers are also one of the most
widely used protecting groups for alcohols in organic
synthesis.1 There are numerous ways to incorporate ether
linkages into organic molecules. However, retrosynthetic
analyses of such molecules tend to focus on two consonant
disconnects employing either alkoxides or oxonium ions.
Alkoxides are capable of reacting with various electrophiles
to form C-O bonds (eq 1), while oxonium ions react with
might prove useful for the synthesis of protected aryl- and
heteroaryl alcohols in a single-step process, thereby avoiding
a multistep process consisting of carbonylation/carboxylation,
reduction, and protection (Scheme 1).
Scheme 1
soft nucleophiles to form C-C bonds (eq 2).
(1)
(2)
(3)
The preparation of numerous alkoxymethyl anions or their
equivalents has been reported,2 but the majority of these
synthons has found very little use in organic synthesis owing
to their limited substrate scope, tedious preparation, and low
functional group tolerance.
Relevant to the discussion herein, alkoxymethylstannanes
have been used as hydroxymethylating agents in palladium
catalyzed cross-coupling reactions, but to a limited extent
(eqs 4-6).3 One possible reason for the minimal use of these
A dissonant disconnect employing nucleophilic alkoxy-
methylating agents would provide a nontraditional approach
to the construction of the alkoxymethyl linkage in straight-
chain ethers and heterocycles (eq 3). This strategic disconnect
(2) (a) Tamao, K.; Ishida, N.; Ito, Y.; Kumada, M. Org. Synth. 1990,
8, 315–320, and references cited therein. (b) Hutchinson, D. K.; Fuchs, P. L.
J. Am. Chem. Soc. 1987, 109, 4930–4939.
(1) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
Synthesis; John Wiley: New York, 1999.
10.1021/ol800532p CCC: $40.75
Published on Web 04/26/2008
2008 American Chemical Society

otherwise useful synthons is the inherent toxicity and
difficulty in purification that organostannanes are well-known
to possess.
bromomethyltrifluoroborate (1) with various alkoxides. To
access large quantities of the SN2 precursor 1 (Table 1), we
Table 1. Preparation of Potassium Alkoxymethyltrifluoroboratesa
(4)
(5)
(6)
The corresponding alkoxymethylboronate esters are known,4
but to the best of our knowledge, these have never been used
in cross-coupling reactions. Furthermore, the R-alkoxy substit-
uents are reported to sensitize the boronates to air oxidation,
thereby making them more difficult to handle.4
We envisioned that these limitations could be easily
avoided through the use of potassium organotrifluoroborates.
Organotrifluoroborates have several advantages over orga-
nostannanes: they are relatively nontoxic, air- and moisture-
stable crystalline solids, atom-economic, and easily prepared
by the addition of inexpensive KHF2 to various organoboron
intermediates.
In 2006, our group published the preparation of various
potassium organotrifluoroborates, including alkoxymeth-
yltrifluoroborates, via the direct nucleophilic substitution
of potassium halomethyltrifluoroborates.5 Soon after,
Tanaka et al. patented the preparation and cross-coupling
of alkoxymethyltrifluoroborates with various halides.6
These organotrifluoroborates were prepared from the
corresponding alkoxymethylstannanes in a cumbersome
and atom-inefficient multistep process. Additionally, the
desired products were isolated in low to moderate yields
(eq 7). The cross-coupling reactions themselves were
substrate dependent and capricious, with the products
being obtained in highly variable yields (eq 8).
a Conditions: ROH (3 equiv), NaH (3 equiv), THF (0.2 M), 0 °C-rt.
b Commercially available alkoxide was used.
first optimized and scaled our previous conditions until we
could routinely produce 100 g batches of highly pure
compound.7 With 1 in hand, we optimized the SN2 reaction
and found that 3 equiv of the alkoxides was needed for an
efficient reaction. Because the alkoxymethyltrifluoroborates
had low solubility in organic solvents (e.g., acetone and
acetonitrile), separation from the inorganic byproducts was
difficult and the desired products were at first isolated in
low yields. This obstacle was circumvented through the use
of continuous Soxhlet extraction. Using this technique, the
desired alkoxymethyltrifluoroborates were obtained in excel-
lent yields (Table 1). Of special note: some of the alkoxides
employed may be viewed as hydroxyl protecting groups,
which are stable to the conditions of a Suzuki-Miyaura
cross-coupling but easily removed later in a synthetic se-
quence (Table 1, entries 1-5). It is also worth noting that
silanols, including TIPSOH and TESOH, were not good
nucleophiles for alkylation, presumably the direct result of
the inductively stabilized and thus less reactive oxyanion.
With the requisite alkoxymethyltrifluoroborates in hand,
we next examined the Suzuki-Miyaura cross-coupling of
these compounds. Toward this end, we chose 4-bromoben-
Herein, we report a more practical and convenient syn-
thesis of potassium alkoxymethyltrifluoroborates and the
Suzuki-Miyaura cross-coupling of these agents with various
aryl- and heteroaryl halides.
(7)
(8)
Potassium alkoxymethyltrifluoroborates can be routinely
and easily prepared via SN2 displacement of potassium
2136
Org. Lett., Vol. 10, No. 11, 2008

zonitrile and benzyloxymethyltrifluoroborate 2a as our model
electrophile and nucleophile, respectively. We screened a
wide variety of catalyst/ligandcombinations, solvents, bases,
and temperatures.8 Even though several ligands afforded
promising results (Table 2), RuPhos9proved to be the most
During the course of this investigation, our group dem-
onstrated that potassium N,N-dialkylaminomethyltrifluo-
roborates were effective cross-coupling partners with various
aryl- and heteroaryl chlorides.10 Encouraged by these results,
we sought to determine whether our optimized conditions
for the cross-coupling of alkoxymethyltrifluoroborates with
aryl bromides would also be applicable to aryl chlorides.
To our surprise, we obtained comparable or better results
with these electrophiles. Consequently, we utilized the more
stable and less expensive aryl chlorides as the coupling
partner throughout the remainder of the study.
Table 2. Cross-Coupling of 2a and 4-Bromobenzonitrile with
Diverse Ligandsa
Initially, we investigated the cross-coupling of potassium
benzyloxymethyltrifluoroborate (2a) with electron-rich, electron-
neutral, and electron-poor aryl chlorides (Table 3) using the
Table 3. Cross-Coupling of Potassium Benzyloxytrifluoroborate
(2a) with Various Aryl Chloridesa
a All reactions were carried out using 0.5 mmol of 4-bromobenzonitrile
and 0.55 mmol of 2a.
general ligand for the cross-coupling reactions (Table 2, entry
1). The best coupling conditions were determined to be 3
mol % of Pd(OAc)2, 6 mol % of RuPhos, and 10:1 dioxane/
H2O, using Cs2CO3 as the base.
a All reactions were carried out using 0.5 mmol of aryl chloride and
0.55 mmol of 2a.
(3) (a) Majeed, A. J.; Antonsen, O.; Benneche, T.; Undheim, K.
Tetrahedron 1989, 45, 993–1006. (b) Ferezou, J. P.; Julia, M.; Li, Y.; Liu,
L. W.; Pancrazi, A. Synlett 1991, 53–56. (c) Kosugi, M.; Sumiya, T.;
Ohhashi, K.; Sano, H.; Migita, T. Chem. Lett. 1985, 997–998. (d) Falck,
J. R.; Patel, P. K.; Bandyopadhyay, A. J. Am. Chem. Soc. 2007, 129, 790–
793.
optimized conditions. The desired alkoxymethylated products
were isolated in good yield in all cases studied. Additionally,
esters, pyrroles, and nitriles were tolerated. Even sterically
hindered electrophiles coupled in good yield (Table 3, entries
2, 3, and 6). Surprisingly, electron-rich products, 3b-e were
obtained in yields comparable to that of the electron-poor
product 3g (Table 3, entries 2-5 and 7).
(4) Matteson, D. S. Sci. Synth. 2004, 6, 607–622.
(5) Molander, G. A.; Ham, J. Org. Lett. 2006, 8, 2031–2034.
(6) Tanaka, K.; Inoue, S.; Ito, D.; Murai, N.; Kaburagi, Y.; Shirotori,
S.; Suzuki, S.; Ohashi, Y. Chem. Abstr. 2006, 145, 356920, JP304894,
September 21 2006.
(7) See Supporting Information for the improved procedure to synthesize
potassium bromomethyltrifluoroborate.
(8) Variables changed in coupling optimization included: catalyst/ligand
combinations [PdCl2/PPh3, Pd(TFA)2/PPh3, Pd(OAc)2/PPh3, Pd(OAc)2/XPhos,
Pd(OAc)2/DavePhos, Pd(OAc)2/(o-tolyl)3P, Pd(OAc)2/dppe, Pd(OAc)2/dppb,
PdCl2(dppf) and Peppsi]. Catalyst/ligand ratios: (2/4 mol % and 5/10 mol %);
solvents [THF, toluene, cyclopentyl methyl ether (CPME), and MeOH]; and
bases (Cs2CO3, K2CO3, CsOH, and NEt3).
(9) Milne, J. E.; Buchwald, S. L. J. Am. Chem. Soc. 2004, 126, 13028–
13032.
(10) Molander, G. A.; Gormisky, P. E.; Sandrock, D. L. J. Org. Chem.
2008, 73, 2052–2057.
Org. Lett., Vol. 10, No. 11, 2008
2137

To demonstrate the scope of this method further, we cross-
coupled various alkoxymethyltrifluoroborates with 4-chlo-
robenzonitrile (Table 4). Most alkoxymethyltrifluoroborates
5, entries 1 and 2). Nitrogen-containing heteroaryl chlorides
were especially difficult to cross-couple. However, when we
switched to bromide electrophiles, we were able to couple
3-bromopyridine (5c) and 3-bromopyrimidine (5d) in 70% and
51% yields, respectively (Table 5, entries 3 and 4).
Table 4. Cross-Coupling of Aryl Chlorides with Various
Potassium Alkoxymethyltrifluoroboratesa
Table 5. Cross-Coupling of 2d with Heteroaryl Halidesa
a All reactions were carried out using 0.5 mmol of heteroaryl halide
and 0.55 mmol of 2d.
In summary, we have prepared a variety of potassium
alkoxymethyltrifluoroborates via SN2 reactions from potas-
sium bromomethyltrifluoroborate with alkoxides. Under
optimized conditions, alkoxymethyltrifluoroborates were
successfully coupled with various aryl chlorides in good
yields. Unfortunately, these optimized conditions lacked
generality for the cross-coupling of heteroaryl halides, but
several heteroaryl chlorides and bromides coupled in moder-
ate to good yields. This method represents a fundamentally
unique dissonant disconnect that allows greater flexibility
than those protocols reported in previous synthetic ap-
proaches to aryl- and heteroaryl ethers.
a All reactions were carried out using 0.5mmol of aryl chloride and
0.55 mmol of alkoxymethyltrifluoroborate.
were found to couple effectively,11 providing the respective
products 4a-d,g in good yield (Table 4, entries 1-4 and
6). Unfortunately, phenoxymethyltrifluoroborate (2f) gave the
desired product in only moderate yield (Table 4, entry 5).
4-Chloroanisole was a more sensitive substrate as several
alkoxymethyltrifluoroborates (2c-d,f) did not couple ef-
fectively (Table 4, entries 3-5). However, we were able to
cross-couple 2a,b,g in good to moderate yields (Table 4,
entries 1, 2, and 6).
The scope of the cross-coupling was expanded to heteroaryl
chlorides. Although we screened numerous heteroaryl chlorides,
the couplings of these substrates proved to be a challenging
endeavor because either the products were obtained in low
yields or the starting material was recovered. General conditions
for the cross-coupling of heteroaryl chlorides were not found
in these preliminary screening efforts. However, we were
nonetheless able to couple several heteroaryl halides (Table 5)
using our previously optimized conditions. Heteroaryl chlorides
5a,b coupled and provided the products in moderate yield (Table
Acknowledgment. The authors thank NIH (R01 GM-
081376), Merck Research Laboratories, and Amgen for
their generous support of our program. Johnson Matthey
and Frontier Scientific are acknowledged for their donation
of palladium catalysts. Dr. Rakesh Kohli (University of
Pennsylvania) is acknowledged for obtaining HRMS data.
We thank Dr. Jungyeob Ham (Korea Institute of Science
and Technology) for his seminal contributions to this
project. We also thank Paul Gormisky (University of
Pennsylvania) for his help with the preparation of potas-
sium bromomethyltrifluoroborate.
Supporting Information Available: Experimental proce-
dures, compound characterization data, and NMR spectra for
all compounds prepared in this investigation. This material is
available free of charge via the Internet at http://pubs.acs.org.
(11) The cross-coupling of 2h with 4-chlorobenzonitrile and 4-chloro-
anisole gave the products in low yield (34% and 41%, respectively). The
cross-coupling of 2i with 4-chlorobenzonitrile gave the desired product along
with two alkene-isomerized products in 78% yield. Attempted intramolecular
cyclizations of 2j and 2k were unsuccessful.
OL800532P
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