reaction conditions are mild, the hydroxymethyl group is
introduced directly, no CO gas is required, and aryl
bromides are inexpensive and readily available. The meth-
od was recently used in the total syntheses of various
natural products.6 However, the method has the following
disadvantages: (i) it is shown that the reaction cannot be
applied to aryl bromides bearing electron-withdrawing
substituents, (ii) only a few examples have been reported
for aryl and heteroaryl chlorides,7 and (iii) organostannic
reagents are toxic.
Scheme 1. Preparation of Potassium Acetoxymethyltrifluoro-
borate 1
Therefore, we have been working on the development of
a novel method for direct hydroxymethylation of aryl
halides that addresses the issues of reaction generality,
functional group compatibility, and safety.
With 1 in hand, we optimized the conditions for the
coupling reaction with 2-chloronaphthalene as a model
substrate. For the initial reactions, we selected Pd(OAc)2/
S-phos14 as the catalyst, Cs2CO3 as the base, and dioxane/
H2O as the solvent. Because we obtained comparable
results with conventional heating (45% yield, reflux, 12 h)
and microwave heating (41% yield, 120 °C, 35 min)
in preliminary studies, we used microwave heating for
the initial studies. A higher-than-usual S-phos/Pd ratio
(2.2À3.0/1.0 compared to 2.0/1.0) was required for high
reproducibility with commercially available solvents that
had not been distilled prior to the reaction. Under these
initial reaction conditions, we investigated various ligands,
palladium sources, and bases (Table 1 and Figure 1).
The Ru-phos15 ligand afforded the best yield from
the coupling reaction (Table 1, entry 3). Reactions with
bidentate ligands such as (S)-BINAP and DPE-phos
afforded only trace amounts of the desired product
(Table 1, entries 7 and 8). The newly reported BI-DIME16
and Cy-vBRIDP17 ligandswere notaseffective asRu-phos
(Table 1, entries 9 and 10). Next, we examined various
palladium sources (Table 1, entries 11À17). When we used
Pd2(dba)3•CHCl3, Pd2(dba)3, or Pd(dba)2, the desired
alcohol was obtained in yields ranging from 65% to 68%
(Table 1, entries 15À17). The cross-coupling reaction did
not proceed in the presence of Pd2(dba)3•CHCl3 without
the phosphine ligand (Table 1, entry 18).
A number of SuzukiÀMiyaura cross-coupling reac-
tions8 of aryl halides with trifluoroborates have been
reported over the past decade.9 Among them, reactions
for the introduction of a one-carbon unit into aryl halides
were developed by Molander et al.10 and our group.11
In 2005, we succeeded in the direct hydroxymethylation
of aryl halides using acyloxymethyltrifluoroborates.11a
However, the chemical yield of the direct hydroxymethyla-
tion was low in some cases; for example, chloropyridine
was converted to hydroxymethylpyridine in only 14%
yield. Therefore, a more effective direct hydroxymethyla-
tion method that would enable us to obtain a variety of
products in higher yields was still lacking.
Herein, we describe a versatile method for direct hydro-
xymethylation of various aryl and heteroaryl halides with
potassium acetoxymethyltrifluoroborate 1.
Potassium acetoxymethyltrifluoroborate 1 was pre-
pared from pinacol in two steps without the need for
column chromatography (Scheme 1). 2-(Bromomethyl)-
4,4,5,5,-tetramethyl-1,3,2-dioxaborolane was prepared in
72% yield from pinacol via a one-pot distillation process
based on a literature procedure.12 Subsequent reaction
with potassium acetate and potassium hydrogen fluoride
smoothly provided 1 (81% yield), which showed satisfac-
tory stability to air and moisture.13
We found that Na2CO3 was the optimal base, affording
the desired alcohol in 80% yield (Table 1, entry 19). The
catalyst loading could be reduced to 5 mol % of Pd(dba)2
and 12 mol % of Ru-phos (Table 1, entries 20 and 21).
Moreover, the amounts of 1 and sodium carbonate could
be reduced to 1.5 equiv (Table 1, entry 20). Using conven-
tional heating (reflux, 24 h) instead of microwave heating
(120 °C, 35 min), we obtained the desired alcohol in 85%
yield (Table 1, entry 21).
(7) Richard, P. V. PCT Int. Mar. WO 2006031852 A1, 2006.
(8) For reviews, see: (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95,
2457. (b) Kotha, S.; Lahiri, K.; Dhurke, K. Tetrahedron 2002, 58, 9633.
(9) For reviews, see: (a) Molander, G. A.; Canturk, B. Angew. Chem.,
Int. Ed. 2009, 48, 9240. (b) Darses, S.; Genet, J.-P. Chem. Rev. 2008, 108,
288. (c) Stefani, H. A.; Cella, R.; Vieira, A. S. Tetrahedron 2007, 63, 3623.
(d) Molander, G. A.; Ellis, N. Acc. Chem. Res. 2007, 40, 275.
(10) (a) Molander, G. A.; Beaumard, F. Org. Lett. 2011, 13, 3948. (b)
Molander, G. A.; Shin, I. Org. Lett. 2011, 13, 3956. (c) Raushel, J.;
Sandrock, D. L.; Josyula, K. V.; Pakyz, D.; Molander, G. A. J. Org.
Chem. 2011, 76, 2762. (d) Molander, G. A.; Colombel, V.; Braz, V. A.
Org. Lett. 2011, 13, 1852. (e) Molander, G. A.; Flury-Bregeot, N.;
Hiebel, M.-A. Org. Lett. 2011, 13, 1694. (f) Molander, G. A.; Beaumard,
F. Org. Lett. 2011, 13, 1242. (g) Molander, G. A.; Hiebel, M.-A. Org.
Lett. 2010, 12, 4876. (h) Molander, G. A.; Canturk, B. Org. Lett. 2008,
10, 2135.
Next, we applied the optimized reaction condi-
tions to various aryl halides and triflates (Table 2).
(14) Barder, T. E.; Buchwald, S. L. Org. Lett. 2004, 6, 2649.
(15) Milne, J. E.; Buchwald, S. L. J. Am. Chem. Soc. 2004, 126, 13028.
(16) Tang, W.; Capacci, A. G.; Wei, X.; Li, W.; White, A.; Patel,
N. D.; Savoie, J.; Gao, J. J.; Rodriguez, S.; Qu, B.; Haddad, N.; Lu,
B. Z.; Krishnamurthy, D.; Yee, N. K.; Senanayake, C. H. Angew. Chem.,
Int. Ed. 2010, 49, 5879.
(11) (a) Tanaka, K.; Inoue, S.; Ito, D.; Murai, N.; Kaburagi, Y.;
Shirotori, S.; Suzuki, S.; Ohashi, Y. WO2006098270, priority applica-
tion Oct. 2005 and Mar. 2005. (b) Tanaka, K. WO2008007670, priority
application Jul. 2006. (c) Tanaka, K.; Murai, N.; Shirotori, S.; Nagao, S.;
Watanabe, Y. WO2008032702, priority application Sep. 2006.
(12) Michnick, T. J.; Matteson, D. S. Synlett 1991, 631.
(13) The NMR spectrum of 1 showed no change after the compound
was stored in a vial at room temperature for more than a year (data
not shown).
(17) (a) Suzuki, K.; Fontaine, A.; Hori, Y.; Kobayashi, T. Synlett
2007, 20, 3206. (b) Suzuki, K.; Hori, Y.; Nishikawa, T.; Kobayashi, T.
Adv. Synth. Catal. 2007, 349, 2089.
Org. Lett., Vol. 14, No. 5, 2012
1279