communication, we report a unique “tricomponent” cat-
alytic system for R,R-difluorination that involves a main
group Lewis acid (Sn(OTf)2), a catalytic nucleophile
that also serves as a reagent (pyridine), and an anionic
phase transfer catalyst (KBARF)10 (potassium tetrakis-
(pentafluorophenyl)borate).
Unfortunately, these attempts resulted in unsatisfactory
yields of difluorinated product. At this point, we sought a
means to increase Selectfluor solubility À namely, we
imagined that the addition of an anionic phase transfer
catalyst (anionic-PTC) could act to bring Selectfluor into
solution more effectively.
Table 1. Screening of Lewis Acid Catalysts
Figure 1. Reaction conditions for selective R,R-difluorination.
entry
Lewis acid
2a:3a
yield %
1a
2a
3a
4a
5a
6a
7a
8a
9a
10b
BF3-Et20
Sc(0Tf)3
ln(OTf)3
À
0
These three catalysts work synergistically to effect
the efficient R,R-difluorination of a variety of acid chlor-
ides employing Selectfluor (1-chloromethyl-4-fluoro-1,4-
diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)11 as a
fluorinating agent and MeCN as solvent (Figure 1). This
new method illustrates the power of catalysts acting co-
operatively to produce a positive outcome; in this case, the
combination of three catalysts is especially notable.
Our screening began by the treatment of phenylace-
tylchloride (PAC) 1a with Selectfluor in MeCN. Not
surprisingly, no reaction occurred. When several equiva-
lents of pyridine were added as a nucleophilic catalyst and
dehydrohalogenating agent (followed by a quench with
H2NPh) only a trace amount of the desired difluorinated
amide was present. Unfortunately, raising the temperature
of the reaction produced a complex mixture of undesired
byproducts. At this point, we decided to introduce a
second catalyst in order to enhance the yield of difluori-
nated product. A number of metal salts were screened for
this purpose, although the large majority proved ineffec-
tive; Table 1 illustrates the futility of these early attempts.
Fortunately, Zn(OTf)2 and Sn(OTf)2 produced a signifi-
cant increase in both yield and selectivity; Sn(OTf)2 proved
to be especially efficacious, and further screening centered
on its use.
À
0
À
0
(PPh3)2PdCI2
(dppp)NiCI2
LiCIO4
À
trace
trace
trace
12%
23%
57%
82%
À
À
TiCI4
1:1
2:1
11:1
50:1
Zn(OTf)2
Sn(OTf)2
Sn(OTf)2
a Reactions perfomed with 20 mol % catalyst loading; product ratios
and yields determined after 3 h. b Run with 10 mol % KBARF as
cocatalyst.
Consequently, we screened KBARF8 as a third catalyst
and found a notable increase in reaction rate, cleanliness,
and yield; the role of the KBARF cocatalyst is therefore
suggestive of a solubilizing agent for Selectfluor. Such
tricomponent catalytic systems are fairly rare in synthetic
chemistry,13 a fact stemming from their inherent complex-
ity, difficulty of study, and potential for deleterious inter-
catalyst interactions.14 In the present method, it is ap-
parent that the anionic-PTC is unlikely to engage detri-
mentally with the Lewis acid Sn(OTf)2 and pyridine
and, thus, makes an ideal complement to a polycatalytic
system.
Early on, it was found that shorter reaction times
resulted in increased difluorination; in general, reaction
times of 1 to 3 h were found to be optimal for most sub-
strates. The necessity for brief reaction times may be
attributed to putative degradation of the highly reactive
acylpyridinium salt following initial difluorination. A
representative comparison of reaction time to yield of
difluorinated product is illustrated for PAC following a
quench with aniline (Table 2). We also sought to assess the
One of the most notable limitations on the use of
Selectfluor is its relative insolubility in commonly used
organic solvents. Even in MeCN, the solvent of choice for
many reactions with Selectfluor, its solubility is undesir-
ably low and presents a limitation in its overall use as a
fluorinating agent.12 In our reaction, increased ratios of
difluorinated product were achieved utilizing a minimal
amount of solvent; however, substantial quantities of
ketene dimer were likewise prevalent. In an effort to
minimize dimer formation, lower reaction temperatures
and slower addition times of acid chloride were examined.
(13) (a) Erb, J.; Paull, D. H.; Dudding, T.; Belding, L.; Lectka, T. J.
Am. Chem. Soc. 2011, 133, 7536–7546. (b) Paull, D. H.; Scerba, M. T.;
Alden-Danforth, E.; Widger, L. R.; Lectka, T. J. Am. Chem. Soc. 2008,
130, 17260–17261. (c) Erb, J.; Alden-Danforth, E.; Kopf, N.; Scerba,
M. T.; Lectka, T. J. Org. Chem. 2010, 75, 969–971. (d) Abraham, C. J.;
Paull, D. H.; Bekele, T.; Scerba, M. T.; Dudding, T.; Lectka, T. J. Am.
Chem. Soc. 2008, 130, 17085–17094. (e) Paull, D. H.; Abraham, C. J.;
Scerba, M. T.; Alden-Danforth, E.; Lectka, T. Acc. Chem. Res. 2008, 41,
655–663.
(10) For a review of fluorinated tetraarylborates as anionic phase-
transfer catalysts, see: Ichikawa, J.; Kobayashi, H.; Sonada, T. Rep. Inst.
Adv. Mater. Study 1988, 2, 189–207.
ꢀ
(11) For a review of Selectfluor, see: Nyffeler, P. T.; Duron, S. G.;
Burkart, M. D.; Vincent, S. P.; Wong, C.-H. Angew. Chem., Int. Ed.
2005, 44, 192–212.
(12) Wong, C.-H.; et al. Angew. Chem., Int. Ed. 2005, 44, 192–212.
(14) Garnier, J. M.; Liu, F. Org. Biomol. Chem. 2009, 7, 1272–1275.
Org. Lett., Vol. 13, No. 19, 2011
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