stability of aryl triflates also sometimes causes crucial
problems during their chemical transformations.7 There-
fore, an alternative method for the generation of 1 under
mild conditions has been necessary for the further devel-
opment of the benzyne chemistry. In this communication,
we describe a novel preparation of benzynes 1 from
o-(trimethylsilyl)phenols 3 by the domino process using
nonafluorobutanesulfonyl fluoride (NfF) (Scheme 2).
Table 1. Optimization of Reaction Conditions of Domino
Nonaflation, Benzyne Generation, and Diels-Alder Reactiona
entry
base
NaH
(equiv)
additive
(equiv)
4a:6ab
Scheme 2. o-(Trimethylsilyl)phenols 3 As New, Easy-to-Handle
Benzyne Precursors
1
2
3
4
(3.0)
(3.0)
(3.0)
(1.5)c
-
-
100:0
70:30
30:70
0:100d
K2CO3
Cs2CO3
Cs2CO3
-
-
-
-
18-c-6
(0.6)
a Conditions: With 1.0 equiv of 3a, 4.0 equiv of NfF, and 10 equiv of
5a in MeCN (0.10 M). 3a was completely consumed in every case.
b Determined by 1H NMR. c With 1.5 equiv of NfF and 3.0 equiv of 5a.
d 86% isolated.
We anticipated that the use of perfluoroalkanesulfonyl
fluorides, instead of the above-mentioned triflating re-
agents, would be more beneficial because they could
directly generate the benzynes from more primitive and
easy-to-handle o-(trimethylsilyl)phenols 3 via the nonafla-
tion of the hydroxyl group of 3 followed by the immediate
desilylation by the produced fluoride ion. This method
does not need the isolation of the unstable intermediates,
the o-(trimethylsilyl)aryl perfluoroalkanesulfonates, and is
therefore much more convenient and useful compared to
the known method shown in Scheme 1. It is also attractive
from the viewpoint of atom economy because both com-
ponents, the perfluoroalkanesulfonyl and fluoride moi-
eties, are effectively utilizable. Among a variety of the
perfluoroalkanesulfonyl fluorides, we chose NfF,8,9 which
is anair stable and lessexpensivereagent and has been used
for the synthesis of the C4 homologues of the triflates.10
First, we examined the feasibility of this domino process
using o-(trimethylsilyl)phenol 3a as a test substrate. Thus,
3a was reacted withNfF (4.0 equiv) at 60 °C in the presence
of a base and 2-butylfuran 5a (10 equiv) to trap the
generated benzyne 1a as the Diels-Alder adduct 6a
(Table 1). The use of NaH as a base for 4.5 h only gave
the nonaflate 4a (entry 1), which showed that the in situ
benzyne generation was not easy.11 On the other hand, the
use of K2CO3 produced a small amount of the desired 6a
(entry 2, 4a:6a = 70:30). After extensive optimization of
the reaction conditions, Cs2CO3 was found to enhance the
desilylation to give a better ratio of 6a to 4a (entry 3).
Finally, we were delighted to find that the reaction of 3a
with NfF (1.5 equiv), Cs2CO3 (1.5 equiv), and 18-crown-6
(18-c-6) (0.6 equiv) in MeCN12 achieved the complete
conversion of 4a into 6a (86% isolated yield) (entry 4).
As a control experiment, the isolated 4a was treated with
CsHCO3 (1.0 equiv), Cs2CO3 (0.5 equiv), and 18-c-6 (0.6
equiv) in MeCN at 60 °C for 7.5 h to provide 6a in 45%
yield. These reaction conditions corresponded to those
afterthenonaflation, except forthe presenceofthe fluoride
ion. This result suggests that the combination of Cs2CO3
and 18-c-6 may have played a role in the generation of 1a
from 3a. More importantly, this result also reveals that the
fluoride ion liberated from NfF plays a crucial role in the
prompt and complete generation of the benzyne (for de-
tails, see Supporting Information).
We then applied our optimized conditions in Table 1 to
the reactions of the precursors 3b-g (Table 2). Our
experience and literature search13 have shown that the
triflation of electron-rich substrates causes some problems.
For instance, the triflation of 3b with Tf2O and Cs2CO3
mainly resulted in the formation of the desilylated product,
3,4-dimethoxyphenol (61%),14 while the reaction of 3b
with NfF, Cs2CO3, 18-c-6, and 5a gave the Diels-Alder
product 6b in 86% isolated yield (entry 1). A similar
product 6c was also obtained from 3c (entry 2). Our
method was similarly applicable to other precursors (3d
and 3e) possessing electron-withdrawing group(s) and
provided adducts (6d and 6e) in good yields (entries 3 and
4). It is worth noting that the TBDMS group of
(7) Choy, P. Y.; Chow, W. K.; So, C. M.; Lau, C. P.; Kwong, F. Y.
Chem.;Eur. J. 2010, 16, 9982–9985.
(12) For an example of the activation of CsF with 18-c-6 and
MeCN, see: Nishikawa, T.; Shibuya, S.; Isobe, M. Synlett 1994,
482–484. For the complexation of CsF with 18-c-6, see: Takeda, Y.;
Kawarabayashi, A.; Endo, K.; Yahata, T.; Kudo, Y.; Katsuta, S.
Anal. Sci. 1998, 14, 215–223.
(13) Tadross, P. M.; Gilmore, C. D.; Bugga, P.; Virgil, S. C.; Stoltz,
B. M. Org. Lett. 2010, 12, 1224–1227.
(14) The use of nBuLi as a base would be a solution; however, careful
control of the reaction temperature at -100 °C was essential, and such
harsh reaction conditions hamper their application to functionalized
(8) NfF is less expensive than any of the common triflating reagents
because it can be easily generated. For the synthesis of NfF, see: Zimmer, R.;
Webel, M.; Reissig, H.-U. J. Prakt. Chem. 1998, 340, 274–277.
(9) Trifluoromethanesulfonyl fluoride (TfF) is another candidate of
the dual activation reagent; however, it requires special care due to its
low boiling point (-22 °C).
€
(10) For a recent review, see: Hogermeier, J.; Reissig, H.-U. Adv.
Synth. Catal. 2009, 351, 2747–2763.
(11) The use of nonaflates 4 as benzyne precursors has never been
reported.
~
ꢀ
ꢀ
compounds; see: Pena, D.; Cobas, A.; Perez, D.; Guitian, E. Synthesis
2002, 1454–1458.
Org. Lett., Vol. 13, No. 7, 2011
1731
Ikawa, Takashi
