Pd-catalyzed acetoxylation reaction. Also, we provide evi-
dence that the acetoxylation of electron-rich heterocycles
such as pyrroles and indoles under Crabtree conditions
most likely occurs via the initial formation of heteroarylio-
donium acetates (eq 1).11 The latter are transformed into an
acetoxylated product in the presence of a Pd catalyst.
Initially, Crabtree acetoxylation conditions were exam-
ined for synthesis of acetoxypyrroles and the progress of
thereaction was followed byNMR methods. Thus, stirring
the pyrrole 1a with Pd(OAc)2 (5 mol %) and PhI(OAc)2
(2 equiv) in AcOH-d4 showed complete conversion within
2 h at ambient temperature.12 Two sets of signals in a 3.5:1
Table 1. Reactivity of Arylpyrrolyliodonium Acetate 2a
catalyst
(mol %)
t
time
products
(yield, %)
entry
solvent (°C) (h)
1
2
3
4
ꢀ
AcOH rt
AcOH rt
18
18
2a
1
ratio were observed in the H NMR spectrum of the
Pd(OAc)2 (5)
Pd(OAc)2 (5)
ꢀ
3a (90%)
reaction mixture. The minor set of signals corresponded
to acetoxypyrrole 3a, whereas the major set of signals was
assigned to a structure of pyrrolyliodonium acetate 2a
based on 1H NMR, 13C NMR, MS data and X-ray
crystallographic analysis of purified 2a.
MeCN 60 18
AcOH 100 24
3a (91%)
3a (45%) þ 4 (20%) þ
1a(27%)
5
ꢀ
HFIP
100 18
2a
6
PtCl2 (5)
PtCl4 (5)
AcOH 80 48
AcOH 80 48
3a:1a = 3:2
7
2a
The iodonium acetate 2awas stable in AcOH-d4 solution
atrt(entry 1, Table1). However, inthe presenceof 5mol %
Pd(OAc)2 in AcOH-d4, 2a was converted into the target
acetoxypyrrole 3a (90% yield) within 18 h (entry 2).
Acetonitrile was equally efficient to AcOH, affording 3a
8
BF3•OEt2 (400) CH2Cl2 rt
Cu(OTf)2 (10) CH2Cl2 35 24
TMS-OTf (200) HFIP rt
3
2a
9
2a
10
2
products mixture
in 91% yield (entry 3). Additional experiments were
performed to investigate the reactivity of iodonium salt
2a. Heating of 2a without the Pd catalyst yielded a mixture
of products 3a, 4, and the starting 1a (entry 4). Interest-
ingly, only unreacted 2a was observed after prolonged
heating in (CF3)2CHOH, a solvent of choice for oxida-
tive nucleophilic acetoxylation of alkylphenyl ethers
(entry 5).13 PtCl2 was inferior to Pd(OAc)2 as a cata-
lyst5e (entry 6), whereas PtCl4 did not catalyze the
(8) It has been shown that cyclopalladation is the rate-limiting step of
the acetoxylation reaction: Stowers, K. J.; Sanford, M. S. Org. Lett.
2009, 11, 4584.
(9) (a) Powers, D.; Ritter, T. Top. Organomet. Chem. 2011, 35, 129.
(b) Powers, D. C.; Ritter, T. Nat. Chem. 2009, 1, 302.
(10) (a) The 3-hydroxypyrrole subunit is incorporated into Obatoclax,
an experimental drug candidate for the treatment of various types of
cancer: Drugs Future, 2007, 32, 228. Substituted 3-hydroxypyrroles have
also been employed: (b) as anti-tumor agents: Cholody, W. M.; Petukhova,
V.; O’Brien, S.; Ohler, N.; Pikul, S. WO 011675 A1, 2005; Chem. Abstr.
2005, 142, 197868. (c) in the design of DNA-binding ligands: Wellenzohn,
B.; Loferer, M. J.; Trieb, M.; Rauch, C.; Winger, R. H.; Mayer, E.; Liedl,
K. R. J. Am. Chem. Soc. 2003, 125, 1088.
(11) Consequently, the acetoxylation with PhI(OAc)2 does not in-
volve a CꢀH activation step by a Pd catalyst. The role of transitionmetal
catalysts has recently been reinvestigated also in other PhI(OAc)2
mediated reactions; see: (a) Kang, Y.-B.; Gade, L. H. J. Am. Chem.
Soc. 2011, 133, 3658. (b) Cho, S. H.; Yoon, J.; Chang, S. J. Am. Chem.
Soc. 2011, 133, 5996.
(12) The use of Pd(OAc)2 together with other oxidants such as
PhCO3tBu (2 equiv, 65 °C, Ac2O, 21 h), m-CPBA (2 equiv, 100 °C,
AcOH, 2 h), K2S2O8 (2 equiv, 100 °C, AcOH, 2 h), and Oxone (2 equiv,
100 °C, AcOH, 2 h) did not afford the acetoxylated pyrrole 3a.
(13) Kita, Y.; Tohma, H.; Hatanaka, K.; Takada, T.; Fujita, S.;
Mitoh, S.; Sakurai, H.; Oka, S. J. Am. Chem. Soc. 1994, 116, 3684.
(14) Dohi, T.; Morimoto, K.; Takenaga, N.; Goto, A.; Maruyama,
A.; Kiyono, Y.; Tohma, H.; Kita, Y. J. Org. Chem. 2007, 72, 109.
(15) Phipps, R. J.; Grimster, N. P.; Gaunt, M. J. J. Am. Chem. Soc.
2008, 130, 8172.
14
conversion of 2a (entry 7). Likewise, BF3•OEt2 in
DCM (entry 8) and Cu(OTf)2 in DCM15 were not
efficient as catalysts (entries 8, 9), whereas addition of
TMS-OTf16 resulted in the formation of an inseparable
mixture of products (entry 10).
A series of pyrrolyliodonium acetates 2bꢀk was subse-
quently prepared in the reaction of pyrroles 1bꢀk with
1.2 equiv of PhI(OAc)2 in AcOH at ambient temperature
(63ꢀ79% yields; see Table 2). The iodonium acetates2bꢀk
were sufficiently stable to be isolated and characterized,17
and they can be stored in the freezer for several months. To
the best of our knowledge, pyrrolyl-3-iodonium acetates
have not been previously prepared in a direct electrophilic
substitution of pyrrole.18
(16) Dohi, T.; Ito, M.; Yamaoka, N.; Morimoto., K.; Fujioka, H.;
Kita, Y. Angew. Chem., Int. Ed. 2010, 49, 3334.
The yields of iodonium salts 2aꢀk were found to be
sensitive to the electronic properties of substituents on
the pyrrole ring.19 Iodonium acetates were formed from
N-unsubstituted pyrroles 2h,k (entries 8,11, Table 2). The
regioselectivity of pyrrolyliodonium salt formation appar-
ently is a result of the combined directing effects of pyrrole
substituents.20 Nevertheless, there is a strong preference
for the formation of iodonium salts at the R-position
(entries 2, 3, 9, 10),21 and β-pyrrolyliodonium salts could
be obtained only for 2,5-disubstuted heterocycles 1a,eꢀh,k
(entries 1, 5ꢀ8, 11, Table 2).
(17) The majority of solid aryliodonium acetates 2bꢀk are hygro-
scopic and decompose at temperatures above 25 °C. However, they are
stable in acetic acid solutions.
(18) Single report on preparation of pyrrolyl-3-iodonium triflates
from 3-trimethylsilylpyrrole: Liu, J.-H.; Chan, H.-W.; Xue, F.; Wang,
Q.-G.; Mak, T. C. W.; Wong, H. N. C. J. Org. Chem. 1999, 64, 1630.
(19) Correlation between yields of phenyliodonium salts and
Hammett σ constants of substituents has been reported: Dohi, T.;
Yamaoka, N.; Kita, Y. Tetrahedron 2010, 66, 5775. See also the Sup-
porting Information, p S26.
(20) For substituent effect on regioselectivity of SEAr reactions of
pyrroles, see: Joule, J. A.; Mills, K. Heterocyclic Chemistry, 5th ed.; John
Wiley & Sons: Chichester, 2010; pp 289ꢀ323.
(21) For other examples, see: (a) Dohi, T.; Yamaoka, N.; Kita, Y.
Tetrahedron 2010, 66, 5775. (b) Reference 16. (c) Martin-Santamaria, S.;
Carroll, M. A.; Carroll, C. M.; Carter, C. D.; Pike, V. W.; Rzepa, H. S.;
Widdowson, D. A. Chem. Commun. 2000, 649.
In the presence of 5 mol % Pd(OAc)2 in AcOH
solution at ambient temperature iodonium salts 2aꢀk
4325
Org. Lett., Vol. 13, No. 16, 2011