regioselectively. Similarly to the 3-methoxy aryne (2),
4-methoxy aryne 7 also reacts in a regioselective manner at
C(1),5 although more modestly than aryne 2 (Scheme 2).
On the basis of these data, we chose to examine two silyl
aryl triflates (8 and 9) bearing alkoxy groups at both C(3)
and C(5), in which it is possible for the two alkoxy
substitutents to favor opposing sites of nucleophilic attack
upon the aryne triple bond (12 and 13). Investigation of the
reactivity of precursors 8 and 9 would establish whether the
influence exerted by the C(3) substituent can override that
of the C(5) alkoxy group. Two additional silyl aryl triflates
(10 and 11) we have targeted feature methoxy groups at C(3)
and C(4) of the arynes (14 and 15), offering the potential
for enhanced selectivity due to cooperative electronic
polarization of the triple bond. Furthermore, precursors 10
and 11 incorporate additional substitution at C(5); to the best
of our knowledge, arynes 14 and 15 are the first examples
of trisubstituted arynes derived from silyl aryl triflate
precursors.6
As a demonstration of the advantages of this strategy, we
report the synthesis and regioselective reactions of four novel
silyl aryl triflates (8-11) and the application of one of these
precursors to the synthesis of a simple hydroxynaphtho-
quinone natural product. In fact, these particular aromatic
substitution motifs (e.g., 12-15) were targeted for their
prevalence in classes of natural products that possess both
diverse structures and significant biological activity (17-19).
Scheme 2. Targeted Polyalkoxy Arynes
Figure 1. Natural products containing highly oxygenated arenes.
The first aryne precursor we targeted was a protected
resorcinylic silyl aryl triflate (8) (Scheme 3). Preparation of
dimethoxy silyl aryl triflate 8 began with bromination of
commercially available 3,5-dimethoxyphenol (20) at low
temperature to form bromophenol 21. This compound was
then converted to the silyl aryl triflate (8) by a known one-
pot procedure involving silylation of the phenol, lithium-
halogen exchange, silyl group migration, and triflation.8
Scheme 3. Preparation of Silyl Aryl Triflate 8
On the basis of the observation that aryne adducts derived
from the 3-methoxy silyl aryl triflate (1) have been employed
in the context of total synthesis (Figure 1, 16),7 we believe
that these more highly substituted nonsymmetrical precursors
(8-11) will provide valuable entry points into more complex
natural products (e.g., 17-19) if they too react in a
regioselective manner. In general, the use of aryne-based
methods enables the convergent construction of functional-
ized arenes, thereby circumventing the difficulties associated
with traditional late-stage elaboration of embedded aromatic
rings.
Although dimethoxy silyl aryl triflate 8 contains function-
ality present in several natural products, removal of the
methyl groups would be required to access a large number
these targets.9 To avoid the potentially harsh Lewis acidic
conditions commonly used to cleave the methyl groups (e.g.,
BCl3),10 we designed a dibenzyl variant of precursor 8
(Scheme 4). Beginning with phloroglucinol (22), a sequence
including monosilylation, dibenzylation, and desilylation
generated phenol 23, which was subsequently brominated
(5) For examples of regioselective reactions of aryne 7, see: (a) Yoshida,
H.; Morishita, T.; Ohshita, J. Org. Lett. 2008, 10, 3845–3847. (b) Ni, C.;
Zhang, L.; Hu, J. J. Org. Chem. 2008, 73, 5699–5713. (c) Liu, Z.; Larock,
R. C. J. Am. Chem. Soc. 2005, 127, 13112–13113.
(6) Trisubstituted arynes derived from precursors other than silyl aryl
triflates are known.
(8) Pen˜a, D.; Cobas, A.; Pe´rez, D.; Guitia´n, E. Synthesis 2002, 1454–
1458.
(7) Allan, K. M.; Stoltz, B. M. J. Am. Chem. Soc. 2008, 130, 17270–
17271.
(9) Macrolide Antibiotics: Chemistry, Biology, and Practice, 2nd ed.;
Omura, S., Ed.; Academic Press: San Diego, CA, 2002.
Org. Lett., Vol. 12, No. 6, 2010
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Tadross, Pamela M.
