We have developed a divergent route to ortho-substituted
benzophenones based on cationic arene iron complexes, and
in this Letter we describe its application to the synthesis of
nucleophiles under similarly mild conditions should allow
this synthetic approach to accommodate significant diversity.
After hydrolysis of the methyl and aryl esters with lithium
hydroxide in a mixture of water and methanol, the xanthone
complex 9 was obtained through an intramolecular Friedel-
Crafts reaction in concentrated methanesulfonic acid at room
temperature. The use of methanesulfonic acid for this
8
balanol appendage 3.
The known η -o-chlorotoluene-η -cyclopentadienyliron
6
5
9
hexafluorophosphate (4) was oxidized, using aqueous potas-
10
sium permanganate, to the benzoic acid complex 5, which
could be converted into the methyl ester 6, in high overall
1
3
transformation turned out to be superior to our previously
1
1
8
yield, via reflux in thionyl chloride followed by reaction
with excess methanol (Scheme 1).
described method utilizing hot polyphosphoric acid, due to
the easier handling of the former reagent, a simpler workup
procedure, fewer degradation products, and a significantly
higher yield. Noteworthy is the excellent regioselectivity for
9
over 10 (30:1 according to NMR) (Scheme 2).
Scheme 1a
6
5
Treatment of η -xanthone-η -cyclopentadienyl iron hexa-
8
14
fluorophosphate with oxygen, nitrogen, or stabilized
1
4b
carbon nucleophiles has been shown to result in neutral
pentahapto oxo-, imino-, or methylenecyclohexadienyl com-
plexes (tautomeric to the corresponding zwitterionic com-
pounds), from the regioselective ring opening at the iron-
bearing arene. The latter are easily transformed into the
corresponding cationic complexes by protonation or alkyl-
ation. Importantly, in the present context, this key ring-
opening reaction provides an opportunity to gain access to
benzophenones carrying different heteroatom substituents in
the 2- and 2′-positions. Our initial experiments on carrying
out the transformation from 9 to 12 (Scheme 3) involved
a
(
a) (i) KMnO
4 4 2 6
, MgSO , H O, reflux; (ii) HPF (60% in water),
8
3%; (b) SOCl
2
, reflux; (c) MeOH, rt, 91% for two steps.
Treatment of 6 with the phenol 712 and potassium
carbonate in dimethylformamide at room temperature smoothly
and regioselectively produced the diaryl ether 8 (Scheme 2).
Scheme 2a
Scheme 3a
a
4 2 2
(a) KOH, MeI, DMSO, rt, 59%; (b) n-Bu NCN, DDQ, CH Cl ,
rt, 72%.
a
(a) K
2 3 2
CO , DMF, rt, 79%; (b) LiOH, MeOH/H O, rt, 95%; (c)
3
MeSO H (concentrated), rt, 72%.
the isolation, in quantitative yield, of the neutral oxocyclo-
hexadienyl complex 11, a task accomplished by treating 9
with sodium hydroxide in a mixture of water and methanol.
However, a wide range of methods investigated for exhaus-
tive alkylation of 11 resulted in either incomplete reaction
Since the methyl o-chlorobenzoate complex 6 is highly
activated toward nucleophilic aromatic substitution of chlo-
ride, the introduction of a wide range of suitable substituted
(
5) (a) Nicolaou, K. C.; Koide, K.; Bunnage, M. E. Chem. Eur. J. 1995,
1
, 454. (b) Lai, Y.-S.; Mendoza, J. S.; Jagdmann, G. E., Jr.; Menaldino, D.
(10) Oleinik, I. I.; Litvak, V. V.; Shteingarts, V. D. Metalloorg. Khim.
1991, 4, 626 (Organomet. Chem. USSR. 1991, 4, 307).
(11) All yields refer to material purified by chromatography and/or
recrystallization.
S.; Biggers, C. K.; Heerding, J. M.; Wilson, J. W.; Hall, S. E.; Jiang, J. B.;
Janzen, W. P.; Ballas, L. M. J. Med. Chem. 1997, 40, 226 and references
therein.
(
6) Heerding, J. M.; Lampe, J. W.; Darges, J. W.; Stamper, M. L. Bioorg.
Med. Chem. Lett. 1995, 5, 1839.
7) Koide, K.; Bunnage, M. E.; Paloma, L. G.; Kanter, J. R.; Taylor, S.
S.; Brunton, L. L.; Nicolaou, K. C. Chem. Biol. 1995, 2, 601.
(12) All new compounds were characterized by NMR, IR, and HRMS
spectroscopy.
(13) Premasagar, V.; Palaniswamy, V. A.; Eisenbraun, E. J. J. Org. Chem.
1981, 46, 2974.
(
(
(
8) Nilsson, J. P.; Andersson, C.-M.; Tetrahedron Lett. 1997, 38, 4635.
9) Khand, I. U.; Pauson, P. L.; Watts, W. E. J. Chem. Soc. C 1968,
(14) (a) Lee, C. C.; Pi o´ rko, A.; Steele, B. R.; Gill, U. S.; Sutherland, R.
G. J. Organomet. Chem. 1983, 256, 303. (b) Lee, C. C.; Gill, U. S.;
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2
261.
1452
Org. Lett., Vol. 1, No. 9, 1999