Angewandte
Chemie
similar mechanism may be active.[5] To effect the conversion
of 13 into 15, oxidant 14 was employed because it has been
firmly established by the scholarly studies of Jahn et al. to
convert enolates into radical species by an outer-sphere
single-electron-transfer pathway.[12] Remarkably, FeIII-based
oxidant 14 is ineffective for the couplings in Scheme 1 as are
CuII-based oxidants for the annulation (13!15).
In summary, we have developed a new method for the
one-step construction of a variety of pyrroles that would
ordinarily require multistep sequences to synthesize. The
method is scalable, practical, and reliable. The intermolecular
heteroarylation of enolates (Scheme 1) uses a CuII-based
oxidant, whereas the intramolecular variant proceeds by a
different mechanism that functions using the FeIII-based
oxidant 14 (Scheme 2). The waste associated with protecting
groups, prior modification of the substrates (such as halogen-
ation or any other disposable functionalities), and expensive
metals is eliminated. These studies point to a unique approach
for the synthesis of p-electron-rich heterocyclic systems
through coupling of unfunctionalized C(sp2) and C(sp3)
atoms.[17]
Scheme 2. Short, enantioselective synthesis of (S)-ketorolac. Reagents
and conditions: a) Et3N (1.1 equiv), MeOCOCl (1.0 equiv), THF
(0.1m), 08C, 1 h; then 12, 100%; b) LHMDS (1.2 equiv), Et3N
(2.0 equiv), THF (0.01m), ꢀ788C, 30 min; then 128C, 14 (0.75 equiv),
5 min, 65% bsm; (c) BzCl, 708C, 4 h; then TBAH (2.0 equiv), H2O2
(2.0 equiv), 2-methylbut-2-ene (3.0 equiv), DME (0.25m), ꢀ108C, 3 h,
38%. Xc =camphor sultam auxiliary, bsm=based on recovered start-
ing materials, Bz=benzoyl, TBAH=tetra-n-butylammonium hydroper-
oxide, DME=1,2-dimethoxyethane.
hydroperoxide[14] furnished S-ketorolac (1, 90% ee deter-
mined by chiral HPLC, 38% isolated yield over 2 steps) along Experimental Section
General Procedure for Direct Pyrrole Coupling: The carbonyl
with recovered auxiliary. From the vantage point of synthetic
design, certain details are worth noting: 1) the oxidation state
of 11 is conserved (reduction, decarboxylation, and halogen-
ation processes avoided),[15] 2) protecting groups are absent,
3) decent stereocontrol is observed in the ring closure despite
the readily enolizable[9] nature of the newly formed stereo-
center, and 4) overall brevity of the sequence (ꢁ 25% overall
unoptimized yield from pyrrole in four operations).
Although conceptually similar, the direct coupling of
carbonyl compounds with pyrroles (Scheme 1) by using a CuII
oxidant probably differs mechanistically from the intramo-
lecular cyclization (13!15) by using FeIII-based 14. As shown
in Figure 2, we believe that in the former case an intermediate
compound (0.25 mmol) was dissolved in benzene (1.0 mL) and the
solvent was removed in vacuo. Pyrrole (0.75 mmol) was then added
and the starting materials were dissolved in THF (8.0 mL). The
solution was cooled to ꢀ788C and a solution of LHMDS (0.50m,
2.0 mL) was added. The reaction mixture was allowed to stir for
30 min, after which time the septum was removed and copper(II)-2-
ethylhexanoate (131 mg, 0.38 mmol) was rapidly added as a solid and
then the septum was replaced. The reaction was allowed to warm to
ꢀ608C and stirred for 3 h. The reaction was subsequently warmed
slowly to ambient temperature and quenched by pouring into 5%
aqueous NH4OH (15 mL). The aqueous layer was partitioned with
EtOAc (20 mL). The organic layer was separated and washed
successively with water (15 mL) and then brine (15 mL), dried
(MgSO4), and filtered, and the solvent was removed in vacuo. Flash
chromatography (silica gel) of the crude reaction mixture afforded
pure coupled product. With the exception of compound 2, all the
pyrroles began to darken in color immediately after concentration,
but NMR spectroscopic analysis showed no loss in purity. In general it
was found that the couplings of ketones, amides, lactones, and lactams
worked well with the exception of esters, which proved to be more
unpredictable.
Received: September 21, 2004
Published online: December 6, 2004
Figure 2. Proposed mechanism for the direct coupling of pyrroles with
carbonyl compounds by using CuII.
ꢀ
Keywords: C C coupling · copper · enantioselectivity ·
heterocycles · total synthesis
.
CuIII-chelated species (A) may be involved.[16] Reductive
elimination and loss of CuI should lead to B, followed by
tautomerization to yield the product. Several observations
support this tentative mechanistic model: 1) dimerization of
the pyrrole is never observed, as expected from geometrical
constraints, 2) N-protected pyrroles do not react, 3) only
1 equivalent of oxidant is necessary, although the use of
1.5 equivalents gives a slight improvement in yield, and 4) the
characteristic red-brown color of copper(i) salts is often
observed at the end of the reaction. The same trends are seen
for the analogous coupling with indoles and implies that a
[1] J. A. Joule, K. Mills, Heterocyclic Chemistry, Blackwell, Oxford,
2000, p. 589.
[2] a) J. J. Li, G. W. Gribble, Palladium in Heterocyclic Chemistry,
Pergamon, Amsterdam, 2000, p. 413; b) A. F. Littke, G. C. Fu,
Angew. Chem. 2002, 114, 4350 – 4386; Angew. Chem. Int. Ed.
2002, 41, 4176 – 4211, and references therein.
[3] a) For a review of metal-mediated couplings of this type, see: M.
Miura, M. Nomura, Top. Curr. Chem. 2002, 219, 211 – 241; b) For
recent advances in this area, see: B. Sezen, D. Sames, J. Am.
Angew. Chem. Int. Ed. 2005, 44, 609 –612
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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