C O M M U N I C A T I O N S
Table 1. Substrate and Functional Group Scope
Figure 2. Pyridine and pyrimidine as permanent directing groups. These
less reactive substrates required higher catalyst loading and/or longer reaction
b
time: a10 mol % Ru3(CO)12 used; 3.3 mol % Ru3(CO)12 used.
compounds such as 15-17 can now be prepared in two steps from
the corresponding amines.
Last, the source of relatively poor stereoselectivity of these
arylation reactions was identified by submitting each stereoisomer
of diphenyl product 15 (trans and cis) to the reaction conditions.
These control experiments clearly showed that the product isomer-
ization was more rapid (∼2 h) than the arylation reaction (complete
in 24 h, see Supporting Information). Nevertheless, this new method
is operationally simple, reactions can be performed in capped glass
vials with standard benchtop handling of reagents,15 and the isomers
are readily separable by chromatography. Exploration of both the
substrate scope and the mechanism of this interesting reaction is
under way in our laboratories.
a Isolated yields after flash chromatography are shown; all reactions were
run on a 0.5 mmol scale. Diastereomeric ratio was obtained from the isolated
yields of each isomer. For exact reaction times, see the Supporting
Information. b Reaction run using 6.6 mol % of Ru3(CO)12. c Pinacol-derived
ester used. d Reaction run on 1.0 mmol scale.
Acknowledgment. This work was supported by NIGMS, NSF,
and Bristol-Myers Squibb (the Unrestricted Grants in Synthetic
Organic Chemistry Award). We thank Daniela Buccella and
Professor Gerard Parkin (X-ray).
Scheme 2. Deprotection of 2,5-Disubstituted Amidines
Supporting Information Available: Experimental procedures,
spectral data, kinetics of product isomerization. This material is available
References
(1) Godula, K.; Sames, D. Science 2006, 312, 67-72
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Toure´, B. B.; Lane, B. S.; Sames, D. Org. Lett. 2006, 8, 1979-1982.
amidine directing group for the metal center. The TBS-protected
prolinol substrate also underwent regioselective phenylation to
provide 10 as the major product. Saturated six-membered hetero-
cycles have been shown to be less reactive in comparison to their
five-membered ring counterparts.14 We were pleased to see that
the protected piperidine underwent R-arylation to afford product
11, albeit in modest yield. Optimization of piperidine substrates is
underway in our laboratory.
(3) Dangel, B. D.; Godula, K.; Youn, S. W.; Sezen, B.; Sames, D. J. Am.
Chem. Soc. 2002, 124, 11856-11857.
(4) (a) Kalyani, D.; Deprez, N. R.; Desai, L. V.; Sanford, M. S. J. Am. Chem.
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2001, 918-919.
The next key question centered on the ability to remove the
directing group from the sterically hindered 2,5-disubstituted
amidines (Scheme 2). While treatment with NH2NH2/AcOH worked
well for monoarylated heterocycles (see Supporting Information),
these conditions were inefficient for the more hindered products.
The use of stronger acid (e.g., TFA) in place of AcOH (taking
advantage of significant difference in basicity between amidine and
hydrazine) produced a major improvement, affording an efficient
deprotection method (see Supporting Information for details). Thus,
1-pyrroline represents an attractiVe directing group; it can be both
installed and remoVed in a straightforward manner.
Next, we investigated the reactivity of related substrates contain-
ing pyridine or pyrimidine rings as permanent directing groups
(Figure 2).8 The corresponding 2-aminopyridines or pyrimidines
are desirable pharmacophore substructures in medicinal chemistry.
These substrates were less reactive in comparison to the corre-
sponding amidines discussed above, requiring higher catalyst
loading and/or longer reaction time to obtain good yields. Attractive
(7) Jun, C.-H.; Hwang, D.-C.; Na, S.-J. Chem. Commun. 1998, 1405-1406.
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(9) Deboef, B. D.; Pastine, S. J.; Sames, D. J. Am. Chem. Soc. 2004, 126,
6556-6557.
(10) For examples of Boc group-directed R-lithiation/arylation of protected
pyrrolidines: (a) Dieter, R. K.; Li, S.-J. J. Org. Chem. 1997, 62, 7726-
7735. (b) Campos, K. R.; Klapars, A.; Waldman, J. H.; Dromer, P. G.;
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(12) See the Supporting Information for the identity of these complexes.
(13) The substrate may act as an oxidant in the absence of ketone (2-
phenylpyrrolidine was produced). In the case of the pyridine directing
group, 15 was obtained in only 7% yield in the absence of ketone.
(14) (a) Boutry, O.; Gutie´rrez, E.; Monge, A.; Nicasio, M. C.; Pe´rez, P. J.;
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(15) Preliminary experiments suggest that similar yields may be achieved in
shorter reaction times (<1 h) in a microwave reactor.
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