ORGANIC
LETTERS
2013
Vol. 15, No. 6
1214–1217
Copper-Catalyst-Controlled Site-Selective
Allenylation of Ketones and Aldehydes
with Propargyl Boronates
Keith R. Fandrick,* Junichi Ogikubo, Daniel R. Fandrick, Nitinchandra D. Patel,
Jaideep Saha, Heewon Lee, Shengli Ma, Nelu Grinberg, Carl A. Busacca, and
Chris H. Senanayake
Chemical Development, Boehringer-Ingelheim Pharmaceuticals Inc., 900 Ridgebury
Road, P.O. Box 368, Ridgefield, Connecticut 06877-0368, United States
Received January 15, 2013
ABSTRACT
A practical and highly site-selective copper-PhBPE-catalyst-controlled allenylation with propargyl boronates has been developed. The
methodology has shown to be tolerant of diverse ketones and aldehydes providing the allenyl adducts in high selectivity. The BPE ligand and
boronate substituents were shown to direct the site selectivity for which either propargyl or allenyl adducts can be acquired in high selectivity. A
model is proposed that explains the origin of the site selectivity.
The organometallic addition to carbonyl compounds
has been a fundamental method for the construction of
carbonÀcarbon bonds.1 In this capacity, efforts have been
afforded toward the alleneylation of ketones and alde-
hydes as the resulting allenyl carbinols are an effective
handle for the synthesis of complex architectures.2 The
direct allenylation of carbonyls via a metallic propargyl
intermediate has been shown with B,3 Al,4 Si,5 Cr,6 Zn,7
and Lewis acid mediated processes.8 The site selectivity of
these methods is dictated by the selective formation of
the propargyl intermediate. The metallic propargyl/allenyl
intermediate is often in a state of equilibration in which the
site selectivity is dictated by the relative stability of the
respected allenyl or propargyl metallic species. In this
capacity, Knochel9 and others10 have shown that the site
selectivity can be directed by the substitution pattern on
the propargyl/allenyl unit, whereas the more sterically
demanding substituted propargyl reagents favor the me-
tallic propargyl intermediates, thus providing the allenyl
carbinols selectively. However, the site selectivity of these
methodologies is limited to either selective formation of
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Whiley-VCH: Weinheim, 2004.
(2) For selected examples, see: (a) Bonazzi, S.; Binaghi, M.; Fellay,
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G. J. Org. Chem. 1995, 60, 8130–8131. (b) Roy, C. D.; Soundararajan,
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(7) Fandrick, D. R.; Saha, J.; Fandrick, K. R.; Sanyal, S.; Ogikubo,
J.; Lee, H.; Roschangar, F.; Song, J. J.; Senanayake, C. H. Org. Lett.
2011, 13, 5616–5619.
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2010, 16, 9829–9834.
(10) For selected examples, see: (a) Lin, M.-J.; Loh, T.-P. J. Am.
Chem. Soc. 2003, 125, 13042–13043. (b) Banerjee, M.; Roy, S. Org. Lett.
2004, 6, 2137–2140. (c) Yu, C.-M.; Yoon, S.-Y.; Baek, K.; Lee, J.-Y.
Angew. Chem., Int. Ed. 1998, 37, 2392–2394.
(6) For selected examples, see: (a) Inoue, M.; Nakada, M. Angew.
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ꢀ
Chem., Int. Ed. 2006, 45, 252–255. (b) Duran-Galvan, M.; Connell, B. T.
Eur. J. Org. Chem. 2010, 2445–2448.
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10.1021/ol400124f
Published on Web 02/25/2013
2013 American Chemical Society