Copper-catalyst-controlled site-selective allenylation of ketones and aldehydes with propargyl boronates

Article abstract of DOI:10.1021/ol400124f

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. T

Full text of DOI:10.1021/ol400124f

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
keith.fandrick@boehringer-ingelheim.com
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
(1) Handbook of Functionalized Organometallics; Knochel, P., Ed.;
Whiley-VCH: Weinheim, 2004.
(2) For selected examples, see: (a) Bonazzi, S.; Binaghi, M.; Fellay,
C.; Wach, J.-Y.; Gademann, K. Synthesis 2010, 4, 631–642. (b) Yang,
D.; Cwynar, V.; Donahue, M. G.; Hart, D. J.; Mbogo, G. J. Org. Chem.
2009, 74, 8726–8732. (c) Zhang, Q.; Yang, L.; Tong, X. J. Am. Chem.
Soc. 2010, 132, 2550–2551.
(3) For selected examples, see: (a) Brown, H. C.; Khire, U. R.; Narla,
G. J. Org. Chem. 1995, 60, 8130–8131. (b) Roy, C. D.; Soundararajan,
R.; Brown, H. C. Monatsh. Chem. 2008, 139, 241–249. (c) Corey, E. J.;
Yu, C.-M.; Lee, D.-H. J. Am. Chem. Soc. 1990, 878–879. (d) Herandez,
E.; Soderquist, J. A. Org. Lett. 2005, 7, 5379–5400.
(4) For selected examples, see: (a) Mesnard, D.; Miginiac, L.
J. Organomet. Chem. 1990, 397, 127–137. (b) Daniels, R. G.; Paquette,
L. A. Tetrahedron Lett. 1981, 22, 1579–1582.
(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.
(8) Alcaide, B.; Almendros, P.; Aragoncillo, C.; Rodrı
R. J. Org. Chem. 2001, 66, 5208–5216.
´
guez-Acebes,
(5) For selected examples, see: (a) Kobayashi, S.; Nishio, K. J. Am.
Chem. Soc. 1995, 117, 6392–6393. (b) Shnneider, U.; Sugiura, M.;
Kobayashi, S. Tetrahedron 2006, 62, 496–502.
(9) Guo, L.-N.; Gao, H.; Mayer, P.; Knochel, P. Chem.;Eur. J.
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.
ꢀ
ꢀ
Chem., Int. Ed. 2006, 45, 252–255. (b) Duran-Galvan, M.; Connell, B. T.
Eur. J. Org. Chem. 2010, 2445–2448.
r
10.1021/ol400124f
Published on Web 02/25/2013
2013 American Chemical Society

propargyl intermediates or by the inherent preference of
the substituted allenyl subunit. To date, there has not been
a system reportedthat can direct the site selectivity through
the catalyst structure alone.
prepared TMS-propargyl boronate 1a.14 A control experi-
ment without a catalyst forms the propargyl adduct 7a in
high site selectivity and low conversion (entry 1, Table 1).
Although the conversion can be improved by employing
catalytic amounts of either Cu(iButyrate)2, LiOtBu, or the
combination of the two, the system forms the propargyl
adduct selectively.
As previously shown12,13 the presence of bisphosphine
and monophosphine ligands in the reaction provides high
site selectivity for the propargyl adduct (Figure 2). This
effect appears to be general for a wide structural class of
ligands. We felt that by selecting ligands that can more
effectively encapsulate the Cu metal we could perturb
the propargyl/allenyl Cu equilibrium to favor the propar-
gyl intermediate. This effect was observed with PhBPE,
whereas complete site selectivity was observed to favor the
allenyl adduct 8a (99:1 dr) withcomplete conversion and in
moderate enantioselectivity (32% ee). This result appears
to represent the first reported site-selective Cu-catalyzed
allenylation of carbonyl compounds.
After establishing the Cu-PhBPE system for the site-
selective allenylation of the model ketone 6a, a survey of
different ketones was conducted (Figure 3). The catalyst
system has been shown to be tolerant of electronically
diverse acetephenones (6aÀ6c, 6e) aswell asa cyclic ketone
6d providing high selectivity for the allenyl adducts.
Figure 1. Site selective propargylations and allenylations.
Recently the CuÀB exchange has been shown to be an
effective method for the catalytic propargylation of car-
bonyl compounds.11 The site-selective propargylations of
aldehydes12 and ketones13 have recently been shown with
TMS-propargyl boronates mediated by copperÀbisphosphine
complexes. By inference, the active intermediate is the
allenyl cuprate thus providing the propargyl adduct selec-
tively (Figure 1). By destabilizing the allenyl cuprate 2 the
equilibrium can shift to the propargyl cuprate 3, thus
providing the allenyl substrate 5 directly. Herein, we wish
to report the site-selective allenylation of aldehyde and
ketones catalyzed by Cu-PhBPE complexes.
Table 1. Initial Survey for the Site-Selective Allenylationa
temp
entry
catalyst
(°C) conversionb (7a:8a)b
1
2
3
4
none
0
0
0
0
20%
68%
99%
99%
99:1
Figure 2. Ligand survey for the site-selective allenylation. Typi-
cal conditions: 1.2 mmol of ketone, 1.7 mmol of propargyl
boronate in 3 mL of THF. Molar conversion and site selectivity
determined by HPLC analysis.
2.5 mol % Cu(iButyrate)2
2.5 mol % LiOtBu
82:18
99:1
2.5 mol % Cu(iButyrate)2
and 2.5 mol % LiOtBu
85:15
a Typical conditions: 1.2 mmol of ketone, 1.7 mmol of propargyl
boronate in 3 mL of THF. b Molar conversion and site selectivity
determined by HPLC analysis.
Furthermore, an aliphatic methyl ketone is also well
tolerated providing for high site selectivity for 8g.
The Cu-PhBPE catalyst was also shown tobe effective in
the site-selective allenylation of a wide variety of aldehydes
(Figure 4). The methodology was applicable for a diverse
array of electronically differentiated aldehydes providing
for ∼10:1 selectivity for the allenyl adducts (11). The cor-
responding naphthyl (9g) and alkene (9h) aldehydes were
Initial surveys of the allenylation employed 4-chloro-
acetophenone 6a as a model substrate and the readily
(11) Shi, S.-L.; Zu, L.-W.; Oisaki, L.; Kanai, M.; Shibasaki, M.
J. Am. Chem. Soc. 2010, 132, 6638–6639.
(12) Fandrick, D. R.; Fandrick, K. R.; Reeves, J. T.; Tan, Z.; Tang,
W.; Capacci, A. G.; Rodriguez, S.; Song, J. J.; Lee, H.; Yee, N. K.;
Senanayake, C. H. J. Am. Chem. Soc. 2010, 132, 7600–7601.
(13) Fandrick, K. R.; Fandrick, D. R.; Reeves, J. T.; Gao, J.; Ma, S.;
Li, W.; Lee, H.; Grinberg, N.; Lu, B.; Senanayake, C. H. J. Am. Chem.
Soc. 2011, 133, 10332–10335.
(14) Fandrick, D. R.; Roschangar, F.; Kim, C.; Hahm, B.; Cha,
M. H.; Kim, H. Y.; Yoo, G.; Kim, T.; Reeves, J. T.; Song, J. J.; Tan, Z.;
Qu, B.; Haddad, N.; Shen, S.; Grinberg, N.; Lee, H.; Yee, N.;
Senanayake, C. H. Org. Process Res. Dev. 2012, 16, 1131–1140.
Org. Lett., Vol. 15, No. 6, 2013
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tolerant in the system providing for 7.3 to 20:1 selectivity
for the allenyl products.
the intermediate Cu-allenyl/propargyl species can readily
interconvert. However, the placement of a terminal substi-
tuent on the propargyl boronate (Ph, 1d; TMS 1a) provides
the corresponding allenyl adduct in high site selectivity
(>90:10). Identical results were obtained with aldehyde 9b
(Supporting Information).
Figure 3. Site-selective allenylation of ketones catalyzed by
Cu-PhBPE. Typical conditions: 1.2 mmol of ketone, 1.7 mmol
of propargyl boronate in 3 mL of THF. Site selectivity deter-
mined by 1H NMR analysis of the crude reaction mixture.
Figure 5. Hammett plot for the asymmetric allenylation of
aldehydes catalyzed by Cu-PhBPE.
As mentioned previously, moderate enantioselectivity is
obtained with the chiral PhBPE ligand. A Hammett plot15
of the enantioselectivity (log(ratio of enantiomers)) of the
allenylation of a series of aldehydes with respect to the
σ-values shows a negative and near-linear relationship
(Figure 5). Whereas, for electronically donating substitu-
ents an enantioselectivity of 82:18 (er, p-NMe2 9f) can be
obtained. However, for the p-NO2 9c almost no enantio-
control is observered (1.1:1 er).
The substitution pattern on the BPE ligands was found
to be vital for the site selectivity of the process (Table 3).
Whereas, the MePBE and EtPBE ligands provide the
corresponding propargyl adducts exclusively. However,
the iPrPBE ligand shows a slightly lower preference for
the propargyl product. Whereas the PhBPE ligand reverses
the site selectivity preference and provides the allenyl
adduct with good selectivity (20:1). These results would
imply the substituent on the PBE ligand plays an intimate
role in the site selectivity.
Table 2. Survey of Substituted Boronates 1 with Cu-Ph-PBe
Catalysta
Figure 4. Site-selective allenylation of aldehydes catalyzed Cu-
PhBPE. Typical conditions: 1.2 mmol of ketone, 1.7 mmol of
propargyl boronate in 3 mL of THF. Site selectivity determined
by 1H NMR analysis of the crude reaction mixture.
Attention then was turned to the effects of the substi-
tuent on the boronate (Table 2). As expected, the less
sterically demanding boronates (both allenyl boronate 1b
and propargyl boronate 1c7) provide the propargyl adduct
exclusively (99:1 selectivity). Since both substrates con-
verge to the same propargyl product, this would imply that
a Typical conditions: 1.2 mmol of ketone, 1.7 mmol of propargyl
boronate in 3 mL of THF. Conversion and site selectivity determined by
1H NMR analysis.
(15) (a) Hammett, L. P. J. Am. Chem. Soc. 1937, 59, 96–103. (b)
Hansch, C.; Leo, A.; Taft, R. W. Chem. Rev. 1991, 91, 165–195.
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Org. Lett., Vol. 15, No. 6, 2013

Table 3. Effects of BPE Ligand Substitution on the Site Selec-
tivitya
a Typical conditions: 1.2 mmol of ketone, 1.7 mmol of propargyl
boronate in 3 mL of THF. Molar conversion and site selectivity
determined by HPLC analysis.
Molecular modeling16 based on the Cu-R-BINAP crys-
tal structure of Anslyn17 of the proposed cyclic inter-
mediates12,13 for the CuPhPBE and CuMePBE complexes
shows marked differences in the available space for the
TMS group (Figure 6). With the Cu-MePBE system there
is available space for the TMS fragment in the Cu-allenyl
complex thus allowing the system to provide the preferred
propargyl adducts. However, for the Cu-PhPBE system
this space is limited by the appended Ph-rings thus desta-
bilizing the seemingly preferred allenyl-Cu complex and
favoring the Cu-propargyl complex, which in turn pro-
vides the allenyl product. This model would also explain
the reversed site selectivity for the unsubsituted boronates
1b and 1c (Table 2).
Figure 6. Molecular models for the Cu-PhBPE allenylation and
Cu-MeBPE propargylation.
propargylation or an allenylation of carbonyl compounds
with a common TMS-propargyl boronate reagent depend-
ing on the PBE substitution. A model was proposed that
supports the observed site-selectivity preferences for the
PBE ligand and boronate substitution. This system repre-
sents the first catalyst-controlled site-selective allenylation
and propargylation of carbonyl compounds.
In conclusion, the Cu-PBE catalyst has been shown
to be an effective complex which can undergo either a
Supporting Information Available. Optimization stud-
ies, additional experiments employing aldehyde 9a and
9b, experimental procedures, ee for all substrates, and
characterization data (1H and 13C NMR spectra for all
products, and chiral HPLC data and copies of chroma-
tograms). This material is available free of charge via the
Internet at http://pubs.acs.org.
(16) The molecular model was generated by replacing the appended
couterions on the Cu-BINAP crystal structure with the aldehyde
followed by the TMS-allene or TMS-propargyl unit. The BINAP ligand
was then replaced with the BPE ligand. The distance between the
terminus of the allene/propargyl carbon and the carbonyl carbon was
constrained to 2.9 A, after which a single-point energy minimization was
performed using Spartan ’08 (version 1.1.1).
(17) Nieto, S.; Lynch, V. M.; Anslyn, E. V.; Kim, H.; Chin, J. Org.
Lett. 2008, 10, 5167–5170.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 6, 2013
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