Copper-catalyzed diboration of ketones: Facile synthesis of tertiary α-Hydroxyboronate esters

Article abstract of DOI:10.1021/ol100468f

Figure presented The diboration of ketones with the (ICy)CuOt-Bu catalyst was developed to provide access to tertiary α-hydroxyboronate esters. The (ICy)CuOt-Bu catalyst was generated in situ with (ICy)CuCl and NaOt-Bu to afford a more efficient catalyst than the preformed (ICy)CuOt-Bu. These conditions result in the diboration of various ketones in toluene at 50 °C in 2-22 h. Treatment of the resulting products with silica gel affords the corresponding α-hydroxyboronate esters.

Full text of DOI:10.1021/ol100468f

ORGANIC
LETTERS
2010
Vol. 12, No. 9
1996-1999
Copper-Catalyzed Diboration of Ketones:
Facile Synthesis of Tertiary
r-Hydroxyboronate Esters
Melissa L. McIntosh, Cameron M. Moore, and Timothy B. Clark*
Department of Chemistry, Western Washington UniVersity, 516 High Street,
Bellingham, Washington 98225
clark@chem.wwu.edu
Received February 24, 2010
ABSTRACT
The diboration of ketones with the (ICy)CuOt-Bu catalyst was developed to provide access to tertiary r-hydroxyboronate esters. The (ICy)CuOt-
Bu catalyst was generated in situ with (ICy)CuCl and NaOt-Bu to afford a more efficient catalyst than the preformed (ICy)CuOt-Bu. These
conditions result in the diboration of various ketones in toluene at 50 °C in 2-22 h. Treatment of the resulting products with silica gel affords
the corresponding r-hydroxyboronate esters.
The versatility of the carbon-boron bond in synthesis has
resulted in an emergence of interest in transformations that
incorporate boron substituents with high regio- and stereo-
selectivity.1-3 Traditional reactions used to introduce boron
substituents into substrates include hydroboration and dibo-
ration of alkenes and alkynes,4-6 Miyaura borylation reac-
tions,7 addition of organometallic reagents to trialkyl bo-
rates,8,9 and C-H borylation reactions.10-14
The incorporation of boron substituents alpha to heteroa-
toms, however, has received limited attention even though
the resulting compounds are known to have synthetic and
pharmaceutical applications.15-20 Baker and co-workers
developed the rhodium-catalyzed diboration of thiocarbon-
yls21 to form R-thiolboronate esters and the platinum-
catalyzed diboration of aromatic aldimines to generate
R-aminoboronate esters,22 which are known pharmacophores
with serine protease inhibition.17,18,23-25
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10.1021/ol100468f  2010 American Chemical Society
Published on Web 04/14/2010

Until recently, however, the diboration of carbonyls was
unknown. In 2006, Sadighi and co-workers found that a
copper complex [(ICy)CuOt-Bu; ICy ) N,N-dicyclohexy-
limidazolyl] efficiently catalyzed the diboration of aldehydes
at ambient temperature (eq 1).26,27 A subsequent report by
Ellman and co-workers demonstrated that Sadighi’s catalyst
could be used in combination with a chiral auxiliary to
achieve the asymmetric diboration of tert-butanesulfiny-
laldimines.28 Ellman also demonstrated the synthetic utility
of this transformation in the synthesis of the boropeptide
Bortezomib, an FDA-approved treatment of multiple
myeloma and mantle cell lymphoma.23 Although these
reactions represent an elegent solution for the synthesis
of R-amino- and hydroxyboronate esters, there are no
known general methods for the synthesis of tertiary
R-hydroxyboronate esters from ketones. Development of
such a method would allow access to new potential
pharmacophores and valuable precursors in organic syn-
thesis. We report herein the first example of the diboration
of ketones, providing optimized reaction conditions for
the formation of the corresponding R-hydroxyboronate
esters under mild reaction conditions.29,30
Table 1. Effect of Additives on Acetophenone Diboration (eq 2)
entry
additive
temp, °C time, h % conversiona
1
2
3
4
5
6
7
a
none
70
70
50
50
50
50
50
68
20
20
68
68
68
68
90
0
0
59
46
85
71
3 Å mol sievesb
MgSO4
K2CO3
NaO2CCH3
NaHCO3
none
1
Reaction progress monitored by H NMR spectroscopy, using a 10 s
relaxation delay to ensure integral integrity. b Crushed, activated 3 Å
molecular sieves.
on studies reported by Nolan and co-workers in the copper-
catalyzed hydrosilylation of ketones,31 the in situ generation
of (ICy)CuOt-Bu was explored. The active catalyst could
be generated in situ from the (ICy)CuCl species in the
presence of sodium tert-butoxide (eq 3). Using these condi-
tions (50 °C, 3 mol % (ICy)CuCl, 20 mol % NaOt-Bu) the
32
1
reactions were monitored by H NMR spectroscopy. The
in situ generated catalyst increased the reaction rate and
resulted in complete conversion and high yields of the
corresponding diboration products 1-4 (Table 2).
Initial experiments probed the reactivity of the (ICy)CuOt-
Bu catalyst developed by Sadighi in the diboration of
acetophenone. Under these conditions, the catalyst system
was much less efficient with ketones than those reported for
the diboration of aldehydes, providing 90% conversion after
70 h at 70 °C (as compared to 22 h at 22 °C with
aldehydes).26 Various additives were explored in an effort
to increase catalyst turnover. Because the catalyst is highly
sensitive to moisture, it was postulated that adventitious water
may result in the loss of catalyst activity. Addition of
common drying agents (entries 2-4, Table 1) did not
improve catalyst turnover, and 3 Å molecular sieves and
MgSO4 shut down the reaction completely. The return of
catalyst activity in the case of K2CO3 prompted the examina-
tion of additional bases as additives (entries 4-6). Although
most bases resulted in lower conversion than (ICy)CuOt-
Bu alone, sodium bicarbonate provided an increased catalyst
efficiency. Continued optimization, however, did not result
in full conversion to 1.
Table 2. Diboration Reactions of Simple Ketones (eq 3)
a As determined by 1H NMR spectroscopic analysis of the product
relative to an internal standard (PhSiMe3) and with a 10 s relaxation delay
to ensure integral integrity. See the Supporting Information for details.
Further reaction optimization revealed conditions that
achieved full conversion of acetophenone to 1 (eq 3). Relying
Control experiments were conducted to probe the increase
in catalyst activity resulting from in situ formation of
(ICy)CuOt-Bu. Addition of 20 mol % of NaOt-Bu to
(26) Laitar, D. S.; Tsui, E. Y.; Sadighi, J. P. J. Am. Chem. Soc. 2006,
128, 11036–11037
.
(27) Laitar, D. S.; Mu¨ller, P.; Sadighi, J. P. J. Am. Chem. Soc. 2005,
127, 17196–17197
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(28) Beenen, M. A.; An, C.; Ellman, J. A. J. Am. Chem. Soc. 2008,
130, 6910–6911.
(29) Matteson, D. S.; Kandil, A. A. J. Org. Chem. 1987, 52, 5121–
5124.
Org. Lett., Vol. 12, No. 9, 2010
1997

(ICy)CuOt-Bu provided an increased reaction rate over
reactions involving (ICy)CuOt-Bu alone (eq 4). Our current
hypothesis is that the added base can coordinate to the
diboron reagent and increase the rate of σ-bond metathesis
in the regeneration of the active copper-boryl species (see
Scheme 1, step e).33 In the absence of the base additive, slow
diboration of enones.34 Under their reaction conditions
(catalytic N-heterocyclic carbene with B2pin2) the NHC
activates B2pin2 by coordination to one Lewis acidic boron.
The activated diboron reagent then adds to the unsaturated
alkene. To rule out dissociation of the NHC from (ICy)CuCl
under our reaction conditions, a control experiment was
conducted under Hoveyda’s metal-free conditions. Under
these conditions, no diboration was observed, discounting a
metal-free mechanism.
Scheme 1.
Proposed Catalytic Cycle33
Tertiary R-hydroxyboronate esters could be isolated by
selective cleavage of the O-B bond of the diboration
products (eq 6). Diboration reactions were run using 1-3
mmol of ketone, 3 mol % of (ICy)CuCl, and 5 mol % of
NaOt-Bu in toluene at 50 °C for 3-22 h. Selective
protonolysis of the O-B bond in the presence of the C-B
bond was achieved upon purification by silica gel chroma-
tography to provide R-hydroxyboronate esters 6-12 (Table
3). In the case of diboration product 1, however, treatment
catalyst degradation takes place, resulting in deactivation of
the catalyst over the course of the reaction.
Table 3. Isolation of R-Hydroxyboronate Esters (eq 6)
The catalytic cycle of the diboration reaction is believed
to be similar to the calculated mechanism reported by Marder
and Lin in the copper-catalyzed diboration of aldehydes
(Scheme 1).33 The only expected difference from the
calculated catalytic cycle is in the formation of (ICy)CuOt-
Bu from the precatalyst (ICy)CuCl (step a). The formation
of the copper-boryl species proceeds by σ-bond metathesis
(step b), followed by coordination of the ketone (step c).
The coordinated ketone can undergo migratory insertion (step
d) to form the copper alkoxide, which will react with B2pin2
through σ-bond metathesis (step e) to regenerate the active
copper-boryl catalyst.
An alternative metal-free mechanism was considered.
Hoveyda and co-workers recently reported the metal-free 1,4-
(30) Carme´s, L.; Carreaux, F.; Carboni, B.; Mortier, J. Tetrahedron Lett.
1998, 39, 555–556.
(31) D´ıez-Gonza´lez, S.; Kaur, H.; Zinn, F. K.; Stevens, E. D.; Nolan,
S. P. J. Org. Chem. 2005, 70, 4784–4796.
(32) Reactions were conducted in resealable J. Young tubes and heated
to 50 °C in an oil bath. Due to the small reation scale, 20 mol % of NaOt-
Bu was required to allow the solid to be weighed out accurately. Reactions
on larger scale utilize 5 mol % of NaOt-Bu.
(33) Zhao, H.; Dang, L.; Marder, T. B.; Lin, Z. J. Am. Chem. Soc. 2008,
130, 5586–5594.
1998
Org. Lett., Vol. 12, No. 9, 2010

with silica gel resulted in decomposition rather than forma-
tion of the corresponding R-hydroxyboronate ester. The facile
decomposition of 1 is consistent with studies reported by
Sadighi that show analogous decomposition of benzaldehyde-
derived diboration products.26 Sadighi attributed the decom-
position to an oxygen-mediated process. Attempts to purify
1 by silica gel chromatography in the absence of oxygen (in
an inert atmosphere glovebox), however, still resulted in
decomposition rather than selective O-B bond cleavage.
The high diastereoselectivities observed for these substrates
likely result from the extensive steric congestion required
in the migratory insertion of the carbonyl into the Cu-Bpin
bond (Figure 1).33 The steric congestion imposed by the Bpin
The optimized conditions for the diboration reaction were
compatible with a variety of ketones. Cyclic and dialkyl
ketones provided moderate to high yields at 50 °C (Table 3,
entries 1-3). The presence of several functional groups was
also tolerated under the optimized reaction conditions,
providing selective diboration of the ketone in the presence
of a furan (entry 4), alkene (entry 5), ester (entry 6), and
nitrile (entry 7). Isolation of R-hydroxyboronate esters 11
and 12 required purification with Davisil grade silica gel to
prevent acid-mediated decomposition of the these function-
alized products.
Diboration of chiral ketones was examined, resulting in
diastereoselective formation of the corresponding R-hydroxy-
boronate esters. 2-Methylcyclohexanone was subjected to the
optimized reaction conditions to provide 13 in g99:1
diastereoselectivity (Scheme 2).35 Acyclic ketone 14 was also
Figure 1. Source of diastereoselecive diboration reactions.
substituent increases the selectivity that would normally be
observed for Felkin-Anh-controlled addition to carbonyl
compounds.39,40 The ability to control the facial selectivity
of diboration with pendant substituents in chiral ketones is
consistent with the asymmetric induction observed by Ellman
and co-workers in the diboration of tert-butanesulfinylaldi-
mines.28
In summary, optimized reaction conditions were developed
that provide high-yielding diboration of ketones. In situ
formation of (ICy)CuOt-Bu provides convenient reaction
conditions to achieve high catalyst efficiency. Diboration of
several functionalized ketones provided selective reaction at
the ketone in moderate to high yields. High diastereoselec-
tivity was also observed in the diboration of chiral ketones.
Scheme 2. Diastereoselective Diboration of Ketones
Acknowledgment. This research was supported by a
Research Corporation for Science Advancement Cottrell
College Science Award (7339), a Research Corporation for
Science Advancement and M. J. Murdock Charitable Trust
Department Development Grant, and Western Washington
University. C.M.M. thanks the American Chemical Society
Division of Organic Chemistry for a Summer Undergraduate
Research Fellowship. The authors thank Charles Wandler
for assistance with NMR spectrometry and Dr. John Greaves
(University of California, Irvine) for assistance with mass
spectrometry.
found to react with high diastereoselectivity (11:1 dr) in the
formation of 15.35-38
Supporting Information Available: Experimental pro-
cedures and spectroscopic and analytical data for all products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(34) Lee, K.-S.; Zhugralin, A. R.; Hoveyda, A. H. J. Am. Chem. Soc.
2009, 131, 7253–7255.
(35) Diastereomeric ratios determined by GC analysis. See the
Supporting Information for details on establishing the relative stereo-
chemistry.
(36) Typical diastereoselectivities of hydride additions to 14 range from
1.5:1 to 6:1 except in the case of L-Selectride (>99:1 dr).
(37) Kruger, D.; Sopchik, A. E.; Kingsbury, C. A. J. Org. Chem. 1984,
OL100468F
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