Lanthanum tricyanide-catalyzed acyl silane - Ketone benzoin additions

Article abstract of DOI:10.1021/ol901314w

Figur Presented Lanthanum tricyanide efficiently catalyzes a benzoin-type coupling between acyl silanes and ketones. Yields range from moderate to excellent over a broad substrate scope encompassing aryl, alkyl, electron-rich, and sterically hindered keto

Full text of DOI:10.1021/ol901314w

ORGANIC
LETTERS
2009
Vol. 11, No. 17
3870-3873
Lanthanum Tricyanide-Catalyzed Acyl
Silane-Ketone Benzoin Additions
James C. Tarr and Jeffrey S. Johnson*
Department of Chemistry, UniVersity of North Carolina at Chapel Hill,
Chapel Hill, North Carolina 27599-3290
jsj@unc.edu
Received June 11, 2009
ABSTRACT
Lanthanum tricyanide efficiently catalyzes a benzoin-type coupling between acyl silanes and ketones. Yields range from moderate to excellent
over a broad substrate scope encompassing aryl, alkyl, electron-rich, and sterically hindered ketones.
R-Hydroxycarbonyls are valuable building blocks for numer-
ous targets in organic synthesis.1 The benzoin addition
provides direct access to R-hydroxy ketones, and its strategic
application has grown in the past decade. In addition to
traditional metal cyanide catalysts,2 N-heterocyclic carbenes
and metallophosphites have been identified as efficient
asymmetric catalysts for intramolecular and intermolecular
benzoin reactions3 and the cross silyl benzoin reaction.4
Despite the wide range of electrophiles that have been
successfully engaged by acyl anion equivalents in the benzoin
and cross silyl benzoin reactions, the direct catalytic coupling
of acyl anion equivalents to ketones remains a challenge due
to the lower reactivity of ketones that presumably permits
nonproductive enolization to become competitive. Stoichio-
metric methods for ketone acylation do exist; however,
general strategies are not in place for conducting those
reactions asymmetrically.5 Suzuki,6,3c Enders,7,3d and You8
have reported carbene-catalyzed intramolecular aldehyde-
ketone benzoin cyclization for the formation of five- and six-
membered rings (Figure 1). Asymmetric variants for the
Figure 1. Previous examples of aldehyde-ketone benzoin reactions.
intramolecular reaction have also been reported that proceed
in up to 98% yield and 99% ee.6b,7,8
The single example of intermolecular catalytic ketone
acylation comes from the recent work of Demir and
co-workers,9 who described the cyanide-catalyzed coupling
of acyl phosphonates10 with ketones in chemical yields of
(1) (a) Coppola, G. M.; Schuster, H. F. R-Hydroxy Acids in Enantiose-
lectiVe Synthesis; Wiley-VCH: Weinheim, Germany, 1997. (b) Hanessian,
S. Total Synthesis of Natural Products: The Chiron Approach; Pergamon:
New York, 1983; Chapter 2.
(2) Lapworth, A. J. Chem. Soc. 1903, 83, 995–1005.
(3) (a) Enders, D.; Kalfass, U. Angew. Chem., Int. Ed 2002, 41, 1743–
1745, and references therein. (b) Dunkelmann, P.; Kolter-Jung, D.; Nitsche,
A.; Demir, A. S.; Siegert, P.; Lingen, B.; Baumann, M.; Pohl, M.; Muller,
M. J. Am. Chem. Soc. 2002, 124, 12084–12085. (c) Hachisu, Y.; Bode,
J. W.; Suzuki, K. AdV. Synth. Catal. 2004, 346, 1097–1100. (d) Enders,
D.; Oliver, N. Synlett 2004, 2111–2114.
(5) Deprotonation of silyl cyanohydrins: (a) Bunnelle, E. M.; Smith,
C. R.; Lee, S. K.; Singaram, S. W.; Rhodes, A. J.; Sarpong, R. Tetrahedron
2008, 64, 7008–7014. (b) Wessig, P.; Glombitza, C.; Mueller, G.; Teubner,
J. J. Org. Chem. 2004, 69, 7582–7591. Lithiation of vinyl ethers: (c) Palomo,
C.; Oiarbide, M.; Arceo, E.; Garcia, J. M.; Lopez, R.; Gonzalez, A.; Linden,
A. Angew. Chem., Int. Ed 2005, 44, 6187–6190. Deprotonation of dithianes:
(d) Nicolaou, K. C.; Magolda, R. L.; Sipio, W. J.; Barnette, W. E.; Lysenko,
Z.; Joullie, M. M. J. Am. Chem. Soc. 1980, 102, 3784–3793.
(4) Linghu, X.; Potnick, J. R.; Johnson, J. S. J. Am. Chem. Soc. 2004,
126, 3070–3071.
10.1021/ol901314w CCC: $40.75
Published on Web 08/05/2009
 2009 American Chemical Society

41-95%; however, the reaction is largely limited to electron-
poor ketones. In general, enolizable protons were replaced
with fluorine while ortho-substituted aryl and aryl-methyl
ketones typically failed to give the desired product. Tuning
of the reaction conditions and/or addition of a cocatalyst
(Cu(OTf)2 or thiourea) was required for certain substrate
combinations.
Our laboratory has developed the use of acyl silanes as
acyl anion equivalents in the racemic11 and enantioselective4
cross silyl benzoin reaction. Additionally, we have found
La(CN)3 to be a particularly reactive catalyst for promoting
the cross silyl benzoin between acyl silanes and aldehydes,
with reaction times under 5 min.12 We postulated that under
La(CN)3 catalysis we might be able to engage ketone
electrophiles with acyl silanes. We were hopeful that these
conditions might lead to a more general reaction for
intermolecular ketone acylation. Pitfalls to be navigated in
this variant include undesired dimerization of the acyl silane,
nonproductive proton transfer between the (silyloxy)nitrile
anion intermediate and the ketone electrophile, and potential
retro-benzoin reaction13 of the R-siloxy ketone product
(Figure 2).
THF to deliver the desired R-hydroxyketone product in
approximately 40% yield within 20 min. Competing with
desired product formation was the deprotonation of ac-
etophenone, leading to the quenched silyl cyanohydrin (3).
In contrast to the aldehyde silyl benzoin reaction,11 the ketone
benzoin addition is apparently reversible: subjection of the
product 2a to the reaction conditions led to the formation of
3a and acetophenone. For the reaction of 1a with acetophe-
none, the retro-benzoin occurs at a much slower rate than
the forward reaction and was minimized by shorter reaction
times. Employing 2 equiv of ketone proved to be optimal,
as a slight decrease in yield was observed when 3 equiv was
used. We screened a number of metal cyanide catalysts and
found that numerous M(CN)n species effectively promoted
the reaction and gave complete conversion (Table 1);
Table 1. Catalyst Screen and Optimizationa
entry catalystb x mol % convn (%)c
2a:3d
yield (%)e
1
2
3
4
5
6
7
8
Ce(CN)3
Y(CN)3
20
20
20
20
20
20
20
10
5
100
100
100
100
100
100
100
100
100
62
3.2:1
4.5:1
6.5:1
6.8:1
8.0:1
8.6:1
10.5:1
nd
nd
nd
nd
nd
nd
nd
nd
95
94
nd
nd
Yb(CN)3
Sc(CN)3
Er(CN)3
Hf(CN)4
La(CN)3
La(CN)3
La(CN)3
La(CN)3
La(CN)3
9
10
11
nd
nd
nd
2
1
7
a Conditions: 1.0 equiv of 1a, 2.0 equiv of ketone, THF, [1a]0 ) 0.04
M, rt, 20 min. b Catalyst prepared in situ as described in the Supporting
Information c Conversion determined by 1H NMR spectroscopy. d Ratio of
2a:3 determined by 1H NMR spectroscopy. e Yields of analytically pure
material after SiO2 column chromatography.
Figure 2. Proposed acyl silane-ketone benzoin reaction.
Gratifyingly, acyl silane 1a reacted with 1 equiv of
acetophenone in the presence of 20 mol % of La(CN)3 in
however, La(CN)3 provided the highest ratio of desired
product to the quenched cyanohydrin.14 Optimization of the
catalyst loading showed that the benzoin product could be
obtained in up to 95% yield with 10 mol % catalyst loading.
Lowering the catalyst loading to 5 mol % provided the
product with no change to the conversion or yield. Upon
further reduction of the catalyst loading to 2 mol % and 1
mol %, the reaction stalled with incomplete conversion after
24 h.
With optimized conditions in hand, we wished to examine
the scope of the reaction. Using acyl silane 1a, we varied
the ketone employed (Table 2). The reactions proceeded with
complete consumption of acyl silane, with isolated yields
ranging from 40 to 95%. It should be noted that all examples
(6) (a) Hachisu, Y.; Bode, J. W.; Suzuki, K. J. Am. Chem. Soc. 2003,
125, 8432–8433. (b) Takikawa, H.; Hachisu, Y.; Bode, J. W.; Suzuki, K.
Angew. Chem., Int. Ed. 2006, 45, 3492–3494. (c) Takikawa, H.; Suzuki,
K. Org. Lett. 2007, 9, 2713–2716.
(7) (a) Enders, D.; Niemeier, O.; Balensiefer, T. Angew. Chem., Int.
Ed. 2006, 45, 1463–1467. (b) Enders, D.; Niemeier, O.; Raabe, G. Synlett
2006, 2431–2434.
(8) Li, Y.; Feng, Z.; You, S.-L. Chem. Commun. 2008, 2263–2265.
(9) Demir, A. S.; Esiringu, I.; Gollu, M.; Reis, O. J. Org. Chem. 2009,
74, 2197–2199.
(10) (a) Bausch, C. C.; Johnson, J. S. AdV. Synth. Catal. 2005, 347,
1207–1211. (b) Demir, A. S.; Reis, B.; Reis, O.; Eymu¨r, S.; Go¨llu¨, M.;
Tural, S.; Saglam, G. J. Org. Chem. 2005, 72, 7439–7442.
(11) (a) Linghu, X.; Johnson, J. S. Angew. Chem., Int. Ed. 2003, 42,
2534–2536. (b) Linghu, X.; Bausch, C. C.; Johnson, J. S. J. Am. Chem.
Soc. 2005, 127, 1833–1840.
(12) Bausch, C. C.; Johnson, J. S. J. Org. Chem. 2004, 69, 4283–4285.
(13) Chiang, P.-C.; Kaeobamrung, J.; Bode, J. W. J. Am. Chem. Soc.
2007, 129, 3520–3521.
Org. Lett., Vol. 11, No. 17, 2009
3871

most of the remaining mass balance. For some substrates, it
was convenient to deprotect the silyl ether to the alcohol
using TBAF at 0 °C to separate the benzoin product from
the ketone starting material. In all cases, the deprotection
proceeded smoothly within 10 min, and elimination to the
alkene was never observed.
Table 2. Scope of Ketone Coupling Partnera
As the feasibility of coupling sterically unhindered
electron-deficient ketones had previously been demon-
strated with acyl phosphonates, we focused our attention
on expanding the scope of our reaction to include
previously problematic substrates. Aromatic, heteroaro-
matic, and aliphatic ketones were well tolerated without
any additional optimization of the reaction conditions or
experimental procedure. The reaction also proved ame-
nable to electron-neutral and electron-rich ketones. Ortho
substitution was tolerated, although the yields were
moderately lower. Entries 1, 8, and 9 demonstrate that
the reaction is sensitive to the steric bulk of the alkyl
substituent, with a decrease in yield observed moving from
2a to 2h to 2i. Interestingly, cyclobutyl phenyl ketone
allowed us to obtain 2i in 60% yield, whereas isobuty-
rophenone (not shown) gave ∼10% yield, despite a
relatively small difference in the steric environments of
each ketone. Unhindered aliphatic ketones were tolerated
equally as well as aryl-alkyl ketones. Steric hindrance
in 2-methylcyclohexanone led to a lower isolated yield
of 2m. Both 2l and 2m were isolated as single diastere-
omers. Ketones that failed to give appreciable coupling
yields include isobutyrophenone, benzophenone, biscy-
clohexylketone, pinacolone, and methyl pyruvate (not
shown).
In addition to varying the ketone component, we wished
to examine the reaction’s tolerance to the acyl silane
coupling partner. The results of this survey are shown in
Table 3. Electron-rich acyl silanes deliver a more nucleo-
philic (silyloxy)nitrile anion intermediate and performed
the best, as expected.9,15 Yields of the coupling product
decrease as a function of electron density on the aryl ring,
as evidenced by entries 1, 3, and 4. The effect of steric
hindrance in the acyl silane component was examined with
entry 6, which delivered the desired product with a modest
decrease in yield. In addition to aromatic acyl silanes, both
heteroaromatic and aliphatic silanes were reasonably well
tolerated. The more sterically demanding TES group was
also tolerated with almost no decrease in yield (4a).
Products 2l and 2m demonstrate the stereoselectivity
of the reaction with cyclic electrophiles, each being
isolated as a single diastereomer. To determine the relative
stereochemistry of the existing alkyl group and the newly
introduced acyl group, 2-D NOESY was employed (Figure
3). In 2l, an NOE was observed between the hydroxyl
proton and the two axial γ-protons, as well as between
the ortho-aryl protons and the axial ꢀ-protons on the
cyclohexane ring. Similar NOE’s were observed for
a Conditions: 1.0 equiv of 1a, 2.0 equiv of ketone, 0.10 equiv of La(CN)3,
THF, [1a]0 ) 0.04 M, rt, 20 min. b Yields of analytically pure material
after SiO2 column chromatography. c Product was treated with 1.0 equiv
of TBAF at 0 °C for 10 min to enable purification. Yield reported over two
steps.
(14) The metallophosphite catalysts developed by our laboratory failed
to successfully catalyze the reaction. See ref 4 and: Nahm, M. R.; Linghu,
X.; Potnick, J. R.; Yates, C. M.; White, P. S.; Johnson, J. S. Angew. Chem.
Int. Ed 2005, 44, 2377–2379.
employed enolizable electrophiles. The major byproduct in
all cases was the quenched cyanohydrin, which accounts for
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Org. Lett., Vol. 11, No. 17, 2009

alkyl group, arising from an equatorial attack of the acyl
silane to generate an axial alcohol.
Table 3. Scope of Silane Coupling Partnera
Figure 3. NOESY analysis to determine equatorial attack.
In conclusion, we have developed a new intermolecular
ketone acylation through a La(CN)3-catalyzed silyl benzoin
reaction employing acyl silanes as the acyl anion donor.
The reaction works well for a number of aryl-alkyl and
alkyl-alkyl ketones, greatly expands the scope of suitable
ketones that can engage in benzoin-type reactions with
acyl anion equivalents, and is operationally simple to
perform. Efforts toward an asymmetric variant are un-
derway.
Acknowledgment. Funding for this work was provided
by the National Institutes of Health (National Institute of
General Medical Sciences - GM068443) and Novartis (Early
Career Award to J.S.J.).
Supporting Information Available: Experimental pro-
cedures and analytical data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
a Conditions: 1.0 equiv of 1a, 2.0 equiv of ketone, 0.10 equiv of La(CN)3,
THF, [1a]0 ) 0.04 M, rt, 20 min. b Yields of analytically pure material after
SiO2 column chromatography. c Product was treated with 1.0 equiv of TBAF
at 0 °C for 10 min to enable purification. Yield reported over two steps.
OL901314W
compound 2m. This leads us to propose the illustrated
stereochemistry with the hydroxyl group cis to the existing
(15) Nahm, M. R.; Potnick, J. R.; White, P. S.; Johnson, J. S. J. Am.
Chem. Soc. 2006, 128, 2751–2756.
Org. Lett., Vol. 11, No. 17, 2009
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