Lanthanum tricyanide-catalyzed acyl silane-ketone benzoin additions and kinetic resolution of resultant α-silyloxyketones

Article abstract of DOI:10.1021/jo100312w

We report the full account of our efforts on the lanthanum tricyanide-catalyzed acyl silane-ketone benzoin reaction. The reaction exhibits a wide scope in both acyl silane (aryl, alkyl) and ketone (aryl-alkyl, alkyl-alkyl, aryl-aryl, alkenyl-alkyl, alkynyl-alkyl) coupling partners. The diastereoselectivity of the reaction has been examined in both cyclic and acyclic systems. Cyclohexanones give products arising from equatorial attack by the acyl silane. The diastereoselectivity of acyl silane addition to acyclic α-hydroxy ketones can be controlled by varying the protecting group to obtain either Felkin-Ahn or chelation control. The resultant α-silyloxyketone products can be resolved with selectivity factors from 10 to 15 by subjecting racemic ketone benzoin products to CBS reduction.

Full text of DOI:10.1021/jo100312w

pubs.acs.org/joc
Lanthanum Tricyanide-Catalyzed Acyl Silane-Ketone Benzoin
Additions and Kinetic Resolution of Resultant r-Silyloxyketones
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 February 24, 2010
We report the full account of our efforts on the lanthanum tricyanide-catalyzed acyl silane-ketone
benzoin reaction. The reaction exhibits a wide scope in both acyl silane (aryl, alkyl) and ketone (aryl-
alkyl, alkyl-alkyl, aryl-aryl, alkenyl-alkyl, alkynyl-alkyl) coupling partners. The diastereoselectivity
of the reaction has been examined in both cyclic and acyclic systems. Cyclohexanones give products
arising from equatorial attack by the acyl silane. The diastereoselectivity of acyl silane addition to
acyclic R-hydroxy ketones can be controlled by varying the protecting group to obtain either
Felkin-Ahn or chelation control. The resultant R-silyloxyketone products can be resolved with
selectivity factors from 10 to 15 by subjecting racemic ketone benzoin products to CBS reduction.
Introduction
coupling of acyl anion equivalents to ketones has proved more
challenging. Stoichiometric methods for ketone acylation do
exist; however, general strategies are not in place for perform-
ing those reactions asymmetrically.5 Suzuki,3c,6 Enders,3d,7
and You8 have achieved NHC-catalyzed intramolecular
aldehyde-ketone benzoin cyclization for the formation of
five- and six-membered rings (Figure 1). Asymmetric variants
for the intramolecular reaction have also been reported that
proceed in up to 98% yield and 99% ee.6b,7a
An important example of intermolecular catalytic ketone
acylation was reported by Demir and co-workers, who
described the cyanide-catalyzed coupling of acyl phospho-
nates9 with ketones in chemical yields of 41-95%.10 Most of
the examples employed electron-deficient ketones and eno-
lizable protons were often replaced with flourine. While a
limited number of aliphatic ketones could be successfully
Polarity umpolung has evolved into a powerful synthetic
tool for making otherwise challenging carbon-carbon
bonds.1 The archetypical example of this strategy is the
benzoin reaction, the mechanism of which was elucidated
by Lapworth in 1903 in his report on the homodimerization
of aldehydes under cyanide anion catalysis.2 Since then, both
N-heterocyclic carbene (NHC) and metallophosphite cata-
lysts have been developed to promote the asymmetric ben-
zoin3 and cross silyl benzoin (acyl silane-aldehyde benzoin)4
reaction, respectively. Despite the recent advances in the
scope and utility of the benzoin reaction, the direct catalytic
(1) Corey, E. J.; Seebach, D. Angew. Chem., Int. Ed. 1965, 4, 1077–1078.
(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 cited 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.
(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) (a) Bausch, C. C.; Johnson, J. S. Adv. Synth. Catal. 2005, 347, 1207–
1211. (b) Demir, A. S.; Reis, B.; Reis, O.; Eymur, S.; Gollu, M.; Tural, S.;
Saglam, G. J. Org. Chem. 2005, 72, 7439–7442.
(10) Demir, A. S.; Esiringu, I.; Gollu, M.; Reis, O. J. Org. Chem. 2009, 74,
2197–2199.
(4) Linghu, X.; Potnick, J. R.; Johnson, J. S. J. Am. Chem. Soc. 2004, 126,
3070–3071.
(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.
DOI: 10.1021/jo100312w
r
Published on Web 04/14/2010
J. Org. Chem. 2010, 75, 3317–3325 3317
2010 American Chemical Society

Tarr and Johnson
JOCArticle
TABLE 1. Optimization of M(CN)3 Catalysta
FIGURE 1. Previous examples of intra- and intermolecular-
ketone benzoin reactions.
employed, they required modification of the reaction condi-
tions and/or addition of various cocatalysts. Notably, the
reaction was incompatible with methyl-aryl ketones and
ortho-substituted aryl ketones. We recently published an
initial report of the La(CN)3-catalyzed coupling betweeen
acyl silanes and a variety of aryl-alkyl and alkyl-alkyl
ketones.11 The purpose of this paper is to fully describe the
development and expansion of this methodology, which
encompasses a broad range of ketone substrates, achieves
substrate-controlled diastereoselectivity, and enables a sub-
sequent kinetic resolution that allows access to enantioen-
riched products.
entry
catalyst
x mol %
convn (%)b
2a:3b
yield (%)c
1
2
3
4
5
6
7
8
9
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
nd
nd
nd
10
11
2
1
7
aConditions: 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. bDetermined by 1H NMR
spectroscopy. Yields of analytically pure material after SiO2 column
chromatography.
c
Results
Reaction Development and Optimization. Having pre-
viously found La(CN)3 to be an effective catalyst for pro-
moting the cross silyl benzoin between acyl silanes and
aldehydes,12 we were hopeful that we might be able to engage
ketone electrophiles with acyl silanes using the same catalyst.
Gratifyingly, acyl silane 1a reacted with 1 equiv of aceto-
phenone in the presence of 20 mol % of La(CN)3 in THF to
deliver the desired R-silyloxyketone product in approxi-
mately 40% yield within 20 min. Competing with the desired
product formation was the deprotonation of acetophenone,
leading to the quenched silyl cyanohydrin (3a). A retro-
benzoin pathway was also found to be operative, as subjec-
tion of the product 2a to the reaction conditions led to the
formation of 3a and acetophenone. Employing 2 equiv of
ketone proved to be optimal, as the product 2a was obtained
in greater that 90% yield when these conditions were applied.
In a screen of metal cyanide catalysts, we found that numer-
ous M(CN)n species effectively promoted the reaction and
gave complete conversion (Table 1); however, La(CN)3
provided the highest ratio of desired product (2a) to the
quenched cyanohydrin (3a). 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 and 1 mol %, the reaction stalled
with incomplete conversion after 24 h.
FIGURE 2. NOESY analysis to determine equatorial attack.
which accounts for most of the remaining mass balance. For
some substrates, it was convenient to deprotect the silyl
ether to the alcohol by using TBAF at 0 °C in order to
separate the benzoin product from the ketone starting
material. In all cases, this desilylation proceeded smoothly
within 10 min, and elimination to the alkene was never
observed.
Products 2l and 2m demonstrate the high degree of
stereoselectivity possible in the reaction with cyclic electro-
philes, each being isolated as a single diastereomer. To
determine the relative stereochemistry between the existing
alkyl group and the newly introduced acyl group, 2-D
NOESY was employed (Figure 2). 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 β-protons on the cyclohexane ring. Similar NOE’s were
observed for compound 2m. This leads us to propose the
illustrated stereochemistry with the hydroxyl group cis to
the existing alkyl group, arising from an equatorial attack of
the acyl silane to generate an axial alcohol.
Scope: Ketone Partner. To probe the scope of the reaction,
we used acyl silane 1a and varied the ketone employed
(Table 2). The reactions proceeded with complete consump-
tion of acyl silane, with isolated yields ranging from 40% to
95%. All examples employed enolizable electrophiles. The
major byproduct in all cases was the quenched cyanohydrin,
We also hoped to couple acyl silanes with diaryl ketones.
While lacking enolizable protons, the additional steric
constraints make this a challenging transformation. Initial
attempts at employing benzophenone under the normal
reaction conditions led to less than 20% yield of the desired
coupling product. Cyanohydrin formation (presumably
(11) Tarr, J. C.; Johnson, J. S. Org. Lett. 2009, 11, 3870–3873.
(12) (a) Linghu, X.; Bausch, C. C.; Johnson, J. S. J. Am. Chem. Soc. 2005,
127, 1833–1840. (b) Bausch, C. C.; Johnson, J. S. J. Org. Chem. 2004, 69,
4283–4285.
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JOCArticle
SCHEME 1. Addition of Acyl Silane to Diaryl Ketones
TABLE 2. Scope of Ketone Coupling Partnera
pump over fifty min allowed us to isolate the desired
product in 80% yield after silyl deprotection and column
chromatography. This procedure works for both carbo-
cyclic and heterocyclic diaryl ketones, as evidenced by
Scheme 1.
Felkin-Ahn and Chelation Control. After achieving high
levels of diastereocontrol with cyclic electrophiles, we sought
to determine if we could extend this control to acyclic
systems. We hoped that we could use an R-stereocenter to
exert either Felkin-Ahn13 or chelation14 diastereocontrol on
the ketone-benzoin coupling. We found that acyl silane 1a
did couple with various protected acetoins to yield R,β-
dihydroxy ketones. As with the diaryl ketone substrates, a
slow addition of the acyl silane to a suspension of the ketone
and catalyst provided increased yields. We screened a num-
ber of hydroxyl protecting groups and reaction conditions,
summarized in Table 3. While we achieved minimal ketone
facial selectivity with the benzyl protecting group, we found
that the MOM group afforded moderate levels of diaste-
reocontrol (2.7:1) favoring the chelation product (MOM=
CH2OCH3). A solvent screen identified Et2O and MTBE as
giving similar diastereoselectivity; however, Et2O afforded
higher yields in the reaction. Metal salt additives and various
Ln(CN)3 catalysts were examined; however, none of the
results improved upon the La(CN)3 catalyst system.
To investigate the feasibility of obtaining the opposite
(Felkin-Ahn) diastereomer, we investigated nonchelating
silyl protecting groups (Table 4). As expected, we found that
as the size of the silyl group was increased from TMS to TES
to TBS, the dr likewise increased (this trend did not extend to
the TIPS group). Upon varying the reaction temperature, we
found that we could increase the dr of the reaction up to 10:1
by running the reaction at -20 °C; however, the diastereo-
selectivity came at the expense of yield as competing side
reactions could not be suppressed even with slow addition of
1a at the lower temperature. To verify chelation and Felkin-
Ahn controlled products were formed under the respective
conditions, the products were converted to the free diols and
thence to their acetonides. 2D-NOESY analysis of the
resultant acetonides confirmed that 4a (Figure 3) was indeed
the syn-diol arising from chelation control and 5c was
consistent with the anti-diol and Felkin-Ahn control.
Scheme 2 shows the final optimized conditions, yields, and
dr values for both the chelation- and Felkin-Ahn-controlled
ketone benzoin reactions.
aConditions: 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. bYields of analytically pure
material after SiO2 column chromatography. cProduct was treated with
1.0 equiv of TBAF at 0 °C for 10 min to enable purification. Yield
reported over two steps.
(13) (a) Cherest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968, 9,
2199–2204. (b) Anh, N. T.; Eisenstein, O. Tetrahedron Lett. 1976, 17, 155–
158. (c) Anh, N. T.; Eisenstein, O. Top. Curr. Chem. 1980, 88, 145–162.
(14) (a) Cram, D. J.; Abd Elhafez, F. A. J. Am. Chem. Soc. 1952, 74, 5828–
5835. (b) Reetz, M. T.; Hullmann, M.; Seitz, T. Angew. Chem., Int. Ed. 1987,
26, 477–480.
from adventitious water), acyl silane dimerization, and
desilylation of the acyl silane were all observed. We found
that by freshly distilling the benzophenone prior to use and
employing a slow addition of the acyl silane via syringe
J. Org. Chem. Vol. 75, No. 10, 2010 3319

Tarr and Johnson
JOCArticle
TABLE 3. Optimization of Chelation Control in Addition to Protected Acetoinsa
entry
R
M(CN)3
solvent
THF
Et2O
additive
yield (%)b
4a:4bb
1c
2c
3
4
5
6
7
8
9
Bn
Bn
La(CN)3
La(CN)3
La(CN)3
La(CN)3
La(CN)3
La(CN)3
La(CN)3
La(CN)3
La(CN)3
Ce(CN)3
Er(CN)3
Yb(CN)3
none
none
none
none
none
none
LiCl
MgBr2
ZnBr2
none
none
none
49
45
42
80
10
71
70
1:1.4
1.1:1
1.4:1
2.7:1
1.2:1
2.1:1
2.1:1
MOM
MOM
MOM
MOM
MOM
MOM
MOM
MOM
MOM
MOM
THF
Et2O
MeOcC5H9
MeOtBu
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
NDPd
NDPd
76
72
49
10
11
12
2.0:1
1.8:1
1.2:1
aConditions: 1.0 equiv of 1a added via slow addition, 2.0 equiv of ketone, 0.10 equiv of La(CN)3, THF, [1a]0 = 0.04 M. bYields and dr determined by
1H NMR. c1a added via normal addition. dNDP = no desired product
TABLE 4. Optimization of Felkin-Ahn Control in Addition to
SCHEME 2. Optimized Conditions for Achieving Felkin-Ahn
or Chelation Control
Protected Acetoinsa
entry
R
T (°C)
yield (%)b
5c:5db
1
2
3
4
5
TMS
TES
TBS
TIPS
TBS
0
0
0
65
70
80
74
48
2:1
4:1
6:1
3.5:1
10:1
The major product in the reaction was the 4-silyloxycyano-
hydrin ketone resulting from Stetter-type 1,4-addition to the
enone (Table 5, entry 1).15 The La(CN)3 catalyst loading was
increased to 33 mol % (stoichiometric in -CN) for substrates
that gave a large amount of 1,4 addition byproduct (Table 5,
entries 1-4 and 6). The silyl cyanohydrins exist as inseparable
mixtures of diastereomers. Cleavage of the silyl group with
TBAF converted both diastereomers to the 1,4-diketone.
Fortunately, we found that the yield of the 1,2-addition
product increased when enones with more steric hindrance at
the β-position were employed. Additionally, acyclic enones
gave more of the 1,2-addition product than comparably sub-
stituted cyclic alkenes. An ynone was also found to be a com-
petent coupling partner as evidenced by the formation of 6j. No
conjugate addition product was observed with this ynone.
Scope: Acyl Silane. In addition to varying the ketone
component, we examined the reaction’s tolerance with re-
spect to the variation of the acyl silane coupling partner. The
results of this survey are shown in Table 6. Electron-rich acyl
silanes deliver a more nucleophilic (silyloxy)nitrile anion
intermediate and performed the best, as expected.10,16 Yields
of the coupling product decreased as a function of electron
density on the aryl ring, as evidenced by entries 1, 4, and 5.
0
-20
aConditions: 1.0 equiv of 1a, 2.0 equiv of ketone, 0.10 equiv of
La(CN)3, THF, [1a]0 = 0.04 M. bYields and dr were determined by
1H NMR.
FIGURE 3. NOESY analysis to confirm Felkin-Ahn and chela-
tion controlled addition.
Scope: Enones. After expanding the scope of the reaction
to include alkyl-alkyl, aryl-alkyl, and aryl-aryl ketones, we
turned our attention to enones and ynones. Choosing cyclo-
hexenone as our initial model system, we were disappointed
to isolate only a small amount (9%) of the desired product.
(15) Degl’Innocenti, A.; Ricci, A.; Mordini, A.; Reginato, G.; Colotta, V.
Gazz. Chim. Ital. 1987, 117, 645–648.
(16) Nahm, M. R.; Potnick, J. R.; White, P. S.; Johnson, J. S. J. Am.
Chem. Soc. 2006, 128, 2751–2756.
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JOCArticle
TABLE 5. Scope of R,β-Unsaturated Coupling Partnersa
TABLE 6. Scope of Acyl Silane Coupling Partner
aConditions: 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. bYields of analytically pure
material after SiO2 column chromatography. cProduct was treated with
1.0 equiv TBAF at 0 °C for 10 min to enable purification. Yield reported
over two steps.
aromatic acyl silanes, both heteroaromatic and aliphatic
silanes were tolerated. The more sterically demanding TES
and TBS groups were also tolerated with almost no decrease
in yield (7b, 7c).
Kinetic Resolution. Having established the scope of the
reaction with respect to both coupling partners, we turned
our attention to accessing the products in an asymmetric
fashion. Our attempts to develop a catalytic asymmetric
variant have been thus far unsuccessful. Demir demonstra-
ted that both Lewis and Brønsted acid cocatalysts were capable
of accelerating the intermolecular coupling of acyl phospho-
nates and ketones.10 We observed that addition of a thio-
urea cocatalyst did increase the relative rate of the reaction at
-30 °C as compared to just the La(CN)3; however, we saw no
asymmetric induction in the products when chiral variants
were applied. Similarly, box- and pybox-complexes with Ln-
(CN)3 also led to isolation of racemic product. Upon examin-
ing metallophosphite catalysts, which our group has used with
success in other acyl silane coupling reactions, we found that
no desired product was obtained.4,16,17 We conjecture that this
aConditions: 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. bYields of analytically pure
material after SiO2 column chromatography, dr determined by 1H NMR
spectroscopy. cStoichiometric cyanide was employed. dProduct was
treated with 1.0 equiv of TBAF at 0 °C for 10 min to provide diketone,
which was used for characterization. Yield refers to yield of the
silylcyanohydrin.
The effect of steric hindrance in the acyl silane compo-
nent was examined with entry 7, which delivered the desi-
red product with a slight decrease in yield. In addition to
(17) (a) 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. (b) Garrett,
M. R.; Tarr, J. C.; Johnson, J. S. J. Am. Chem. Soc. 2007, 129, 12944–12945.
J. Org. Chem. Vol. 75, No. 10, 2010 3321

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JOCArticle
SCHEME 3. Kinetic Resolution of R-Silyloxy Ketones via CBS Reduction
may be due to steric repulsion between the phosphite-silane
adduct and the ketone electrophile.
SCHEME 4. Determination of Absolute Configuration of
Enantioenriched Product
In lieu of a direct asymmetric addition, we explored other
possibilities for obtaining optically enriched products. When
the silyloxyketone 2a was subjected to a CBS reduction,18
the remaining starting material was enantioenriched when
the reaction was quenched at partial conversion. We there-
fore decided to examine a kinetic resolution of the silyloxy-
ketones obtained from the acyl silane-ketone benzoin reac-
tion using the CBS reduction catalyst.19
We chose to use silyloxyketone 2a in optimizing the kinetic
resolution. Upon screening a number of reaction conditions,
we found BH3 THF to be the optimal borane source. Two
3
The absolute stereochemistry of product (þ)-7d was deter-
mined to be R by comparison to a sample of ent-7d, prepared
by Sharpless asymmetric dihydroxylation, oxidation, and
silylation (Scheme 4). The remaining absolute configurations
were assigned by analogy. Silyloxyketone 2a was subjected to
the CBS reduction and the reaction monitored by SFC of
aliquots. Following chromatography, enantioenriched (þ)-2a
was recovered in 44% yield and 88% ee.
equivalents of the hydride source worked best, as lower
loadings often resulted in the reaction stalling at low con-
versions and er. The reaction proceeded in both ethereal and
aromatic solvents, but Et2O gave the shortest reaction time
while maintaining high selectivity factors. Higher selectivity
factors were obtained at lower temperatures at the expense of
reaction rate, with -10 °C being the best compromise.
With the optimized conditions in hand, we sought to
explore the scope of the kinetic resolution. Selectivity factors
obtained with methyl-aryl ketones were between 10 and 15
(Scheme 3). The reaction works well for aryl-methyl ketones;
however, other substrates (including dialkyl, vinyl-alkyl, and
alkynyl-alkyl) resulted in very little discrimination between
enantiomers. The bulkier TBS group can be substituted for
the TMS protecting group, which results in a slightly higher
selectivity factor.
Discussion
Challenges to the Ketone Benzoin. As can be inferred from
the relative dearth of literature precedent, the intermolecular
ketone-benzoin reaction poses significant challenges as
compared to the intermolecular aldehyde-benzoin and the
intramolecular ketone-benzoin. Some of these potential
pitfalls are illustrated in Figure 4.
The principal source of the challenges lies in the lower
reactivity of ketones relative to aldehydes due to the extra
steric demand posed by the second carbonyl substituent.
This lower desired reactivity may lead to side reactions,
including dimerization of the acyl silane starting material
or deprotonation of the ketone by the silyloxycyanohydrin
anion. A third potential side reaction is a retro-benzoin
reaction. Bode has recently reported an NHC-catalyzed
(18) (a) Corey, E. J.; Shibata, S.; Bakshi, R. K. J. Org. Chem. 1988, 53,
2861–2863. (b) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37,
1986–2012.
(19) (a) Schmalz, H.-G.; Jope, H. Tetrahedron. 1998, 54, 3457–3464. (b)
Bringmann, G.; Hinrichs, J.; Pabst, T.; Henschel, P.; Peters, K.; Peters, E.-M.
Synthesis 2001, 155–167. (c) Dorizon, P.; Martin, C.; Darah, J.-C.; Fiaud, J.-C.;
Kagan, H. B. Tetrahedron: Asymmetry 2001, 12, 2625–2630. (d) Velcicky, J.;
Lanver, A.; Lex, J.; Prokop, A.; Wieder, T.; Schmalz, H.-G. Chem.;Eur. J.
2004, 10, 5087–5110.
3322 J. Org. Chem. Vol. 75, No. 10, 2010

Tarr and Johnson
JOCArticle
employed. We were pleased to find that a slow addition
of the acyl silane effectively generated a large excess of
ketone, which inhibited silane dimerization with challenging
substrates.
Scope of the Reaction. The system described herein for acyl
silane-ketone benzoin reactions offers a substantial improve-
ment in the reaction scope of ketone-benzoin methodology.
As Demir had illustrated the coupling of electron-deficient
and nonenolizable ketones, we chose to address substrates
with no general procedure for their synthesis in place. The
coupling of aryl-methyl ketones was accomplished in a very
general manner: electron-rich, neutral, and heteroaromatic
substrates were tolerated, as well as those with ortho sub-
stituents (albeit in moderately lower yield). Dialkyl sub-
strates were well tolerated, although R-branching exerts a
strong negative impact on the yields via competitive quench-
ing of the silylcyanohydrin. Sterically encumbered diaryl
ketones underwent coupling in high yields once side reac-
tions were minimized via a slow addition.
FIGURE 4. Proposed mechanistic pathway for acyl silane-ketone
benzoin reaction (black) and possible side reactions (gray).
In exploring the diastereoselectivity of the reaction, we
found that with cyclohexanone-derived ketones, the acyl
silane adds equatorially to avoid 1,3-diaxial interactions,
even in the case of 2-methylcyclohexanone, where the vicinal
methyl group also occupies the equatorial position. In each
case, a single diastereomer was obtained. In the fused decalin
systems, the dr was decreased to 2.5:1. Diastereocontrol was
also achieved in acyclic systems by employing a protected
R-hydroxy group to direct either Felkin-Ahn or chelation
control. Chelation control was achieved by employing the
MOM protecting group in conjunction with a noncoordinat-
ing ethereal solvent, albeit in a modest 2.7:1 dr. Attempts to
achieve higher dr were made by adding a soluble metal
cocatalyst. The La(CN)3 is a heterogeneous catalyst, which
we felt might preclude efficient chelation to the protected
acetoin. The soluble metal additives we examined led to
either no change or a decrease in the reaction yield and dr.
Switching to a coordinating solvent (THF) and a TBS pro-
tecting group allowed us to access the Felkin-Ahn product
in 6:1 dr and 80% yield.
In the addition of acyl silanes to enones, we encountered
competing 1,2-benzoin-type and 1,4-Stetter-type reactivity.
In the Stetter-type reaction, the resultant enolate was not
sufficiently nucleophilic to undergo silyl transfer and initiate
catalyst turnover. This is consistent with previous work in
our lab on the metallophosphite-catalyzed alkene silylacyl-
ation reaction, where R,β-unsaturated amides were neces-
sary as enolates derived from enones were not sufficiently
nucleophilic to initiate silyl transfer and achieve catalyst
turnover.16 Thus, the reactions between acyl silanes and
some enones became stoichiometric in cyanide and required
use of a full equivalent to achieve complete conversion in the
cases where substantial 1,4-addition occurred. In cyclohexene-
derived enones, γ-substitution was particularly effective at
preventing conjugate addition as the substituents extend above
or below the plane of the alkene to block the incoming
nucleophile.
FIGURE 5. NHC-catalyzed retro-benzoin reaction of tertiary
R-hydroxyketone.
retro-benzoin reaction of R-hydroxyketones as a strategy to
mask unstable enal functionality (Figure 5).20 The viability
of retro-benzoin reaction was established in the following
control experiments: when product 2a or 7f was treated with
La(CN)3 in THF, acetophenone and the corresponding
silyloxycyanohydrin were obtained.
In the course of our studies, we encountered byproduct
arising from each of the three possible side reactions noted.
Ketone enolization was largely a function of the steric
hindrance and acidity of the ketone substrate, and mani-
pulation of the reaction conditions was typically unsuccess-
ful in suppressing this pathway. For example, sterically
hindered pinacolone and enolizable methyl pyruvate failed
to provide useful yields of the coupling products under a
variety of conditions. Entries 8 and 9 in Table 2 and
isobutyrophenone (not tabulated) demonstrate the sensiti-
vity to even small changes in sterics. While 2h can be
obtained in good yield (73%) from propiophenone, employ-
ing isobutyrophenone as the ketone leads to a yield of
<10%, despite propiophenone having a lower pKa (24.4
as compared to 26.3).21 However, cyclobutyl phenyl ketone
coupled to give 2i in 63% yield, despite possessing a very
similar steric environment to isobutyrophenone. It should
be noted that, with the exception of the diaryl ketones, all of
the substrates employed are enolizable. In some substrates,
drying and distillation of the ketone to remove adventitious
water slightly reduced the amount of quenched silyloxy-
cyanohydrin obtained. Dimerization of the acyl silane was
observed with some of the more encumbered ketones,
notably when diaryl ketones and protected acetoins were
Kinetic Resolution. To obtain enantioenriched products
from this reaction, we developed a kinetic resolution based
on the CBS reduction. While there are reports employing the
CBS catalyst in kinetic resolutions,19 none of the accounts
examined R-hydroxyketones as the substrate. We found that
the silyl protecting group was necessary for successful kinetic
(20) Chiang, P.-C.; Kaeobamrung, J.; Bode, J. W. J. Am. Chem. Soc.
2007, 129, 3520–3521.
(21) Bordwell, F. G.; Harrelson, J. A., Jr. Can. J. Chem. 1990, 68, 1714–
1718.
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Tarr and Johnson
JOCArticle
resolution: when the free R-hydroxyketone was employed,
no rate difference was observed for the two enantiomers.
Thus, the acyl silane-ketone benzoin reaction directly fur-
nishes the substrate necessary for the resolution. It stands to
reason that the tertiary carbinol acts as Rlarge, with the aryl
group functioning as Rsmall, as increasing the steric bulk of
the silyl group from TMS to TBS led to an increase in the
selectivity factor.
2.0 Hz, 2H), 3.78 (s, 3H), 1.76 (s, 3H), 0.06 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ 199.1, 162.7, 145.5, 133.3, 128.4,
127.6, 127.0, 124.1, 112.9, 83.5, 55.2, 30.2, 1.8; TLC (20%
EtOAc/petroleum ether) Rf 0.44, (5% Et2O/petroleum
ether) Rf 0.29; LRMS (ESI) calcd for C19H25O3Si 329.2,
found 329.0.
General Procedure for Deprotection of r-Silyloxyketones (B).
The title compound was dissolved in dry THF (10 mL) in a
100-mL flame-dried round-bottomed flask and cooled to 0 °C.
Tetrabutylammonium flouride (0.50 mL, 1.0 M solution in
THF, 1.0 equiv based on 100% yield from initial coupling)
was added. The reaction turned yellow and rapidly faded to
colorless. The reaction was monitored by TLC (20% EtOAc/
petroleum ether) and was complete within 10 min for all sub-
strates. The reactions were poured into 1:1 Et2O/H2O (40 mL),
and the aqueous layer was extracted with two 20-mL portions of
Et2O. The organic extracts were combined, dried over MgSO4,
and concentrated on a rotary evaporator. The crude material
was purified by flash chromatography on silica gel with use of
3:7 Et2O/petroleum ether as the eluent to furnish the desired
product in analytically pure form. Yields for these products are
reported over two steps.
Conclusion
In conclusion, we have developed a broadly applicable
and operationally simple method for intermolecular ketone
acylation through a La(CN)3-catalyzed silyl benzoin reac-
tion. Various ketone classes including aryl-alkyl, alkyl-alkyl,
aryl-aryl, enones, and ynones have been employed. The
reaction can be done in a diastereoselective fashion on both
cyclic and acyclic systems. In cyclic systems, equatorial
attack is favored, and in acyclic systems both chelation and
Felkin-Ahn products can be selected by judicious choice of
protecting group and solvent with acetoin electrophiles.
Products arising from aryl-methyl ketones can be resolved
through a novel kinetic resolution that makes use of the CBS
reduction.
2-Hydroxy-2-(2-methoxyphenyl)-1-(4-methoxyphenyl)propan-
1-one (Table 2, 2f). The title compound was prepared according
to General Procedure A, followed by General Procedure B, using
100 mg of acyl silane, 145 mg of 20-methoxyacetophenone, 12 mg
of LaCl3, 105 μL of nBuLi, and 15 mg of TMSCN in 11 mL of
THF. After chromatography, 84 mg (61% yield) of the title
compound was isolated as a white solid (mp 89-90 °C). Analy-
tical data for 2f: IR (thin film, cm-1) 3435, 2965, 2932, 1667,
Experimental Section
General Procedure for La(CN)3-Catalyzed Ketone Benzoin
Reaction (A). In the glovebox, a 25-mL round-bottomed
flask was charged with LaCl3 (12 mg, 0.049 mmol), a stir bar,
and THF (3 mL). A second 10-mL flask was charged with
0.48 mmol of acyl silane, 1.00 mmol of ketone, and 8 mL of
THF. The flasks were capped with a septum, removed from the
glovebox, and placed under positive pressure of N2. The
suspension of LaCl3 was cooled to -78 °C for 5 min, then
nBuLi (1.4 M in hexanes, 105 μL, 0.147 mmol) was added. The
cloudy suspension was stirred for 10 min at -78 °C and
warmed to 0 °C for 15 min. TMSCN was added as a solution
in THF (∼0.5 M, 15 mg, 0.152 mmol). The catalyst suspension
was stirred at 0 °C for 10 min and allowed to warm to rt over
30 min. After the catalyst suspension reached room tempera-
ture, the solution of acyl silane (0.48 mmol, 1 equiv) and ketone
(0.96 mmol, 2 equiv) was added via syringe. The reaction
was monitored by TLC (20% EtOAc/petroleum ether) and
all substrates showed complete consumption of starting ma-
terial within 20 min. Upon completion, the reaction mixture
was poured into 40 mL of 1:1 Et2O/H2O in a separatory funnel.
The layers were separated and the aqueous layer was extra-
cted with two 20-mL portions of Et2O. The organic extracts
were combined, dried over MgSO4, filtered, and concen-
trated on a rotary evaporator. Column chromatography of
the crude material on silica gel with 5:95 Et2O/petroleum
ether as the eluent furnished the desired product in analyti-
cally pure form or as a mixture of product and ketone start-
ing material (see General Procedure for Deprotection of
R-Silyloxyketones).
1
1600, 1509, 1489, 1464, 1251, 1174, 1123, 1026, 965, 844; H
NMR (400 MHz, CDCl3) δ 7.75 (d, J=8.8 Hz, 2H), 7.66 (d, J=
7.6 Hz, 1H), 7.30 (t, J=8.0 Hz, 1H), 7.06 (t, J=7.2 Hz, 1H),
6.79-6.73 (m, 3H), 4.98 (s, 1H), 3.79 (s, 3H), 3.49 (s, 3H), 1.85 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 200.4, 163.1, 157.0, 132.5,
131.6, 129.6, 126.2, 121.1, 113.3, 112.1, 76.7, 55.3, 55.2, 26.2;
TLC (20% EtOAc/petroleum ether) Rf 0.12, (30% Et2O/petro-
leum ether) Rf 0.11; LRMS (ESI) calcd for C17H18O4Na 309.1,
found 309.1.
General Procedure for Kinetic Resolution of r-Silyloxyketones
(C). The R-silyloxyketone was massed into a dry Teflon coated
screw-cap vial with a stir bar, then purged with N2. Diethyl ether
(2 mL) was added, and the reaction was capped and brought into
the glovebox. A 0.1 M toluene solution of the CBS catalyst
(10 mol %) was added, and the reaction was capped and
removed from the glovebox. The reaction was then cooled to
-10 °C, and a 1.0 M THF solution of BH3 THF was added
3
to the reaction. The reaction was monitored by quenching
aliquots in MeOH. To stop the reaction, MeOH was added,
and the contents were poured into 1:1 Et2O/saturated NH4Cl.
The organic layer was separated, washed with brine, dried
over MgSO4, filtered, and concentrated. The resolved material
was separated from the monosilylated diol by column chro-
matography on silica gel with 1:9 Et2O/petroleum ether as the
eluent.
(R)-1-(4-Methoxyphenyl)-2-phenyl-2-((trimethylsilyl)oxy)pro-
pan-1-one (Scheme 3, (þ)-2a). The title compound was pre-
pared according to General Procedure C with use of 30 mg of
(()-2a, 100 μL of the CBS catalyst as a 0.1 M solution in
1-(4-Methoxyphenyl)-2-phenyl-2-(trimethylsilyloxy)propan-1-
one (Table 2, 2a). The title compound was prepared according
to General Procedure A with 100 mg of acyl silane, 120 mg of
acetophenone, 12 mg of LaCl3, 105 μL of nBuLi, and 15 mg of
TMSCN in 11 mL of THF. After chromatography, 151 mg
(96% yield) of the title compound was isolated as a colorless
oil. Analytical data for 2a: IR (thin film, cm-1) 2959, 1675,
toluene, and 75 μL of BH3 THF as a 1.0 M solution in THF.
3
The reaction was stopped at partial conversion after 3 h.
Conversion was determined by 1H NMR spectroscopy and
the enantiomeric excess of the recovered starting material was
determined by SFC (OD column, 150 psi, 1.5 mL/min, and
0.5% MeOH modifier, tmajor=12.6 min, tminor=13.5 min). The
reaction was stopped after 56% conversion and the starting
material was recovered in 85% ee, with a selectivity factor of s=
13.2. The starting material was separated from the diol by flash
1
1600, 1508, 1253, 1175, 1154, 1127, 868, 844; H NMR (400
MHz, CDCl3) δ 7.93 (dd, J=6.8, 2.0 Hz, 2H), 7.48-7.46 (m,
2H), 7.33-7.29 (m, 2H), 7.23-7.19 (m, 1H), 6.74 (dd, J=6.8,
3324 J. Org. Chem. Vol. 75, No. 10, 2010

Tarr and Johnson
JOCArticle
chromatography. Analytical data are identical with those of
(()-2a, [R]25 136.0 (c 3.30, CH2Cl2). Deprotection of (þ)-2a
[R]25D -30.4 (c 0.70, CH2Cl2).
Medical Sciences, GM068443) and Novartis (Early Career
Award to J.S.J.).
D
with TBAF cleanly yielded the free hydroxyl product,
Supporting Information Available: Characterization data
for all compounds, copies of 1H and 13C NMR spectra,
and racemic and enantioenriched SFC traces of compounds
subjected to kinetic resolution. This material is available free of
charge via the Internet at http://pubs.acs.org.
Acknowledgment. Funding for this work was provided by
the National Institutes of Health (National Institute of General
J. Org. Chem. Vol. 75, No. 10, 2010 3325