The mechanism and an improved asymmetric allylboration of ketones catalyzed by chiral biphenols

Article abstract of DOI:10.1002/anie.200904715

Giving it a boost: A mechanistic study of the enantioselective asymmetric titled reaction with allyldiisopropoxyborane catalyzed by chiral biphenols revealed a key ligand exchange process which liberates isopropyl alcohol. The addition of iPrOH to the rea

Full text of DOI:10.1002/anie.200904715

Angewandte
Chemie
DOI: 10.1002/anie.200904715
Allylations
The Mechanism and an Improved Asymmetric Allylboration of
Ketones Catalyzed by Chiral Biphenols**
David S. Barnett, Philip N. Moquist, and Scott E. Schaus*
The asymmetric allylboration reaction is an extensively
studied synthetic method.[1] The operational simplicity and
chiral building blocks afforded readily account for the utility
of the reaction.[2] Studies aimed at the development of a
catalytic enantioselective allylboration of ketones[3] identified
chiral biphenols as effective promoters of the reaction;
however, the reaction required the use of relatively high
catalyst loadings [Eq. (1)].[4] Reducing catalyst loadings
employed in organocatalytic reactions has proven challenging
Scheme 1. Proposed catalytic cycle for asymmetric allylboration reac-
tion catalyzed by chiral biphenols.
but recent advances in this area have been successful
(2 mol% or lower),[5] especially when coupled with experi-
ments designed to provide insight into the reaction mecha-
nism.[6] We initiated a study of the allylboration reaction
mechanism with the aim of simultaneously identifying a
reaction which requires less catalyst and also addresses the
scope and limitations of the method. Herein we report the
results of our mechanistic experiments which led to the
development of a reaction that uses 2 mol% of the catalyst
under solvent-free reaction conditions at room temperature
to afford the products in greater than or equal to 98:2
enantiomeric ratio (e.r.).
Our study began by evaluating the role of both the catalyst
and isopropyl alcohol in the catalytic cycle. The key steps
include a crucial ligand exchange processes at the beginning
and end of the catalytic cycle; a process crucial for activation
of the boronate (Scheme 1).[4,7,8] The catalyst 1 reacts with the
allylboronate 2 to afford the exchange product 3, a species
that can be detected by direct ESI-MS analysis of the reaction
mixture. We presumed this step to be reversible. Spectro-
scopic analysis of the reaction mixture using 1H NMR
methods indicated the formation of 3 along with free catalyst
1. Our previous studies determined the rate dependence on
catalyst 1 to be first order.[4] However, the order in isopropyl
alcohol had not been established. If the overall rate of
reaction was dependent on the initial exchange process, the
addition of isopropyl alcohol to the reaction should inhibit the
observed rate. This dependence would indeed be the case for
a single or double exchange process leading to 3 or a cyclic
boronate.[9] We performed experiments designed to ascertain
the effect of isopropyl alcohol on both the rate and
enantioselectivity in the allylboration of acetophenone
(Figure 1).
The formation of product was monitored by in situ
monitoring of the reaction as a function of the isopropyl
alcohol concentration ([iPrOH]), using IR methods. For
operational simplicity the reactions were performed at room
temperature using 10 mol% 1. Under these reaction condi-
tions, and in the absence of iPrOH the enantiomeric ratio
(e.r.) of the product formed was 2.2:1. As a preliminary study,
we chose to monitor the dependence of both the rate and e.r.
on [iPrOH] over a two-fold concentration range relative to
boronate. The observed rate increased almost three-fold
(Figure 1); coincident with the rate increase was a substantial
increase in the observed enantioselectivity. With the addition
of one equivalent iPrOH relative to boronate the reaction
rate doubled and the enantioselectivity increased to 65:1 e.r.
At a concentration of iPrOH which was 1.5 times that of
[boronate], the reaction rate began to plateau at three-fold
[*] D. S. Barnett, P. N. Moquist, Prof. Dr. S. E. Schaus
Department of Chemistry, Center for Chemical Methodology and
Library Development at Boston University (CMLD-BU)
Life Science and Engineering Building, Boston University
24 Cummington Street, Boston, Massachusetts, 02215 (USA)
Fax: (+1)617-353-6466
E-mail: seschaus@bu.edu
[**] This research was supported by the NIH (R01 GM078240).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200904715.
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Communications
in a hydrolytically unstable boronate reagent. We sought to
identify a boronate possessing a desirable balance of kinetic
reactivity and thermodynamic stability. Cyclic boronates such
as dioxaborolanes and dioxaborinanes are substantially more
stable.[10] They can be prepared and purified with greater ease
and stored for longer periods than acyclic boronates. In
addition to the enhancement of stability, cyclic boronates
would produce a tethered alcohol upon catalyst exchange,
which would more readily liberate the catalyst at the end of a
reaction cycle (Scheme 1). Use of the allyldioxaborinane 9 in
the allylboration reaction with 15 mol% 1 and acetophenone
8a (0.1m in PhCH3) at room temperature resulted in good
yields of the product in 4:1 e.r. after 24 hours. We postulated
that the addition of another alcohol may facilitate the
reaction. Isopropyl alcohol was added to the reaction of 8a
and 9 to yield the product 10a with low yields (60% after
3 days) but high enantiopurity (99:1 e.r.). The addition of
iPrOH effectively reduced the background reaction while
coincidentally inhibiting the catalytic reaction. This observa-
tion can be understood by the Lewis acid–base coordination
of B-allyldioxaborinane and iPrOH. We reasoned that a less
coordinating alcohol such as tBuOH would still accelerate the
catalyzed reaction by facilitating ligand exchange, but not
inhibit the overall rate of the reaction. The addition of tBuOH
to the reaction in a slight excess (> 1 equiv) relative to the
boronate concentration ([9]) afforded the desired product in
near quantitative yields with excellent enantioselectivity
(>99:1 e.r.). While investigating the reaction of 8a and 9 we
found that the reaction proceeded well in the absence of
solvent[11] with complete conversion and no loss in enantio-
selectivity. The optimized reaction conditions using the
allyldioxaborinane 9 required the use of 2 mol% 1 and two
equivalents tBuOH relative to ketone at room temperature.
The catalyst concentration should be noted. The catalyst
loading is calculated based on ketone concentration. Since the
catalyst activates the boronate, relative to [boronate] the
catalyst loading is 1.3 mol%. The use of lower catalyst
loadings resulted in lower rates of reaction with no loss in
enantioselectivity. Finally, the reaction of acetophenone could
be scaled to 5 grams, achieving similar yields and enantiose-
lectivities. The catalyst could be recovered in 90% yield from
the reaction.
The reaction conditions proved general for a number of
substrates (Table 1). Excellent yields and enantioselectivies
were achieved for a broad range of ketones (> 90% yield,
> 97:3 e.r.). In some examples, the reaction proved slow. For
these substrates, additional catalyst was used to improve the
rate (entries 6–8, 11, 13, and 16). The reaction using 9 also
exhibited a broader scope than the previous reaction. Phenyl
acetophenone 8i was found to be a poor substrate under the
previous reaction conditions (< 15% yield, low enantioselec-
tivities). However, the reaction of 8i with 9 afforded the
allylboration product in 98% yield and 99:1 e.r. (entry 9). The
boronate 9 was also reacted in high enantioselectivities with
b-ketoester 8p (entry 16), a particularly difficult substrate
because of facile enolization. Crotylation reactions with 8a
using E- (11a) and Z-crotyldioxaborinane (11b) provided
products 12a and 12b, respectively, in excellent yields with
high enantio- and diastereoselectivities (Scheme 2).
Figure 1. The effect of isopropyl alcohol on reaction rate and enantio-
selectivity. Reactions were run with 0.075 mmol 1, 1.5 mmol boronate
2, and 0.75 mmol acetophenone in PhCH3 (0.25m) for 15 h under Ar
at RT, with subsequent purification by flash chromatography on silica
gel (n-hexane/EtOAC 50:1). Enantiomeric ratios were determined by
chiral HPLC methods.
greater than the parent rate and the enantioselectivity was
determined to be 99:1 e.r. The inclusion of more than one
equivalent iPrOH resulted in a substantially improved
reaction process exhibiting higher enantioselectivities and
increased rates in comparison to the parent reaction at room
temperature.
The improved reaction may be understood using the
proposed catalytic cycle (Scheme 1). Our observations dem-
onstrate that the rate-determining exchange process is not the
initial formation of the active boronate species 3 but the
liberation of the catalyst 1 from allylation product 6 (kex).
Although the parent catalyzed reaction was nominally
selective (2.2:1 e.r.), there is a four-fold increase over the
reaction run in the absence of catalyst. The catalyst 1 serves to
increase the overall rate of reaction; however, the effective
catalyst concentration is reduced by the formation of 6 in
addition to the other species in the reaction ([1] =
[cattotal]À[3]À[5]À[6]). The inclusion of iPrOH in the cata-
lyzed reaction increases the overall catalyst concentration
([1]), thereby increasing the overall rate and consequently
changing the rate-limiting step of the reaction process. The
effective catalyst concentration approaches the actual catalyst
concentration as the exchange rate increases by the addition
of iPrOH (kex[6][iPrOH]). The apparent rate of reaction is the
maximum rate possible for the allylboration bond-formation
process. Observations made from our investigations led us to
consider additional improvements of the reaction.
We focused our attention on the identity of the boronate
utilized in the reaction and catalyst concentration as areas for
improvement. The characteristic of the allyldiisopropoxybor-
onate 2 that makes it ideal for use in the catalytic reaction is
the same characteristic that makes it a difficult reagent to
prepare and store; the lability of the isopropoxy groups result
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Table 1: Asymmetric allylboration of ketones.[a]
Entry Ketone
Product Yield [%][b] E.r.[c]
1
2
3
4
8a: R1 =Ph, R2 =CH3
10a
96
88
93
97
95
95
93
92
98
93
95
99:1
99:1
99:1
99:1
99:1
98:2
>99:1
99:1
>99:1
99:1
>99:1
8b: R1 =4-CH3OC6H4, R2 =CH3 10b
8c: R1 =4-NO2C6H4, R2 =CH3
8d: R1 =4-BrC6H4, R2 =CH3
8e: R1 =3-FC6H4, R2 =CH3
8 f: R1 =2-BrC6H4, R2 =CH3
8g: R1 =2-thienyl, R2 =CH3
8h: R1 =3-thienyl, R2 =CH3
8i: R1 =Ph, R2 =-CH2Ph
10c
10d
10e
10 f
10g
10h
10i
5
6[d]
7[e]
8[e]
9
10
8j: R1 =Ph, R2 =-(CH2)3Ph
8k: R1 =Ph, R2 =-CH2CH2Cl
10j
10k
Scheme 2. Asymmetric crotylboration of acetophenone.
11[e]
12
8l: n=1, X=CH2
8m: n=2, X=CH2
8n: n=2, X=O
10l
10m
10n
95
97
95
98:2
99:1
99:1
13[e]
14
15
8o
8p
10o
10p
96
98
98:2
99:1
16[e]
[a] Reactions were run with 0.02 mmol (S)-1, 2.0 mmol tBuOH,
1.0 mmol of ketone 8, and 1.5 mmol B-allyl-1,3,2-dioxaborinane 9 at RT
for 24 h under Ar, with subsequent purification by flash chromatography
on silica gel (n-hexane/EtOAC 50:1). [b] Yield of isolated product.
[c] Determined by chiral HPLC methods. [d] Reaction was run in
PhCH3 (0.25m) with 0.075 mmol (S)-1. [e] Reaction was run with
0.04 mmol (S)-1.
Figure 2. The effect of tert-butyl alcohol on reaction rate and enantio-
selectivity. Reactions were run with 0.15 mmol 1, 1.5 mmol boronate 9,
and 0.75 mmol acetophenone in PhCH3 (0.3m) for 15 h under Ar, with
subsequent purification by flash chromatography on silica gel
(n-hexane/EtOAC 50:1). Enantiomeric ratios were determined by chiral
HPLC methods.
We performed mechanistic experiments to determine if
the allylboration reaction of 9 either proceeded according to
the previously proposed reaction mechanism or through an
alternative reaction process. The reaction exhibited a first-
order rate dependence on [1], consistent with our previous
findings. We also observed the formation of the correspond-
ing exchange product complex of boronate 8 and 1 by using
In summary, a mechanistic investigation of the asymmet-
ric allylboration reaction of ketones catalyzed by chiral
biphenols has resulted in the development of a highly
optimized reaction. Key observations about the ligand
exchange process aided the design of a reaction that uses
less catalyst (from 15 mol% to 2 mol%) at ambient temper-
atures (from À358C to room temperature). The new reaction
exhibits similar mechanistic characteristics to the original
with a first-order rate dependence on catalyst concentration
and chiral biphenol–boronate complex formation. Insight
afforded by this study will enable additional reaction devel-
opment, application of the method to asymmetric synthesis,
and identification of novel catalytic processes.
1
ESI-MS and H NMR methods, which were consistent with
our proposed mechanism (Scheme 1).[4,7c,8] The reaction rate
and enantioselectivity were also monitored as a function of
[tBuOH] (Figure 2). Similar to the observations obtained
using boronate 2 and iPrOH, there was a coincident increase
in rate and enantioselectivity with increasing concentrations
of tBuOH. However, at [tBuOH]/[9] greater than one, the
rate became slower. Based on our previous observations using
iPrOH with 9, the rate may be inhibited by a weakly
coordinating Lewis acid–base coordination of B-allyldioxa-
borinane.[10] Whereas the cyclic boronate 9 appears to be
more sensitive to Lewis base coordination, the mechanism by
which 9 proceeds is consistent with our previous observations.
Received: August 24, 2009
Published online: October 8, 2009
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Communications
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Keywords: boron · homogeneous catalysis ·
reaction mechanisms · synthetic methods
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