Enantioselective β-arylation of ketones enabled by lithiation/borylation/1,4-addition sequence under flow conditions

Article abstract of DOI:10.1002/anie.201202221

The first multistep asymmetric catalysis in flow has been realized using a lithiation/borylation/rhodium-catalyzed 1,4-addition sequence. The three-step sequence starts from readily available and inexpensive aryl bromides, affording β-arylated ketones in

Full text of DOI:10.1002/anie.201202221

Angewandte
Chemie
DOI: 10.1002/anie.201202221
Continuous Asymmetric Synthesis
Enantioselective b-Arylation of Ketones Enabled by Lithiation/
Borylation/1,4-Addition Sequence Under Flow Conditions**
Wei Shu and Stephen L. Buchwald*
In the past decade, continuous flow methods have attracted
much attention from both industry and academia due to their
several well-defined advantages over batch procedures.[1,2]
Recently, multistep synthesis in continuous flow has emerged
as a powerful alternative to traditional procedures as it often
allows one to circumvent time-consuming and labor-intensive
isolation of intermediates.[3] Despite recent advances, multi-
step synthesis under flow conditions remains challenging due
to its increased complexity as compared to single-step flow
processes. Solvent and/or catalyst compatibility, flow rate
synergy, as well as the effect of byproducts and impurities
from upstream reactions on the downstream ones must be
considered.[4] Additionally, the precipitation of solids is one of
Scheme 1. Three-step strategy for the synthesis of chiral b-arylated
the biggest obstacles in the implementation of reactions into
continuous flow, which often leads to irreversible blocking of
the reactor. Although several techniques have been devel-
oped to address this problem, such as segmented liquid–liquid
flow,[5] ultrasonication,[4a,6] and mechanical vibration,[7] the
handling of solid in multistep continuous flow processes still
remains a challenge.
Despite the many advantages associated with asymmetric
catalysis,[8] reports of asymmetric catalysis under continuous
flow conditions with good levels of enantioselectivity are still
rare.[9,10] One reason might be that reactions in flow are
usually conducted at elevated temperatures to decrease
residence time, while most asymmetric catalytic methods
are conducted at low temperatures.[11] Pioneered by
Miyaura,[12] Hayashi,[12b,13] and Carreira,[14] the rhodium-
catalyzed asymmetric 1,4-addition of boronic acids to a,b-
unsaturated compounds is an important method for the
ketones under flow conditions.
1,4-addition, using lithium aryltriisopropylborates generated
in a lithiation/borylation sequence.
Notably, this process is enabled by the efficient handling
of solids under acoustic irradiation conditions. The use of
a flow process allows for the rapid, safe and efficient lithiation
of aryl bromides at room temperature, their conversion into
aryl triisopropylborates, and subsequent utilization in rho-
dium-catalyzed asymmetric 1,4-addition.
We began our studies on the lithiation/borylation/1,4-
addition sequence using the setup depicted in Figure 1 with 4-
bromoanisole and 2-cyclohexenone 3a as substrates. First,
a solution of 4-bromoanisole (2.2m in THF, 42 mLminÀ1) was
mixed with nBuLi (2.5m in hexanes, 42 mLminÀ1) using a T-
mixer and introduced into a reactor (0.01 inch inner diameter,
2.6 cm of perfluoroalkoxyalkane (PFA) tubing) at room
temperature. Under batch conditions, this reaction would
require cryogenic temperatures and the slow addition of
nBuLi. However, using flow conditions, the lithium–bromide
À
construction of C C bonds to afford enantioselective b-
substituted carbonyl compounds.[15,16] Many arylboronic acids
are, unfortunately, innately unstable, as well as expensive
starting materials. Thus, we sought to develop a process that
enabled the preparation of the requisite boron reagents
in situ, followed by asymmetric 1,4-addition under flow
conditions (Scheme 1). Herein, we report our success in
developing the continuous rhodium-catalyzed asymmetric
[*] Dr. W. Shu, Prof. Dr. S. L. Buchwald
Department of Chemistry, Massachusetts Institute of Technology
77 Massachusetts Avenue, Cambridge, MA 02139 (USA)
E-mail: sbuchwal@mit.edu
Homepage: http://mit.edu/chemistry/buchwald/
[**] W.S. and S.L.B. thank Novartis International AG for funding. The
Varian NMR instrument used was supported by the National
Institutes of Health (Grant No. CHE 9808061). We thank Dr.
Meredeth A. McGowan and Dr. Christine Nguyen for assistance
with the preparation of this manuscript.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201202221.
Figure 1. Continuous-flow setup for the lithiation/borylation/asymmet-
ric 1,4-addition sequence.
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Table 1: Ligand effect on the rhodium-catalyzed asymmetric 1,4-addition
of 2a to 2-cyclohexenone 3a.
exchange was complete in 2 s, accompanied by a minimum
amount of 4-n-butylanisole. Upon exiting the first reactor, the
aryllithium was mixed with a stream of B(OiPr)3 in THF
before entering a second reactor, in which the lithium
aryltriisopropylborate was generated. The reaction mixture
was quenched by an aqueous solution of KOH (0.2m,
60 mLminÀ1), and then the combined solution was mixed
with THF solutions of 2-cyclohexenone (1.0m, 20 mLminÀ1)
and a catalyst (0.0030m rhodium and 0.0036m ligand,
130 mLminÀ1). This combination was allowed to flow through
a third reactor, after which, the product-containing solution
was collected. The second and the third reactors were both
submerged in a preheated 608C sonication bath to help mix
the three phases of the reaction and prevent clogging. Due to
the poor solubility of lithium triisopropyl(4-methoxyphenyl)-
borate 2a, the B(OiPr)3 used must be dilute in order to
prevent clogging. After testing several concentrations, we
found that a 0.12m solution of B(OiPr)3 in THF could be
successfully applied in this flow sequence.
Next, we tested various chiral ligands under biphasic
conditions using the optimal lithiation/borylation conditions
(Table 1). It was found that when bicyclo[2.2.2]octadiene-
based chiral diene ligands L1[17] or L2[18] were used, 4a was
obtained in good yield with good enantioselectivity in 10 min
(Table 1, entries 1 and 2). In contrast, the use of L3[19] gave the
desired product 4a in only 33% yield (83% ee) under the
same conditions (Table 1, entry 3). Chiral phosphite ligands[20]
(L4 and L5) were not suitable for this reaction under biphasic
conditions (Table 1, entries 4 and 5). The reaction was
sluggish with biaryl-based chiral ligands (L6 and L7),[12,21]
despite 4a being formed with good enantioselectivity
(Table 1, entries 6 and 7). Employing (R,R)-1,2-bis-(4-
methoxyphenyl)phenylphosphino)ethane (L8) gave racemic
4a in 92% yield (Table 1, entry 8). The best result was
obtained with (R,R)-QuinoxP (L9)[22] as 4a was produced in
96% yield with 99% ee in only 10 min (Table 1, entry 9).
Interestingly, it has been reported that a lower ee (94%) was
obtained when a boronic acid was used with this ligand
employing conventional procedures.[22]
Entry
Ligand
Yield of
ee [%][b]
4a [%][a]
1
2
3
4
5
6
7
8
9
L1
L2
L3
L4
L5
L6
L7
L8
L9
83
90
33
18
–
14
19
92
96 (R)
91 (R)
83 (S)
84 (S)
–
93 (S)
95 (R)
4 (S)
96 (90)
99 (R)
[a] GC yields based on 3a with biphenyl as an internal standard. The
number in the parenthesis is the yield of isolated product after flash
chromatography. [b] The ee values were determined by HPLC analysis
using a Chiracel OJ-H 250 mm column.
We next examined the scope for this lithiation/borylation/
rhodium-catalyzed asymmetric 1,4-addition sequence under
flow conditions and the results are summarized in Table 2.
The process could be successfully carried out with a variety of
substituted aryl bromides containing either electron-donating
or -withdrawing substituents. This circumvented the use of
relatively expensive boronic acids,[23] and afforded the corre-
sponding b-arylated products in good yields with excellent
levels of enantioselectivity. Five-, six-, and seven-membered
cyclic enones were all good substrates. In addition, acyclic
enones with phenyl or aliphatic substituents were also
efficiently transformed. Notably, even a small substituent,
such as a methyl group at the b-position, also led to the
desired product 4i in 86% yield with 93% ee. Relatively
hindered ortho-substituted aryl bromides also reacted in
minutes to give the conjugate addition product 4j in 91%
yield with 97% ee.
the first example of a multistep asymmetric catalytic sequence
in flow. Of importance is that this process uses readily
available and inexpensive aryl bromides instead of arylboron
reagents, operates at mild temperature and obviates the need
for isolation or purification of intermediates. The protocol is
quite general and can be accomplished in minutes. These
features should render this process amenable to the synthesis
of enantioenriched b-arylated ketones on large scale.
Experimental Section
General procedure: A THF solution of aryl bromide was loaded into
a plastic syringe and a solution of n-butyllithium (2.5m in hexanes)
was loaded into a second plastic syringe. These two solutions were
mixed at a T-mixer and delivered to the first microreactor made of
PFA (perfluoroalkoxyalkane) tubing (0.01–0.04 inch inner diameter)
using a Harvard Apparatus syringe pump. A second syringe pump
was used to deliver a solution of B(OiPr)3 (0.12m in THF), and it was
mixed with the stream exiting the first reactor at a second T-mixer.
The combined stream was introduced into the second microreactor
In summary, we have demonstrated an efficient three-step
protocol for the synthesis of enantiopure b-arylated ketones
in continuous flow under sonication conditions, representing
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Received: March 20, 2012
Published online: && &&, &&&&
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Keywords: 1,4-addition · b-arylation · asymmetric catalysis ·
flow chemistry · multistep reactions
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Angew. Chem. Int. Ed. 2012, 51, 1 – 5
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Angewandte
Chemie
Communications
Continuous Asymmetric Synthesis
W. Shu, S. L. Buchwald*
&&&& — &&&&
Enantioselective b-Arylation of Ketones
Enabled by Lithiation/Borylation/1,4-
Addition Sequence Under Flow
Conditions
The first multistep asymmetric catalysis
in flow has been realized using a lithia-
tion/borylation/rhodium-catalyzed 1,4-
addition sequence. The three-step
sequence starts from readily available and
inexpensive aryl bromides, affording b-
arylated ketones in good yields with high
levels of enantioselectivity.
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!