Computationally Assisted Mechanistic Investigation and Development of Pd-Catalyzed Asymmetric Suzuki-Miyaura and Negishi Cross-Coupling Reactions for Tetra- ortho-Substituted Biaryl Synthesis

Article abstract of DOI:10.1021/acscatal.8b02509

Metal-catalyzed cross-coupling reactions are extensively employed in both academia and industry for the synthesis of biaryl derivatives for applications to both medicine and material science. Application of these methods to prepare tetra-ortho-substituted

Full text of DOI:10.1021/acscatal.8b02509

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Article
Computationally Assisted Mechanistic Investigation and Development
of Pd-Catalyzed Asymmetric Suzuki-Miyaura and Negishi Cross-
Coupling Reactions for Tetra-ortho-Substituted Biaryl Synthesis
Nitinchandra Dahyabhai Patel, Joshua D. Sieber, Sergei Tcyrulnikov, Bryan J Simmons, Daniel Rivalti,
Krishnaja Duvvuri, Yongda Zhang, Donghong A. Gao, Keith R. Fandrick, Nizar Haddad, Kendricks So
Lao, Hari Prasad Reddy Mangunuru, Soumik Biswas, Bo Qu, Nelu Grinberg, Scott Pennino, Heewon
Lee, Jinhua J. Song, B. Frank Gupton, Neil K. Garg, Marisa C Kozlowski, and Chris H Senanayake
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b02509 • Publication Date (Web): 20 Sep 2018
Downloaded from http://pubs.acs.org on September 20, 2018
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Computationally Assisted Mechanistic Investigation and Development of Pd-Catalyzed
Asymmetric Suzuki-Miyaura and Negishi Cross-Coupling Reactions for Tetra-ortho-
Substituted Biaryl Synthesis
,
a
,a,b
c
d
a,e
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Nitinchandra Dahyabhai Patel,* Joshua D. Sieber,* Sergei Tcyrulnikov, Bryan J. Simmons, Daniel Rivalti,
f
a
a
a
a
g
Krishnaja Duvvuri, Yongda Zhang, Donghong A. Gao, Keith R. Fandrick, Nizar Haddad, Kendricks So Lao,
a,e
a
a
a
h
a
Hari Prasad Reddy Mangunuru, Soumik Biswas, Bo Qu, Nelu Grinberg, Scott Pennino, Heewon Lee, Jinhua J.
a
e
d
c
,a,i
Song, B. Frank Gupton, Neil K. Garg, Marisa C. Kozlowski,* and Chris H. Senanayake*
a
Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Rd., Ridgefield, CT 06877, USA
b
Department of Chemistry, Virginia Commonwealth University, 1001 West Main St. Richmond, VA 23284-3028, USA
c
Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104-6323, USA
d
Department of Chemistry and Biochemistry, University of California, Los Angeles, CA 90095, USA
e
Department of Chemical and Life Science Engineering, Virginia Commonwealth University, 601 Main St./P.O. Box 843028,
Richmond, VA 23284-3028, USA
f
th
Department of Chemistry and Biochemistry, The Ohio State University, 100 West 18 Avenue, Columbus, OH 43210, USA
g
Department of Chemistry, University of Connecticut, 55 North Eagleville Rd., Storrs, CT 06269, USA
h
Material and Analytical Sciences, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Rd., Ridgefield, CT 06877, USA
i
Astatech BioPharmaceutical Corporation, 488 Kelin West Road, Wengjiang, Chendu, Sichuan 611130, P. R. China
nitinchandra.patel@boehringer-ingelheim.com
jdsieber@vcu.edu
marisa@sas.upenn.edu
chris@astatech.com.cn
Abstract: Metal-catalyzed cross-coupling reactions are extensively employed in both academia
and industry for the synthesis of biaryl derivatives for applications to both medicine and material
science. Application of these methods to prepare tetra-ortho-substituted biaryls leads to chiral
atropisomeric products that introduces the opportunity to use catalyst-control to develop
asymmetric cross-coupling procedures to access these important compounds. Asymmetric Pd-
catalyzed Suzuki-Miyaura and Negishi cross-coupling reactions to form tetra-ortho-substituted
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biaryls were studied employing a collection of P-chiral dihydrobenzooxaphosphole (BOP) and
dihydrobenzoazaphosphole (BAP) ligands. Enantioselectivities of up to 95:5 and 85:15 er were
identified for the Suzuki-Miyaura and Negishi cross-coupling reactions, respectively. Unique
ligands for the Suzuki-Miyaura reaction vs the Negishi reaction were identified. A computational
study on these Suzuki-Miyaura and Negishi cross-coupling reactions enabled an understanding
in the differences between the enantiodiscriminating events between these two cross-coupling
reactions. These results support that enantioselectivity in the Negishi reaction results from the
reductive elimination step, whereas all steps in the Suzuki-Miyaura catalytic cycle contribute to
the overall enantioselection with transmetalation and reductive elimination providing the most
contribution to the observed selectivities.
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Keywords: cross-coupling, Palladium, catalysis, asymmetric, phosphines
INTRODUCTION
2
2
Transition metal catalyzed sp -sp cross-coupling is one of the most powerful and
extensively utilized reactions in organic synthesis and materials science to access biaryl
1
2
3
compounds. Of these methods, the Pd-catalyzed Suzuki-Miyaura and Negishi cross-coupling
1
,4
have received considerable development over the past 40 years. Significant advances in the
5
development of highly active Pd-catalysts to achieve efficient processes have even allowed for
6
7
these reactions to be employed on industrial scale. In general, bulky electron-rich phosphines
8,9
and N-heterocyclic carbenes have been the ligands of choice to enable these cross-coupling
reactions. Despite these advances, cross-coupling catalysts for the formation of sterically
9
demanding biaryls, such as tetra-ortho-substituted systems, remains limited. Additionally,
because appropriately substituted tri- and tetra-ortho-substituted biaryls exist as chiral
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atropisomers about the biaryl axis, methods to forge this bond in an enantioselective fashion are
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0
11
important since many biologically active natural products and potential pharmaceuticals
contain single atropisomeric biaryl groups within their structure (Scheme 1). Therefore, one
desirable strategy to access the biaryl functionality in these compounds is to utilize a catalyst-
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controlled asymmetric Suzuki-Miyaura or Negishi sp – sp cross-coupling. While transition
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3
14
2
2
metal catalyzed asymmetric Suzuki-Miyaura and Negishi sp – sp cross-coupling reactions
have been developed, significantly fewer methods are available for the asymmetric construction
13c,d,p-t,14,15
of tetra-ortho-substituted biaryls.
OH
Me
Me
NH2
Me OH
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OH
H
HN
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O
OH
OH
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Me
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OH OMe
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Cl
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NH
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NH2
HO C
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OH
Michellamine B (2)
Vancomycin (1)
HO
OH OMe
O
iꢀPr
Me
Me
Me
OH
Me
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OH
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Me
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HO
HO
HO
OH
NH
OH CHO
O
Me
(M)ꢀgossypol (3)
N
Me
OH Me
Korupensamine A (4)
iꢀPr
5
HIV integrase inhibitor
Scheme 1: Natural Products and Bioactive Atropisomeric Compounds
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The first highly selective sp – sp cross-coupling reaction was reported in 1988 by
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Hayashi and coworkers to afford atopisomeric binaphthalenes in up to 95% ee using a
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Kumada-Corriu coupling. It was not until the year 2000 that the first reports of Pd-catalyzed
asymmetric Suzuki-Miyaura cross-coupling reactions were disclosed by the groups of
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Cammidge
and Buchwald.
Cammidge applied Hayashi’s chiral ferrocene ligand
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(
PFNMe) to access tri-ortho-substituted biaryl 8a with modest enantioselection (82:18 er,
Scheme 2). At the same time, Buchwald discovered that KenPhos could be employed as the
chiral ligand affording high enantioselectivities in the cross-coupling if the R-substituent of the
aryl halide coupling partner contained a Lewis basic donating group at the ortho-position (8b-d).
13b
11b,13n,x
Mechanistic studies on this class of cross-coupling by Buchwald and others
typically
consider reductive elimination as the enantiodetermining event in the catalytic cycle and have
shown that these Lewis basic ortho-substituents aid in the stabilization of the dominating
transition state. However, restricted rotation of the intermediate Pd-complexes as a function of
the ortho-substitution pattern of the aryl halide coupling partner can lead to scenarios where
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3f
13d,f
17
oxidative addition and transmetalation
may be involved in enantioselection. After these
initial reports, intense research into the area of catalyst-controlled asymmetric biaryl synthesis by
a variety of groups has led to the introduction of multiple chiral ligands that affect this
1
1,13
transformation (Scheme 2).
The majority of these studies have focused on the investigation
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1,13a,b,e-o,u-bb
of the formation of tri-ortho-substituted binapthalene derivatives.
Of these,
asymmetric synthesis of the aryl phosphonate products (8b – 8d) by asymmetric cross-coupling
have been one of the more common systems studied between different chiral catalysts with
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3a,b,j,n,u-y
11,13n,o
variable results.
For example, our group
introduced the P-chiral
dihydrobenzooxaphosphole (BOP) class of ligands (BIDIME, 9, 10) that are effective in
asymmetric cross-coupling reactions and are highly tunable to enable ligand modification for
enhancement of stereoselectivities. Suzuki-Miyaura cross-coupling to afford 8b employing BOP
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13n
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ligand 9b gave improved enantioselectivity to that of KenPhos; however, in the coupling to
produce 8b, KenPhos resulted in improved selectivity over ligand 9b. These results highlight the
fact that asymmetric cross-coupling reactions are typically very substrate dependent. Synthesis of
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b – 8d has also been acheived by asymmetric cross-coupling employing the atropisomeric,
13w
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13v
hemi-labile ligands Cy-MOP,
phosphine ligand (PQXPhos).
11,
and 12,
and using a helically-chiral polymeric
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13h
Other ligand classes including chiral dienes (13),
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13p
bis(hydrazones) (14), and a resin-supported chiral ligand (15) have all been shown to afford
high enantioselectivities in certain asymmetric Suzuki-Miyaura cross-coupling reactions. Despite
these significant advances in asymmetric cross-coupling methodologies, a general catalyst for a
wide-array of substitution patterns is still and unsolved problem. However, these technologies
13k,o
11
have found utility in natural product
and API synthesis (e.g. 5 via 8).
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Scheme 2: Asymmetric Suzuki-Miyaura Cross-Coupling Reactions to Prepare Tri-ortho-
Substituted Biaryls
While asymmetric Suzuki-Miyaura cross-coupling to generate tri-ortho-substituted
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3a,b,e-o,u-bb
biaryls (Scheme 2) has been successful with a variety of chiral ligand types,
synthesis of tetra-ortho-substituted biaryls by the same means has proven more difficult.
the
13c,d,p-t
1
3c,d,p-q
Tetra-ortho-substituted biaryl product 16 (Scheme 3)
has typically been the standard cross-
1
2c
coupling reaction analyzed when developing new catalysts for this challenging coupling.
16
15
While the Ni-catalyzed Kumada-Corriu coupling to prepare 16 was reported by Hayashi with
good enantioselectivity, the analogous Suzuki-Miyaura coupling has proven more
1
3c,d,p-t
13c,d
challenging.
Cammidge’s initial report
demonstrated that the PFNMe ligand gave good
enantioselectivity (93:7 er) in this reaction; however, long reaction time (6 days) was required
1
3r
affording only modest yield (Scheme 3). Espinet was able to optimize this result to reduce the
reaction time to 3 days at 5 mol % Pd loading by using Pd (dba) •CHCl as the Pd-source in the
2
3
3
presence of excess ligand (20 mol %) to improve the yield to 85%. The catalyst loading could be
reduced to employ 3 mol % Pd and 12 mol % ligand by utilizing Pd(MeCN) (BF ) in place of
4
4 2
Pd (dba) •CHCl as the precatalyst with an improvement in enantioselectivity of up to 95:5 er.
2
3
3
However, only 55% yield was obtained after 4 day reaction time. While these conditions can be
applied to the synthesis of 16, reaction times are still quite long (days), and the scope of the
reaction to other substrates is limited or has not been further investigated. Of the catalytic
1
3p
systems reported for the synthesis of 16 by Suzuki-Miyaura cross-coupling, Uozumi’s
conditions employing resin-supported phosphine ligand 15 are performed in water under
heterogeneous conditions that allow for recycling of the catalyst and show the most generality in
terms of reaction scope and enantioselectivity; however, only simple substituted naphthalenes
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have been disclosed in the coupling. Recently there has been increased focus on the development
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of Suzuki-Miyaura cross-coupling reactions performed using water
potential “greenness” of replacing typical organic solvents by water.
as the solvent due to the
2
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However, none of these
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methods have been extended to enantioselective cross-coupling. Uozumi’s report represents
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the only known catalytic asymmetric cross-coupling carried out in neat water. Future studies
are needed in this area to determine if improvements in catalytic asymmetric coupling reactions
can be achieved using water as solvent.
Scheme 3. Asymmetric Suzuki-Miyaura Cross-Coupling Reactions to Prepare Tetra-ortho-
Substituted Biaryls
As noted above (Scheme 2), previous work in our laboratories identified the P-chiral
dihydrobenzooxaphosphole (BOP) ligand class (BIDIME, 9, 10) as a highly tunable scaffold for
applications in many different types of asymmetric transformations by modulating the
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substituents of ligand structure 23 (Scheme 4). By variation of the oxaphosphole C-2 R-
7
p-
substituent and the bis(alkoxy)phenyl aryl-group of ligand 23, catalysts for Suzuki-Miyaura
t,9a,19a,23
11,13n-o
24
and asymmetric Suzuki-Miyaura
cross-coupling, Buchwald-Hartwig amination,
2
5
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27
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borylation, asymmetric propargylation of aldehydes and imines, asymmetric conjugate
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addition, asymmetric addition of boronic acids to imines, asymmetric allenylation of imines,
3
1
32
asymmetric hydrogenation of polar and unfunctionalized alkenes, asymmetric hydrogenation
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35
of heterocycles, asymmetric hydroformylation, and asymmetric hydrogenation of ketones
have all been developed. Due to the lack of a general solution for the asymmetric synthesis of
tetra-ortho-substituted biaryls using the Suzuki-Miyaura cross-coupling reaction, we sought to
investigate application of ligand family 23 as a potential solution to this problem because of the
modular nature of 23 and because of its good activity in the asymmetric cross-coupling to furnish
1
1,13n,o
tri-ortho-substituted biaryls.
In this article, we disclose our studies towards the application
of the dihydrobenzooxaphosphole (23, X = O, BOP) and dihydrobenzoazaphosphole (23, X =
NR, BAP) ligand scaffold for both the asymmetric Pd-catalyzed Suzuki-Miyaura and Negishi
cross-coupling reaction to form tetra-ortho-substituted biaryls (Scheme 4). The differences in the
enantiodiscrimination mechanism between these two processes was probed computationally and
is also disclosed herein.
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5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 4. Tunable P-Chiral Phosphine Ligands for Asymmetric Pd-Catalyzed Cross-
Coupling.
RESULTS AND DISCUSSION
Ligand Synthesis.
The ligands employed in the current study were prepared by the general strategy outlined
1
3n,35b
7t
in Scheme 5. Starting from the known P-chiral triflates (26, 27),
Negishi or Suzuki-
Miyaura cross-coupling was used to install the lower aryl ring of the ligand biaryl axis affording
oxides 29 or 30. Deprotonation of 29 or 30 with LDA followed by electrophilic trapping allowed
for substitution of the C-2 position of the oxaphosphole or azaphosphole ring providing 31 or 32,
respectively. Oxide reduction then provided the final BOP (X = O) or BAP (X = NR) ligands
(33). Additionally, the 3,5-positions of the lower aryl ring of the biaryl group of 34 can be
1
1b
functionalized by bromination to afford 35 followed by cross-coupling and alkylation to afford
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ligand family 36. These procedures have enabled the synthesis of a tunable family of P-chiral
phosphine ligands. The ligands prepared and used in this study are shown in Chart 1.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 5. Ligand Synthesis.
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2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
O
P
O
P
O
O
P
O
P
Me
tBu
Et
iꢀPr
tBu
tꢀBu
P
tBu
tBu
tBu
MeO
MeO
OMe MeO
OMe MeO
OMe MeO
OMe MeO
OMe
L5
JatanPhos
L1
L2
L3
L4
O
O
O
O
P
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
t
Et
OMe
O Bu
Ph
P
P
P
tBu
tBu
OMe
tBu
tBu
OMe
MeO
MeO
OMe
MeO
OMe
L7
NitinPhos
iꢀPr
L6
L8
L9
iꢀPr
O
P
Me
O
P
O
O
P
O
Me
tBu
Me
iꢀPr
tBu
Me
tBu
P
iꢀPr
tBu
P
iPrO
i
iPrO
i
tBu
MeO
OMe
PhO
OPh
OPr
OPr
MeO
OMe
L10
L11
L12
O Me Me
L13
L14
O
Me
O
P
O
P
O
P
Me
tBu
OMe
P
P
OMe
tꢀBu
OMe
tBu
iPrO
i
OPr
tBu
tꢀBu
OMe
OMe
L18
OMe
L19
L15
L16
L17
O
Me
tBu
Piv
O
P
O
P
P
N
iꢀPr
tBu
Me
tBu
iPrO
OPr
i
P
iPrO
i
tꢀBu
MeO
Me
OMe
OPr
MeO
OMe
RO
OR
Me
Me
Me
L20
L21
OMe L22
Ph
i-Pr
OMe
L23: R = Me
L24: R = iꢀPr
Ph
Ph
Ph
i-Pr
N
N
N
N
Me
tꢀBu
iꢀPr
P
P
P
tꢀBu
i-Pr
i-Pr
MeO
P
tꢀBu
i-Pr
i-Pr
tꢀBu
RO
OR
OMe
L27
OMe
OMe
L28
L29
L25: R = Me
L26: R = iꢀPr
Chart 1. Ligands Used in This Study.
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Asymmetric Suzuki-Miyaura cross-coupling.
To investigate the Suzuki-Miyaura cross-coupling to prepare tetra-ortho-substituted
1
2c”
biaryls, we initially examined the “benchmark
substituted biaryl compound 18 (Table 1) employing 1-bromo-2-methylnaphthalene (17b) and
2-methylnaphthalen-1-yl)boronic acid (16a) as the coupling partners. Initial experiments probed
conditions that previously were shown to be suitable for hindered cross-coupling reactions
Entries 1 – 3). These consisted of the use of K PO as base and employing BIDIME (L1),
cross-coupling reaction to form tetra-ortho-
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
(
3
4
AntPhos, or C2-i-Pr-BIDIME (L4) as the ligand. Gratifyingly, under these conditions, product
8 was observed. While almost no enantioinduction was observed using BIDIME (L1) or
1
AntPhos, which lack substitution at the C-2 position of the oxaphosphole ring (entries 1 and 2),
C2-i-Pr-BIDIME (L4) afforded modest enantioselectivity and yield in the reaction (entry 3). As
1
3d,r
has been previously noted for reactions forming tetra-ortho-substituted biaryls,
protodeboronation was a significant side-reaction that prevented the coupling from proceeding to
full conversion. To circumvent this issue, alternate bases were examined in an effort to reduce
protodeboronation; however, no improvements over the use of K PO were identified (entries 3 –
3
4
8
). Additionally, solvents such as toluene and 1,4-dioxane were found to be equally effective in
the coupling and did not improve enantioselectivity or yield (entries 9 and 10). Finally, to
achieve full reaction conversion, the effect of catalyst loading was examined (entries 11 – 14).
Use of 5 mol % Pd was needed to achieve full conversion and allowed for high yield in the
desired reaction (entry 13). Addition of water as a co-solvent to these reactions when employing
THF or n-BuOH as solvent afforded < 10% yield of product due to significant amounts of
protodeboronation (data not shown) that is not uncommon considering that the addition of excess
9
,13
water is often avoided in sterically demanding and asymmetric cross-coupling reactions.
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9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Table 1. Asymmetric Suzuki-Miyaura Cross-Coupling Towards Tetra-ortho-Substituted
Biaryls: Base and Solvent Survey.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a
b
Entry Mol %
Pd
Ligand
(mol%)
L1 (2)
Base
(3 equiv)
K PO4
3
Solvent
%Yield
er
1
1
THF
40
55:44
2
3
4
5
6
1
1
1
1
1
(R)-AntPhos (2)
L4 (2)
K PO4
THF
THF
THF
THF
THF
30
50
18
< 5
9
50:50
86:14
ND
ND
ND
3
K PO4
3
L4 (2)
L4 (2)
L4 (2)
CsF
KF
K CO3
2
7
8
9
1
1
1
1
L4 (2)
L4 (2)
L4 (2)
L4 (2)
Na CO3
NaOtBu
THF
THF
Toluene
1,4-dioxane
< 2
< 3
48
ND
ND
85:15
85.5:
2
K PO4
3
10
K PO4
3
50
14.5
1
1
1
1
2
3
3
3
5
5
L4 (6)
L4 (6)
L4 (10)
L4 (10)
K PO4
THF
Toluene
THF
64
56
90
85
86:14
85:15
86:14
85:15
3
K PO4
3
K PO4
3
14
K PO4
3
Toluene
a
b
Isolated yield. Determined by chiral HPLC analysis with Chiralpak OD-H column.
With moderate conditions in hand for the Suzuki-Miyaura cross-coupling reaction (Table
1
2
, entry 13), we next attempted to modify the ligand structure to improve enantioselection (Table
). The substitution at the C-2 position of the oxaphosphole ring of the ligand was first examined
(entries 1 – 6). This enabled the identification of a ligand that provided enantioselectivities of up
to 95:5 er when a dimethylmethoxy (DMM) substituent was at the C-2 position of the
oxaphosphole ring (L7, NitinPhos, entry 4). Furthermore, it was critical that the ligand contained
a dimethoxyphenyl ring as part of the biaryl axis of the ligand. When this group was replaced
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with phenyl, anthracene, or methoxy, inferior yields and selectivities were obtained (entry 4 vs
entries 9 – 11). The importance of the lower dimethoxyphenyl ring in enhancing
enantioselectivities through an interaction between one methoxy-group and Pd has been
1
1b,13n
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
postulated previously,
and is further supported by DFT modeling of this system (vide infra).
Replacement of the methoxy-groups on this lower aryl ring with iso-propoxy groups afforded no
improvement (entry 1 vs entries 7 – 8).
Table 2. Ligand Survey in the Asymmetric Suzuki-Miyaura Cross-Coupling Towards
Tetra-ortho-Substituted Biaryls.
a
b
Entry Ligand
% yield
er
1
L4
92
86:14
2
3
4
5
6
7
8
9
1
1
L5
L6
L7
L8
L10
L13
L14
L16
L17
L18
L20
80
75
97
45
91
73
75
75
35
50
89
90:10
86:14
94.5:5.5
81.5:18.5
83:17
84.5:15.5
83:17
73:27
0
1
88:12
64:36
78:22
12
a
b
Isolated yield. Determined by chiral HPLC analysis with Chiralpak OD-H column.
The effect of Pd-precatalyst and Pd:ligand loading was next examined (Table 3). The use
of excess ligand enabled the highest reaction yield (entry 1 vs 2). Additionally, Pd(OAc) gave
2
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
less side-product formation than compared to the use of Pd (dba) or [PdCl(allyl)] (entry 2 vs
2
3
2
entries 3 – 4).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Table 3 Effect of Pd-Precatalyst and Pd:Ligand Loading.
a
b
Entry Pd Source (mol %)
Mol % L7
% yield
97%
Er
1
2
3
Pd(OAc) (5)
10
94.5:5.5
2
c
Pd(OAc) (5)
5
75%
94.5:5.5
2
d
Pd (dba) (2.5)
5
5
64%e
55%
94:6
93.7:6.3
2
3
4
[PdCl(allyl)] (5)
2
a
b
c
Isolated yield. Determined by chiral HPLC analysis with Chiralpak OD-H column. 1-2% side
products were observed with 23 % of bromide substrate remaining, 5-7% side products were
observed with 29% of bromide substrate, 8-9% side products were observed with 35% of
d
e
bromide substrate.
In an effort to further reduce the loading of the boron coupling partner, we next examined
other boron derivatives in the coupling reaction in an effort to reduce protodeboronation side-
13d
reactions (Scheme 6). Use of the glycol ester (16b) that was optimal in Cammidge’s system
and has been recently shown to give improved transmetalation rates in Suzuki-Miyaura cross-
3
0
coupling reactions gave similar enantioselectivities as that observed with boronic acid 16a but
did not afford full conversion in the reaction, even at prolonged reaction times. Use of the
pinacol ester 16c allowed for reduction of the boron coupling partner to 2 equiv; however, long
reaction times were required and a slight loss in enantiopurity was obtained. The change in
enantioselectivity based off of the nature of the boronate employed has been observed
1
3d
previously and hints that the transmetalation step in the catalytic cycle for this reaction may be
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involved in the enantiodeterming event (vide infra). Finally, use of the potassium trifluoroborate
3
7
salt (16d), which are known for their resistance to protodeboronation, was not effective in the
cross-coupling reaction.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 6 Effect of Boronate Coupling Partner.
With identification of a reactive catalytic system to form tetra-ortho-substituted biaryl
product 18 with good enantioselectivities, the scope of this catalytic system was then briefly
examined (Scheme 7). Unfortunately, it was quickly determined that the present system did not
show good generality, as has been a common problem in asymmetric Pd-catalyzed Suzuki-
Miyaura reactions providing tetra-ortho-substituted biaryls. Only subtle modification to the
coupling partners led to decreased reaction efficiency due to increased amounts of
protodeboronation.
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2
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6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 7. Asymmetric Suzuki-Miyaura Cross-Coupling Reaction Scope.
Asymmetric Negishi cross-coupling.
Because of the issues identified with the Suzuki-Miyaura cross-coupling reaction (poor
generality, high boronate loading), we decided to investigate the analogous reaction employing
Negishi cross-coupling with aryl-zinc reagent 40 prepared by lithium-halogen exchange of 17b
with t-BuLi followed by addition of a THF solution of anhydrous ZnBr . ZnBr was our
2
2
preferred choice over ZnCl due to its higher solubility in THF. Towards this end, we surveyed
2
our family of P-chiral oxaphosphole and azaphosphole ligands in the Negishi cross-coupling
reaction (Table 4). The highest yield and selectivity was obtained with L13 having iso-propoxy
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groups on the lower aryl-ring of the ligand biaryl axis (entry 10). Surprisingly, the optimal ligand
for the asymmetric Suzuki-Miyaura reaction (NitinPhos, L7, entry 5) gave poor yield and
selectivity in the Negishi coupling considering that the presumed enantiodetermining step of
reductive elimination should be identical for the Negishi and Suzuki-Miyaura reactions. This
difference in selectivity was something we wanted to understand further (vide infra). In general,
C2-substituion on the oxaphosphole or azaphosphole ring of the ligand was required for good
selectivity (entry 1 vs entries 2 – 10, and entries 15 – 16 vs entries 17 – 21). Further increasing
the steric bulk at this C2-position by introducing a second methyl group enabled similar
selectivities but led to a reduction in yield (entries 8 & 12). Additionally, a trend was observed
where increasing the electron-donating ability of the lower aryl-ring bearing the alkoxy-
substituents led to improved enantioselection (compare entries 2, 9, and 10). Lastly, the
azaphosphole series of ligands were extremely efficient in terms of reaction yield; however,
enantioselectivities were lower with this series (entries 15, 17, 18, 19).
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Table 4. Ligand Survey in the Asymmetric Negishi Cross-Coupling Towards Tetra-ortho-
Substituted Biaryls.
a
b
Entry Ligand
% yield
69
er
1
L1
52.5:47.5
2
3
4
5
L2
L3
L4
L7
49
ND
38
78.5:21.5
81.5:18.5
82.5:17.5
80.5:19.5
10
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8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
6
7
8
9
1
1
1
1
14
15
1
1
1
1
L9
82
89
69
81
93
45
24
67
36
91
68
96
89
99
76
82
76.5:23.5
L10
L11
L12
L13
L14
L15
L21
L22
L23
L24
L25
L26
L27
L28
L29
83.0:17.0
85.5:14.5
71.3:28.7
85.0:15.0
82.0:18.0
83.0:17.0
77.0:23.0
65.0:35.0
60.5:39.5
61.0:39.0
82.5:17.5
79.0:21.0
53.0:47.0
60.0:40.0
78.0:22.0
0
1
2
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
6
7
8
9
20
2
1
a
b
Isolated yield. Determined by chiral HPLC analysis with Chiralpak OD-H column.
With identification of L13 as the best ligand out of the ligand survey in Table 4, we
further optimized parameters for the Negishi coupling reaction with ligand L13 in an effort to
improve enantioselection (Table 5). The Pd-precatalyst, metal-ligand ratio, Zn-source, and
solvent were examined in the reaction (Table 5). The choice of Pd-precatalyst had little impact
on the reaction enantioselectivity, but the yield varied from 70 – 80 % (entries 1, 4, 5, 7). The
metal-ligand ratio also had no impact on selectivity; however, the yield improved if a 1:1.5
Pd:L13 ratio was employed (entries 8 – 10). Finally, use of other Zn-salt precursors or other
solvents did not lead to improvements in reaction efficiency (entries 2, 3, 6, 7).
Table 5. Survey of Pd-precatalyst, Pd:L13 ratio, Zn-source, and solvent in the Negishi
Cross-Coupling Reaction.
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1
1
1
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1
1
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1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
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5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
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9
0
1
2
3
4
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8
9
0
a
b
Entry
Pd
Metal:L13
ZnX2
Solvent Yield %
Er
ratio
1
2
3
4
5
6
Pd(OAc) 2
Pd (dba)
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:1.5
1:1
ZnBr2
ZnBr2
THF
Toluene
Dioxane
THF
81
80
90
71
73
56
77
80
93
76
85.0:15.0
85.0:15.0
85.0:15.0
82.0:18.0
83.0:17.0
78.0:22.0
84.0:16.0
85.0:15.0
85.0:15.0
85.0:15.0
2
3
3
Pd (dba)
ZnBr2
2
PdCl (PhCN)
ZnBr2
2
2
[crotylPdCl]2
Pd (dba)
ZnBr2
THF
Zn(OAc)2
Zn(OPiv)2
ZnBr2
THF
2
3
3
3
c
7
Pd (dba)
THF
2
8
Pd (dba)
THF
2
9
Pd (dba)
ZnBr2
THF
2
3
10
Pd (dba)
ZnBr2
THF
2
3
a
b
c
Isolated yield. Determined by chiral HPLC. The zinc reagent was prepared from the Grignard according to
Knochel’s protocol (ref 38a).
To determine if enantioselection in the reaction was variable with reaction progress, the
o
enantioselectivity was monitored over time at both 40 and 60 C (Scheme 8). Enantioselection
was independent of conversion implying that the active catalyst was not changing over time.
Reduction of the reaction temperature led to slight improvements in enantioselectivity, but
o
incomplete conversion was obtained at 40 C.
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
7b
(1.5 equiv)
tꢀBuLi
THF, ꢀ78 o
C
then ZnBr2
ZnBr
Me
Pd (2.5 mol%)
L13 (10 mol%)
Me
Me
+
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Me
THF
Br
7b
1.0 equiv)
1
40
1
8
(
o
(a) 60 C:
o
(
b) 40 C:
1
00
80
60
%
Conv.
4
2
0
0
0
%S
0
20
40
60
Time (h)
o
Scheme 8. Enantioselectivity vs Time at 40 and 60 C.
The most efficient catalyst conditions identified in our studies (Table 5, entry 9) were
next utilized to examine the scope of the Negishi cross-coupling to afford other tetra-ortho-
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9
substitued biaryls (Scheme 9). Notably, the Negishi reaction showed much better scope in terms
of reaction yield relative to the Suzuki-Miyaura reaction albeit with lower enantioselection. For
the first time, a variety of R-alkyl substituents other than R = Me or OMe have been analyzed in
an asymmetric cross-coupling reaction to provide tetra-ortho-substituted products (39d-f). In
general, the cross-coupling employing 35 with R = n-alkyl afforded comparable results (18,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
9a,c-f). Methoxy-substitution (39b) was not well tolerated and afforded reduced yield due to
significant amounts of reduction of the aryl bromide as a byproduct. Adding an additional
methyl-substituent on the naphthalene ring also led to decreased reaction efficiency and
enantioselectivity (39c); however, product formation was observed whereas the corresponding
Suzuki-Miyaura coupling afforded no reaction with this substrate class (Scheme 7). Finally, the
present system was specific to coupling naphthalene derivatives. Cross-coupling to afford 43
proceeded in moderate to good yields, but almost no enantioselection was observed despite the
nature of the alkoxy-substituent.
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3
3
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0
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9
0
1
2
3
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0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 9. Asymmetric Negishi Cross-Coupling Reaction Scope.
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9
Mechanistic Modeling by DFT Analysis.
The results of our combined studies of the asymmetric Suzuki-Miyaura and Negishi
cross-coupling reactions employing ligand series 33 and 36 prompted us to investigate the
mechanistic differences between these two reactions in terms of the enantiodiscrimination steps.
Specifically, these ligands gave very different results in the coupling reaction when employed in
a Suzuki-Miyaura vs a Negishi type protocol, yet mechanistically, the final step in the catalytic
cycle for both processes would presumably proceed through the same reductive elimination
intermediate (vide supra). To help understand these differences and to aid in the development of
new ligand structures to improve enantioselectivity, we modeled the cross-coupling process
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
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3
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3
3
3
3
3
4
4
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4
4
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4
4
4
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5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
9
using density functional theory (DFT) calculations.
Negishi Cross-Coupling
Most analyses of the stereoselectivity in cross-couplings regard the final step as
1
1b,13b,n,x
stereodetermining.
Such an approach assumes equal accessibility to all of the different
conformers of the transition state precursors. The percentage of product that forms via each of
the possible reductive elimination transitions states can then be determined by Boltzmann
analysis of their relative energies.
For the system in question here, a defining feature of the Pd biaryl intermediates
preceding reductive elimination is the hindered rotation along the aryl-Pd bonds due to the large
1
3f,15a
size of the aryl groups employed. As such, direct interconversion
of the different
conformations of these intermediates does not occur. However, we hypothesize that all the
conformers will be equally accessible due to the reversibility of transmetalation and oxidative
4
0
addition in the Negishi coupling. In such a scenario, a classical analysis of just the reductive
elimination transition states pertains. Thus, all four of the possible biaryl palladium isomers need
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1
1
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2
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2
2
2
2
2
2
2
2
3
3
3
3
3
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3
3
4
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6
to be considered, each giving rise to two reductive elimination transition states, pro-S and pro-R
(Figure 1).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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6
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9
0
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0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 1. Stereoselection in Negishi Coupling
Analyzing reductive eliminations for the Me-BOP ligand L2 in such a fashion, we found
that there is one dominant transition state for each of pro-S and pro-R sets, controlling the overall
selectivity (Figure 2).
Figure 2. Lowest energy pro-S and pro-R reductive elimination transition states for Me-BOP
ligand L2. Total of 8 transition states were located and analyzed. Free energies were computed
using M06/6-311+G(d,p)-LANL2DZ(Pd)-SMD-THF//B3LYP/6-31G(d)-LANL2DZ(Pd); values
are in kcal/mol.
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Coordination of Pd to the methoxy-group of the lower aryl ring of the Me-BOP ligand
provides extra stabilization for the pro-S transition state, resulting in highly S-selective reaction.
For the pro-R transition state, such an arrangement is not favorable due to the steric interactions
with the ligand. A correlation between the electron-donating properties of the lower ring
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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2
3
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9
0
1
2
3
4
5
6
7
8
9
0
substituent (σ ) and the experimental er of the product supports the contribution of this specific
p
substituent to the enantioselection mechanism (Figure 3).
ln(er)
1.8
ln(er)= ꢀ1.9σ + 0.8
p
R² = 0.98
1.3
σp
0.8
ꢀ0.5
ꢀ0.25
0
Figure 3. Efficiency of the chiral Me-BOP ligand vs electron donating property of the lower aryl-
ring substituent.
When the Negishi coupling is performed with the alternate DMM-substituted BOP ligand
(NitinPhos, L7), enantioselectivity drops. This result can be rationalized using the same
approach. Analysis of the selectivity-determining transition states revealed that the additional
coordinating group of the DMM-substituent of NitinPhos ligand L7 allows selective stabilization
of the higher energy pro-R transition state (Figure 4), which diminishes the pro-R – pro-S energy
gap and hence the selectivity of the overall process.
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0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 4. Lowest energy pro-S and pro-R reductive elimination transition states for the DMM-
BOP ligand (NitinPhos, L7). Total of 32 transition states were located and analyzed. Free
energies were computed using M06/6-311+G(d,p)-LANL2DZ(Pd)-SMD-THF//B3LYP/6-
3
1G(d)-LANL2DZ(Pd); values are in kcal/mol.
This analysis of the reductive elimination transition states for the Negishi reaction
rationalizes the experimentally observed enantioselectivities and highlights the key interactions
(Figure 5).
Figure 5. Comparison of the experimental and calculated efficiencies of the ligands in Negishi
coupling.
Suzuki-Miyaura Coupling
The different performance of the DMM-BOP ligand (NitinPhos, L7) in the Suzuki-
41
Miyaura coupling requires a different enantioselection mechanism. Irreversible transmetalation
in Suzuki-Miyaura coupling would prevent pre-equilibration of pre-reductive elimination Pd(II)
species. As such, enantioselectivity of the overall process would be determined not only by the
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energetics of reductive elimination, but also by the relative population of the pre-reductive
elimination Pd(II) intermediates. Thus, it is necessary to consider the relative rates of formation
of corresponding species by modeling the transmetalation step. Based on the proposed structures
4
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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3
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3
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0
1
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1
2
3
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0
of the pre-transmetalation intermediates, the same hindered rotation issues are expected as for
the pre-reductive elimination intermediates. Therefore, pre-transmetalation intermediates
partition into two groups that react via independent pathways. In turn, the population of the pre-
transmetalation intermediates is controlled by the energetics of oxidative addition. Therefore, all
three major steps of the cross-coupling mechanism contribute to the overall selectivity of the
reaction (Figure 6). Earlier computational studies of the stereoselectivity in Suzuki-Miyaura
4
3
cross-coupling suggest that oxidative addition is the stereodetermining step. We further develop
42a,b
this idea of early enantioinduction by employing the experimental findings of Denmark,
4
2c
42d,e
Hartwig, and others
that point to the mechanism of the transmetalation step proceeding
17
through a Pd-OH complex. The exact mechanism for the transmetalation step in Suzuki-
3
9
44
Miyaura cross-coupling is still somewhat controversial as there are some reports that support
45
the alternate “boronate”-transmetalation pathway. The studies reported herein are calculated
4
2
using the Pd-OH transmetalation pathway; however, we would like to stress that the model
4
4,45
proposed herein is also compatible with the “boronate”-transmetalation
mechanism: both
possibilities ultimately lead to the same transmetalation transition states. The nature of the
incoming boron species (boronate vs boronic acid) is not crucial for the selection of the
productive oxidative addition step (discussed later) as the same steric interactions are present.
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