Chiral-Anion-Mediated Asymmetric Heck-Matsuda Reaction of Acyclic Alkenyl Alcohols

Article abstract of DOI:10.1021/acs.orglett.1c00152

Acyclic internal alkenes are a class of challenging substrates in asymmetric Heck-type reactions due to difficulties related to both reactivity and selectivity control. Employing acyclic alkenyl alcohols, an asymmetric Heck-Matsuda reaction is developed through the strategy of chiral anion phase transfer. Various chiral ketones could be obtained in high levels of enantioselectivity. A catalytic amount of dimethyl sulfoxide (DMSO) as an additive is crucial for the reaction to suppress the palladium-hydride-mediated side reactions.

Full text of DOI:10.1021/acs.orglett.1c00152

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Letter
Chiral-Anion-Mediated Asymmetric Heck−Matsuda Reaction of
Acyclic Alkenyl Alcohols
Tao Zhang, Wen-Ao Li, Hong-Cheng Shen, Shu-Sen Chen, and Zhi-Yong Han*
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ABSTRACT: Acyclic internal alkenes are a class of challenging
substrates in asymmetric Heck-type reactions due to difficulties
related to both reactivity and selectivity control. Employing acyclic
alkenyl alcohols, an asymmetric Heck−Matsuda reaction is
developed through the strategy of chiral anion phase transfer.
Various chiral ketones could be obtained in high levels of enantioselectivity. A catalytic amount of dimethyl sulfoxide (DMSO) as an
additive is crucial for the reaction to suppress the palladium-hydride-mediated side reactions.
he Heck−Matsuda arylation reaction,1 utilizing more
Scheme 1. Chiral-Anion-Mediated Asymmetric Heck−
Matsuda Reaction and Related Reactions with Terminal
T
reactive aryl diazonium salts readily prepared from
corresponding anilines,2 exhibits remarkable advantages over
traditional cross-coupling chemistry.3 Due to the feasibility for
oxidative addition of the diazonium salts, oxidation-sensitive
electron-rich ligands are not required, and the reactions can
typically be performed under mild conditions without strict
exclusion of oxygen.4 On the other hand, the enantioselective
variants of the Heck−Matsuda reaction are more challenging
largely because of the incompatibility between common
phosphine-based ligands and diazonium salts.5 One strategy
to overcome this challenge is applying nitrogen-based chiral
ligands, as successfully demonstrated by the groups of Correia6
and Sigman.7 More specifically, Correia’s group has reported a
series of desymmetric Heck−Matsuda arylations of cyclic and
acyclic olefins using chiral bisoxazolines, while Sigman’s group
has developed enantioselective arylations of acyclic alkenyl
alcohols utilizing chiral pyridine oxazolines.
Alkenes, Dienes, and Cyclic Alkenes
As an alternative approach, Toste’s group first discovered
that chiral anion phase-transfer (CAPT) catalysis could
successfully enable related processes.8−10 Toste and co-workers
have reported enantioselective 1,1-arylborylation,9a 1,1-diary-
lation,9g and Heck−Matsuda arylation of alkenes.9h,i Our group
also established an asymmetric multicomponent reaction of
diazonium salts, diborates, aldehydes, and 1,3-dienes (Scheme
1a).9j Albeit that CAPT has proven to be a potent strategy in
asymmetric Heck−Matsuda-type reactions, the scope of the
reactions has been limited to terminal alkene and dienes and
cyclic alkenes.9a,g−j To date, acyclic inner alkenes are still not
applicable for the Matsuda-type reactions under CAPT
conditions. In enantioselective intermolecular Heck-type
reactions, cyclic alkenes are usually more preferable for the
feasibility to control the selectivity of β-hydride elimination
because of the conformational rigidity (Scheme 1b, left).11 On
the other hand, it is much more challenging to distinguish
between similar C−H bonds in the β-hydride elimination
event of acyclic sterically and electronically nonbiased internal
Received: January 14, 2021
Published: February 1, 2021
https://dx.doi.org/10.1021/acs.orglett.1c00152
Org. Lett. 2021, 23, 1473−1477
© 2021 American Chemical Society
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alkenes (Scheme 1b, right).7,12 Although these issues have
been overcome through rational design of ligands by Sigman’s
group and others,6,7,13 it still remains unclear and challenging
under CAPT conditions, where the regioselectivity of the β-
hydride elimination as well as the migratory insertion mainly
relies on the chiral counteranion. Further, since the unactivated
acyclic internal alkenes generally exhibit lower reactivity in
Heck-type reactions compared to terminal and cyclic alkenes, it
is still questionable if sufficient reactivity could be achieved in
the CAPT catalysis scenario for these substrates. Despite these
challenges, to extend the application scenarios of CAPT,
herein, we report our efforts on the investigation of the chiral-
anion-mediated asymmetric Heck−Matsuda reaction of acyclic
alkenyl alcohols (Scheme 1c).
a
Table 1. Reaction Optimization
b
c
d
entry
8
additives solvent yield (3a, %)
er
3a/4a
1
2
3
4
5
6
7
8
9
10
11
12
8a
8a
8a
8a
8a
8a
8a
8a
8a
8a
8a
8a
8b
8c
none
none
none
none
6a
Et2O
MTBE
THF
DCM
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
41
45
44
trace
60
57
61
68
82
75
57
47
75
95:4
85.5:14,5
87.5:12.5
-
2.5:1
4:1
2.3:1
-
The hypothesized chiral-anion-mediated asymmetric Heck−
Matsuda reaction is outlined in Scheme 2 with phenyl
Scheme 2. Chiral Anion-Mediated Asymmetric Heck-
Matsuda Reaction of Acyclic Alkenyl Alcohols
94:6
2.6:1
2.8:1
3:1
>20:1
>20:1
>20:1
>20:1
5:1
6b
6c
93.5:6.5
93.5:6.5
91:9
94.5:5.5
95:5
6a, 7a
6a, 7a
6a, 7b
6a, 7c
6a, 7d
6a, 7a
6a, 7a
e
e
e
95:5
95:5
e
e
13
14
87.5:12.5
95:5
>20:1
>20:1
e
f
82(75 )
a
Unless noted otherwise, the reaction of 1a (0.1 mmol) with 2a (0.2
mmol) was carried out with Pd2dba3 (0.005 mmol), 8 (0.013 mmol),
Na2CO3 (0.2 mmol), additive 6 (0 or 0.015 mmol), and additive 7 (0
or 0.016 mmol) in 2.0 mL of solvent at 25 °C for 12 h; a trace amount
b
c
of 5a was observed. NMR yield. Determined by HPLC analysis.
d
Determined by 1H NMR analysis of the crude reaction mixture.
The reaction was carried out at 0 °C. Isolation yield.
e
f
dazonium salt 1a and allylic alcohol 2a as the typical substrates
and chiral phosphoric acid 8a as the source of the chiral anion.
In this strategy, insoluble diazonium salt is transferred into the
solution phase to give ion-pair I9a,g−j,10 via anion exchange
with sodium phosphate generated from 8a and sodium
carbonate. The ion pair then undergoes oxidative addition by
the Pd(0) species to give Pd(II) intermediate II3,9b with the
chiral phosphate as the counteranion, which generates
intermediate III after migratory insertion of alkene 2a. In
this stage, two possible β-H elimination processes are possible
to form either byproduct 5a or intermediate IV. It requires the
chiral anion to govern the selectivity for a preferred β-Hb
elimination process. Olefin dissociation and tautomerization of
the enol afford the desired chiral ketone 3a and Pd hydride
species V, which then undergoes formal reductive elimination
and regenerates Pd(0) and sodium phosphate as suggested by
Toste and co-workers.9h On the other hand, the alkene
isomerization issue has been previously observed in Heck−
Matsuda reactions.14,9h In this case, terminal alkene 9 can be
formed and undergoes another Heck reaction to produce
byproduct 4a.
observed as the main byproduct, and only a trace amount of 5a
was detected. Employing methyl tert-butyl ether as the solvent
to furnish the reaction provided the product with a slightly
higher chemoselectivity, moderate yield, and lower enantiose-
lectivity (entry 2). Switching the solvent to THF led to no
better results, and the reaction turned completely unproductive
when using DCM as reaction media (entries 3 and 4). Inspired
by previous observations by Fairlamb,15 Trost,9a and Sigman13j
that dibenzylideneacetone (dba) derivatives can possibly
stabilize palladium species along the catalytic cycle and thus
affect the catalytic performance, several dibenzylideneacetone
(dba) derivatives (6a−6c) were tested as additives for the
reaction in ether (entries 5−7). It was found that in all these
reactions a significant boost in the yield was observed but with
lower enantioselectivity, and the generation of byproduct 4a
could not be surpressed (vs entry 1). To further optimize the
reaction and inhibite the side reaction, we noticed that
dimethyl sulfoxide (DMSO) was frequently used as the solvent
or ligand for the palladium-catalyzed reaction.16 Beller and co-
workers found that DMSO as a cosolvent could tune the
selectivity of the Heck arylation of cyclohexene with aryl
bromides.16g It was found that the addition of 15 mol %
DMSO (7a) in the reaction sufficiently suppressed the
generation of 4a and led to a slight increase in the yield,
albeit that slightly lower enantioselectivity was obtained (entry
8 vs entry 5). Lowering the temperature to 0 °C rendered the
reaction with 82% yield, excellent chemoselectivity, and a
94.5:5.5 er (entry 9). At this stage, due to the significant
To verify the feasibility of the hypothesized reaction,
phenyldiazoniumtetrafluoroborate 1a and (E)-pent-3-en-2-ol
2a were subjected to 5 mol % of Pd2dba3 and 13 mol % of
chiral phosphoric acid 8a with Na2CO3 in ether (Table 1, entry
1). Encouragingly, the reaction did afford chiral ketone 3a with
moderate yield and excellent enantioselectivity. At the same
time, a notable amount of compound 4a was surprisingly
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influence of DMSO, a series of sulfoxides (7b, 7c) were
examined, and DMSO 7a was found to be the optimal additive
(entries 10−12). Notably, while dialkyl sulfoxides 7b and 7c
could also efficiently avoid the generation of 4a, diaryl
sulfoxide 7d with lower coordination ability exhibited much
less of an effect on surpressing the side reaction. Further,
slightly enhanced enantioselectivity and yield could be
obtained when 8H-BINOL-based phosphoric acid 8c was
used (entries 9 and 13 vs 14).
reaction due to lower reactivity, in accordance with previous
reports. Next, various allyl alcohols were investigated for the
reaction (3m−3q). Switching R1 from a methyl to ethyl (3m)
or n-propyl (3n) group also led to smooth reactions, providing
the corresponding product with 90.5:9.5 and 89:11 er,
respectively. On the other hand, when the R2 group of the
allylic alcohols was altered to other alkyl groups, e.g., n-butyl
(3o), n-heptyl (3p), and isopentyl (3q), similar levels of yield
and high to excellent enantioselectivities could be achieved. In
the case of 3r, when an allylic alcohol bearing an aryl group
was employed, the desired product could also be obtained in
moderate yield with high enantioselectivity.
Under the optimized reaction conditions, we first explored
the scope of aryl diazonium salts for the reactions with allylic
alohol 2a (Scheme 3). A broad scope of aryldiazonium salts
To gain insight into the effect of DMSO in the reaction, the
reaction processes with or without DMSO were monitored.
Besides the effect to suppress the formation of byproduct 4a, as
shown in Figure 1a, the presence of a catalytic amount of
a
Scheme 3. Substrate Scope
Figure 1. DMSO effect in the reaction and control experiments.
DMSO also led to a considerable boost of the apparent
reaction rate in the early stage (Table 1, entry 8 vs 5). Side
product 4a could indeed be isolated when homoallylic alcohol
9 was subjected to the standard conditions without DMSO,
verifying that 4a should arise from compound 9 caused by Pd-
hydride-mediated isomerization (Figure 1b). In the unopti-
mized Heck−Matsuda reaction of cyclic alkene 10 and 2d, a
clear suppression effect of the Pd-hydride-mediated alkene
isomerization could also be observed (Figure 1c). Thus, we
postulate that DMSO in the system might be able to accelerate
the dissociation and reduce the lifetime of palladium hydride
species V, presumably through coordination to the palladium
center. This is in accordance with the fact that diaryl sulfoxide
7d with low coordination ability had little effect on suppressing
the formation of 4a. The boost of the initial reaction rate could
be explained by the accelerated dissociation of V and
avoidance of undesired pathways, both leading to fast turnover
of the palladium catalyst.
a
Unless noted otherwise, the reaction of 1 (0.1 mmol) and 2 (0.2
mmol) was carried out with Pd2dba3 (0.005 mmol), 8c (0.013 mmol),
6a (0.016 mmol), 7a (0.015 mmol), and Na2CO3 (0.2 mmol) in Et2O
(2.0 mL) at 0 °C for 12 h. 25 °C.
b
bearing 4-substitutuents, either electron-donating (3b, 3c) or
-withdrawing (3d−3k), could be well-tolerated, giving rise to
the corresponding chiral ketone in 51 to 80% yield with good
to excellent enantioselectivity (up to 96:4 er). Notably, a
bromo substituent at the phenyl ring (3f) could remain
unchanged during the Pd(0)-catalyzed reaction, probably due
to the high reactivity toward oxidative addition of the
diazonium group. A similar level of yield and enantioselectivity
were observed when the reaction yielding 3g was performed in
a 1 mmol scale. Meta-substituted diazonium salts could also
undergo the reaction smoothly, albeit with slightly lower
enantioselectivity (3l). Ortho-substituted diazonium salts, e.g.,
2-methylphenyl diazonium salt, were not ideal subtrates for the
In summary, we have developed chiral-anion-mediated
enantioselective Heck−Matsuda reactions with challenging
acyclic alkenyl alcohols as the substrates, extending the
application teritory of CAPT in transition metal catalysis.
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00152.
Experimental details and characterization data (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Zhi-Yong Han − Hefei National Laboratory for Physical
Sciences at the Microscale and Department of Chemistry,
University of Science and Technology of China, Hefei
230026, China; orcid.org/0000-0002-9225-5064;
Email: hanzy2014@ustc.edu.cn
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Authors
Tao Zhang − Hefei National Laboratory for Physical Sciences
at the Microscale and Department of Chemistry, University of
Science and Technology of China, Hefei 230026, China
Wen-Ao Li − Hefei National Laboratory for Physical Sciences
at the Microscale and Department of Chemistry, University
of Science and Technology of China, Hefei 230026, China
Hong-Cheng Shen − Hefei National Laboratory for Physical
Sciences at the Microscale and Department of Chemistry,
University of Science and Technology of China, Hefei
230026, China
Shu-Sen Chen − Hefei National Laboratory for Physical
Sciences at the Microscale and Department of Chemistry,
University of Science and Technology of China, Hefei
230026, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00152
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful for the financial support from NSFC (Grants
21971231, 21772184, 21831007).
■
(7) Werner, E. W.; Mei, T.-S.; Burckle, A. J.; Sigman, M. S.
Enantioselective Heck Arylations of Acyclic Alkenyl Alcohols Using a
Redox-Relay Strategy. Science 2012, 338, 1455−1458.
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