Rhodium-Catalyzed Asymmetric Conjugate Addition of Organoboronic Acids to Carbonyl-Activated Alkenyl Azaarenes

Article abstract of DOI:10.1002/adsc.202000211

The enantioselective synthesis of chiral azaarenes by rhodium-catalyzed asymmetric conjugate addition of organoboronic acids to carbonyl-activated alkenyl azaarenes was reported. Diverse chiral azaarenes were produced in up to 99percent yield and with up

Full text of DOI:10.1002/adsc.202000211

Title: Rhodium-Catalyzed Asymmetric Conjugate Addition of
Organoboronic Acids to Carbonyl-Activated Alkenyl Azaarenes
Authors: Huilong Zhu, Long Yin, Zhiqian Chang, Yuhan Wang, and
Xiaowei Dou
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.202000211
Link to VoR: http://dx.doi.org/10.1002/adsc.202000211

10.1002/adsc.202000211
Advanced Synthesis & Catalysis
Very Important Publication
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Rhodium-Catalyzed Asymmetric Conjugate Addition of
Organoboronic Acids to Carbonyl-Activated Alkenyl Azaarenes
Huilong Zhu,a,# Long Yin,a,# Zhiqian Chang,a Yuhan Wang,a and Xiaowei Doua,*
a
Department of Chemistry, School of Science, China Pharmaceutical University, Nanjing 211198, China
Fax: (+86)-25-8618-5179 E-mail: dxw@cpu.edu.cn
These authors contributed equally.
#
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
Abstract. The enantioselective synthesis of chiral azaarenes dexbrompheniramine were realized by using the developed
by rhodium-catalyzed asymmetric conjugate addition of method.
organoboronic acids to carbonyl-activated alkenyl azaarenes
was reported. Diverse chiral azaarenes were produced in up
to 99% yield and with up to 99% ee (>60 examples).
Catalytic asymmetric syntheses of dexchlorpheniramine and
Keywords: Asymmetric Catalysis; Conjugate Addition;
Rhodium; Organoboronic Acid; Azaarene
Introduction
Azaarenes (e.g., pyridine, pyrimidine, quinoline) are
among the most important structural components of
pharmaceuticals, since they can form crucial
hydrogen-bonding interaction with the drug target
and adjust the physicochemical properties of the lead
compound.[1] On the other hand, chiral centers are
introduced to increase the saturation of lead
compounds for achieving clinical success.[2] In this
context, chiral azaarenes are of remarkable
significance in development of pharmaceutical drugs.
According to the FDA’s policy statement on the
development of stereoisomeric drugs, it is crucial to
produce a single enantiomer of a chiral drug.[3]
Therefore, there is significant interest from medicinal
chemists and industry in innovative methodologies
that enable efficient asymmetric synthesis of chiral
azaarenes.
Great successes have been achieved on asymmetric
synthesis of chiral molecules bearing aryl groups,
however, most of the known methods showed poor
compatibility with azaarenes due to their basicity and
coordinating nature. Nevertheless, some significant
approaches have been developed for the
enantioselective construction of chiral azaarenes,
including asymmetric reduction,[4] cross-coupling,[5,6]
and the Minisci-type reaction,[7] among others.[8]
Catalytic asymmetric conjugate addition represents
one of the most useful strategies to generate chiral
molecules.[9] In this regard, alkenyl azaarenes were
used in asymmetric conjugate addition to generate
chiral azaarenes.[10] Upon activation of the olefin by
electron-deficient azaarenes, β-selective conjugate
Figure 1. Selected Pharmaceuticals Featuring the Chiral
Azaarene Motif Bearing an Adjacent Aryl-Substituted
Stereogenic Center.
addition proceeded to give azaarenes bearing a β-
stereogenic center.[11-13] In contrast, construction of
azaarenes bearing an adjacent stereogenic center by
conjugate addition to alkenyl azaarene has been
rarely exploited.[14] In particular, a general method to
incorporate aryl groups to the adjacent stereogenic
center is not known. Given the importance of chiral
azaarenes bearing an adjacent aryl-subsituted
stereogenic center (Figure 1), we sought to develop a
practical method for asymmetric synthesis of these
structures.
1
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10.1002/adsc.202000211
Advanced Synthesis & Catalysis
Table 1. Model Reaction and Optimization.a)
Scheme 1. Asymmetric Synthesis of Chiral Azaarenes by
Conjugate Addition.
Entry Ligand L*
Solvent
Yield ee
[%]b)
[%]c)
1
2
3
4
(R,R)-Ph-bod
L1
L2
THF/H2O
THF/H2O
THF/H2O
THF/H2O
THF/H2O
THF/H2O
THF/H2O
THF/H2O 98
66
dioxane/H2O 91
toluene/H2O 95
EtOH/H2O 92
5
4
3
3
92
95
87
83
91
94
95
88
89
92
98
93
98
90
94
The rhodium-catalyzed asymmetric conjugate
arylation can effectively install aryl groups to alkenyl
substrates with high selectivity.[15] The groups of
Lam[12] and Lautens[13] have reported elegant works
on rhodium-catalyzed asymmetric β-arylation of
alkenyl azaarenes, respectively. For the rhodium-
catalyzed Michael-type addition, the reacting site is
the electronic deficient position. To realize the -
selective addition to alkenyl azaarenes, the solution is
to install an appropriate EWG (electron-withdrawing
group) to reverse the regioselectivity (- vs. -
selectivity). Inspired by the umpolung approach for
rhodium-catalyzed conjugate addition, which was
conceptualized by Lautens in the rhodium catalyzed
α-arylation of secondary amides,[16] we envisioned
exploiting the rhodium-catalyzed arylation of alkenyl
azaarenes by installing appropriate EWG as the
activating group. Herein, as part of ongoing efforts on
the study of rhodium-catalyzed asymmetric
synthesis,[17] we report the rhodium-catalyzed
asymmetric conjugate addition of organoboronic
acids to carbonyl-activated alkenyl azaarenes. This
catalytic system features good tolerance with
azaarenes, commercially available catalyst, as well
as high yields and excellent enantioselectivities, thus
granting practical access to diverse chiral azaarenes
bearing an adjacent stereogenic center (Scheme 1).
L3
5d)
6d)
7d)
8d)
9d)
10d)
11d)
12d)
(R)-binap
(R)-biphep
(R)-segphos
(R)-DM-segphos
(R)-DTBM-segphos THF/H2O
(R)-DM-segphos
(R)-DM-segphos
(R)-DM-segphos
a)1a (0.20 mmol), 2a (0.30 mmol), Rh catalyst (2 mol %
Rh), and KOH (5 mol %) in solvent (1.0 mL/0.10 mL
H2O). b)Yield of the isolated 3aa. c)Determined by HPLC
analysis. d)The catalyst was generated in situ from
[RhCl(coe)2]2 (2 mol % Rh) and the bisphosphine ligand
(2.4 mol %). coe: cyclooctene.
arylation of chalcones, much lower yield and
enantioselectivity (34% yield, 48% ee) was obtained
with the 2-pyridinyl one.[18] The difficulty of this
reaction is caused by the neighboring coordinating N-
atom (possibly poisoning the Rh catalyst). To
overcome this issue, first, an appropriate catalyst
should be used; second, a higher reaction temperature
might be employed. At the outset of our study, we
first tried the rhodium/chiral diene catalytic
system,[19] which proved to be one of the best
methods for rhodium-catalyzed asymmetric 1,4-
addition. Several commonly used chiral diene-ligated
rhodium catalysts were investigated (entries 14),
however, only very low yields were obtained
(3%5%). In all the cases, phenylboronic acid 2a
remained in the mixture at the end of reaction,
indicating that the rhodium catalyst probably existed
in a resting state. Deactivation of the catalyst might
be attributed to strong binding of pyridine nitrogen to
Results and Discussion
As shown in Table 1, we commenced our
investigation with a benzoyl group-activated 2-
pyridinyl olefin substrate, the enone 1a. The
azaarene-substituted enones remained a class of
challenging
substrates
in
rhodium-catalyzed
asymmetric conjugate addition. In an early study by
the Liao group on rhodium-catalyzed asymmetric
2
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10.1002/adsc.202000211
Advanced Synthesis & Catalysis
Table 2. Scope of Organoboronic Acids and 2-Pyridinyl
(3ah3al),
and
electron-withdrawing
groups
Enones.a)
(3am3an) at different positions, as well as multi-
substituted ones (3ao3aq) were all suitable, high
yields and excellent enantioselectivities were
attainable. Naphthyl (3ar3as) and heteroaryl
(3at3au) boronic acids also worked well. In
addition, both cyclic and acyclic alkenylboronic acids
were well tolerated (3av3aw). However, the
remaining limitation was that the electron-deficient
pyridinylboronic acids did not work in this system.
Different keto activating groups were introduced, and
good compatibility with the current catalytic system
was observed. As shown in Table 2, in addition to the
benzoyl group, the keto moiety can be other
(hetero)aryl carbonyls such as 2-naphthoyl (3ba),
thiophene-2-carbonyl (3ca), and furan-2-carbonyl
(3da). Moreover, the azaarene-containing nicotinoyl
(3ea) and isonicotinoyl (3fa) groups were also
tolerated, thus producing chiral molecules bearing
multiple azaarenes. The activating keto groups were
not limited to (hetero)aryl carbonyls, the alkyl ones
also worked well (3ga3ha).
Table 3. Scope of Azaarenes.a)
a)Reactions were performed with 0.20 mmol of 1 and 0.30
mmol of 2. b)0.40 mmol of 2 was used. c)Catalyst loading
was increased to 10 mol % Rh.
the rhodium center, and we speculated that a stronger
σ-donor ligand on rhodium may help weaken this
coordination and release the catalyst. Indeed, the
high-yielding asymmetric phenylation was realized
with the bis(phosphine) ligand (entries 57), which
has stronger σ-donating ability than diene. Among
these chiral bis(phosphine) ligands, segphos gave the
best enantioselectivity (entry 7, 92% ee). The
differences in enantioselectivities can be attributed to
the different bulkiness and bite angles of the chiral
bis(phosphine) ligands.[20] Further studies on the
segphos-type ligands led to the optimal ligand DM-
segphos (entry 8, 98% yield, 98% ee), a ligand with
strong σ-donating and weak π-accepting abilities.
DTBM-segphos gave an inferior result (entry 9),
probably due to the bulkiness of the ligand. With
DM-segphos as the optimal ligand, the solvent effect
on the reaction was further studied. The reaction also
proceeded with dioxane, toluene, and ethanol as the
solvent, but either diminished yield or lower
enantioselectivity was obtained (entries 1012). Thus,
we chose the conditions of entry 8 as the optimal
conditions for further studies. Note that the high
a)Reactions were performed with 0.20 mmol of 1 and 0.30
mmol of 2. b)0.40 mmol of 2 was used. c)Reaction time was
24 h.
Under the optimal conditions found for the
asymmetric phenylation of 1a (Table 1, entry 8), the
scope of azaarenes was next examined (Table 3), and
o
reaction temperature (80 C) was necessary for the
the
current
method
showed
extraordinary
observed high reactivity.
compatibility with diverse azaarenes. The
corresponding arylation products 3ia3na were
obtained in high yields (84%99%) and with
excellent enantioselectivities (94%98% ee) from
The scope of organoboronic acids and different 2-
pyridinyl enones was first investigated. As
summarized in Table 2, arylboronic acids bearing
electron-donating groups
(3ab3ag), halides
3
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10.1002/adsc.202000211
Advanced Synthesis & Catalysis
various substituted 2-pyridine substrates. 3-Pyridine
and 4-pyridine substrates also worked well
(3oa3pa). Other azaarenes including quinoline,
isoquinoline, thiazole, pyrimidine, benzoimidazole,
and quinoxaline were all found to be appropriate
substrates. The corresponding phenylation products
(3qa3za) were obtained in high yields (80%97%)
and with good to excellent enantioselectivities
(83%99% ee).
As depicted in Scheme 2, the first asymmetric
syntheses
of
dexchlorpheniramine
and
dexbrompheniramine,[22] which are the APIs (active
pharmaceutical ingredients) of marketed chiral drugs
Polaramine®/Trimeton® and Disomer®, were
realized based on the developed method (at 2 mmol
scale). The synthesis involved the asymmetric
arylation of ester-activated 2-pyridinyl alkene as the
key step to construct the stereogenic center, followed
by hydrolysis, amide coupling, and BH3-mediated
reduction to give the tertiary amine products in high
yields and with excellent enantioselectivities. Note
that the borane reduction was found to be optimal, as
dehalogenation was observed under other reduction
conditions.
Table 4. Different Activating Groups.a)
a)Reactions were performed with 0.20 mmol of 4 and 0.40
mmol of 2. EWG = electron-withdrawing group.
Scheme 3. Stereochemical Pathway and the Absolute
Configuration of Product.
Other activating groups beyond ketones were
further studied (Table 4). Although amide, cyano, or
pyridinyl substrates, which are less reactive than keto
substrates, were not suitable in this catalytic system,
we were delighted to find that the ester-activated
substrate worked very well (5aa, 96%, 96% ee),[21]
and the reaction showed a broad scope of arylboronic
acids (5ab5an). The generated products are highly
useful chiral building blocks, as the ester moiety
provides a good handle for further synthetic
manipulations.
A model for the stereochemistry of the asymmetric
arylation process was illustrated in Scheme 3.
According to the highly skewed structure of transition
metal complexes coordinated with a segphos-type
ligand,[23] the (R)-DM-segphos/Rh catalyst recognizes
the enantioface of substrate by the steric repulsions
between the carbonyl moiety and the aryl group
sticking out from the phosphorus atom of the ligand.
The olefinic double bond of both enone and ester
substrates coordinates to rhodium with its re-face,
which undergoes migratory insertion to form a
stereogenic carbon center. The absolute configuration
of product 3aj is assigned to be S by single-crystal X-
ray diffraction analysis,[24] which is consistent with
the proposed stereochemical pathway.
Conclusion
In summary, we have developed a rhodium-catalyzed
asymmetric addition reaction for the synthesis of
chiral azaarenes bearing an adjacent stereogeneric
center. The reaction features readily available
reagents, commercially available catalyst/ligand, and
broad substrate scope with excellent enantio control
(>60 examples, up to 99% ee). The synthetic utility of
the new method was demonstrated through
Scheme 2. Asymmetric Syntheses of Dexchlorpheniramine
and Dexbrompheniramine.
4
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10.1002/adsc.202000211
Advanced Synthesis & Catalysis
asymmetric
syntheses
of
marketed
drugs
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dexchlorpheniramine and dexbrompheniramine. The
chiral azaarene building blocks produced from the
method we describe may find broad utility in drug
discovery endeavors.
Experimental Section
A general procedure for the rhodium-catalyzed asymmetric
conjugate addition reaction: [RhCl(coe)2]2 (1.4 mg, 2
mol % Rh) and (R)-DM-segphos (3.5 mg, 2.4 mol %) were
placed in an oven-dried Schlenk tube under nitrogen. THF
(0.6 mL) was added, and the mixture was stirred at room
temperature for 30 min. Then azaarene substrate 1 (0.20
mmol), organoboronic acids 2, aqueous KOH (5 mol %,
0.10 mL, 0.10 M), and another portion of THF (0.4 mL)
were added under nitrogen. The resulting mixture was
stirred at 80 ℃ for 12 h. Upon completion, the reaction
mixture was diluted with EtOAc (5 mL) and water (5 mL).
The layers were separated, and the aqueous layer was
extracted again with EtOAc for two more times (5 mL × 2).
The combined organic layers were then concentrated in
vacuo, and the residue was purified by silica gel
chromatography eluting with petroleum ether/EtOAc to
give the product.
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Acknowledgements
We are grateful for the financial support from the “Double First-
Class” University project (CPU2018GY35) of China
Pharmaceutical University.
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10.1002/adsc.202000211
Advanced Synthesis & Catalysis
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Rhodium-Catalyzed Asymmetric Conjugate
Addition of Organoboronic Acids to Carbonyl-
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Huilong Zhu, Long Yin, Zhiqian Chang, Yuhan
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