Selective Hydroarylation of 1,3-Diynes Using a Dimeric Manganese Catalyst: Modular Synthesis of Z-Enynes

Article abstract of DOI:10.1002/anie.201807851

The transition-metal-catalyzed selective hydroarylation of unsymmetrical alkynes represents the state-of-art in organic chemistry, and still mainly relies on the use of precious late-transition-metal catalysts. Reported herein is an unprecedented Mn^I-catalyzed hydroarylation of unsymmetrical 1,3-diyne alcohols with commercially available arylboronic acids with predictive selectivity. This method addresses the challenges in regio-, stereo-, and chemoselectivity. It offers a general, convenient and practical strategy for the modular synthesis of multisubstituted Z-configurated conjugated enynes. This protocol is distinguished by its operational simplicity, complete selectivity, excellent functional-group compatibility, and gram-scale potential. A dimeric Mn^I species, Mn₂(CO)₈Br₂, was proven to be a much more efficient catalyst precursor than Mn(CO)₅Br.

Full text of DOI:10.1002/anie.201807851

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Accepted Article
Title: A Dimeric Mn-Catalyzed Completely Selective Hydroarylation of
1,3-Diynes for the Modular Synthesis of (Z)-Enynes Library
Authors: Jin Xie
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201807851
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10.1002/anie.201807851
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A Dimeric Mn-Catalyzed Completely Selective Hydroarylation of
1,3-Diynes for the Modular Synthesis of (Z)-Enynes Library
Zhongfei Yan, Xiang-Ai Yuan, Yue Zhao, Chengjian Zhu and Jin Xie*
Abstract: The transition-metal-catalyzed selective hydroarylation of
unsymmetrical alkynes represents the state-of-art in organic
chemistry, which still mainly relies on the use of precious late
transition-metal catalysts. In this communication, we have developed
an unprecedented Mn(I)-catalyzed hydroarylation of unsymmetrical
1,3-diyne alcohols with commercially available arylboronic acids in a
predictive selectivity. This method well addresses the challenges in
regio-, stereo- and chemoselectivity. It offers a general, convenient
and practical strategy for the modular synthesis of multisubstituted
(Z)-configurated conjugated enynes. This protocol is distinguished by
its simple operation, complete selectivity, excellent functional group
compatibility and gram-scale capacity. A dimeric Mn(I) species,
Mn2(CO)8Br2, was proven to be a much more efficient catalyst
precursor than Mn(CO)5Br.
activation has been successfully reported by Wang’s and
Ackermann’s group (Scheme 1b).[7] However, installing proximal
directing groups onto arenes in advance is required, and the
regioselectivity remains unsolved for internal alkynes. Therefore,
the development of a general and highly selective hydroarylation
of internal alkynes with commercially available Ar-B(OH)2 is still a
tremendous challenge in manganese catalysis.
The transition metal-catalyzed selective hydroarylation of C-C
triple bonds with organometallic reagents,[1] particularly moisture
and air-stable arylboronic acids,[2] is emerging as a reliable
strategy for the streamlined synthesis of multisubstituted alkenes.
Despite the important progress, regio- and chemoselective
hydroarylation of unsymmetrical internal alkynes remains highly
attractive. In comparison with Rh-[2a-f] and Pd-[2g-k] catalyzed
hydroarylation, hydroarylation catalyzed by more earth-abundant
and less toxic manganese has not yet been reported regardless
of the potential importance of such a transformation. To date, the
direct formation of Ar-Mn species from Ar-B(OH)2 has remained a
fundamentally unexplored topic.[3] The major barrier for this stems
from the strong oxidation ability of high valent Mn-complexes[4a]
and the low reactivity of Mn(I)-based catalysts toward
transmetalation[4b] (Scheme 1a). Furthermore, almost all the
known cases of alkyne insertion into C(aryl)-Mn bonds are based
on the chelation-promoted 5-membered manganacycle model[5]
because nonchelated Ar-Mn(CO)5 species are prone to
intramolecular rearrangement.[6] To the best of our knowledge,
Scheme 1. Mn(I)-catalyzed hydroarylation of alkynes and our design.
Conjugated enynes are prevalent structural motifs in a broad
range of bioactive compounds[8a,8b] and also are versatile building
blocks in synthetic chemistry.[8c] However, a general and
completely selective strategy accessing to conjugated enynes
remains challenging as the alkyne dimerization[8d, 8e] and cross-
coupling strategies[8f, 8g] would potentially result in the formation of
a mixture of regio- and stereoisomers. With this in mind, we
selected unpolarized 1,3-diynes to start the study of Mn(I)-
catalyzed hydroarylation with Ar-B(OH)2 (Scheme 1c). Notably,
for selective hydroarylation, the use of unsymmetrical 1,3-diynes
faces more challenges than the use of terminal monoalkynes: (1)
the regioselectivity in one alkyne unit for the insertion process into
the C(aryl)-Mn σ bond; (2) the chemoselectivity between two
unbiased alkyne moieties; (3) the stereoselectivity in the
migratory insertion (syn vs anti), and (4) the ability to control
whether single or double hydroarylation occurs. An improved
manganese catalyst precursor, Mn2(CO)8Br2 was considered,[9]
as the resulting vacant active coordination state of Mn(I)
intermediates could potentially coordinate with alkynes instead of
ligand rearrangement and then rapidly undergo syn-
only
chelation-controlled
Mn(I)-catalyzed
(E)-selective
hydroarylation of terminal alkynes with directed arenes via C-H
Z. Yan, Dr. Y. Zhao, Prof. Dr. C. Zhu, Prof. Dr. J. Xie,
State Key Laboratory of Coordination Chemistry, Jiangsu Key
Laboratory of Advanced Organic Materials, School of Chemistry and
Chemical Engineering, Nanjing UniversityNanjing 210023, China
Email: xie@nju.edu.cn
Homepage: http://hysz.nju.edu.cn/xie
Prof. Dr. X.-A. Yuan
School of Chemistry and Chemical Engineering, Qufu Normal
University
Qufu 273165, China
Prof. Dr. C. Zhu
State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry
Shanghai 200032, China
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/anie.201807851
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hydroarylation for the modular synthesis of multisubstituted (Z)-
enynes (Scheme 1c).
With 5 mol% Mn2(CO)8Br2 as the catalyst precursor and NaOAc
as additives, the selective hydroarylation reaction could smoothly
occur to afford enyne alcohol (3c) in 89% yields when performed
under air using hexane instead of DCE (entry 1). The solid-state
molecular structure of 3c was determined by single crystal X-ray
structure analysis. The other solvents and bases resulted in lower
[2h]
yields (entries 2-5). Significantly, the use of Pd(PPh3)4
and
[Rh(acac)(C2H4)2][2a] instead of Mn2(CO)8Br2 resulted in only trace
product as regio- and stereoisomers under reported
hydroarylation conditions (entries 6 and 7), further underlining the
unique catalytic reactivity of Mn(I)-based catalyst. The control
experiment demonstrated that Mn2(CO)8Br2 was crucial for a
success (entry 8).
Table 2: Diyne scope.
Scheme 2. Initial investigation of suitable 1,3-diyne type.
Initially, several substituted 1,3-diynes bearing different
functional groups were employed to investigate the suitability of
substrate type (Scheme 2). Fortunately, we found that diyne
alcohol 1c and its ether 1d could undergo Mn(I)-catalyzed
arylmetalation on the β-carbon only to afford the corresponding
hydroarylation products (3c and 3d) in 16% and 15% yields
respectively, with complete regio-, stereo- and chemoselectivity
by using Mn2(CO)8Br2 as the catalyst precursor, whereas other
substituted diynes (1a-b and 1e) were rather recalcitrant to
undergo the hydroarylation. It can clearly be concluded that
Mn2(CO)8Br2 is a much more efficient catalyst precursor than
Mn(CO)5Br, which is consistent with the mechanistic model
hypothesis in Scheme 1c.
Table 1: Optimization of reaction conditions.[a]
With the optimized reaction conditions (Table 1, entry 1) in
hand, we next investigated the substrate scope with regard to the
unsymmetrical 1,3-diynes (Table 2). Both homopropargylic
alcohols (3c and 3f) and ether (3d) were effective substrate types.
All aryl- and heteroaryl-substituted 1,3-diynes tested could
undergo Mn(I)-catalyzed selective hydroarylation to furnish 3g-l
in 31-96% yields. Importantly, the regioselectivity was not affected
by the proximal heteroaryl substituents (3j-l). When the trialkyne
and enediyne alcohols were employed under standard conditions,
they gave the desired enediyne (3m) in 75% yield and dieneyne
(3n) in 94% yield. Various undifferentiated aliphatic 1,3-diynes
(3o-r) could uniformly proceed this hydroarylation reaction
regardless of the steric and electronic effects of their substituents.
The ferrocene-based diyne alcohol is a competent substrate, and
the resulting ferrocenyl enyne (3s) may attract considerable
interest in material science owing to the unique electronic property.
Beside primary alcohols, several functionalized diyne secondary
alcohols reacted smoothly with organoborons to give 3t-w in 84-
92% yields. Of note, the reactive alkene (3n, 3t and 3u) and
electron-rich heteroaryl (3j, 3k, 3s and 3v) units keep intact in Mn-
catalyzed hydroarylation, which showcases a very attractive
Entry
1
Variation in standard conditions
none
Yield[b](%)
89
2
DCE instead of hexane
73
3
benzene instead of hexane
LiOAc instead of NaOAc
Cy2NH instead of NaOAc
Pd(PPh3)4 instead of Mn2(CO)8Br2
[Rh(acaca)(C2H4)2] instead of Mn2(CO)8Br2
without Mn2(CO)8Br2
48
4
65
5
nd
6[c]
7[d]
8
trace
trace
nd
[a] Standard reaction conditions: Mn2(CO)8Br2 (5 mol%), 1c (0.2 mmol), 4-
MeC6H4B(OH)2 (0.6 mmol), NaOAc (2 equiv), hexane (5 mL), 90 °C, air, 24 h.
[b] Isolated yield. nd = not detected. [c] Pd(PPh3)4 (3 mol%), AcOH (10 mol%),
1,4-dioxane (1 mL), 60 °C, argon. [d] Rh(acac)(C2H4)2 (3 mol%), dppf (6.6
mol%), 1,4-dioxane/H2O (10:1, 1 mL), 100 °C, argon.
With these intriguing initial results, the reaction of 5-
phenylpenta-2,4-diyn-1-ol (1c) and p-tolylboronic acid (2a) was
chosen as a model reaction to optimize the reaction conditions
(Table 1). We found that solvents and additives tremendously
influenced the yield of 3c (See Supporting Information for details).
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10.1002/anie.201807851
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synthetic advantage in organometallic chemistry. However, the
introduction of a tertiary alcohol moiety almost blocked the
hydroarylation due to the steric hindrance effect (3x). In addition,
Mn(I)-catalyzed hydroarylation of a skipped 1,4-diyne[10] provided
an important alternative means of stereoselectively constructing
skipped enyne alcohol (3y) in 68% yield. Notably, it appears that
there is no significant effect of electronics (3g-i) and steric
hindrance (3t-w) on the hydroarylation regioselectivity.
stereoselectivity and good yield. A Pd-catalyzed C(sp2)-C(sp3)
coupling of enyne alcohol derivative with arylboronic acid to afford
product 7 (63% over two steps) further illustrated the synthetic
robustness in the modular synthesis of a wide range of substituted
enynes.
Subsequently, a wide range of commercially available
arylboronic acids were evaluated (Table 3). In general, both
electron-rich (-Me, -Et, -OMe, -tBu etc.) and electron-poor (-F, -Cl,
-CN, -CF3, -NO2 etc.) functional groups in the para-, meta- and
ortho-positions of the phenyl rings could tolerate the reaction
conditions well, which suggests that the electronic and steric
effect of substituents on arylboronic acids have little influence.
The resulting enyne alcohols (3c and 3z-nn) were isolated in 54-
95% yields with exclusive Z-selectivity. The compatibility of bromo
substituents further highlighted the synthetic advantages of this
protocol (3aa, 3ii and 3zz). Meanwhile, 2-naphthylboronic acid
and (9,9-dimethyl-9H-fluoren-2-yl)boronic acid proceeded the
hydroarylation smoothly to afford 3rr and 3ss in 63% and 74%
yield respectively. The heterocycle-containing boronic acids,
including furan-, thiophen-, quinoline- and pyridine-based
heteroarylboronic acids, were efficient coupling partners under
Mn catalysis, affording the expected products (3tt-aaa) in
synthetically useful yields.
Table 3: Arylboronic acid scope.
Scheme 3. Synthetic application. For the reaction conditions please see
Supporting Information for details.
As outlined in Scheme 4, some mechanistic experiments were
carried out to elucidate the possible mechanism. According to the
calculated NBO charge distribution results, the electronic effect of
the alkyne may not be the key factor in Mn(I)-catalyzed
hydroarylation because the arylation occurred only on the -
carbon even when the relatively more positive C() was present
(Scheme 4a).[11] Deuterium-labeling experiment demonstrated
that the hydrogen atom at the vinyl position should come from
protons in the reaction media (Eq. 1). Interestingly, switching the
substrate from diyne alcohol 1c to monoyne alcohol 8 allowed the
desired product 9 to be obtained in 83% yield in a complete
selectivity (Eq.
2
and 3). However, for unsymmetrical
monoalkynes 10 and 13, the regioselectivity of alkyne migratory
insertion into the Mn-C(sp2) σ bond significantly decreased,[12]
which indicates that both the hydroxyl group and aryl or alkynyl
group substituents in the substrates are crucial for the origin of
selectivity in the present catalysis (Eq. 4 and 5).
As shown in Scheme 3a, when the model reaction was
scaled-up to 10 mmol, a satisfying yield of 81% was obtained.
Importantly, there are several synthetic advantages of using a
readily transformable hydroxyl group in the substrates. It can not
only avoid the requirement of installing and removing an external
polarized directing group, but also is a versatile functional group
for downstream synthetic transformations to deliver the
corresponding ester (4) and aldehyde (5) in good yields.
To verify whether the Mn-Ar species was generated via
transmetalation during the catalytic cycle, we mixed
stoichiometric Mn2(CO)8Br2 with arylboronic acid under reaction
conditions (Scheme 4d). As the proposed nonchelated Ar-Mn
species are too reactive to obtain[13] (Eq. 6), (2-(pyridin-2-
yl)phenyl)boronic acid (16) was subsequently employed with the
aim to stabilize the resulting reactive Ar-Mn species (Eq. 7). To
our delight, a stable 5-membered manganacycle (17) was
successfully isolated in 21% yield and its structure was further
determined by X-ray single crystal structure analysis, constituting
Additionally, enyne alcohol 3c can be converted into
a
trisubstituted conjugated dieneyne (6) in excellent
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one solid evidence for the postulated intermediate via
transmetalation.
the coordination of diyne 1c to the vacant coordination state of
Mn(I) center could occur prior to transmetalation with Ar-B(OH)2.
Scheme 5. Proposed mechanism.
In conclusion, a highly efficient Mn(I)-catalyzed regio-, stereo-
and chemoselective hydroarylation of unsymmetrical 1,3-diynes
with commercially available arylboronic acids has been described.
It affords a general, practical and convenient access to the
streamlined construction of a wide array of trisubstituted (Z)-
configurated conjugated enyne alcohols in moderate to excellent
yields. The resulting products are versatile building blocks that
can participate in a series of useful downstream synthetic
transformations to rapidly populate a complex small-molecule
enyne library. Although an excess of arylboronic acids is still
necessary for good yield at present, this protocol represents an
important step-forward toward fundamentally rarely explored
transmetalation and nonchelation-controlled alkyne insertion
chemistry in manganese catalysis. The exploration of new
reactions catalyzed by dimeric Mn(I)-complex and of mechanistic
studies is currently ongoing in our group.
Scheme 4. Mechanistic studies.
According to the aforementioned mechanistic studies, a
plausible mechanism was proposed in Scheme 5. First, in the
presence of NaOAc at 90 °C, the dimeric Mn2(CO)8Br2 catalyst
precursor breaks into reactive Mn(I) species 18, which can
undergo transmetalation with arylboronic acid 2a to generate
nonchelated Ar-Mn intermediate 19 (16 e-). The vacant active
coordination state of 19 readily coordinates to substrate 1c to form
complex 20. To better understand the origin of regioselectivity, we
computed the possible transition state of alkyne migratory
insertion step. It was found that the weak O-H...π interaction
between the hydroxyl group in substrate 1c and aryl group in Ar-
Mn species would promote the -carbon selectivity.[14] Then, syn-
1,2-migratory insertion of the alkyne unit adjacent to the hydroxyl
group to the Ar-Mn σ bond can give intermediate 21, in which the
alkyne motif may stabilize this intermediate via conjugative effect.
Finally, protodemetalation with H2O which can be generated in
situ during the formation of the triarylboroxin species[15]
regenerates the reactive Mn(I) species 18. The DFT calculation
results indicate that (Z)-enyne 3c might be the kinetically
controlled product because the free energy of (E)- and (Z)-
isomers are very comparable (ΔE < 0.5 kcal/mol). Alternatively,
Acknowledgements
We gratefully acknowledge National Natural Science Foundation
of China (21702098, 21672099, 21732003 and 21703118), the
Fundamental Research Funds for the Central Universities (No.
020514380158, 020514380131), Shandong Provincial Natural
Science Foundation (No. ZR2017MB038) and “1000-Youth
Talents Plan” for financial support.
Keywords: manganese • homogeneous catalysis • alkyne •
arylation • enynes
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Z. Yan, X.-A. Yuan, Y. Zhao, C. Zhu and
J. Xie*
Page No. – Page No.
A Dimeric Mn-Catalyzed Completely
Selective Hydroarylation of 1,3-
Diynes for the Modular Synthesis of
(Z)-Enynes Library
Text for Table of Contents
Two Mn are better than one: The first dimeric Mn(I)-catalyzed hydroarylation of unsymmetrical 1,3-diyne alcohols with arylboronic acids
has been achieved in a predictive regio-, stereo- and chemoselectivity. It offers a general, convenient and practical strategy for the modular
synthesis of multisubstituted (Z)-configurated conjugated enynes library.
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