Ni-catalyzed reductive antiarylative cyclization of alkynones

Article abstract of DOI:10.1021/acs.orglett.0c02534

A new catalyst system for the antiarylative cyclization of alkynones and aryl halides through a reductive cross-coupling strategy is developed. The transformation proceeds smoothly in the absence of organometallic reagents and features high functional group tolerance. This method provides an effective platform to access a wide variety of synthetically useful endocyclic tetrasubstituted allylic alcohols in a stereoselective manner.

Full text of DOI:10.1021/acs.orglett.0c02534

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Letter
Ni-Catalyzed Reductive Antiarylative Cyclization of Alkynones
Zhijun Zhou,† Wenfeng Liu,† and Wangqing Kong*
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ABSTRACT: A new catalyst system for the antiarylative cyclization of alkynones and aryl halides through a reductive cross-coupling
strategy is developed. The transformation proceeds smoothly in the absence of organometallic reagents and features high functional
group tolerance. This method provides an effective platform to access a wide variety of synthetically useful endocyclic
tetrasubstituted allylic alcohols in a stereoselective manner.
Scheme 1. Ni-Catalyzed Coupling Reaction of Alkynes and
Carbonyls for the Synthesis of Tetrasubstituted Allylic
Alcohol
he cyclic tetrasubstituted allylic alcohol motif is commonly
Tfound in numerous biologically important compounds and
natural products, including brasilenol, illudol, guadalupol, and
conocephalenol (Figure 1).1
Figure 1. Representative natural products containing an endocyclic
tetrasubstituted allylic alcohol moiety.
However, approaches for synthesizing these structures are still
limited and still pose a significant synthetic challenge, especially
in a regio- and stereocontrolled manner. Among various
methods, Ni-catalyzed cis-1,2-addition cyclization of organo-
metallic reagents and aldehydes or ketones onto alkynes has
been well-developed and has become one of the most
straightforward and attractive methods for the preparation of
exocyclic tetrasubstituted allylic alcohols (Scheme 1a).2−4
Alternatively, Lam et al. recently reported the Ni-catalyzed
formal trans-1,2-addition of arylboronic acids and ketones to
alkynes via an alkenyl−Ni(II) intermediate, providing an elegant
protocol for endocyclic tetrasubstituted allylic alcohols (Scheme
1b).5,6 Nevertheless, these methods are not without drawbacks.
Received: July 30, 2020
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© XXXX American Chemical Society
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A

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a
They are usually limited in substrate scope and require the use of
stoichiometric organometallic reagents.
Table 1. Optimization of the Reaction Conditions
In recent years, the Ni-catalyzed cross-couplings of two
carbon electrophiles under reducing conditions have attracted
considerable attention from synthetic chemists.7 Compared
with the classic redox-neutral cross-couplings, the main
advantage of this strategy is that it does not require the use of
organometallic reagents and exhibits excellent functional group
compatibility. Despite the tremendous progress made, difunc-
tionalization of alkynes by trans-addition of two carbon
electrophiles across the triple bond remains unexploited.8
Martin’s group described reductive anti-dicarbofunctionaliza-
tion of alkynes via Ni-catalyzed cyclization/carboxylation of
alkyne-tethered alkyl halides with CO2.8a Montgomery et al.
reported reductive syn-dicarbofunctionalization of alkynes
through Ni-catalyzed oxidative cyclization of alkynals and
coupling with alkyl halides.8b In continuation of our studies
on Ni-catalyzed reductive arylfunctionalization of unsaturated
carbon−carbon bonds,9 we envisioned that with the proper
combination of nickel catalyst, ligand, and reducing agent, the
reductive arylative cyclization of alkynone and aryl halide may
produce a more nucleophilic alkenyl−nickel(I) intermediate,
which would provide a new and effective platform for the
synthesis of endocyclic tetrasubstituted allylic alcohols (Scheme
1c).
b
entry
ligand
reducing agent
yield of 3aa (%)
1
2
3
4
5
6
7
8
L1
L1
L1
L2
L3
L4
L5
L6
Zn
28
43
trace
17
trace
32
Mn
B2Pin2
Mn
Mn
Mn
Mn
Mn
Mn
Mn
Mn
Mn
Mn
Mn
56
trace
trace
trace
trace
79 (69)
0
9
L7
10
11
dppe
PPh3
L5
L5
L5
c
12
d
13
e
14
0
a
Unless noted otherwise, reactions were carried out in 2 mL of DMF
Based on our previous studies on the Ni-catalyzed reductive
difunctionalization of alkenes,10 we chose alkynone 1a and
phenyl bromide 2a as model substrates to test our reaction
design. We were very delighted to find that, by employing a
combination of NiBr2·dme (10 mol %) as catalyst, bpy (L1, 20
mol %) as ligand, Zn0 (3 equiv) as reducing agent, and NaI (50
mol %) as additive in DMF, the reaction did indeed take place,
leading to the desired 5,5-bicyclic 3aa in 28% yield (Table 1,
entry 1). Among the different reducing agents investigated, Mn0
powder gave the highest yield, whereas B2Pin2 gave only a trace
amount of 3aa (entries 2 and 3). Subsequently, a survey of
bidentate nitrogen ligands was performed (entries 4−9), and
1,10-phenanthroline L5 proved to be the most effective (56%,
entry 7). The formation of target product 3aa was not detected
when the nitrogen ligands were replaced with phosphine ligands
such as PPh3 or dppe (entries 10 and 11). Finally, we found that
an excess of PhBr was needed to isolate the desired 3aa in 69%
yield (entry 12). Nevertheless, most of the PhBr can be
recovered after the reaction, and only a trace of homocoupling
byproduct biphenyl was observed. Unsurprisingly, the reaction
did not proceed in the absence of NiBr2·dme or Mn0 (entries 13
and 14).
at 80 °C for 24 h on a 0.1 mmol scale using 1 equiv of 1a, 2 equiv of
2a, 10 mol % of NiBr2·dme, 20 mol % of ligand, and 3 equiv of
b
reductant. GC yield using adamantane as the internal standard. The
value in brackets is the yield of isolated 3aa after column
c
chromatography purification on silica gel. 4 equiv of 2a was used.
d
e
No NiBr2·dme. No Mn0.
a
Scheme 2. Substrate Scope of Organic Halides
Using the optimal reaction conditions described in Table 1,
entry 12, we first evaluated the effects of various aryl halides 2
(Scheme 2). Bicyclic product 3aa was obtained in 83% yield
from phenyl iodide, whereas phenyl chloride was not reactive at
all. Although a higher yield can be obtained using phenyl iodide,
considering that aryl bromides are typically cheaper and more
widely available, we decided to explore the substrate scope using
aryl bromides. Aryl bromides adorned with electron-donating
groups such as methoxy and amino group at the para-position
proceeded smoothly to produce the corresponding products
3ab and 3ac in 84 and 73% yield, respectively. Whereas an
electron-withdrawing group on the aromatic ring, such as a
fluorine group, reduced the reaction efficiency, product 3ad was
obtained in 33% yield. It is worth noting that the reductive
cyclization reaction could be carried out without affecting the
aryl borate entity, thereby providing opportunities for further
a
Reactions were conducted using 0.2 mmol of 1a; 4 equiv of 2 was
b
used. Yields are of isolated products. The reaction was conducted on
a 1 mmol scale using 5 mol % of NiBr2·dme and 10 mol % of L5.
derivatization through the Suzuki coupling technique (3ae). 2-
Naphthyl bromide was also tolerated to deliver 3ag in 87% yield.
In addition, various (hetero)aryl bromides were also tested.
Dibenzofuran, dibenzothiophene, benzothiophene, pyridine,
and indole were all successfully incorporated into the
corresponding products 3ah−3al in 23−94% yields. Excitingly,
vinyl bromide 2m was also a viable substrate to afford the
B
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corresponding 1,3-diene 3am in 36% yield. However, for
propargyl bromide 2n and alkyl bromide 2o, the desired
products were not obtained.
Next, we studied the substrate scope of alkynone 1 (Scheme
3). The influence of the substituents (R1) at the terminus of the
a
Scheme 3. Substrate Scope of Alkynones 1
Figure 2. Results with substrates possessing different carbon skeletons.
bicyclic product 3va in 40% yield (Figure 2a). The reaction does
not rely on the 1,3-diketone backbone, and the monoketone
substrate 1w could also undergo reductive arylative cyclization
to produce the cyclopentanol 3wa in 70% yield (Figure 2b). In
addition, the one-carbon homologous monoketone substrate 1x
was also tested, and the trans-6-endo arylative cyclization
product 3xb was obtained in 80%. Remarkably, the possible
cis-5-exo arylative cyclization was not detected (Figure 2c).
More interestingly, the substrate bearing a phthalimide
moiety could also smoothly undergo reductive cyclization
reaction, and the target tricyclic pyrrolizinone 3ya was afforded
in 36% yield through the dehydration and isomerization of the
initial cyclization product. It is worth mentioning that the
pyrrolizinone skeleton containing a bridgehead nitrogen is a
common structural unit in many naturally occurring alkaloids
with various degrees of biological activities (Scheme 4).11 The
reaction of 1y with phenylboronic acid under the previously
reported redox-neutral reaction conditions was attempted;5a
however, no target product was detected.
a
Reactions were conducted using 0.2 mmol of 1; 4 equiv of 2a was
used. Yields are of isolated products.
Scheme 4. Construction of Tricyclic Pyrrolizinone Skeleton
alkyne was first investigated. Under the standard reaction
conditions, the reactions tolerate the presence of various
functional groups such as ether (3ca), chloride (3da), fluoride
(3ea), trifluoromethyl (3fa), ester (3ga), borate (3ha), and
cyano (3ia). 2-Naphthyl substrate reacted smoothly to give 3ja
in 70% yield. This methodology was compatible with a wide
array of heteroarenes, such as 3,4-benzodioxole (3ka), 3,4-
dihydrobenzodioxine (3la), indole (3ma), dibenzothiophene
(3na), dibenzofuran (3oa), and pyridine (3pa) at the terminal
end of the triple bond. More excitingly, estrone could also be
successfully incorporated into product 3qa in 79% yield (1/1
dr), indicating that our mild reaction conditions allow late-stage
modification of complex molecules. In addition, the reaction is
not restricted to the aryl group at the terminal of the triple bond,
and an alkyne bearing a sterically hindered trimethysilyl group
was also compatible with this transformation, albeit in a low
yield (3ra). However, no desired product (3sa) was observed
when methyl substituted alkynone substrate was used. Terminal
alkyne 1t produced complex mixtures. The introduction of a
benzyl group (R2) to the 2-position of the indan-1,3-dione-
containing substrate was also amenable to this transformation,
and the tricyclic product 3ua was isolated in 94% yield.
A series of chiral ligands was screened for achieving
asymmetric induction in this tandem reaction (for details, see
Tables S1 and S2 in the Supporting Information). It was found
that (S)-Ph-Phox (L8) was the most effective ligand to afford
3aa in 65% yield with 81% ee (Figure 3), which is comparable to
the results previously reported by Lam et al. (86% ee).5a
To further clarify the possible catalytically active intermedi-
ates in the reaction, we synthesized 2-tolyl-Ni(II) complex 4
according to the previously reported method.9a Under our
standard conditions, treatment of complex 4 with alkynone 1a
We decided to further explore other alkynone skeletons
(Figure 2). Under the standard reaction conditions, the reaction
of cyclohexane-1,3-dione 1v with 2a afforded the expected 5,6-
C
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target endocyclic tetrasubstituted allylic alcohol 3 was formed by
the nucleophilic attack of D to the carbonyl and subsequent
protonolysis with water. The catalytically active Ni(0) species was
then regenerated upon Mn0 reduction. However, the pathway
for the direct cyclization of Ni(II) intermediate C to form nickel
alkoxide E cannot be ruled out at the current stage.
In summary, we have successfully developed a new catalyst
system for the antiarylative cyclization of alkynones and
organohalides. This transformation does not require the use of
organometallic reagents and exhibits excellent functional group
tolerance. Various highly functionalized endocyclic tetrasub-
stituted allylic alcohols were prepared in good yields with high
regio- and enantioselectivity. Preliminary mechanistic inves-
tigation indicates that either alkenyl−Ni(I) or alkenyl−Ni(II)
species may be the key intermediate of the reaction.
Figure 3. Asymmetric reductive antiarylative cyclization of alkynone.
furnished the desired 3af in 17% yield. However, in the absence
of Mn0, the reaction of complex 4 with 1a afforded 3af in 20%
yield (Figure 4). The above results indicate that both alkenyl−
Ni(I) and alkenyl−Ni(II) intermediates may be the active species
in the catalytic cycle.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02534.
Experimental procedures and spectra data for all new
compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Figure 4. Mechanistic study.
Although many types of electrophiles have been found to
capture alkenyl−Ni(II) species, the amide carbonyl group is
rarely investigated,12 and this is not surprising due to its poor
electrophilicity. A direct evidence is that, under redox-neutral
conditions, the reaction of phenylboronic acid with phthalimide
1y cannot produce the expected tricyclic pyrrolizinone 3ya
(Scheme 4). This result seems to support the hypothesis that a
more nucleophilic alkenyl−Ni(I) intermediate is involved under
reducing conditions.
Wangqing Kong − The Institute for Advanced Studies, Wuhan
University, Wuhan, Hubei 430072, P.R. China; orcid.org/
0000-0003-3260-0097; Email: wqkong@whu.edu.cn
Authors
Zhijun Zhou − The Institute for Advanced Studies, Wuhan
University, Wuhan, Hubei 430072, P.R. China
Wenfeng Liu − The Institute for Advanced Studies, Wuhan
University, Wuhan, Hubei 430072, P.R. China
As displayed in Scheme 5, a possible reaction mechanism for
the reductive arylative cyclization of alkynone was proposed.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02534
Scheme 5. Proposed Reaction Mechanism
Author Contributions
†Z.Z. and W.L. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We acknowledge support from the “1000-Youth Talents Plan”,
NSFC (21702149), and Wuhan University.
■
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