Copper(II)-Mediated Ring Opening/Alkynylation of Tertiary Cyclopropanols by Using Nonmodified Terminal Alkynes

Article abstract of DOI:10.1021/acs.orglett.0c01828

The copper(II)-mediated ring opening/alkynylation of cyclopropanol by employing inexpensive and commercially available terminal alkyne is developed. The reactions proceeded efficiently to afford synthetically useful alk-4-yn-1-ones in moderate to good yie

Full text of DOI:10.1021/acs.orglett.0c01828

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Letter
Copper(II)-Mediated Ring Opening/Alkynylation of Tertiary
Cyclopropanols by Using Nonmodified Terminal Alkynes
Bu-Qing Cheng, Si-Xuan Zhang, Yan-Ying Cui, Xue-Qiang Chu, Weidong Rao, Haiyan Xu,
Guo-Zhi Han,* and Zhi-Liang Shen*
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ABSTRACT: The copper(II)-mediated ring opening/alkynylation of
cyclopropanol by employing inexpensive and commercially available
terminal alkyne is developed. The reactions proceeded efficiently to afford
synthetically useful alk-4-yn-1-ones in moderate to good yields with good
functional group tolerance. Control experiments showed that the reaction
presumably proceeds via the formation of intermediates of copper
homoenolate and/or alkynylcopper species.
n recent decades, strained tertiary cyclopropanes and their
methods employed premodulated activated alkynes as
substrates, especially in cases where alkynyl benziodoxole
(BI-alkyne)4−6 was used as an alkyne source, which should be
preprepared and is somewhat less atom-economical. We
envisioned that, if commercially available terminal alkynes
could be directly utilized as alkyne sources, the method would
be more straightforward and practical for the synthesis of alk-4-
yn-1-ones. Herein, we report an efficient method for easy entry
to a range of alk-4-yn-1-ones by means of the ring opening/
alkynylation of cyclopropanes with readily available terminal
alkynes in the presence of inexpensive copper(II) salt.8 The
reactions proceeded smoothly to afford the desired alk-4-yn-1-
ones in moderate to good yields with good functional group
tolerance.
I
derivatives have been demonstrated to be efficient synthons
in organic synthesis,1 which are capable of undergoing a variety
of practical organic transformations.2 Among them, the
alkynylation of cyclopropanols by alkynes3−6 serves as an
efficient strategy for the synthesis of alk-4-yn-1-ones, which are
useful synthetic intermediates for accessing versatile organic
compounds (e.g., furan,3,7a 1,4-dicarbonyl compound,3,7b
pyrrole,7c and bicyclic compounds7d,e).7 (See Scheme 1) For
Scheme 1. Alkynylation of Cyclopropanols
Our investigation commenced by examining the model
reaction of ethynylbenzene (1a) with (1-ethoxycyclopropoxy)-
trimethylsilane (2a) in the presence of various metallic salts (2
equiv) in an attempt to optimize the reaction conditions. The
reaction was performed at 60 °C for 24 h by using N-
methylpyrrolidone (NMP) as the solvent. As shown in Table
1, the employment of several metal salts as reaction mediators
(e.g., FeCl3, CoBr2, NiBr2, Ni(OAc)2, NaOAc, Ce-
(NH4)2(NO3)6, and CuBr) proved to be noneffective for the
above transformation (Table 1, entries 1−7). Interestingly, the
introduction of Cu(OAc)2 as reaction promoter considerably
improved the reaction efficiency, leading to the desired
product 3a in 76% NMR yield (72% isolated yield; 78%
isolated yield on a 4 mmol scale; see Table 1, entry 8). In sharp
instance, Cha and co-workers reported that alk-4-yn-1-ones
could be readily prepared by alkynylation of cyclopropanols
with 1-bromo-1-alkynes (Br-alkyne) in the presence of Et2Zn
and CuCN·2LiCl.3 The groups of Duan,4 Chen,5 and Li6 have
independently disclosed that alkynyl benziodoxole (BI-alkyne)
was also able to efficiently react with cyclopropanols via ring
opening/alkynylation sequence to afford alk-4-yn-1-ones; the
reactions were performed either in the presence of M2S2O8
(w/wo AgNO3)4,6 or by using BI-OAc and Ru(bpy)3(PF6)2
under blue LED irradiation.5 However, all the aforementioned
Received: May 31, 2020
https://dx.doi.org/10.1021/acs.orglett.0c01828
© XXXX American Chemical Society
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A

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a
a
Table 1. Optimization of Reaction Conditions
Table 2. Optimization of Reaction Conditions
b
b
entry
MXn
yield (%)
entry
solvent
NMP
DMF
yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
FeCl3
CoBr2
NiBr2
<5
<5
<5
<5
<5
<5
<5
1
2
3
4
5
6
7
8
9
76
45
39
70
42
23
<5
<5
<5
<5
<5
DMA
Ni(OAc)2
NaOAc
Ce(NH4)2(NO3)6
CuBr
Cu(OAc)2
CuCN
Cu(NO3)2·2H2O
Cu(acac)2
CuSO4
DMSO
MeCN
THF
DME
1,4-dioxane
DCE
c d
e
,
76 (72) (78)
<5
<5
<5
<5
<5
<5
<5
67
<5
56
51
10
11
PhCl
toluene
a
Unless otherwise noted, the reactions were performed at 60 °C for
24 by using ethynylbenzene (1a, 0.4 mmol), (1-
ethoxycyclopropoxy)trimethylsilane (2a, 0.8 mmol), and Cu(OAc)2
(0.8 mmol) in different solvents (3 mL). Yields were determined by
NMR analysis of crude reaction mixture after workup by using 1,4-
Cu(OTf)2
CuBr2
h
b
Cu(TFA)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
f
g
dimethoxybenzene as an internal standard.
h
i
(DCE), chlorobenzene (PhCl), and toluene (Table 2, entries
7−11).
j
42
53
k
We envisioned that the stoichiometric amount of Cu(OAc)2
might be reduced to a catalytic amount by introducing
stoichiometric amounts of other co-oxidants into the reaction
system. However, when we performed the model reaction
under the optimized reaction conditions but in the presence of
20 mol % Cu(OAc)2 and 2 equiv of co-oxidant (including
K2S2O8, ceric ammonium nitrate, ortho-iodoxybenzoic acid
(IBX), m-CPBA, tBuOOBz, cumene hydroperoxide, 2,3-
dichloro-5,6-dicyanobenzoquinone (DDQ), and 2,6-di-tert-
butyl-1,4-benzoquinone), the reaction proceeded sluggishly
to provide the desired product 3a in <5% yield.
a
Unless otherwise noted, the reactions were performed at 60 °C for
24 by using ethynylbenzene (1a, 0.4 mmol), (1-
ethoxycyclopropoxy)trimethylsilane (2a, 0.8 mmol), and metallic
salt MXn (0.8 mmol) in NMP (3 mL). Yields were determined by
NMR analysis of crude reaction mixture after workup by using 1,4-
dimethoxybenzene as an internal standard. Isolated yield. Homo-
coupling product of diyne was obtained in 12% yield. Isolated yield
of a 4 mmol scale reaction. Using 1 equiv of Cu(OAc)2. Using 0.2
equiv of Cu(OAc)2. Room temperature. 12 h. The ratio of 1a/2a is
h
b
c
d
e
f
g
h
i
j
k
1/1. The ratio of 1a/2a is 2/1.
Subsequently, the substrate scope of this copper-mediated
coupling reaction involving various alkynes by using Cu(OAc)2
as a mediator and NMP as solvent was examined under the
optimized reaction conditions. As summarized in Table 3, in
most cases, alkynes 1b−1o bearing either electron-withdrawing
or electron-donating substituents on the phenyl ring effectively
underwent the organic transformation under established
reaction conditions to produce the corresponding products
3b−3o in modest to high yields (Table 3, entries 1−14). In
addition, heterocyclic aryl alkynes 1p and 1q reacted in a same
fashion, affording the expected products 3p and 3q in
moderate yields (Table 3, entries 15 and 16). Note that the
mild reaction conditions also allowed the existence of a range
of functional groups or substituents (e.g., CN, CF3, Cl, Br,
OMe, and NMe2) in the substrate, which could potentially be
retained for downstream derivatization. However, as for the
reaction using alkyl-substituted terminal alkyne (e.g., 1-
hexyne) as a substrate, the reaction did not work under the
optimized reaction conditions.
contrast, the same reaction conducted in the presence of other
copper (I or II) additive almost could not take place (Table 1,
entries 9−15). In addition, it was observed that the use of 2
equiv of Cu(OAc)2 was necessary for the efficient progress of
the reaction, as the decrease of the amount of Cu(OAc)2 led to
lowered product yield (Table 1, entries 16 and 17). Moreover,
survey of other reaction parameters by performing the present
reaction either at room temperature or for only 12 h both
resulted in reduced reaction performance (Table 1, entries 18
and 19). Furthermore, changing the ratio of 1a/2a from 1/2 to
1/1 and 2/1 both led to decreased product yields of 42% and
53%, respectively (Table 1, entries 20 and 21).
With Cu(OAc)2 being recognized as the optimal mediator
for the present reaction, we proceeded to investigate the
solvent effect on the reaction by employing various solvents as
reaction medium under the above reaction conditions, hoping
to further improve the reaction performance. As shown in
Table 2, the reaction could proceed with differing efficiency in
N-methyl-2-pyrrolidinone (NMP), dimethyl formamide
(DMF), dimethylacetamide (DMA), dimethylsulfoxide
(DMSO), acetonitrile (MeCN), and tetrahydrofuran (THF)
(Table 2, entries 1−6), with the highest product yield being
obtained by utilizing NMP as solvent (Table 2, entry 1). In
comparison, the transformation almost could not occur in
other solvents, such as DME, 1,4-dioxane, dichloroethane
Next, the substrate scope of the reaction was further
examined by using different cyclopropanes 2 as starting
materials. Our initial studies showed that trimethyl(1-
phenylcyclopropoxy)silane (2b) and 1-phenylcyclopropan-1-
ol (2c) worked with comparable efficiency under the
optimized reaction conditions, leading to the expected product
4a in 74% and 69% yields, respectively (see Scheme 2). Given
B
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a
Table 3. Substrate Scope Study by Employing Different Alkynes
a
The reactions were performed at 60 °C for 24 h by using alkynes 1b−1q (0.4 mmol), (1-ethoxycyclopropoxy)trimethylsilane (2a, 0.8 mmol), and
b
Cu(OAc)2 (0.8 mmol) in NMP (3 mL). Isolated yields.
cyclopropanols 2d−2i containing either electron-rich or
electron-deficient phenyl group (Table 4, entries 1−6) which
reacted well under the optimized reaction conditions, cyclo-
propanol 2j possessing heteroaryl substituent (entry 7) and
2k−2m bearing alkyl group (Table 4, entries 8−10) were also
proven to be suitable substrates for the present protocol. In
addition, substrate 2i containing an acidic hydroxyl group in
the phenyl ring also participated well in the reaction, exhibiting
good compatibility with the mild reaction conditions (Table 4,
entry 6). However, when 1,2-disubstituted cyclopropanol of 2-
ethyl-1-phenylcyclopropan-1-ol was utilized as a substrate, the
reaction could not occur. Moreover, when four-membered 1-
phenylcyclobutan-1-ol was employed as a substrate, the
reaction could not proceed under the established reaction
conditions.
Interestingly, the formed alk-4-yn-1-one 4d could easily
undergo an intramolecular cyclization in the presence of
tBuOK (1.2 equiv),4 giving rise to the corresponding furan
derivative in 53% yield (see Scheme 3).
To probe the mechanism of the reaction, four controlled
experiments were performed. As shown in Scheme 4A,
subjecting presynthesized alkynylcopper11 species 5a to
Cu(OAc)2-mediated reaction with (1-ethoxycyclopropoxy)-
trimethylsilane (2a) afforded the desired product 3a in 50%
yield, along with the formation of 38% yield of the undesired
Scheme 2. Copper(II)-Mediated Reaction of
Phenylacetylene (1a) with Siloxycyclopropane 2b or
Cyclopropanol 2c
that cyclopropanol compound could be readily accessed via the
Kulinkovich reactions9 or samarium(II)-induced cyclopropa-
nation,10 a spectrum of cyclopropanols, instead of siloxycyclo-
propanes, which should be further prepared by the silylation of
the preprepared cyclopropanol, were employed to investigate
the substrate scope of the present reaction. Note that the
formation of homocoupling product (1,6-diketone) and ring-
opening product (e.g., propiophenone for 2c) derived from
cyclopropanol derivative was also observed in the reaction,
which is in accordance with the observation that an excess of
cyclopropanol derivative (2 equiv) should be employed in the
reaction (see Table 1, entries 8, 20, and 21).
As outlined in Table 4, the ring-opening reaction of alkyne
1a with a broad range of cyclopropanols 2d−2m proceeded
smoothly under the established reaction conditions to give the
anticipated products 4b−4k in 44%−87% yields. In addition to
C
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Table 4. Substrate Scope Study by Employing Different
Cyclopropanols
Scheme 4. Control Experiments
a
situ-formed copper homoenolate 7a was treated with copper
acetylide 5a under the optimized reaction conditions (Scheme
4C), the corresponding cross-coupled product 3a was
generated in 35% yield, suggesting that the reaction might
proceed via the simultaneous formation of two copper
intermediates 7a and 5a. Furthermore, when ethyl acrylate
(8), which is supposed to be possibly generated from (1-
ethoxycyclopropoxy)trimethylsilane (2a), was subjected to
copper(II)-mediated direct cross-coupling with phenylacety-
lene (Scheme 4D), no expected product 3a was furnished,
implying that ethyl acrylate might not be the intermediate of
the present transformation.
Based on the aforementioned experiments and results, a
possible pathway was tentatively proposed to elucidate the
reaction mechanism (Scheme 5). Initially, cyclopropane 2
Scheme 5. Proposed Reaction Mechanism
a
The reactions were performed at 60 °C for 24 h by using alkyne 1a
(0.4 mmol), cyclopropanols 2d−m (0.8 mmol), and Cu(OAc)2 (0.8
mmol) in NMP (3 mL). Isolated yields.
b
Scheme 3. Further Transformation of Product 4d to Furan
Derivative
undergoes ring-opening reaction with Cu(OAc)2 to afford a
copper homoenolate 7. In parallel, arylacetylene 1 is converted
to copper acetylide 5, which then undergoes transmetalation
with copper homoenolate 7 to produce a diorganocopper
species 9. Finally, a reductive elimination of intermediate 9
occurs, leading to the expected product 3 or 4. Alternatively,
the reaction might proceed via the initial formation of an
alkynylcopper species 5, which then undergoes ring-opening
reaction with cyclopropane 2 to deliver the common
intermediate 9 shown in Scheme 5. However, other
possibilities also could not be ruled out at the current stage.
In conclusion, an efficient Cu(OAc)2-mediated ring open-
ing/alkynylation of cyclopropanes with terminal alkynes has
been developed. The reactions proceeded efficiently in the
presence of inexpensive copper(II) promoter to afford the
homocoupling product 6 derived from phenylacetylene. The
formation of diyne 6 also indirectly proved the generation of
copper acetylide species 5a in the reaction. In addition, when
copper homoenolate12 7a, which was generated from the ring
opening of cyclopropane 2a with Cu(OAc)2,12d was treated
with phenylacetylene (1a), the desired product 3a could also
be obtained in 63% yield (Scheme 4B). Moreover, when in-
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corresponding synthetically useful alk-4-yn-1-ones in moderate
to good yields with good functional group tolerance. Control
experiments showed that the reaction presumably proceeds via
the formation of intermediates of copper homoenolate and/or
alkynylcopper species. Especially noteworthy is the fact that
the reaction could work well even by employing inexpensive
and readily available terminal alkynes as starting materials,
without resorting to preprepared more-reactive alkynes.
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ASSOCIATED CONTENT
* Supporting Information
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The Supporting Information is available free of charge at
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Experimental procedures, characterization data, and
NMR spectra of products (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
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Guo-Zhi Han − Institute of Advanced Synthesis, School of
Chemistry and Molecular Engineering, Nanjing Tech University,
Nanjing 211816, China; Email: han@njtech.edu.cn
Zhi-Liang Shen − Institute of Advanced Synthesis, School of
Chemistry and Molecular Engineering, Nanjing Tech University,
Nanjing 211816, China; orcid.org/0000-0002-3365-9288;
Email: ias_zlshen@njtech.edu.cn
Authors
Bu-Qing Cheng − Institute of Advanced Synthesis, School of
Chemistry and Molecular Engineering, Nanjing Tech University,
Nanjing 211816, China
Si-Xuan Zhang − Institute of Advanced Synthesis, School of
Chemistry and Molecular Engineering, Nanjing Tech University,
Nanjing 211816, China
Yan-Ying Cui − Institute of Advanced Synthesis, School of
Chemistry and Molecular Engineering, Nanjing Tech University,
Nanjing 211816, China
Xue-Qiang Chu − Institute of Advanced Synthesis, School of
Chemistry and Molecular Engineering, Nanjing Tech University,
Nanjing 211816, China
Weidong Rao − Jiangsu Provincial Key Lab for the Chemistry
and Utilization of Agro-Forest Biomass, College of Chemical
Engineering, Nanjing Forestry University, Nanjing 210037,
China; orcid.org/0000-0002-6088-7278
Haiyan Xu − School of Environmental and Chemical
Engineering, Jiangsu University of Science and Technology,
Zhenjiang, Jiangsu 212003, China
Complete contact information is available at:
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the financial support from Nanjing
Tech University (Start-up Grant Nos. 39837118 and
39837146), National Natural Science Foundation of China
(No. 21901087), Natural Science Foundation of Jiangsu
Province (Nos. BK20180690 and BK20190951), Jiangsu
Education Department (No. 19KJB150008), and Nanjing
Forestry University.
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F
https://dx.doi.org/10.1021/acs.orglett.0c01828
Org. Lett. XXXX, XXX, XXX−XXX