Copper-Mediated Deacylative Coupling of Ynones via C-C Bond Activation under Mild Conditions

Article abstract of DOI:10.1021/acs.orglett.9b03684

The intermolecular deacylative coupling of unstrained ynones via C-C bond activation was accomplished by a CuCl-bpy system under mild reaction conditions. This protocol features facile cleavage of the C-C bond at room temperature, broad substrate scope, and efficient construction of important symmetric and unsymmetrical 1,3-diyne adducts through homo or cross coupling of ynones, respectively. The preliminary mechanistic investigations indicated that an acyl copper(III) complex is likely involved in this process.

Full text of DOI:10.1021/acs.orglett.9b03684

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Copper-Mediated Deacylative Coupling of Ynones via C−C Bond
Activation under Mild Conditions
Lili Feng, Tingjun Hu, Saisai Zhang, Heng-Ying Xiong,* and Guangwu Zhang*
Institute of Organic Functional Molecules, Engineering Laboratory of Fire Retardant and Functional Materials, College of Chemistry
and Chemical Engineering, Henan University, Kaifeng 475004, P.R. China
S
* Supporting Information
ABSTRACT: The intermolecular deacylative coupling of unstrained ynones via C−C bond activation was accomplished by a
CuCl−bpy system under mild reaction conditions. This protocol features facile cleavage of the C−C bond at room temperature,
broad substrate scope, and efficient construction of important symmetric and unsymmetrical 1,3-diyne adducts through homo
or cross coupling of ynones, respectively. The preliminary mechanistic investigations indicated that an acyl copper(III) complex
is likely involved in this process.
he inert bonds such as a carbon−hydrogen (C−H),
carbon−oxygen (C−O), carbon−nitrogen (C−N), and
Scheme 1. Approaches for the C−C Bond Activation of
T
Ynones
carbon−carbon (C−C) bonds are prevailed linkages in organic
molecules. Consequently, the transition-metal-promoted acti-
vation of these unactivated bonds in easily accessible
feedstocks has led to a variety of novel C−C bond formations,
benefiting a broad scope of communities such as medicinal
chemistry, agricultural, and material chemistry.1 Although the
C−C bond activation has been comparatively underdevel-
oped,2 the highly selective functionalization of ketones,
through a decarbonylation process, has gained considerable
attention since Teranishi and co-workers’ pioneering work on
Rh-mediated decarbonylation of diketone reported in 1974.3
Thanks to the elegant seminal works of Murakami/Ito,4 Jun,5
Douglas,6 Shi,7 Dong,8 and Wang,9 which either use stained
ring systems or introduce chelation groups to render C−C
bond cleavage, some specific ketones have emerged as suitable
precursors for C−C bond activation. On the other hand, the
contributions from Chatani,10 Dong,11 Lei,12 Jiao,13 and Li14
represented a milestone on functionalization of C−C bonds of
more challenging less strained or unstrained ketones. Despite
these advances, there are several limitations remaining on C−C
bond activation of these substrates: (1) the use of noble metals
in some transformations and (2) the frequent employment of
severe reaction conditions.
ynone structure could tune the reactivity, hence realizing mild
C−C bond cleavage and/or even altering the reaction pathway
since the carbon−alkyne bonds of the fluorinated moieties are
more polarized compared to the nonfluorinated ones.
Inspired by the decarbonylation transformations of ynones
from the Dong group in which aryl ketones were compatible
while alkyl ketones were not well tolerated in most cases
(Scheme 1, top),11c we wondered whether the installation of a
fluorinated alkyl as an electron-withdrawing group onto the
Received: October 18, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03684
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Organic Letters
Letter
However, the key scientific concern in this conception is an
unprecedented insertion of a metal complex into the bond
between the alkynyl and fluorinated carbonyl groups. Besides
the known oxidative addition of Rh(I) into a nonfluorinated
acyl−alkyne bond, Sanford and co-workers have revealed the
mild oxidative addition of a fluorinated carbonyl compound to
a low valent transition metal complex.15 Accordingly, it is
rational to speculate the feasibility of the oxidative addition
step. If it occurs, the putative fluorinated acyl metal complex
could either undergo regularly subsequent extrusion of CO and
reductive elimination to give a fluorinated alkyl substituted
internal alkyne or proceed through a reductive elimination, like
a “Cativa process”,16 to afford a fluorinated acetyl halide and an
alkynyl-metal species (Scheme 1, middle). The latter could
account for various alkynyl transfer reactions. In this regard,
considering that the fluorinated acyl metal species were
reluctant to decarbonylate unless upon the treatment of
harsh reaction conditions,15 the deacylative alkynyl transfer
route should be preferred under regular or even milder
conditions. In this report, we disclose a Cu-promoted mild
deacylation of challenging alkyl ynones to access important
1,3-diyne adducts (Scheme 1, bottom), a core skeleton existing
in a wide range of natural products and materials.17
We initiated our hypothesis by employing phenylethynyl
trifluoromethyl ketone as the model substrate in the presence
of a variety of Rh precatalysts that have proved useful in the
C−C bond cleavage process. Unfortunately, all the attempts
led to either the decomposition of the starting material or an
undefined reaction mixture, confirming the incompatibility of
the alkyl ynones with the Rh system that was formerly
reported.11c In view of the recent interest in copper-promoted
C−C bond activation, we then switched our attention to the
copper system. After intensive endeavors on the exploration of
various reaction parameters, we determined that the
deacylative coupling of trifluoromethyl ynone could be
achieved in the presence of stoichiometric CuCl and the
2,2′-bpy ligand at room temperature, leading to the 1,3-diyne
2a in 90% yield (Table 1, entry 1). The employment of a
catalytic amount of ligand or CuCl resulted in a decreased or
poor yield (entries 2 and 3). Other copper(I) salts showed
medium to good reactivities, providing the coupling product in
55−78% yield (entries 4−6), while copper(II) salts were
totally inefficient upon testing (entries 7−9). These results
indicate that a low valent copper is essential for the oxidative
addition step. Furthermore, other ligands including pyridine,
substituted 2,2′-bpy, and 1,10-phen were less efficient
compared to 2,2′-bpy (entries 10−13). It is worth mentioning
that no desired product was detected when utilizing a
phosphine ligand. The replacement of DMF with other polar
solvents such as THF, CH3CN, or DMSO all led to the
erosion of yields (entries 14−16). The N2 or O2 atmosphere
had a deleterious effect on reaction outcomes (entries 17−18),
revealing that the amount of O2 is crucial for this reaction.
Elevated temperature did not further improve the efficiency
(entry 19). Finally, when the reaction was set to 0 °C, the C−
C bond cleavage also smoothly occurred albeit in slightly lower
yield (entry 20).
Table 1. Impact of Reaction Parameters on Deacylative
Coupling of Trifluoromethyl Ynone
a
b
entry
change from the standard conditions
yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
none
2,2′-bpy (50%)
CuCl (50%)
90
63
13
78
70
55
12
-
15
70
70
20
73
63
77
46
57
77
90
78
CuBr instead of CuCl
CuI instead of CuCl
Cu(MeCN)4PF6 instead of CuCl
CuCl2 instead of CuCl
CuF2 instead of CuCl
Cu(OAc)2 instead of CuCl
pyridine instead of 2,2′-bpy
bis(MeO)-bpy instead of 2,2′-bpy
2,2′-bipyrimidine instead of 2,2′-bpy
1,10-phen instead of 2,2′-bpy
THF instead of DMF
CH3CN instead of DMF
DMSO instead of DMF
in N2 (balloon)
in O2 (balloon)
at 50 °C
at 0 °C
a
Ynone 1a (0.3 mmol, 1 equiv), CuCl (0.3 mmol, 1 equiv), and 2,2′-
bpy (0.3 mmol, 1 equiv) in DMF (2 mL) under an air balloon at
room temperature for 6 h. Isolated yield.
b
nitrogen-, and sulfur-containing hetero cycles were compatible
with the reaction conditions (2g−j, 2m, 2p, and 2r−s).
Moreover, halogens (F and Cl) were also applicable,
showcasing the potential for post functionalization of the
products (2k, 2n, and 2q). Remarkablely, diynes bearing
polyaromatics including naphthalene, benzofuran, benzothio-
phene, anthracene, pyrene, and carbazole, which may have
multiple utilizations in material chemistry, have been
successfully assembled with the current approach (2t−w,
2y−aa). In addition, alkenyl- and alkyl-substituted alkynes
were also proved to be suitable substrates, furnishing the
corresponding diyne products in moderate to good yield
(2ab−ad). Furthermore, the current methodology was not
limited to homo coupling, and cross coupling between two
different alkynes also underwent C−C bond cleavage/C−C
bond formation, producing the unsymmetrical coupling
products as the major products in good yields (2ae−ah).
In terms of substitution on the ketone part, the scope of this
method is also broad as shown in Scheme 3. Alkyl groups
including fluorinated and nonfluorinated linear chains
smoothly undertook the C−C bond activation/homo-coupling
process to give a phenyl diyne in moderate to excellent yield
(1af−an). It was also noticed that there is an apparent “fluoro-
substitution effect” on reaction outcomes, in which increasing
the numbers of fluoride atoms imparted a positive impact on
reaction efficiency. Such a tendency was consistent with our
original hypothesis that, due to the more polarized carbon−
alkyne bond of the fluorinated ynones compared to non- or
less fluorinated ones, the reactivities are enhanced. Interest-
ingly, when the number of a F atom reached 11 (1al), slightly
decreased coupling yield was observed. In addition, the
substitution on ketone with a strong steric hindrance group
With the optimal reaction conditions in hand, we next
probed the scope of the alkyne moiety. As depicted in Scheme
2, the arenes with various substitution patterns were well
tolerated, affording the homo-coupling products in modest to
excellent yields (2b−2aa, Scheme 2). A series of functional
groups including amine, ether, thioether, and oxygen-,
B
DOI: 10.1021/acs.orglett.9b03684
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Letter
a b
,
a,b
Scheme 2. Scope of the Alkyne Moiety
Scheme 3. Scope of the Ketone Moiety
a
Ynone 1 (0.3 mmol, 1 equiv), CuCl (0.3 mmol, 1 equiv), and 2,2′-
bpy (0.3 mmol, 1 equiv) in DMF (2 mL) under an air balloon at
room temperature for 6 h. Isolated yield. At 50 °C.
b
c
To probe the reaction mechanism, several preliminary
investigations were conducted. The addition of the radical
scavenger TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl) led
to decreased yield of diyne, along with the isolated 1,1,1-
trifluoro-4-phenyl-4-((2,2,6,6-tetramethylpiperidin-1-yl)oxy)-
but-3-en-2-one (3) (Scheme 4A). Interestingly, the introduc-
Scheme 4. Investigation of Reaction Mechanism
a
Ynone 1 (0.3 mmol, 1 equiv), CuCl (0.3 mmol, 1 equiv), and 2,2′-
tion of BHT (2,6-di-tert-butyl-p-cresol) into a reaction mixture
totally prohibited the formation of diyne, leading to an
undefined mixture (Scheme 4B). Next, when 1b was treated
with stoichiometric copper phenylacetylide (1 equiv) under
standard reaction conditions (in CH3CN, under air), a mixture
of homo- and cross-coupling products were formed (ratio:
2a:2ai:2b = 1.5:2:1) (Scheme 4C). When this reaction was
carried out under N2, 1,2-addition products of copper acetylide
with ynones 4 were observed (ratio: 4b:4c = 71:28) with a
trace amount of diyne product (Scheme 4D). These results
implied that alkynyl-Cu(I) species might not be the real
intermediate. It is worth mentioning that the formation of 4c
indicated a copper(II) p-tolylacetylide is likely generated
during the process. Upon the treatment of the resulting
propargyl alcohols with standard conditions (in CH3CN,
bpy (0.3 mmol, 1 equiv) in DMF (2 mL) under an air balloon at
b
c
d
room temperature. Isolated yield. At 50 °C. Cross-coupling
reaction conditions are ynone 1 (0.1 mmol, 1 equiv), ynone 1ae (0.15
mmol, 1.5 equiv), CuCl (0.2 mmol, 2 equiv), and 2,2′-bpy (0.2 mmol,
2 equiv) in DMF (2 mL) under an air balloon at room temperature
for 10 h.
such as tBu hampered the coupling process, with only 13%
yield obtained (1ao). It is notable that C−C bond activation of
phenyl ynone also occurred, albeit in a poor yield (1ap). When
a CCl3 group was introduced onto the ynone structure as an
electron-withdrawing group, fast decomposition of this
substrate was observed with no coupling product detected
(1aq).
C
DOI: 10.1021/acs.orglett.9b03684
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Organic Letters
Letter
under air), the starting materials were intact (Scheme 4E),
implying that 1,2-addition adducts were not the intermediates
leading to the diyne products.
Scheme 6. Derivation of the Selected Coupling Adducts
An electrospray ionization mass spectrometry (ESI-MS)
method was also performed to gain insight into the reaction
mechanism. It was shown that an ESI-MS measurement of a
reaction mixture of 1a under standard conditions presented a
base peak at m/z 264.7 at 5 min of reaction time, related to the
existence of the copper-alkyl species [Cu(phenyl ethynyl)2],
which was slowly consumed and finally disappeared within 2 h
(see SI).
Based on the above observations and previous report-
s,2l,11a,b,18,19 we proposed a plausible reaction mechanism
(Scheme 5). First, the oxidative addition of the Cu(I) complex
Scheme 5. Proposed Reaction Mechanism
a
Reaction conditions: diyne (1 equiv), sulfur powder (3 equiv), and
b
NaHS (6 equiv) in 2.0 mL of DMF at rt under N2 for 5 h. Reaction
conditions: diyne (0.1 mmol, 1 equiv), sulfur powder (3 equiv), and
NaHS (6 equiv) in 2.0 mL of DMSO at 80 °C under N2 for 12 h.
c
Reaction conditions: diyne (0.1 mmol, 1 equiv), sulfur powder (0.3
mmol, 3 equiv), and NaOtBu (0.6 mmol, 6 equiv) in 2.0 mL of
DMF/HOtBu (v:v = 3:1) at rt under N2 for 5 h.
onto the acyl−alkyne bond forms the Cu(III) intermediate,
which then releases a acetyl radical to give Cu(II)-alkynyl
species. The latter then follows the Glaser process to give 1,3-
diynes,20 during which the detected [Cu(phenyl ethynyl)2]
might be an important intermediate, leading to the final
product.
2,5-disubstituted thiophenes, which are of great interest for
material purposes. The further systematic investigation of the
reaction mechanism as well as merging the C−C bond
activation of ynones with other transformations are underway
in our laboratory.
In light of the tremendous application of functionalized
thiophenes in materials science such as OPVs, DSSCs, OLEDs,
and OFETs,21 the selected coupling products 1,3-diynes were
cyclized with a sulfur source by following slightly modified
procedures22 to afford thiophene-bridged polycycles in
moderate to good yields (Scheme 6). It is worth noting that
most of these thiophene derivatives are unprecedented
structures, and structures of 5d and 5e were definitely
determined by X-ray diffraction. An initial investigation of
optical properties of these products was conducted. The UV
spectra of 5a−e show absorption maximum bands at 275−372
nm in CH2Cl2, which correspond to the π−π* transition of
arenes and thiophene. Emission maxima were observed at
411−481 nm in the fluorescence spectra of 5a−e in CH2Cl2.
As can be seen from the figures in the SI, the order of
fluorescence intensity of molecules is 5e > 5a > 5b > 5d > 5c,
which is related to the conjugation degree of p electrons. It is
noticed that 5e exhibits an intense blue luminescence peak at
around 416 nm and can be utilized as a blue emitter for
electroluminescence (EL) devices.
In conclusion, we have described the first copper-mediated
deacylative coupling of ynones via C−C bond activation under
mild reaction conditions. This approach demonstrates good
functional group compatibility and broad substrate scope and
is applicable for both homo and cross coupling of ynones,
delivering a range of substituted 1,3-diynes from moderate to
excellent yields. This method could be a complementary
strategy to the traditional Glaser route for the synthesis of 1,3-
diynes. In addition, the detection of the alkynyl-copper species
by ESI-MS indicates the potential of other alkyne transfer
reactions through the deacylation of ynones. Furthermore, the
cyclization of selected 1,3-diynes with a sulfur source furnished
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b03684.
General information; Materials; General procedure for
the synthesis of derivatives 1; Purification and character-
ization of derivatives 1; General procedure for the
synthesis of derivatives 2a−2ad; General procedure for
the synthesis of derivatives 2ae−2ah; Purification and
characterization of derivatives 2; Investigation of
reaction mechanism; Procedure for the synthesis of 5a
and 5c; Procedure for the synthesis of 5b and 5e;
Procedure for the synthesis of 5d; Purification and
characterization of derivatives 5; Procedure for the ESI-
MS study of the reaction mixture; Absorption spectra
(UV) and fluorescence spectra of 5a−e in CH2Cl2;
References; NMR spectra of derivatives 1; NMR spectra
of derivatives 2; NMR spectra of derivatives 3; NMR
spectra of control experiments; and NMR spectra of
derivatives 5 (PDF)
Accession Codes
CCDC 1918953 and 1919696 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
D
DOI: 10.1021/acs.orglett.9b03684
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: gw.zhangchem@hotmail.com
*E-mail: xionghengying@vip.henu.edu.cn
ORCID
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Guangwu Zhang: 0000-0001-8365-4197
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
This research was supported by Henan University, the
National Natural Science Foundation of China (21801061).
Professor Pengtao Ma (HNU) is thanked for the X-ray
structure. Professor Xunyong Liu (LDU) is thanked for the
helpful discussion on optical studies.
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