N-Heterocyclic carbene copper-catalyzed direct alkylation of terminal alkynes with non-activated alkyl triflates

Article abstract of DOI:10.1039/c7cc00891k

(NHC)-Cu-catalyzed C(sp)-C(sp³) bond formation has been successfully achieved under mild conditions. Nonactivated alkyl triflates, which could be easily derived from alcohols, were utilized as C-O electrophiles. Mechanistic studies suggested th

Full text of DOI:10.1039/c7cc00891k

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Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc3N@C2n (2n 68 and 80). Synthesis of the
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N-Heterocyclic Carbene Copper-Catalyzed Direct Alkylation of
Terminal Alkynes with Non-activated Alkyl Triflates
Liqun Jin, *a,b Wangfang Hao,a Jianeng Xu,a Nan Sun,a Baoxiang Hu,a Zhenlu Shen,a Weimin Mo,a
and Xinquan Hu *a,b
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
B: Oxidative Strategy
M2(H)
A: Sonogashira Coupling
Alkyl-Br(I)
(NHC)-Cu-catalyzed C(sp)−C(sp3) bond formaꢀon has been
successfully achieved under mild conditions. Nonactivated alkyl
triflates, which could be easily derived from alcohols, were
utilized as C-O electrophiles. Mechanistic studies suggested that
the copper acetylide was the active species. Scale-up reaction
further demonstrated the practicality and efficiency of the
developed strategy.
Alkyl-M1
+
R
+
R
Alkyl
R
[Pd] (Lei et al)
[Pd]/[Cu]/NHC (Fu, Glorious, et al.)
[Ni]/[Cu]/Ligand (Hu, Liu et al)
[Cu]/[Ni]/[Ag](Lei et al)
C: Umpolung Strategy
Alkyl-M1(H)
+
[Pd] (Knochel, Yu et al)
[Cu] (Cahiez et al)
(Cl)Br
R
Scheme 1. Different protocols for form C(sp)-C(sp3) bonds
Based on the Sonogashira coupling protocol, recent studies
focused on utilizing special catalytic systems to solve the
intractable problems: more sluggish oxidative addition and
reductive elimination steps, as well as facile side destructive
beta-hydride elimination, pioneered by Fu8 and Glorius9 et al.
Hu10 and Liu11 made big contributions with their impressive Ni-
catalyzed transformations (Scheme 1, A). Alternatively,
oxidative12 (Scheme 1, B) and Umpolung13 (Scheme 1, C)
strategies were also reported. Other transition metals, such as
Alkynes are common units existing in a wide range of natural
products, bioactive compounds, and material molecules. They
play an important role in broadening chemical versatility as
fundamental synthons.1 Transition metal-catalyzed direct
transformations from terminal alkynes have been attractive
targets for chemists, especially towards C-C bond formations
involving the sp-hybridized carbon atom.2 Among them, name
reactions, representative by Sonogashira coupling,3 Glaser–
Hay Reaction4 as well as Cadiot-Chodkiewicz coupling,5 have
been widely utilized and studied. Throughout the Sonogashira
coupling reactions, in which palladium or nickel complexes are
usually used as the catalysts, they typically perform coupling of
terminal alkynes with aryl or alkenyl halides/pseudohalides to
construct C(sp)-C(sp2) bonds.6 The Glaser–Hay Reaction and
Cadiot-Chodkiewicz coupling established effective methods
toward C(sp)-C(sp) bond formations.4b, 7 However, introducing
one nonactivated alkyl group into a terminal alkyne to form
C(sp)-C(sp3) bonds seems more challenging and less
developed.
14
15
cobalt and iron, were also used to couple alkyl halides
with alkynyl Grignard reagents. From all remarkable progress,
we considered that most nonactivated alkyl groups are derived
from alkyl halides or its downstream alkyl-metal reagents.
From the aspect of environmentally friendliness, it is still highly
desirable to develop novel approaches for C(sp)−C(sp3) bond
formation, preferably by using simple and cheap catalysts and
easily available halides-free starting materials.
Table 1. Copper-catalyzed cross coupling of phenylacetylene
with unactivated octyl pseudohalides.a
[Cu]
+
Ph
nC8H17
X
Ph
nC8H17
K2CO3, DCM, 40 o
C
1a
2a
3a
Yield (%)b
X =
iPr
iPr
N
0
0
OTf
OTf
OTf
CuI
CuCl
N
SIPrCuCl
43
iPr
iPr
SIPrCuCl
0
0
0
OTs
OMs
ONf
SIPr
SIPrCuCl
SIPrCuCl
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aReaction conditions: 1a (0.3 mmol), 2a (0.45 mmol), catalyst
(5 mol%), K2CO3 (0.45 mmol), solvent (1 mL). Yields were
transformation.23 Other generally used cuprous salts CuI and
CuCl were also tested, which delivering lower yield.
Table 2. NHC-Copper-catalyzed cross coupling of various aryl
alkynes with octyl triflate.a
b
determined by GC using biphenyl as an internal standard.
It is well known that the chemical behavior of alkyl halides
can be used as a reference in discovering analogous reactions
of alcohols, which are much more cheap, safe, and easily
accessible. A simple step toward improving the reactivity of
alcohols would be to modify the –OH functional group,
typically referring to various pseudohalides such as mesylate
(OMs), tosylate (OTs), triflate (OTf) and and nonaflate (ONf).
These nonactivated alkyl sulfonate esters, unlike their aryl
analogs that have been pursued as promising alternatives to
aryl halides in many cross-coupling reactions,16 were lightly
investigated in transition metal-catalyzed C(sp)-C(sp3) bond
formations.17 Although the renaissance of copper in catalysis
led to the development of efficient copper-only procedures in
C-C coupling chemistry, Cu-catalyzed alkynyl-alkyl coupling
remains less touched.18 Herein, we report
a new N-
heterocyclic carbene (NHC) copper-only-catalyzed cross
coupling of terminal alkynes with alkyl triflates, which are
nonactivated halide-free alkyl sources and could be easily
acquired from the corresponding alcohols.
From an aliphatic alcohol, the corresponding OMs, OTs, OTf
and ONf were easily acquired in a large amount. We started to
test our study by attempting the cross coupling between
phenylacetylene and octyl triflate with K2CO3 as the base in
o
dichloromethane at 40 C using simple cuprous salts (CuI and
CuCl) as the catalysts. It is noteworthy that yellow suspensions
could be observed during the reactions. However, no desired
product was formed, suggesting that the copper acetylide has
been formed while no further coupling with octyl triflate
occurred. To improve this Cu-catalyzed cross coupling between
terminal alkynes and octyl pseudohalides, the major
consideration was the activity of copper acetylide. Two issues
should be noticed: one is to improve the nucleophilic ability of
copper acetylide; the other is its inherently fast polymerization
in the case that copper acetylide is formed, leading to
extremely poor solubility in most solvents accompanied by
slowing down the reaction rate.19 In light of these, we
envisioned that NHCs might be a proper ligand for this
a Reaction conditions:
mol%), base (1.5 mmol), solvent (3 mL), 12 h. Isolated yields
1 (1.0 mmol), 2a (1.5 mmol), catalyst (5
b
c
by column chromatography. 2a (3 mmol), monocoupling and
biscoupling products were obtained totally in the ratio of 1:1
determined by NMR. The products mixed with the starting
d
materials (1p or 1q) could not be purified by column
chromatography and NMR yields were given.
Having identified the optimal conditions as 5 mol% of
(IMes)CuCl, 1.5 equiv. of tAmONa as the base in
dichloromethane at 40 C, we then employed various terminal
o
transformation. The strong
σ-donating ability of NHC ligands
aryl alkynes to examine the scope of this alkylation protocol.
As shown in Table 2, aryl alkynes with electron-donating
methyl group, para- (1b), meta- (1c) as well as ortho- (1d),
gave the corresponding alkylation products (3b-d) in high
yields. 2,6-Dimethyl substituted phenylacetylene also occurred
will contribute to the nucleophilicity of the copper acetylide;20
while the isolation of a monocopper acetylide complex
stabilized by carbene suggested that the bulky environment
from the ligand will prevent the formation of inactive
polymeric copper acetylide species.21 Hence, SIPrCuCl was very well in 81% isolated yield, showing that steric
environments can be tolerated (Table 2, entry 5). Meanwhile,
both para-substituted phenyl acetylene with long alkyl chain,
like pentyl group, and methoxyl were successfully coupled with
octyl triflate, furnishing the target products 3f and 3g in 81%
and 70% yields, respectively (Table 2, entry 6 and entry 7).
Moreover, alkynes bearing electron-withdrawing groups, such
as halides (Table 2, entries 8-10) and trifluoromethyl (Table 2,
entry 11), provided the coupling alkynes in good yields. It is
noteworthy that bromide and iodide were well tolerated in
this transformations, which left an active site for further
potential functionalization. The slightly lower yields for
electron deficient substitutes are likely due to the reduced
then tested as the catalyst in this transformation. To our
delight, the cross-coupling product 3a could be detected, with
43% GC yield. When OTs , OMs and ONf 22 were applied as the
leaving groups, no desired coupling product was detected.
With (SIPr)CuCl as the catalyst, the reaction conditions were
then optimized (see Supplementary Information). Screening of
the solvents and bases suggested that dichloromethane and
tAmONa were better choices. Notably, IMes proved to be
superior than SIPr, in line with that the strong σ-donating
ability of NHC ligands will be in favor of this copper-catalyzed
2 | J. Name., 2012, 00, 1-3
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nucleophilicity of the copper acetylide.10b Interesting, 1,4-
diethynylbenzene reacted with 2a with a minor modification,
affording a mixture of monocoupling and biscoupling products
in modest combined yields (Table 2, entry 12). More
importantly, we also examined substrates that were
particularly attractive in material sciences, such as thienyl (1m
and 1n) and
π-extended aromatic (1o, 1p and 1q) ring
substituent acetylenes, and 63% to 72% yields for the desired
alkynyl-alkyl products were obtained (Table 2, entries 13-17).
Under the optimal conditions, we then applied the protocol
for the coupling of aryl alkynes with varied alkyl triflates (Table
3). Alkyl triflates with longer chains proceeded smoothly to
form 4a in 68% yield. Moderate to good isolated yields were
obtained for the coupling of alkyl triflates containing
phenylethyl (4b) and bromides (4c and 4d). In addition, the
alkynylation of octyl triflate with different terminal aliphatic
alkynes were also accomplished with higher copper catalyst
loading to 10 mol% (Table 3). Primary alkyl (5a and 5b),
Figure 1. Solid-state structure of complex I. Hydrogen atoms
were emitted for clarity.
secondary
alkyl
(
5c),
chlorosubstituted
(
5d
)
and
0.20
0.15
0.10
silylsubstituted (5e) alkynes could be coupled, albeit with
lower isolated yields, which is probably due to the difficulty in
isolation arising from the lower selectivity. The relatively
sluggish formation of copper acetylides when utilizing less
acidic aliphatic alkynes might be responsible for the
complicated reaction systems.23
0.05
0.00
complex 1
NHC-Cu-Cl
Table 3. NHC-Copper-catalyzed cross coupling of aryl or alkyl
alkynes with nonactivated alkyl triflates.a
0
30
60
90
120
Time (min)
Figure 2. Kinetic plots of Cu-catalyzed coupling between
phenyl acetylene and octyl triflate.
To clarify the key species in this transformation,
stoichiometric reactions as shown in Eq.1 and Eq.2 were
performed. With t-AmONa as the base, (IMes)CuCl reacted
with equivalent amount of phenyl acetylene smoothly.
Complex
pale white solid in high yield, which was expected as the
monocopper acetylide However, crystallization of complex
I shows good solubility in toluene and was isolated as
.
I
did not give a linear, two-coordinated monocopper acetylide
as reference reported.21a A salt with [(IMes)2Cu]+ as the cation
and [(PhCC)2Cu]− as the anion was shown from X-ray
diffraction study (Figure 1, structure details were given in
supporting information). We envisioned that the equilibrium
between (IMes)CuCCPh and [(IMes)2Cu]+[(PhCC)2Cu]− might
a
Reaction conditions:
1 (1.0 mmol), 2 (1.5 mmol), catalyst (5
mol% for aryl alkynes, 10 mol% for aliphatic alkynes), base (1.5
mmol), solvent (3 mL), 12 h. Isolated yields were obtained by
column chromatography.
exist in the solution and the latter is more stable in the solid
state.21a,
24-25
Moreover, complex I could react with octyl
triflate to quantitatively produce 3a and light yellow solid was
isolated simultaneously.26,27 To further elucidate the activity of
copper acetylide in the whole reaction, kinetic studies were
carefully performed. The reaction rates for this Cu-catalyzed
coupling of phenyl acetylene and octyl triflate were monitored
by in situ IR with (IMes)CuCl and copper acetylide
I as the
catalyst, respectively. As shown in Figure 2, almost identical
reaction rates were observed, further confirming that copper
acetylide
I was the real active species in this catalytic cycle.
This copper acetylide reactivity with alkyl electrophile was
different from the related gold-acetylide chemisty, in which a
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Finally, to further demonstrate the practicality and
efficiency of the developed reaction strategy, we performed a
scale-up reaction as shown in Eq. 3. After two simple
sequential steps, 20 mmol amount of phenyl acetylene was
successfully alkylated to deliver 2.3 g of 3a (54% isolated
yield), directly utilizing octyl alcohol.
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In summary, we have developed an efficient copper-only-
catalyzed C(sp)-C(sp3) cross-coupling reaction between
terminal alkynes and nonactivated alkyl triflates, which avoids
the troubles associated with the oxidative addition and facile
β-H elimination steps found in traditional Pd- or Ni-catalyzed
coupling reactions. NHC as the ligand proved to be important
for the efficiency in this transformation. This work enriched
the NHC-copper catalysis and open
a new avenue as
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alternatives for the classical cross-coupling reactions.
Currently, this catalytic system still limits to primary alkyl
substrate. Future work is on going towards developing more
general reaction system for more efficiency and wider
substrates scope, including secondary and tertiary alkyl
groups.
22. As one referee suggestted, the activity of octyl nonaflate was
examined. Under the same conditions in Talbe 1, no desired
product was detected. Also, we carried out the reactions under
the optimal conditons in table 2 employing octyl nonaflate and
phenyl acetylene, while only 40% yield was obtained. This result
suggest that the leaving group of alkyl electrophile is very
important for this transformation.
The authors gratefully acknowledge the National Natural
Science Foundation of China (21603190, 21473160,
21376224). Jin also thanks the support from Zhejiang
University of Technology and Qianjiang Scholar Program
funded by Zhejiang Province.
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However, (IMes)2CuOTf was crystalized during the slow diffusion
of pentane into the saturated solution in dichloromethane,
leaving yellow precipitation in the bottom. Details were given in
the supporting information. We proposed that (IMes)2CuOTf as
the more stable species might resulted from the decomposition
of (IMes)CuOTf. Nolan and co-workers found that (NHC)2CuX
could react with terminal alkyne to form copper acetylide. See
ref 26
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