Copper-catalysed three-component carboiodination of arynes: Expeditious synthesis of: O -alkynyl aryl iodides

Article abstract of DOI:10.1039/c9cc09160b

A copper-catalysed three-component iodoalkynylation reaction of arynes for the expeditious and versatile synthesis of o-alkynyl aryl iodides has been developed. Mechanism research shows that the reaction goes through two steps enabled by copper catalysis: the formation of 1-iodo-2-arylacetylene and the insertion of the aryne into a C(sp)-I bond.

Full text of DOI:10.1039/c9cc09160b

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Copper-catalysed three-component
carboiodination of arynes: expeditious synthesis
Cite this:DOI: 10.1039/c9cc09160b
of o-alkynyl aryl iodides†
Received 26th November 2019,
Accepted 12th December 2019
Wenxuan Cao, Sheng-Li Niu, Li Shuai and Qing Xiao
*
DOI: 10.1039/c9cc09160b
rsc.li/chemcomm
A copper-catalysed three-component iodoalkynylation reaction of Xu’s group15a and our group15b separately developed copper-
arynes for the expeditious and versatile synthesis of o-alkynyl aryl catalysed multicomponent reactions to produce o-alkynyl aryl-
iodides has been developed. Mechanism research shows that the sulfides or o-alkynyl anilines (Fig. 1B). The fundamental mode
reaction goes through two steps enabled by copper catalysis: the of these reactions can be described as alkynyl-metalation of
formation of 1-iodo-2-arylacetylene and the insertion of the aryne benzynes and successive electrophilic traps of the in situ generated
into a C(sp)–I bond.
ortho-alkynyl aryl copper species. We inferred that the scope of
electrophilic capture reagents used in this transformation can be
As the core building blocks in modern organic synthesis, enlarged by carefully adjusting the catalytic system. Based on this,
aromatic halides have been extensively utilized as precursors we designed and developed a copper-catalysed three-component
to manufacture organometallic reagents1 and as electrophiles reaction of in situ formed benzynes, terminal alkynes, and electro-
in cross-coupling reactions.2 Typically, due to the combination philic iodinating reagents to access o-alkynyl aryl iodides. This
of reactivity of aromatic halides and alkynes, ortho-alkynyl aryl facile strategy can be regarded as a complement to the Sonogashira
iodides have become significant synthons for the rapid and coupling reaction (Fig. 1B).
efficient construction of fused carbo- or heterocyclic skeletons.3,4
Our initial attempts were aimed at optimizing the conditions
Although numerous powerful methods toward formation of of the model reaction of Kobayashi reagent 1a, alkyne 2a, and
aromatic carbon–halogen bonds have been established,5–10 the N-iodosuccinimide (NIS) 3a (Table 1). The 10 mol% IMesCuCl
expeditious routes to access ortho-alkynyl aryl iodides have still catalysed process at 60 1C in acetonitrile in the presence of CsF
been limited. To our best knowledge, the strategies used currently and Cs2CO3 furnished o-alkynyl phenyl iodide 4a in 83% GC
to produce this class of compounds are Sonogashira coupling yield (entry 1). Control experiments (entries 2 and 3) recognized
reactions11 of o-iodoanilines or 1,2-dihaloarenes and subsequent
transformations, such as Br–I exchange1,7 and Sandmeyer
reaction6 (Fig. 1A). However, it is not easy to regulate the coupling
reactions of 1,2-dihaloarenes to afford the monosubstituted
products. Moreover, the procedures of a Br–I exchange and
Sandmeyer reaction are not always compatible with many
sensitive functional groups due to the harsh conditions. In
addition, the indispensable sequential transformations reduce
the step- and atom-economy of this strategy. Therefore, it is highly
desirable yet still challenging to develop versatile protocols to
achieve ortho-alkynyl aryl iodides through other strategies.
The rise of transition-metal-catalysed aryne chemistry has
provided more opportunities for the efficient construction of
1,2-difunctionalized arenes in recent years.12–15 In this field,
College of Pharmacy, Third Military Medical University, Chongqing 400038,
P. R. China. E-mail: xiaoqing@tmmu.edu.cn
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
Fig. 1 Strategies to synthesize ortho-alkynyl aryl iodides.
c9cc09160b
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Table 1 Reaction condition optimization
Entry Variation of the standard conditions
GC yielda (%)
1
2
3
4
5
6
7
8
Noneb
KF instead of CsF
K2CO3 instead of Cs2CO3
1,4-Dioxane/THF/PhMe instead of MeCN
CuI, CuBr, CuCl or IPrCuCl instead of IMesCuCl 24/23/26/63
Volume of MeCN was changed to 1.0 mL or 0.5 mL 18/57
83 (78)c
22
38
o5/22/o5
Room temperature instead of 60 1C
Molar ratio of 1a : 2a : 3a = 1 : 1 : 1
65
49
a
n-Tridecane as an internal standard, the GC yields were calculated from the
standard curve of the product. b 0.2 mmol 1a, 0.3 mmol 2a and 0.3 mmol 3a
in 0.8 mL MeCN in the presence of 0.4 mmol Cs2CO3, 0.4 mmol CsF, and
0.02 mmol IMesCuCl. c The isolated yield is in parentheses.
the importance of the fluorine resource and base in the system.
Replacing the MeCN with 1,4-dioxane, THF or nonpolar
toluene, the yield of 4a decreased greatly (entry 4). The reaction
was also enabled by the catalysis of more easily available
cuprous halides, but in low yields (entry 5). An appropriate
temperature and concentration of substrates were also necessary
for the reaction (entries 6 and 7). When only one equivalent of
each of the three components was used, the product can only be
obtained in a moderate yield (entry 8).
Fig. 2 Scope of the three-component reaction of Kobayashi reagents,
alkynes, and NIS. Isolated yields.
Then, we investigated the range and limitations of the
substrates (Fig. 2). Phenyl alkynes bearing either an electron- in good yields. Additionally, only one regioisomer (4at) could be
donating or electron-withdrawing group at the para-, meta-, and efficiently generated from 3-methoxyl substituted silylphenyl
ortho-position of the benzene ring underwent the three- triflate.
component reaction smoothly to provide the corresponding
Moreover, the downstream transformations of o-alkynyl aryl
products in good to excellent yields (4b–4af). In addition, the iodides produced by our methodology can be effortlessly realized.
reaction conditions were compatible with amino (4b, 4c), ether For instance, the Suzuki–Miyaura coupling product 5 and the
(4d, 4e, 4ae), thioether (4af), trifluoromethoxy (4h), bromide Sonagashira reaction product 6 were successfully achieved in
(4j, 4s, 4y), chloride (4k, 4t, 4z), fluoride (4u, 4aa), ester (4l, 4v, good yields under conventional conditions (Fig. 3a and b). The
4ab), carbonyl (4m), trifluoromethyl (4n), cyan (4o), and nitro product 4a can be competently converted into 2-phenyl benzo[b]-
(4p, 4ac) groups. Notably, the presence of various halogen thiophene 7 using inexpensive sodium sulfide as the sulfur source
substituents in the products provides an opportunity for later enabled by copper catalysis (Fig. 3c). To further demonstrate the
functionalization of the molecule through a stepwise cross- synthetic utility of our strategy, we applied it to the synthesis of
coupling strategy. Further exploration demonstrated that the the fused heterocyclic compound 11 that can be utilized as a
reaction also proceeded successfully with a variety of polycyclic potential block for the construction of organic light-emitting
aromatic substrates (4ag–4ai). Besides, electron rich or poor materials.16 Through the expeditious Cu(I)-catalysed ortho-iodo
heterocyclic alkynes can also participate in this transformation arylation of 1,4-diethynylbenzene, Suzuki–Miyaura coupling, and
to afford the corresponding o-alkynyl phenyl iodides (4aj–4an). Larock electrophilic cyclization17 in sequence, the symmetrical
Terminal alkynes with alkenyl, alkyl and trialkylsilyl substitutions large p conjugated molecule can be easily obtained (Fig. 3d).
have also been investigated. Vinyl alkynes were proven to be
Finally, a preliminary investigation into the mechanism of
useful starting materials for the construction of o-alkynyl phenyl the reaction was made (Scheme 1). Experiments A, B and D
iodides (4ao), although the reactions of alkyl alkynes cannot indicate that phenylacetylene 2a reacts with NIS 3a faster than
proceed under standard or adjusted conditions. Due to the it does with Kobayashi reagent 1a under the standard conditions.
presence of indispensable fluorine anions, trimethylsilyl ethyne Experiments C and E reveal that the in situ generated 13 reacts
and triisopropylsily ethyne were not compatible in this reaction. with 1a smoothly to afford the target product 4a. Experiments E
The strategy was not restricted to benzyne precursors; other aryne and F show that the formation of alkynyl iodine compound18 and
precursors were also viable substrates for the reaction (4ap–4at). the insertion of benzyne into C(sp)–I bond are both enabled by
Remarkably, o-alkynyl naphthyl iodides 4ar and 4as could be copper catalysis. Based on these facts, we prefer the reaction
separately obtained from the corresponding silylnaphthyl triflates to be realized through the catalytic Cycle B (Scheme 1J). It is a
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compound 13: Path I: formation of int-IV via oxidative addition,
generation of int-III via benzyne insertion, and production of 4a
via reductive elimination; and Path II: 13 as a nucleophile
attacks benzyne19 to form int-V, then leading to 4a through
1,3 migration of an alkynyl group. On the other hand, NIS has
not been replaced by N-bromosuccinimide (NBS) or N-chloro-
succinimide (NCS) in our transformation until now (Scheme 1G).
It can also be rationally explained by the plausible mechanism.
Although the corresponding alkynyl bromide can also be formed
under the standard conditions, the reaction rate is significantly
slower than that of alkynyl iodide (Scheme 1B, H). And the
C(sp)–Br bond of 1-bromo-2-phenylacetylene 16a cannot be inserted
by benzyne under the standard conditions (Scheme 1I).20–22
In conclusion, we have disclosed a copper-catalysed three-
component reaction of aryne precursors, terminal alkynes, and
electrophilic iodinating reagents, affording an expeditious and
versatile approach to o-alkynyl aryl iodides which are valuable
synthetic blocks and otherwise difficult to prepare. From the
perspective of the reaction mechanism, the transformation can
be described as two steps enabled by copper catalysis: the
formation of 1-iodo-2-arylacetylene and the insertion of aryne
into the C(sp)–I bond. To our best knowledge, the Cu-catalysed
insertion of aryne into C–I bonds has not been reported
before.23 Although the exact mechanism of the insertion process
is not yet known, we believed that more transition-metal catalysed
carbon–hetero bond insertion reactions with arynes can be
continuously developed inspired by this work and the catalytic
image of this novel reaction model will gradually become
clearer in further research.
Fig. 3 Derivatives of products and application of our strategy for the
efficient construction of polycyclic aromatics.
We thank the National Key Research and Development
Program of China (2018YFA0507900) and the NSFC (21602251)
for financial support.
Conflicts of interest
There are no conflicts to declare.
Notes and references
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