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Synlett 2022; 33(09): 893-897
DOI: 10.1055/a-1733-6254
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Mechanochemical Synthesis of Diarylethynes from Aryl Iodides and CaC2

Pit van Bonn
,
Carsten Bolm  ∗

The financial support by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy – Exzellenzcluster 2186 ‘The Fuel Science Center’ is highly appreciated.
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Abstract

A mechanochemical synthesis of diarylethynes from aryl iodides and calcium carbide as acetylene source is reported. The reaction is catalyzed by a palladium catalyst in the presence of copper salt, base, and ethanol as liquid assisting grinding (LAG) additive. Various aryl and heteroaryl iodides have been converted in up to excellent yields.


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Key words

mechanochemistry - calcium carbide - ball milling - diaryl­ethyne - catalysis - palladium

Mechanochemistry has developed as an alternative tool for the synthesis of organic compounds. Classified by Ostwald beside thermochemistry, photochemistry, and electrochemistry as an activation strategy for chemical reactions, mechanochemistry was neglected for decades.[1] In the last 20 years, features such as shorter reaction times, environmental advantages, and variation in reactivity and selectivity compared to solvent-based protocols moved mechanochemistry more into the focus of various fields of chemistry.[2] [3] Reactions are induced by energy transfer through shearing, pulling, and compression of material. In the simplest case the reaction is conducted by grinding with mortar and pestle. More common is the use of automatic planetary or mixer mills, which are run in batch process and differ in way of motion. Furthermore, twin-screw extruders can be used, which have industrial relevance due to scale-up possibility. Mechanochemical conditions have been successfully applied to important cross-coupling reactions such as Suzuki–Miyaura, Negishi, Mizoroki–Heck, and Sonogashira couplings.[3] In 2009 Mack and co-workers reported the first Sonogashira cross-coupling reaction under mechanochemical conditions performed in a mixer mill to construct diarylethynes or 1-aryl-2-(trimethylsilyl)acetylenes (Scheme [1]).[4] The use of copper salt could be omitted using a jar or balls made of copper. Later, Stolle and co-workers reported a copper-free Sonogashira cross-coupling reaction to couple aryl halides with aryl or alkyl acetylenes (Scheme [1]).[5] Aryl iodides and aryl bromides reacted with DABCO as base after 20 min of milling using optimized palladium catalysts and grinding auxiliaries. The products of these Sonogashira couplings were 1-aryl-2-(alkyl)ethynes or diarylethynes, which are important building blocks in organic synthesis.[6] Although the Sonogashira cross-coupling reaction is a great tool to synthesize diarylethynes compared to elimination from geminal or vicinal alkyl dihalides under strong basic conditions, the supply of the aryl acetylene moieties is often limited, or they need to be synthesized in a prior synthetic step. Therefore, reactions starting from the simplest C≡C unit, acetylene, have been developed.[7] [8] Drawbacks of this strategy are the extremely flammable and explosive properties of acetylene gas and the associated need for specialized high-pressure equipment. A great alternative to the use of acetylene gas is calcium carbide.[9] The solid, easy to handle C≡C building block has gained increasing attention in recent years. In 2006, Cheng and co-workers first applied calcium carbide in the synthesis of diarylethynes from aryl bromides.[10] Later, other groups broadened the scope of the reaction by applying aryl iodides, aryl boronic acids or aryl diazonium salts in the reaction with calcium carbide.[11] Although calcium carbide has already been applied successfully in the field of mechanochemical synthesis,[12] no procedure for the synthesis of diarylethynes from aryl iodides and calcium carbide under mechanochemical conditions has yet been developed. Progress along these lines is reported here (Scheme [1]).

Zoom Image
Scheme 1 Mechanochemical synthesis of diarylethynes

Table 1 Optimization of Reaction Conditionsa

Entry

Pd(OAc)2

PPh3

Base

Solvent

Atmosphere

Yield (%)b

(equiv)

(equiv)

(equiv)

2a

2a′

 1

0.1

0.2

NEt3 (3.0)

–

air

 0

0

 2c

0.1

0.2

K2CO3 (3.0)

–

air

10

0

 3

0.1

0.2

K3PO4 (3.0)

–

air

20

0

 4

0.1

0.2

KOH (3.0)

–

air

19

0

 5

0.1

0.2

NaOt-Bu (3.0)

–

air

30

0

 6

0.1

0.2

K3PO4·H2O (3.0)

–

air

85

traced

 7e

0.1

0.2

K2CO3 (3.0)

cyclohexane

air

11

0

 8

0.1

0.2

K2CO3 (3.0)

EtOH

air

99

traced

 9

0.05

0.1

K2CO3 (3.0)

EtOH

air

99

traced

10f

0.05

0.1

K2CO3 (3.0)

EtOH

air

50

0

11

0.05

0.1

K2CO3 (3.0)

EtOH

ar

88

0

12

0.05

0.1

K2CO3 (2.0)

EtOH

ar

99 (97)

0

13

0.05

0.1

K2CO3 (1.0)

EtOH

ar

68

0

14

–

0.1

K2CO3 (2.0)

EtOH

ar

 0

0

15

0.05

–

K2CO3 (2.0)

EtOH

ar

 0

0

16g

0.05

0.1

K2CO3 (2.0)

EtOH

ar

65

0

a Reaction conditions: 4-Iodotoluene (87.2 mg, 0.4 mmol, 2.0 equiv), CaC2 [25.6 mg, 0.4 mmol, 2.0 equiv of technical grade CaC2 (75.54% purity), real amount added 0.30 mmol], Pd(OAc)2, PPh3, CuI (3.8 mg, 0.02 mmol, 0.1 equiv), base (3.0 equiv) and solvent (0.25 mL·mg–1) were milled in a 5 mL stainless steel milling jar with one ball (diameter: 10 mm) of the same material for 90 min at 30 Hz.

b Yield determined by 1H NMR spectroscopy using ethyl benzene or 1,3,5-trimethoxybenzene as internal standard. Yield after column chromatography is shown in parenthesis.

c Formation of 7% of 1-ethynyl-4-methylbenzene.

d Observed in the 13C NMR spectrum.

e Formation of 20% of 1-ethynyl-4-methylbenzene.

f Without CuI.

g With 3 × 7 mm balls.

Initially, the reaction of 1-iodo-4-methylbenzene (1a) with calcium carbide in the presence of a combination of Pd(OAc)2 and PPh3 as catalyst, CuI, and triethylamine as base under air was investigated. After milling for 90 min at 30 Hz in a stainless steel milling jar (volume: 5 mL) with one ball of the same material (diameter: 10 mm), no formation of the desired product 1,2-di-p-tolylethyne (2a) was observed when analyzing the crude reaction mixture by 1H NMR spectroscopy (Table [1], entry 1). Switching triethylamine to the solid base K2CO3 gave 2a in 10% yield with 7% of 1-ethynyl-4-methylbenzene. Next, the bases K3PO4, KOH and NaOt-Bu were applied. The results indicated a correlation of yield and basicity, with NaOt-Bu as the strongest base giving 2a in 30% yield (entries 2–5). Furthermore, an influence of water was observed when K3PO4·H2O was used as base, providing 2a in 85% yield. In this case, 13C NMR spectroscopy revealed the presence of 2a′ in trace quantities (entry 6). Since formation of terminal aryl alkyne was only observed for K2CO3, the influence of the reaction environment on the selectivity was investigated by applying small amounts of solvents in the reaction. Under these LAG conditions,[13] the use of the nonpolar solvent cyclohexane gave 2a in 11% and 1-ethynyl-4-methylbenzene in a yield of 20% (entry 7). Pleasingly, the polar, protic solvent ethanol gave the desired product 2a in an excellent yield of 99% with only trace amounts of 2a′ observed in 13C NMR spectrum (entry 8). Under these conditions the catalyst loading was reduced from 10 to 5 mol% with maintenance of yield and selectivity (entry 9). A decreased yield was observed in the absence of CuI (entry 10). To our delight, the formation of 2a′ was not observed when the reaction was performed under argon atmosphere (entry 11). Reducing the amount of base from 3 to 2 equivalents revealed the latter quantity to be superior, giving 2a in 99% yield as determined by 1H NMR spectroscopy. Product isolation by column chromatography provided 2a in 97% yield (entry 12).[14] [15] With only 1 equivalent of base, the yield of 2a dropped to 68% (entry 13). Furthermore, no reaction was observed in the absence of palladium or ligand (entries 14 and 15). Varying the amount and size of milling balls to 3 × 7 mm instead of one 10 mm ball led to a decreased yield of 2a (entry 16).

Zoom Image
Scheme 2 Scope of the mechanochemical diarylethyne synthesis

With the optimized conditions in hand, various aryl iodides were applied in reactions with calcium carbide (Scheme [2]). For p-Me- and p-MeO-substituted aryl iodides the yield was excellent (97%). Furthermore, electron-rich substrate 4-iodo-1,2-dimethoxybenzene (1c) was converted into 2c in 88% yield. The presence of p-t-Bu, p-Ph, and p-n-Bu substituents decreased the yield of the corresponding diarylethynes to 76, 67, and 66%, respectively. A p-NMe2 substituent was tolerated, giving 2g in 61% yield. Product 2h, with two m-Me groups, was obtained in 46% yield, indicating a sensitivity of the reaction to steric effects. A p-SMe substituent was tolerated, giving product 2i in 44% yield.[15] Iodobenzene provided 2j in 39%. Furthermore, a free amino group was tolerated, giving 2k in 36% yield. For p-Br-, p-Cl-, p-F-substituted aryl iodides the yields were poor (34, 33, and 26%, respectively). The thiophene coupling product 2o was obtained in 27% yield. Iodobenzenes with o-Me, o-MeO, p-NO2 substituents, and 1-iodonaphthalene did not react under these reaction conditions, underlining the observed sensitivity of the catalytic system towards steric hindrance and the requirement for reasonably electron-rich substrates.[16] Attempts to apply phenyl trifluoromethansulfonate instead of phenyl iodide in the preparation of 2j and to use 4-bromoanisol and 4-chloroanisol as coupling partners for CaC2 were also unsuccessful, revealing the importance of the iodo group for achieving alkyne formations.

In summary, we developed a mechanochemical synthesis of diarylethynes. In the presence of 5 mol% Pd(OAc)2, various aryl and heteroaryl iodides have been converted in moderate to excellent yield. The couplings were affected by steric hindrance and proceeded better with electron-rich than with electron-poor substrates. As a LAG additive, ethanol was found to be essential for both the reactivity and the selectivity of the reaction. Calculation of the EcoScale for the developed protocol (for details see the Supporting Information) revealed acceptable scores from safety, economical, and ecological viewpoints. Furthermore, a fourfold waste reduction was achieved compared to the solution-based protocol. Thus, this approach highlights the efficient and environmentally friendly character of mechanochemical synthesis in ball mills.[17]


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No conflict of interest has been declared by the author(s).

Acknowledgment

We thank Dr. J. G. Hernández (formerly RWTH Aachen University, Germany, now Ruđer Bošković Institute, Zagreb, Croatia) for fruitful discussions at the initial phase of the project.

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-1733-6254.
  • Supporting Information

  • References and Notes

  • 3 Kubota K, Ito H. Trends Chem. 2020; 2: 1066
    CrossrefSearch in Google Scholar
  • 4 Fulmer DA, Shearouse WC, Medonza ST, Mack J. Green Chem. 2009; 11: 1821
    CrossrefSearch in Google Scholar
  • 5 Thorwirth R, Stolle A, Ondruschka B. Green Chem. 2010; 12: 985
    CrossrefSearch in Google Scholar
  • 8 For a general review on the use of acetylene, see: Trotus I.-T, Zimmermann T, Schüth F. Chem. Rev. 2014; 114: 1761
    CrossrefPubMedSearch in Google Scholar
  • 10 Zhang W, Wu H, Liu Z, Zhong P, Zhang L, Huang X, Cheng J. Chem. Commun. 2006; 4826
    CrossrefPubMed
  • 14 1,2-Di-p-tolylethyne (2a); Procedure: A stainless steel milling jar (volume: 5 mL) equipped with one stainless steel milling ball (diameter: 10 mm) was loaded with Pd(OAc)2 (2.3 mg, 0.01 mmol, 5 mol%), PPh3 (5.3 mg, 0.02 mmol, 10 mol%), CuI (3.8 mg, 0.02 mmol, 10 mol%), K2CO3 (55.3 mg, 0.4 mmol, 2.0 equiv) and iodo-4-methylbenzene (87.2 mg, 0.4 mmol, 2.0 equiv). The jar was brought inside a glovebox and CaC2 [25.6 mg, 0.4 mmol, 2.0 equiv of technical grade CaC2 (75.54% purity), real amount added 0.30 mmol] and ethanol (45 μL) were added. The jar was closed tightly under argon atmosphere using Teflon tape for the thread and additional Parafilm was wrapped around the closed jar. After 90 min at 30 Hz the jar was opened in air, the product was extracted with ethyl acetate (5 × 3 mL) and evaporated on silica. The product was purified by flash column chromatography on silica gel [n-pentane; Rf 0.39 (n-pentane)] to give 1,2-di-p-tolylethyne (40.1 mg, 0.194 mmol, 97%) as a pale-yellow solid. 1H NMR (600 MHz, CDCl3): δ = 7.43 (d, J = 8.1 Hz, 4 H), 7.16 (d, J = 7.8 Hz, 4 H), 2.38 (s, 6 H) ppm. 13C{1H} NMR (151 MHz, CDCl3): δ = 138.3, 131.6, 129.2, 120.5, 89.0, 21.6 ppm. The analytic data is consistent with reported data (ref. 11f).
  • 15 When the typical procedure (see ref. 14) was modified by not using the glovebox and adding freshly ground CaC2 and ethanol in air followed by flushing the jar with argon, 2a was obtained in only 80% yield (as determined by 1H NMR spectroscopy). Most likely, the moisture sensitivity of CaC2 and a partial evaporation of ethanol were responsible for this decrease in yield. Also in this case, 2a′ remained undetected.
  • 16 Besides 2i (44% yield), 22% of aryl iodide 1i could be isolated. After the unsuccessful attempt to couple 1-iodonaphthalene, the starting material was recovered in 58%. Except when detailed, no mono-aryl alkynes were observed in any of the couplings.
  • 17 After our submission, Ito, Kubota, and co-workers reported a mechanochemical Sonogashira cross-coupling of aryl bromides and chlorides with triisopropylsilyl acetylene and aryl acetylenes under high-temperature ball-milling conditions. The protocol expands the scope of the mechanochemical Sonogashira cross-couplings developed by Mack and Stolle and highlights the benefits of ball milling compared to solution-based reactions of poorly soluble substrates. See: Gao Y, Feng C, Seo T, Kubota K, Ito H. Chem. Sci. 2021; 13: 430
    CrossrefPubMedSearch in Google Scholar

Corresponding Author

Carsten Bolm
Institute of Organic Chemistry, RWTH Aachen University
Landoltweg 1, 52074 Aachen
Germany   

Publication History

Received: 09 November 2021

Accepted after revision: 07 January 2022

Accepted Manuscript online:
07 January 2022

Article published online:
10 February 2022

© 2022. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

  • References and Notes

  • 3 Kubota K, Ito H. Trends Chem. 2020; 2: 1066
    CrossrefSearch in Google Scholar
  • 4 Fulmer DA, Shearouse WC, Medonza ST, Mack J. Green Chem. 2009; 11: 1821
    CrossrefSearch in Google Scholar
  • 5 Thorwirth R, Stolle A, Ondruschka B. Green Chem. 2010; 12: 985
    CrossrefSearch in Google Scholar
  • 8 For a general review on the use of acetylene, see: Trotus I.-T, Zimmermann T, Schüth F. Chem. Rev. 2014; 114: 1761
    CrossrefPubMedSearch in Google Scholar
  • 10 Zhang W, Wu H, Liu Z, Zhong P, Zhang L, Huang X, Cheng J. Chem. Commun. 2006; 4826
    CrossrefPubMed
  • 14 1,2-Di-p-tolylethyne (2a); Procedure: A stainless steel milling jar (volume: 5 mL) equipped with one stainless steel milling ball (diameter: 10 mm) was loaded with Pd(OAc)2 (2.3 mg, 0.01 mmol, 5 mol%), PPh3 (5.3 mg, 0.02 mmol, 10 mol%), CuI (3.8 mg, 0.02 mmol, 10 mol%), K2CO3 (55.3 mg, 0.4 mmol, 2.0 equiv) and iodo-4-methylbenzene (87.2 mg, 0.4 mmol, 2.0 equiv). The jar was brought inside a glovebox and CaC2 [25.6 mg, 0.4 mmol, 2.0 equiv of technical grade CaC2 (75.54% purity), real amount added 0.30 mmol] and ethanol (45 μL) were added. The jar was closed tightly under argon atmosphere using Teflon tape for the thread and additional Parafilm was wrapped around the closed jar. After 90 min at 30 Hz the jar was opened in air, the product was extracted with ethyl acetate (5 × 3 mL) and evaporated on silica. The product was purified by flash column chromatography on silica gel [n-pentane; Rf 0.39 (n-pentane)] to give 1,2-di-p-tolylethyne (40.1 mg, 0.194 mmol, 97%) as a pale-yellow solid. 1H NMR (600 MHz, CDCl3): δ = 7.43 (d, J = 8.1 Hz, 4 H), 7.16 (d, J = 7.8 Hz, 4 H), 2.38 (s, 6 H) ppm. 13C{1H} NMR (151 MHz, CDCl3): δ = 138.3, 131.6, 129.2, 120.5, 89.0, 21.6 ppm. The analytic data is consistent with reported data (ref. 11f).
  • 15 When the typical procedure (see ref. 14) was modified by not using the glovebox and adding freshly ground CaC2 and ethanol in air followed by flushing the jar with argon, 2a was obtained in only 80% yield (as determined by 1H NMR spectroscopy). Most likely, the moisture sensitivity of CaC2 and a partial evaporation of ethanol were responsible for this decrease in yield. Also in this case, 2a′ remained undetected.
  • 16 Besides 2i (44% yield), 22% of aryl iodide 1i could be isolated. After the unsuccessful attempt to couple 1-iodonaphthalene, the starting material was recovered in 58%. Except when detailed, no mono-aryl alkynes were observed in any of the couplings.
  • 17 After our submission, Ito, Kubota, and co-workers reported a mechanochemical Sonogashira cross-coupling of aryl bromides and chlorides with triisopropylsilyl acetylene and aryl acetylenes under high-temperature ball-milling conditions. The protocol expands the scope of the mechanochemical Sonogashira cross-couplings developed by Mack and Stolle and highlights the benefits of ball milling compared to solution-based reactions of poorly soluble substrates. See: Gao Y, Feng C, Seo T, Kubota K, Ito H. Chem. Sci. 2021; 13: 430
    CrossrefPubMedSearch in Google Scholar

   Permissions and Reprints All articles of this category
Zoom Image
Scheme 1 Mechanochemical synthesis of diarylethynes
Zoom Image
Scheme 2 Scope of the mechanochemical diarylethyne synthesis