Bis-Sonogashira cross-coupling: an expeditious approach towards long-chain, phenylene-modified 1,ω-diols

Abstract

The synthesis of long-chain, phenylene-modified 1,ω-diols can be effectively performed in 60% overall yield using the bis-Sonogashira cross-coupling with 6 mol% of PdCl₂(PPh₃)₂ and tetrabutylammonium fluoride in a copper-, amine- and solvent-free setting followed by hydrogenation.

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An expeditious and highly efficient method for the synthesis of long-chain 1,ω-diols is of high importance in supramolecular chemistry. Especially in the field of bipolar lipid (bolaamphiphile¹) synthesis, these diols play an important role since they represent the hydrophobic part of this class of lipids. These bolaamphiphiles were originally found in the membrane lipids of certain species of Archaea.² In particular, the bipolar archaebacterial model lipids³ are of great interest since their thermal and chemical stability as well as their capability to form closed vesicles are outstanding properties. These properties make this class of amphiphiles applicable in biotechnology, materials science and pharmacy.⁴ For instance, thermally and chemically stable liposomes made from archaebacterial bolaamphiphiles (archaeosomes) are an alternative to conventional liposomes in applications as a drug delivery system.⁵

Long-chain, unmodified 1,ω-diols with 22 or more carbon atoms have already been synthesised using established multistep procedures such as (i) bis-acylation of cyclic enamines with dicarboxylic acid dichlorides, (ii) hydrolysis of enamino ketones and subsequent ring opening, (iii) Wolff–Kishner reduction of bis(oxoacid)s and subsequent reduction with lithium aluminium hydride, or (iv) double Wittig reaction with bis(phosphorylide)s and ω-functionalised aldehydes.⁶ In our group, we use the Grignard reaction under catalysis of dilithium tetrachlorocuprate(II)⁷ for the synthesis of long-chain 1,ω-diols. This coupling reaction can be designed as a homo-coupling⁸ or a bis-coupling reaction.⁹ For the synthesis of the entitled phenylene-modified compounds we previously used the Grignard reaction in a stepwise homo-coupling procedure since the simultaneous bis-coupling reaction resulted in the formation of by-products, which were impossible to separate.¹⁰ Although this homo-coupling approach resulted in pure products and provided the opportunity for the synthesis of unsymmetrical bolalipids, it is a very time-consuming synthetic pathway.¹⁰ Therefore, the expeditious Sonogashira cross-coupling reaction is a rational alternative for the preparation of such phenylene-modified diols.

Sonogashira cross-coupling¹¹ is one of the most powerful and straightforward methods for the formation of carbon–carbon bonds in organic synthesis.¹² Usually, the Pd-catalysed reaction conditions are mild, and many reactions can be carried out at ambient temperatures. However, the Sonogashira reaction often generates homo-coupling products of terminal alkynes,¹³ difficult to separate from the target products due to similar chromatographic properties.¹⁴ Since the formation of these by-products is due to the addition of the co-catalyst CuI, numerous copper-free catalyst systems were developed.¹⁵ Besides the ‘homo’-Sonogashira, bis-Sonogashira cross-coupling reactions have been developed using either middle-chain alkynes (up to 11 carbon atoms) and vinyl halides¹⁶ or aromatic (benzene or pyridine) dialkynes and aryl iodides.¹⁷ However, all these approaches used copper(I), bearing the risk of the formation of homo-coupling side-products. This problem has to be considered in the synthesis presented here, because long-chain 1,ω-diols cannot be separated from their phenylene-modified analogues.¹⁰

The present work describes the preparation of phenylene-modified 1,ω-diols starting from benzene dihalides 1 and the long-chain unprotected alkynol 2, including different substitution patterns (Scheme 1).

Scheme 1 Reagents and conditions: (i) PdCl₂(PPh₃)₂, TBAF·3H₂O, 1 h, 80 °C (43–63%); (ii) H₂, Pd(OH)₂/C (20%), heptane/ethyl acetate/ethanol, 10 atm, 18 h, rt (90–95%).

Due to the very low solubility of compound 2 in common solvents used for Sonogashira coupling reactions, we investigated DMSO and water combined with a micellar system as solvents, and also solvent-free systems. Furthermore, several Pd-catalysts were tested (see Table 1).

Table 1 Experimental conditions for the Sonogashira cross-coupling reactions^a

Entry	Dihalide (mmol)	2 (mmol)	Pd-catalyst (mol%)	Solvent	Additives (mmol)	Temp. (°C)	Time (h)	Yield (%)^b
a Conditions: all reactions were carried out under an argon atmosphere. b Isolated yields after chromatography (MPLC). c TBAB: tetra-n-butylammonium bromide. d Product was contaminated with homo-coupling by-product. e X-Phos: 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl. f PTS: polyoxyethanyl-α-tocopheryl sebacate (3 wt% in H2O; Sigma Aldrich catalogue no. 698 717). g TBAF: tetra-n-butylammonium fluoride trihydrate.
1	1a (0.5)	1.2	Pd(OAc)2 (3)	DMSO	K2CO3 (2), TBAB^c (1)	55	6	10^d
2	1b (0.5)	1.2	Pd(OAc)2 (3)	DMSO	K2CO3 (2), TBAB^c (1)	65	4.5	9
3	1a (0.5)	1.2	Pd(CH2CN)2Cl2 (4.8), X-Phos^e (10.4)	H2O	PTS^f (3 mL), Et3N (2.2)	rt	96	14
4	1a (0.5)	1.2	Pd(CH2CN)2Cl2 (2.4), X-Phos^e (5.2)	H2O	PTS^f (3 mL), Et3N (2.2)	45	8	10
5	1a (0.5)	1.2	PdCl2(PPh3)2 (3)	H2O	PTS^f (3 mL), Et3N (2.2)	rt	24	10
6	1a (1.0)	2.4	PdCl2(PPh3)2 (6)	None	TBAF^g (3)	60	1	42
7	1a (0.8)	1.9	PdCl2(PPh3)2 (6)	None	TBAF^g (2.4)	80	1	63
8	1a (0.5)	1.2	PdCl2(PPh3)2 (6)	None	TBAF^g (1.5)	80	2	56
9	1b (0.8)	1.9	PdCl2(PPh3)2 (6)	None	TBAF^g (2.4)	80	1	45
10	1c (0.8)	1.9	PdCl2(PPh3)2 (6)	None	TBAF^g (2.4)	80	1	61
11	1d (0.8)	1.9	PdCl2(PPh3)2 (6)	None	TBAF^g (2.4)	80	1	43

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At first, we adapted a method described by Li et al.¹⁸ using Pd(OAc)₂ as catalyst combined with the relatively strong base potassium carbonate and tetra-n-butylammonium bromide (TBAB) at elevated temperatures (entries 1, 2). In addition, we changed the solvent from ethanol to DMSO in order to obtain a better solubility of compound 2. However, the desired product (3a) could be obtained only in marginal yields of about 10%. Unexpectedly, while using the bromo derivative 1a, we detected the homo-coupling product of the terminal alkynol 2, which could not be separated from the product (entry 1). When we used the iodide 1b instead (entry 2), the formation of the by-product could be avoided.

In a next step (entries 3, 4), we applied the method described by Lipshutz and co-workers^15a using the micelle-forming amphiphile PTS¹⁹ in aqueous medium, together with Et₃N as a soluble amine and X-Phos²⁰ as ligand in the presence of catalytic amounts of PdCl₂(CH₃CN)₂. The rationale behind this approach was that the use of a micellar system²¹ might enhance the solubility of the educts and, hence, should trigger the Sonogashira cross-coupling reaction. However, both reactions (entries 3, 4), using different amounts of catalyst and ligand, respectively, and working at different temperatures, gave only low yields of the desired product. In contrast with entry 1, the formation of the homo-coupling by-product was not detected. The use of PdCl₂(PPh₃)₂ instead of PdCl₂(CH₃CN)₂ + X-Phos (entry 5) led to no improvement regarding yield. In addition, the PTS/water system combined with the long-chain alkynol caused problems during the purification process since a gel-like suspension was formed.

The next reaction conditions tested (entries 6–11) were inspired by the work of Mori and co-workers:²² they used TBAF as an activator for the amine-free Pd-catalysed Sonogashira cross-coupling reaction. However, organic solvents such as THF were still required. Based on this procedure, Liang et al.²³ used 3 mol% of PdCl₂(PPh₃)₂ combined with TBAF under solvent-free conditions: For the long-chain alkyne (decyne) and substituted aryl mono-bromides and mono-chlorides, respectively, they obtained 51–98% isolated yields within 1 to 25 h of reaction.²³

In our experiments, the reaction of dibromo benzene 1a with the alkynol 2 in a 1.2-fold excess using 6 mol% of PdCl₂(PPh₃)₂ and 3 equivalents of TBAF (entry 6), and without any solvent as medium, afforded 42% of the desired product 3a.²⁴ An increase in reaction temperature from 60 to 80 °C (entry 7) resulted in an increased yield (63%), whereas an increase in reaction time (entry 8) caused a slight decrease in yield. Unexpectedly, the use of diiodo benzene 1b (entry 9) resulted in lower yields of the desired product combined with a higher amount of unknown by-products. This might be due to the higher reactivity of the iodine compound compared to the bromine counterpart. A change in the substitution pattern of the bromo derivative 1a caused only small variations in product composition: the lower yield while using the ortho derivative 1d (entry 11) is due to steric hindrance during the bis-Sonogashira cross-coupling reaction.

In all reactions using the PdCl₂(PPh₃)₂/TBAF system no homo-coupling products of the terminal alkynol were observed. The mono-coupling Sonogashira product, which always occurred in the cross-coupling reaction in 5–20%, could successfully be separated by middle pressure liquid chromatography (MPLC).

Finally, the hydrogenation of the triple bonds of compounds 3 using a solvent mixture of heptane, ethyl acetate and ethanol, to ensure complete dissolution of the product, and Pd(OH)₂ on carbon resulted in the formation of the target products 4. For a complete conversion it is necessary to use increased hydrogen pressure (up to 10 atm) over several hours. Otherwise, mixtures of products with double bonds are formed.

In summary, we have developed a general synthetic approach for the expeditious preparation of long-chain, phenylene-modified 1,ω-diols. We found that the bis-Sonogashira cross-coupling reaction of aryl dibromides with terminal alkynols, using PdCl₂(PPh₃)₂ and TBAF, followed by hydrogenation is the method of choice, which circumvents the formation of homo-coupling products. This synthetic approach is also applicable for other chain lengths and/or biphenyl/terphenyl core-structures, giving rise to a huge variety of different, phenylene-modified 1,ω-diols important in supramolecular chemistry. The synthesis as well as the physicochemical characterisation of the corresponding bolaamphiphiles are currently underway.

Acknowledgements

This work was supported by grants from the Deutsche Forschungsgemeinschaft (projects Bl 182/19-3 and Do 463/4-2).

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24. Experimental procedure for a typical bis-Sonogashira cross-coupling reaction: an oven-dried flask was filled with aryl dihalide 1 (0.5–1.0 mmol), alkynol 2 (1.2–2.4 mmol), PdCl₂(PPh₃)₂ (6 mol%) and TBAF·3H₂O (3 equiv.) under an argon atmosphere. The mixture was subsequently stirred at 80 °C for 1 h until consumption of the starting material was complete. Afterwards, 30 mL H₂O was added and the mixture was extracted with chloroform (3 × 20 mL). The combined organic layers were washed with brine (20 mL), and water (20 mL), dried over sodium sulfate, and evaporated. The residue was purified by middle pressure liquid chromatography (MPLC) using chloroform/diethyl ether as eluents and a gradient technique to afford the diols 3 as white to light yellow crystalline powders. For the subsequent hydrogenation of the triple bonds, diols 3 were dissolved in heptane/ethyl acetate/ethanol (100 mL, 3/1/1, v/v/v) and Pd(OH)₂ (20% on carbon, 50–100 mg) was added. The mixture was stirred under hydrogen (10 atm) at room temperature for 18 h. Afterwards, the catalyst was removed by filtration and the solvent was evaporated in vacuo to give the diols 4 as white crystalline powders.

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures and characterization data. NMR spectra of isolated compounds. See DOI: 10.1039/c2ra20411h

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