A rapid and efficient synthetic route to terminal arylacetylenes by tetrabutylammonium hydroxide- and methanol-catalyzed cleavage of 4-aryl-2-methyl-3-butyn-2-ols

Abstract

Tetrabutylammonium hydroxide with methanol as an additive was found to be a highly active catalyst for the cleavage of 4-aryl-2-methyl-3-butyn-2-ols. The reaction was performed at 55–75 °C and gave terminal arylacetylenes in good to excellent yields within several minutes. Compared with the usual reaction conditions (normally >110 °C, several hours), this novel catalyst system can dramatically decrease the reaction time under much milder conditions.

Introduction

Terminal arylacetylenes are key precursors for the construction of conjugated oligo- or polyarylacetylenes, which have been widely used in the preparation of photoelectric devices such as organic light-emitting diodes (OLEDs) [1–4], field-effect transistors (OFETs) [5–6], and organic photovoltaic cells (OPVCs) [7–9]. The palladium-catalyzed Sonogashira cross-coupling of an aryl halide with a mono-protected acetylene and the subsequent removal of the protecting group is an important synthetic approach to access terminal arylacetylenes [10–13]. The commonly used mono-protected acetylenes are trialkylsilylacetylenes such as trimethylsilylacetylene (TMSA), triisopropylsilylacetylene (TIPSA) and [(3-cyanopropyl)dimethylsilyl]acetylene (CPDMSA), and 2-methyl-3-butyn-2-ol (MEBYNOL). The trialkylsilyl groups can be easily removed by treatment with oxygen-based nucleophiles or fluoride at ambient temperature [10–12]. However, trialkylsilylacetylenes are rather expensive that their use is limited to small-scale synthesis [13]. On the other hand, MEBYNOL ($ 0.3/g) is much cheaper than trialkylsilylacetylenes (TMSA $ 14.0/g, TIPSA $ 20.6/g, from Alfa Aesar). MEBYNOL couples with aryl halides in nearly quantitative yield and the coupling products 4-aryl-2-methyl-3-butyn-2-ols can be easily purified by chromatography because of the very different chromatographic polarities between the products and the aryl halides [13–22]. Nevertheless, the existing methods for the deprotection reaction (cleavage of 4-aryl-2-methyl-3-butyn-2-ols by removal of 2-hydroxypropyl group) to produce arylacetylenes often require harsh conditions [13–22], such as strong base (NaH, NaOH, KOH or t-BuOK), high temperature (in refluxing toluene or butanol) and a long reaction time. Such forcing conditions frequently lead to undesired side reactions and limit the application of MEBYNOL in the preparation of terminal arylacetylenes.

To solve the problem, herein we report a novel efficient catalyst system consisting of tetrabutylammonium hydroxide (Bu₄NOH) and methanol for the removal of the 2-hydroxypropyl group from 4-aryl-2-methyl-3-butyn-2-ols under mild conditions. This deprotection reaction is remarkably facile (5–30 min, 55–75 °C) in comparison to the existing methods (usually several hours, >110 °C) [13–22] and gives the terminal arylacetylene products in good to excellent yields (up to 98%).

Results and Discussion

Initially, we chose 4-(4-(phenylethynyl)phenyl)-2-methyl-3-butyn-2-ol (1a) as the model compound and carried out the deprotection reaction in toluene at 75 °C in the presence of inorganic bases and Bu₄NOH/CH₃OH, respectively (Table 1). It was found that by using inorganic bases, such as NaH, NaOH, NaOAc, KOH and K₂CO₃, no deprotected product 2a was detected by TLC even after 24 h (Table 1, entries 1–5). Terminal arylacetylene 2a was obtained in good yield only by NaOH with the addition of water and Bu₄NI (the phase transfer catalyst), but this reaction required 23 h (Table 1, entry 6). Using Bu₄NOH as the catalyst with CH₃OH as an additive, 2a was obtained in yields as high as 98% after only 5 min (Table 1, entry 7).

Table 1.

Removal of 2-hydroxypropyl group in the presence of different catalysts^a.

Entry	Base (equiv)	Time (h)	Yield (%)b
1	KOH (5)	24	0
2	K2CO3 (5)	24	0
3	NaOAc (5)	24	0
4	NaH (5)	24	0
5	NaOH (5)	24	0
6	5 M aqueous NaOH (75) with Bu4NI (0.1)	23	89
7	Bu4NOH (0.1) with CH3OH (1.2)	0.08	98

^aReaction conditions: 1a (2 mmol), base in toluene (100 mL) at 75 °C, under N₂. ^bIsolated yield.

The influence of the loading of Bu₄NOH and CH₃OH, as well as the effect of temperature on the yield of 2a were then investigated (Table 2). The yield decreased from 98% to 29% when the Bu₄NOH loading relative to 1a decreased from 10 mol % to 2.5 mol % (Table 2, entries 1, 2 and 5), suggesting that 10 mol % of Bu₄NOH was required. The optimum quantity of CH₃OH was 1.2 equiv with respect to the amount of 1a. The yield increased with increasing CH₃OH loading when the mole ratio CH₃OH/1a was lower than 1.2 (Table 2, entries 2–4), but it decreased with increasing CH₃OH loading when the mole ratio CH₃OH/1a was higher than 1.2 (Table 2, entries 5–7). Using 10 mol % of Bu₄NOH and 1.2 equiv of CH₃OH, 2a was obtained in good to excellent yields in a relatively wide temperature range of 55–85 °C (Table 2, entries 5, 8–13). It reached the highest yield of 98% at 75 °C within 5 min. The yield was reduced significantly when the temperature was lower than 55 °C. Compared to the conventional method (>110 °C), this lower reaction temperature of 55–75 °C is especially meaningful for the 4-aryl-2-methyl-3-butyn-2-ols containing temperature-sensitive groups.

Table 2.

Effect of reaction conditions on the yield of 2a.

Entry	Bu4NOH (mol %)	CH3OH (equiv)	Temp (°C)	Time (min)	Yield (%)b
1	2.5	1.2	75	45	29
2	5	1.2	75	30	80
3	5	1.0	75	30	70
4	5	0.6	75	30	68
5	10	1.2	75	5	98
6	10	1.9	75	5	92
7	10	3.2	75	5	80
8	10	1.2	85	5	92
9	10	1.2	65	5	95
10	10	1.2	55	30	87
11	10	1.2	45	30	28
12	10	1.2	35	30	15
13	10	1.2	25	600	0

^aReaction conditions: 1a (2 mmol), Bu₄NOH and CH₃OH in toluene (100 mL), under N₂. ^bIsolated yield.

Thus, the optimal deprotection reaction required 10 mol % of Bu₄NOH with 1.2 equiv of CH₃OH in toluene at 75 °C. Then the deprotection reaction was investigated for different 4-aryl-2-methyl-3-butyn-2-ols. As shown in Table 3, this method was rapid, efficient and worked well with a broad range of 4-aryl-2-methyl-3-butyn-2-ols. Regarding the most studied 4-aryl-2-methyl-3-butyn-2-ols (Table 3, entries 1–4, 6, 7 and 9–11), the deprotection reaction was complete within 5 min at 75 °C, giving the terminal arylacetylenes in good to excellent yields. Products phenylacetylene (2f) was a liquid with a boiling point of 142 °C and 4-bromophenylacetylene (2g) was a solid that sublimed, consequently some of these compounds were lost during purification (Table 3, entries 6 and 7). Arylacetylenes 1e and 1h bearing electron-donating groups showed low reactivity [22], and the reactions required heating at 75 °C for 15 min then at 90 °C for 15 min (Table 3, entries 5 and 8). However, the reaction conditions were still milder than those of existing methods (>3 h) and satisfactory yields were achieved. It is worth mentioning that for the 4-aryl-2-methyl-3-butyn-2-ols containing two or more butynols, complete deprotection was achieved in only 5–30 min with good yields (Table 3, entries 8–11) using our method, whilst by using the conventional method deprotection was incomplete or the yields were low, or longer reaction times were required [22–25]. For example, multifunctional arylacetylenes 2i and 2k were prepared in 85% and 83% yields in 5 min (Table 3, entries 10 and 11), whereas they were obtained in only 38% and 11% yields in 8 h, respectively, when sodium was used in refluxing toluene (Supporting Information File 1). Thus, our novel catalyst system may find applications for the preparation of arylacetylene dendritic macromolecules in high yield.

Table 3.

Synthesis of different terminal arylacetylenes by removal of 2-hydroxypropyl groups under optimal conditions^a.

Entry	4-Aryl-2-methyl-3-butyn-2-ol 1	Terminal arylacetylene 2	Time (min)	Yield (%)b
1	1a	2a	5	98
2	1b	2b	5	88
3	1c	2c	5	85
4	1d	2d	5	89
5	1e	2e	30c	95
6	1f	2f	5	88
7	1g	2g	5	74
8	1h	2h	30c	74
9	1i	2i	5	91
10	1j	2i	5	85
11	1k	2k	5	83

^aReaction conditions: 4-aryl-2-methyl-3-butyn-2-ol (2 mmol), Bu₄NOH (0.1 mol per 1 mol 2-hydroxypropyl group), CH₃OH (1.2 mol per 1 mol 2-hydroxypropyl group) and toluene (100 mL) under a N₂ atmosphere. ^bIsolated yields. ^cThe reaction was carried out at 75 °C for 15 min, then at 90 °C for 15 min.

Conclusion

In summary, a rapid, simple, and efficient method has been developed for the preparation of terminal arylacetylenes by the removal of the 2-hydroxypropyl group from 4-aryl-2-methyl-3-butyn-2-ols. By using 10 mol % Bu₄NOH as the catalyst with the addition of 1.2 equiv of CH₃OH at 55–75 °C complete deprotection was achieved within several minutes with good to excellent yields (up to 98%). This method has good functional group tolerance and shows significant promise for the preparation of arylacetylenes with multiple terminal ethynyl groups such as dendritic macromolecules, which will broaden the application of the low-cost reagent 2-methyl-3-butyn-2-ol in the preparation of arylacetylenes.

Experimental

General procedure for the deprotection reaction using Bu₄NOH as base with CH₃OH in toluene: Under a nitrogen atmosphere, 4-aryl-2-methyl-3-butyn-2-ol (2 mmol) was dissolved into anhydrous toluene (100 mL) and the solution was heated to 75 °C, then Bu₄NOH, 40 wt % solution in CH₃OH (Bu₄NOH: 0.1 mol per 1 mol 2-hydroxypropyl group) was added. The mixture was stirred at 75 °C for the indicated time. After cooling down to room temperature, the mixture was washed successively with 5% HCl and brine, dried over MgSO₄, and concentrated in vacuo. The crude product was then purified by column chromatography to afford the product.

Supporting Information

File 1

General experimental methods, analytical data, ¹H and ¹³C NMR spectra of compounds 1a–k and 2a–k.