Richard M. P.
Veenboer
a and
Steven P.
Nolan
*ab
aEaStCHEM School of Chemistry, University of St Andrews, St Andrews, KY16 9ST, UK. E-mail: snolan@st-andrews.ac.uk
bChemistry Department, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia
First published on 8th May 2015
We report the cross-dehydrative reaction of two alcohols to form unsymmetrical ethers using NHC–gold(I) complexes (NHC = N-heterocyclic carbene). Our progress in developing this reaction into a straightforward procedure is discussed in detail. The optimised methodology proceeds under mild reaction conditions and produces water as the sole by-product. The synthetic utility of this environmentally benign methodology is exemplified by the formation of a range of new ethers from readily available phenols bearing electron withdrawing substituents and secondary benzylic alcohols with various substituents. Finally, we present experimental results to account for the chemoselectivity obtained in these reactions.
Because of the inherent difficulty of activating alcohols for SN1 reactions, π-activated alcohols, such as propargylic and allylic alcohols were most commonly used in early reports.6–8 Benzylic alcohols were later recognised as suitable substrates for this type of reaction.9 The structural arrangement of these alcohols eases the activation of the C–O bond, as the positively charged intermediates are stabilised by the π-electron cloud through resonance.9 Those substrates are now commonly used as sources of “proto-electrophiles” for substitution reactions, and various catalytic methodologies have been developed for the formation of C–C,10,11 C–N,12–14 C–O,15–21 and C–S22 bonds (Scheme 2).
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Scheme 2 Dehydrative bond formation from π-activated alcohols. LA = Lewis acid. BA = Brønsted acid. Z = CH, N, NH2, OH, SH. |
Although Brønsted acids have been successfully used as catalysts in both homogeneous and heterogeneous procedures,23–26 the use of Lewis acids as catalysts constitutes the majority of the reports in literature.27,28 Cationic homogeneous gold complexes have been used as versatile catalysts for a plethora of organic transformations.29,30 More specifically, their Lewis acidic nature has permitted their utilisation in dehydrative reactions with alcohols.31,32 For example, simple chloride salts of gold(III)33,34 or phosphine–gold(I) complexes,35,36 have been used as catalysts for the formation of C–O and C–N bonds.
We previously reported that [Au(NHC)(CH3CN)][BF4] complexes (Fig. 1) catalyse the formation of symmetrical ethers from secondary benzylic alcohols, albeit as a side-reaction (Scheme 3).37 This observation prompted us to explore the capabilities of these well-defined complexes in catalysing the dehydrative formation of ethers.
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Scheme 3 Formation of symmetrical ether 4a as a side-product in hydroalkoxylation (1.1 equiv. of 2a were used).37 |
We herein describe that complex 1c can be used to effectively form unsymmetrical ethers through a cross-dehydrative transformation of benzylic alcohols and phenols. These ethers are also accessible from procedures that use PhenoFluor/TMS-imidazole38 or catalytic amounts of Bi,39 or Ru40 complexes (Scheme 4). These reactions proceed via activation of the phenol (via formation of an imidazolium adduct, an oxocarbenium ion, and C–H activation respectively) instead of via elimination of water from the benzylic alcohol.
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Scheme 4 Catalytic procedures for the formation of aryl ethers. [Ru] = [Ru(C6H6)(PCy3)(CO)(H)][BF4]. [Au] = [Au(IPrCl)(CH3CN)][BF4]. DCE = CH2ClCH2Cl. |
When alcohols 2a and 3a were heated in the absence of a catalyst and solvent, no conversion was observed after 15 minutes (Table 1, entry 1). After 96 hours, 60% of 2a was converted into a 56/44 mixture of ethers 4a and 5aa. This outcome hints at an equilibrium process that is catalysed by weak Brønsted acids such as 3a. Consequently, we continued by testing both gold complexes and Brønsted acids for catalytic activity.
Entry | Catalyst (mol%) | Conversionb (%) (4a/5aa/6aa) |
---|---|---|
a Reaction condition: 2a (0.25 mmol), 3a (0.25 mmol), neat, in air. Cat. = catalytic amount, approximately 1–10 mol%. b Determined by GC analysis, with respect to 2a. Product distribution is given in brackets. | ||
1 | None | 0 |
2 | [Au(IPr)(CH3CN)][BF4] 1a (0.6) | 0 |
3 | [Au(SIPr)(CH3CN)][BF4] 1b (0.6) | 19 (42/58/0) |
4 | [Au(IPrCl)(CH3CN)][BF4] 1c (0.6) | >95 (38/62/0) |
5 | [Au(IPr)(NTf2)] (1.0) | 0 |
6 | [Au(IPrCl)(NTf2)] (1.0) | 0 |
7 | [Au(PPh3)(NTf2)] (1.0) | 60 (57/43/0) |
8 | [{Au(IPr)}2(μ-OH)][BF4] (0.3) | 0 |
9 | [{Au(SIPr)}2(μ-OH)][BF4] (0.3) | 0 |
10 | [{Au(IPrCl)}2(μ-OH)][BF4] (0.3) | 0 |
11 | [Au(IPrCl)(OH)] (0.6) | 0 |
12 | HBF4 (cat.) | >95 (0/23/77) |
13 | H2SO4 (cat.) | >95 (0/0/100) |
14 | p-TsOH (cat.) | >95 (0/0/100) |
Among the series of gold complexes of the type [Au(NHC)(CH3CN)][BF4] (1a–c, Fig. 1), those bearing NHC ligands SIPr (1b) and IPrCl (1c) were particularly active and mixtures of ethers 4a and 5aa were produced (Table 1, entries 3–4). Gratifyingly, the formation of styrene from 2a was not observed despite its formation when using other catalyst systems.41–43 No reaction occurred with NHC-bearing Gagosz-type complexes, [Au(NHC)(NTf2)]44 (Table 1, entries 5 and 6). In contrast, the reaction using [Au(PPh3)(NTf2)]45 gave rapid conversion of the starting alcohols (Table 1, entry 7), but ethers 4a and 5aa were converted to a mixture of side-products 6aa and 7aa (Fig. 2) when the reaction was continued for another 45 minutes to reach complete conversion of 2a. No reaction occurred with complexes [{Au(NHC)}2(μ-OH)][BF4] (Table 1, entries 8–10) or [Au(IPrCl)(OH)] (Table 1, entry 11) as catalysts.46,47 This lack of reactivity can be attributed to the formation of gold phenoxide complexes that are inert under the reaction conditions.48 Reactions with catalytic amounts of different Brønsted acids led to rapid conversion of 2a, but arylakane 6aa was obtained instead of the targeted ether 5aa (Table 1, entries 12–14). Trace amounts of the corresponding di-alkylated product 7aa were observed as well.
These results demonstrate that secondary benzylic alcohols and phenols can be converted to various products (e.g. ethers 4 and 5 and arylalkanes 6 and 7) using either cationic gold complexes or Brønsted acids as catalysts. Control over reactivity appeared to be a challenge that could most elegantly be overcome by the use of gold complex 1c.
We continued our optimisation studies by evaluating product distributions from reactions in solvent (see ESI†), but no improvement was observed over the previous solvent-free conditions.
Next, we tested whether the use of an excess of phenol or a change in the reaction temperature could shift the product distribution towards ether 5aa (Table 2). The amount of phenol present was found to influence the rate of the reaction and we therefore evaluated the product distributions both after 15 minutes and after 1 hour. Gratifyingly, with 5 equivalents of 3a the product distribution shifted from symmetrical ether 4aa to the desired ether 5aa (Table 2, entries 7 and 8).49 Of note, the use of an excess of phenol should not be considered as a major disadvantage from an atom-economic point of view because it can be recycled.50 Of some concern was the observation of side-products 6aa and 7aa when reactions were performed using an excess of phenol (Table 2, entries 1–8). Additionally, extended reaction times led to the formation of these side-products under these reaction conditions.
Entry | 3a (equiv.) | 1c (mol%) | T (°C) | t (h) | Conversionb (%) (4a/5aa/6aa + 7aa)c |
---|---|---|---|---|---|
a Reaction conditions: 2a (0.25 mmol), 3a, neat, in air. b Determined by 1H NMR spectroscopy. Product distribution is given in brackets. c Ratio includes sum of amount of 6aa and 7aa.51 | |||||
1 | 2 | 0.6 | 80 | 0.25 | 61 (21/76/4) |
2 | 2 | 0.6 | 80 | 1 | >95 (19/74/7) |
3 | 3 | 0.6 | 80 | 0.25 | 90 (7/85/8) |
4 | 3 | 0.6 | 80 | 1 | >95 (9/80/11) |
5 | 4 | 0.6 | 80 | 0.25 | >95 (13/83/4) |
6 | 4 | 0.6 | 80 | 1 | >95 (7/87/6) |
7 | 5 | 0.6 | 80 | 0.25 | >95 (9/84/7) |
8 | 5 | 0.6 | 80 | 1 | >95 (2/87/11) |
9 | 5 | 1.0 | 80 | 15 | >95 (0/0/100) |
10 | 5 | 1.0 | 70 | 15 | >95 (0/0/100) |
11 | 5 | 1.0 | 60 | 15 | >95 (0/19/80) |
12 | 5 | 1.0 | 50 | 15 | >95 (7/86/7) |
In an attempt to suppress the detrimental formation of 6aa and 7aa, reactions were examined at lower temperatures (Table 2, entries 9–12). To compensate for potentially lower reaction rates, the catalyst loading was increased to 1 mol% and the reaction time was extended to 15 hours. A control reaction at 80 °C demonstrated clearly that ether 5aa transformed to arylalkanes 6aa and 7aa upon this extended reaction time (Table 2, entry 9). Reactions at 60 °C or 70 °C also led to the formation of mixtures of 6aa and 7aa (Table 2, entries 10 and 11). However, when the reaction was performed at 50 °C, the desired ether 5aa was the major product (Table 2, entry 12).
We had thus established that the use of excess phenol was required to favour the formation of unsymmetrical ether 5aa over symmetrical ether 4a, but that the reaction temperature had to be lowered to suppress the formation of arylalkanes 6aa and 7aa. In order to simplify the procedure, slower reactions that produce the desired product predominantly were chosen over lower catalyst loadings and higher temperatures that requires the optimisation of the reaction time to give the most favourable product distribution. We concluded that ether 5aa could thus be formed most effectively from 2a and 5 equivalents of 3a under solvent-free conditions at 50 °C using 1 mol% 1c as catalyst (Table 2, entry 12). Furthermore, we considered the addition of toluene as a means to lower the rate of the reaction.52
Benzylic alcohols bearing CO2Me, CN or CF3 substituents in the α′-position, did not react (even at 80 °C). This lack of reactivity can be attributed to the deactivating electron-withdrawing nature of these functional groups. 2-Furylethanol was found to decompose under the reaction conditions.37 While secondary benzylic alcohols bearing substituents on the phenyl ring (2e–g) were reactive, we were only able to form the corresponding ethers (5ae–ag) selectively by modifying the reaction conditions slightly. Ether 5ae was obtained from 1-(o-tolyl)ethanol (2e) in very high yield by performing the reaction at 80 °C, but the reaction of 1-(o-chlorophenyl)ethanol (2f) produced a mixture of ether 5af and the corresponding aryl alkane 6af at this temperature. Ether 5af could be formed selectively at 50 °C, but complete conversion of alcohol 2f was not obtained, even after 86 hours. The reaction of 1-(m-chlorophenyl)ethanol (2g) proceeded in a similar fashion to that of alcohol 2f, but toluene had to be added to avoid the formation of the corresponding arylalkane product at 50 °C. Unfortunately, this reaction did not reach completion, even after 86 hours. The standard reaction conditions could be applied for secondary benzylic alcohols with chloro or fluoro substituents in the para position of the phenyl ring (2h–i), and the corresponding ethers (5ah–ai) were obtained in modest and good yields, respectively.
Reactions with p-chlorophenol (3b) were then examined. Once again, reactions with secondary benzylic alcohols bearing substituents in the α′-position (2a–d) proceeded smoothly and the corresponding ethers 5ba–bd were obtained in high yields. Interestingly, for the reaction of 1-phenylethanol (2a), toluene had to be added to the reaction mixture to avoid formation of the corresponding arylalkane. This trend in reactivity suggests that the process that converts ethers 5 to arylalkanes 6 and 7 is faster for ethers derived from p-chlorophenol (3b) compared to those derived from p-fluorophenol (3a), and that the size of the substituent in the α′-position of the benzylic alcohol has a significant influence on this process. Ether 5be could be obtained from 1-(o-tolyl)ethanol (2e) using the standard reaction conditions, but ether 5bf from 1-(o-chloro)ethanol was obtained most effectively at 80 °C. Unfortunately, reaction conditions could not be found which led to complete conversion of 1-(m-chlorophenyl)ethanol (2g) while avoiding the formation of the corresponding arylalkane. The desired ethers 5bh–bi could be formed from alcohols 2h–i and phenol 3b. Finally, the formation of unsymmetrical ethers from 1-phenylethanol (2a) and different phenols was tested as well. Both the use of phenol, and phenols bearing substituents in either the ortho (Cl), meta (F, Cl) or para-position (Br, Me, OMe, CF3) were evaluated. Unsatisfyingly, reactions with these substrates all gave mixtures of the desired unsymmetrical ethers and corresponding arylalkanes.53
Entry | 3a (equiv.) | T (°C) | t (h) | Conversionb (%) (5aa/6aa)c |
---|---|---|---|---|
a Reaction condition: 4a (0.10 mmol), neat, in air. b Determined by 1H-NMR or 19F{1H}-NMR spectroscopy with respect to 4a or 3a, respectively. Product distribution is given in brackets. c Reaction performed in absence of catalyst. | ||||
1 | 1 | 50 | 22 | 29 (91/9) |
2 | 2 | 50 | 22 | 68 (79/21) |
3 | 1 | 80 | 0.25 | 37 (91/9) |
4 | 2 | 80 | 0.25 | 81 (41/59) |
5 | 10 | 80 | 0.25 | >99 (16/84) |
6 | 10 | 80 | 1 | >99 (14/86) |
7 | 10 | 80 | 22 | >99 (0/100) |
8c | 10 | 80 | 1 | 71 (94/6) |
9c | 10 | 80 | 22 | >99 (0/100) |
Symmetrical ether 4a was first subjected to different amounts of phenol 3a under the standard catalytic conditions (Table 3, entries 1 and 2). While the reaction using 1 equivalent of 3a was particularly slow, it produced unsymmetrical ether 5aa and a small amount of 6aa (Table 3, entry 1). When 2 equivalents of 3a were used, the reaction was significantly faster and the product distribution shifted towards arylalkane 6aa (Table 3, entry 2). These results are consistent with previous reports that describe acid-catalysed and thermal rearrangements of phenolic ethers to arylalkanes.54–56 As expected from our catalyst screening (Table 1), the transformation of 4a to mixtures of 5aa and 6aa was much more rapid at 80 °C (Table 3, entries 3 and 4). With 2 equivalents of 3a, the formation of arylalkane 7aa was also observed. The influence of phenol 3a in this transformation was further evaluated by using a ten-fold excess with respect to 4a (Table 3, entry 5). Ether 4a showed complete conversion to arylalkane 6aa upon extended reaction time (Table 3, entries 6 and 7). In this case, only trace amounts of arylalkane 7aa could be observed. When the experiment was repeated in the absence of 1c, we obtained similar results (Table 3, entries 8 and 9). This observation provides another hint that the Brønsted acidity of phenol 3a enables its role as a catalyst in this transformation.
Entry | Catalyst (mol%) | 3a (equiv.) | t (h) | Conversionb (%) (6aa/7aa) |
---|---|---|---|---|
a Reaction condition: 5aa (0.05 mmol), neat, in air. b Determined by 1H-NMR or 19F{1H}-NMR spectroscopy with respect to 5aa. Product distribution is given in brackets. | ||||
1 | 1c (1) | — | 15 | — |
2 | 1c (1) | 1 | 15 | 33 (86/14) |
3 | 1c (1) | 5 | 15 | >99 (96/4) |
4 | — | 5 | 15 | 22 (96/4) |
5 | p-TsOH | — | 1 | 93 (32/68) |
The formation of mixtures of 6aa and 7aa, especially in the reaction with 1 equivalent of phenol 3a (Table 4, entry 2) is intriguing. This result suggests the existence of a pathway that delivers a benzyl-fragment from 5aa that subsequently reacts with 6aa to form 7aa.
![]() | (1) |
![]() | (2) |
![]() | (3) |
The ratio of isomers of 4a evolved upon extended reaction time in the reaction depicted in eqn (1). Therefore, a control experiment was conducted in which an equal mixture of racemic and meso isomers of 4a was subjected to the catalytic conditions (eqn (3)). The ratio of isomers evolved also in this reaction, indicating that an equilibrium process was operative. Of note, this phenomenon was not observed in the absence of a catalyst under otherwise identical conditions. This result is consistent with our observations that symmetrical ether 4 is not merely a side-product in our targeted etherification reaction, but rather a kinetic intermediate that can be converted to the more stable ether 5. The need for an excess of phenol (3) in our procedure can then be justified by the necessity to displace this equilibrium and to drive the reaction to the desired unsymmetrical ether (5).
Footnote |
† Electronic supplementary information (ESI) available: Characterisation data and NMR spectra. See DOI: 10.1039/c5gc00684h |
This journal is © The Royal Society of Chemistry 2015 |