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. 2022 Mar 14;87(7):4692–4701. doi: 10.1021/acs.joc.1c03160

Access to Diarylmethanols by Wittig Rearrangement of ortho-, meta-, and para-Benzyloxy-N-Butylbenzamides

R Alan Aitken 1,*, Andrew D Harper 1, Ryan A Inwood 1, Alexandra M Z Slawin 1
PMCID: PMC9007461  PMID: 35286089

Abstract

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The N-butyl amide group, CONHBu, has been found to be an effective promoter of the [1,2]-Wittig rearrangement of aryl benzyl ethers and thus allow the two-step synthesis of isomerically pure substituted diarylmethanols starting from simple hydroxybenzoic acid derivatives. The method is compatible with a wide range of functional groups including methyl, methoxy, and fluoro, although not with nitro and, unexpectedly, is applicable to meta as well as ortho and para isomeric series.

Introduction

Directed ortho-metalation is now well established as a powerful method for regioselective functionalization of aromatic compounds,1 and subsequent reaction with an electrophile such as an aromatic aldehyde allows facile construction of ortho-substituted diarylmethanols (Scheme 1). In contrast, methods for the analogous meta- or para-functionalization are nowhere near so well developed despite some recent progress.2 In view of the low cost and ready availability of the three isomeric hydroxybenzoic acids, an attractive alternative strategy to access specifically substituted diarylmethanols would be to transform the carboxylic acid into a suitable activating group, O-benzylate the phenolic OH, and then conduct a [1,2]-Wittig rearrangement (Scheme 1). Although this is a well-known aromatic rearrangement,3 it has not been widely exploited in synthesis, most likely due to the strongly basic conditions required, which limit functional group compatibility, and there have been few recent examples of its use.4 Some highlights in recent use of the Wittig rearrangement include rearrangement of benzyl butadienyl ethers,5 benzyl pyridyl ethers,6 tandem anion translocation—Wittig rearrangement and tandem Wittig rearrangement—aldol reaction,7 as well as the study of systems where there is competition between 1,2- and 2,3- or 1,2- and 1,4-Wittig rearrangements.8 The Wittig rearrangement has also been used to access a range of chiral binaphthyl ligands that have been applied in asymmetric catalysis.9 The rearrangement has been carried out in an enantioselective way by adding a chiral bis(oxazoline) catalyst,10 and diastereoselective Wittig rearrangements have been reported directed by adjacent carbohydrate and α-alkoxyamide functions.11 Finally, it is also possible to suppress the Wittig rearrangement if desired in order to make use of the unrearranged α-lithiobenzyloxy group in the synthesis of benzofurans and other heterocycles.12 In this paper, we describe the discovery and development of the facile Wittig rearrangement of isomeric benzyloxy-N-butylbenzamides to furnish the corresponding diarylmethanols in the ortho-, meta-, and para-series.

Scheme 1. Alternative Approaches to Diarylmethanols.

Scheme 1

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Results and Discussion

Our entry into this area came from a serendipitous discovery during attempted ring bromination of the 2,4-bis(benzyloxy)phenyloxazoline 1. Treatment with n-butyllithium followed by bromine gave not the expected product 2 but instead a product identified by spectroscopic methods and X-ray diffraction (see Supporting Information) as 4, presumably formed by Wittig rearrangement to afford the intermediate 3, which was then oxidized by bromine13 to the ketone (Scheme 2).

Scheme 2. Unexpected Reaction Leading to 4.

Scheme 2

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We then examined the reactivity of the simpler 2-benzyloxyphenyl compound 5 and found that, depending upon the reaction conditions, varying mixtures of the Wittig rearrangement product 6, the 3-aminobenzofuran 7 resulting from intramolecular nucleophilic ring opening of the oxazoline by the benzyl anion, and the O-dealkylation product 8 were formed (Scheme 3). As we have already reported elsewhere,14 the process could be optimized toward the formation of 7 using n-butyllithium/potassium tert-butoxide. However, optimized conditions for the formation of 6, namely 2.2 equiv n-BuLi in THF at rt for 1 h, resulted in an isolated yield after chromatographic purification of just 29%. Under the same conditions, the para-isomer 9 gave the rearrangement product 10 but in only 11% isolated yield, and the meta-isomer 11 was recovered unchanged. It was clear that the 4,4-dimethyloxazoline group was not an optimal promoter of the Wittig rearrangement.

Scheme 3. Behavior of Mono(benzyloxy)phenyloxazolines.

Scheme 3

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We next investigated carbamates and tertiary amides, both classic ortho-directing groups,1 as promoters of Wittig rearrangement, but this was uniformly unsuccessful. The diethylcarbamate 12 suffered a nucleophilic attack at carbonyl to give 13 and 14 in low yield while the phenylcarbamate 15 was recovered unchanged (Scheme 4). The N,N-diethyl amide 16 reacted at the carbonyl group to give the ketone 17. In a previous case where an undesired attack of butyllithium at a diethyl amide was encountered,15 this could be suppressed by changing to the N,N-diisopropyl amide but the reaction of 18 took a different course, giving 2-hydroxybenzil 19 in THF, but the 3-aminobenzofuran 20 in toluene. There are only a few other synthetic routes to substituted 3-aminobenzofurans. The formation of both these products involves an initial intramolecular nucleophilic attack of benzyloxy anion on the amide carbonyl with hydrolysis and dehydration giving 20, while loss of diisopropylamine, hydrolysis, and oxidation affords 19. The closely analogous formation of 19 by base treatment and oxidation of methyl 2-benzyloxybenzoate has already been reported.16

Scheme 4. Reaction of Carbamates and Tertiary Benzamides.

Scheme 4

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Success was finally achieved by moving to the secondary N-butylbenzamides and reaction of 21a with 3.3 equiv n-butyllithium in THF at rt for 2 h followed by workup gave an essentially quantitative yield of the diarylmethanol 22a (Scheme 5). This product was, however, found to be unstable and slowly cyclized over a period of weeks to give mainly 3-phenylphthalide 23a (80%) accompanied by a low yield of anthraquinone 24a resulting from an alternative mode of cyclization and subsequent oxidation. Alternatively, treating the crude product 22a with p-toluenesulfonic acid in boiling toluene for 1 h,17 followed by aqueous workup and chromatographic purification led directly to 23a in 90% isolated yield. The need for 3 equiv of n-BuLi is, we believe, due to the first two equivalents reacting to deprotonate the NH and then bring about an amide-directed ortho-metalation. Only with the third equivalent of base is the benzyl group deprotonated. Use of less n-BuLi resulted in progressively lower yields and recovery of unreacted starting material.18 With these optimized conditions in hand, the scope was now explored, and analogues 21b–w were prepared in good yield by O-alkylation of N-butylsalicylamide 25 with benzylic and other halides and potassium carbonate in DMF (Scheme 6).

Scheme 5. Wittig Rearrangement of 2-Benzyloxy-N-butylbenzamide.

Scheme 5

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Scheme 6. Preparation of ortho-substituted N-butylbenzamides.

Scheme 6

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These were now subjected to the Wittig rearrangement conditions used for 21a and a varied pattern of reactivity emerged (Scheme 7). The systems containing methyl, methoxy, and fluoro substituents all reacted to give the corresponding secondary alcohols 22b–j, which were fully characterized (see Supporting Information) but cyclized upon storage or p-toluenesulfonic acid treatment to give the corresponding phthalides 23. In the cases of the fluorobenzyl compounds 21h and 21j, the corresponding anthraquinone products 24h and 24j were also isolated in low yield. The thienyl compound 21q, the α-methylbenzyl compound 21s, and the prenyl compound 21u also underwent rearrangement. However, the remaining compounds bearing more electron-withdrawing substituents did not, and compounds 21k–p, r, v, and w either underwent decomposition or were recovered unchanged. While all the products shown in Scheme 7 were obtained by spontaneous cyclization, those marked *, in addition to 23a, were also prepared by the p-toluenesulfonic acid method.

Scheme 7. Products from Wittig Rearrangement of ortho-Substituted Benzamides.

Scheme 7

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The case of the allyl compound 21t was particularly interesting. It afforded an inseparable mixture of the expected rearrangement product 22t and an isomer, which proved to be the 3-ethyl-3-hydroxyisoindolinone 27. Over a period of months, the mixture converted entirely into the latter, whose structure was confirmed by X-ray diffraction (Scheme 8).

Scheme 8. Isomerization of 22t.

Scheme 8

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We believe this to involve double-bond migration in 22t to give the enol, which tautomerizes to ketone 26, which then undergoes ring closure. Such isomerization of allyl carbinols to ethyl ketones occurs under a range of basic conditions.19

Attention was now turned to the isomeric para-system, and a range of substrates 29a–p were prepared in good yield by O-alkylation of N-butyl-p-hydroxybenzamide 28 (Scheme 9).

Scheme 9. Preparation of para-substituted N-butylbenzamides.

Scheme 9

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These were subjected to the normal rearrangement conditions, and a similar pattern emerged as for the ortho series. The unsubstituted system as well as those with methyl, methoxy, and fluoro substituents rearranged to give the diarylmethanols 30a–h mostly in good yield (Scheme 10). The α-methylbenzyl compound 29o and the prenyl compound 29p also reacted to give 30o and 30p although with a low yield in the latter case. In the case of 30c, the molecular structure was confirmed by X-ray diffraction and the crystal structure featured each molecule involved in two donor and two acceptor interactions, with head-to-tail hydrogen-bonded dimers linked by C=O...H–O interactions, which were then further linked by N–H...O(H)–C interactions with adjacent molecules (see Supporting Information). Again the three isomeric nitro compounds 29j–l as well as the pentafluorophenyl compound 29m, the diphenylmethyl compound 29n and the methoxynaphthyl system 29i either decomposed or were recovered unchanged.

Scheme 10. Products from Wittig Rearrangement of para-Substituted Benzamides.

Scheme 10

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Having established the viability of the rearrangement for both ortho and para isomeric systems, it was of interest to compare the relative ease of the two processes, and for this, the 2,4-bis(benzyloxy)benzamide 31 was prepared. When this was treated with 3.3 equiv n-BuLi, the product was mainly 32 resulting from rearrangement of the ortho group with just a trace of the isomer 33 from the reaction of the para group (Scheme 11). This appears to be the first example of an amide directing lithiation onto an ortho-alkoxy group. Storage of compound 32 over a period of months resulted in spontaneous cyclization to give phthalide 34 in good yield. On the other hand, treatment of 31 with 4.4 equiv of n-BuLi resulted in rearrangement of both groups to give the diol 35 as a 1:1 mixture of diastereomers.

Scheme 11. Reactivity of bis(benzyloxy) Compound 31.

Scheme 11

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Based on the earlier finding that the meta-benzyloxy oxazoline 11 did not react, in contrast to ortho and para-isomers 5 and 9, and assuming that the activating effect of the amide group in the Wittig rearrangement would be via a spiro anionic intermediate (see below, Scheme 17), we expected that meta-benzyloxy N-butylbenzamides 37 would not react. However, to our surprise, the unsubstituted compound 37a did rearrange under the normal conditions to afford 38a, albeit in a somewhat lower yield than for ortho or para-isomers. The structure of 38a was confirmed by X-ray diffraction and again the crystal structure featured each molecule involved in two donor and two acceptor interactions, but in contrast to 30c, this involved head-to-tail hydrogen-bonded dimers linked by N–H...O(H)–C interactions, which were then further linked by C=O...H–O interactions with adjacent molecules (see Supporting Information). Based on this result, a range of substituted examples 37b–n were prepared in good-to-moderate yield by O-alkylation of 36 (Scheme 12). When these were subjected to the standard rearrangement conditions, a somewhat more restricted pattern of reactivity emerged with successful rearrangement only being observed for alkyl, methoxy, and fluoro substituents as well as the thienyl compound 37m and, in all cases, the isolated yields were lower than for the isomeric systems (Scheme 13).

Scheme 17. Opportunities for Charge Stabilization in the Three Isomeric Systems.

Scheme 17

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Scheme 12. Preparation of meta-substituted N-butylbenzamides.

Scheme 12

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Scheme 13. Products from Wittig Rearrangement of meta-Substituted Benzamides.

Scheme 13

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So far substituent effects have only been examined in the benzyl as opposed to the aryl ring. To further examine the scope, we returned to the ortho system and investigated the effect of substituents on the other aryl ring. Starting from the 5-nitrosalicylamide 39, a range of three O-benzyl derivatives 40a–c were prepared, while the corresponding 5-dimethylamino compound 41 led to derivatives 42a–c. However, when these six compounds were subjected to the usual rearrangement conditions, only in the cases of 42a and 42c were the corresponding rearrangement products 43a and 43c obtained (Scheme 14). It is clear that the presence of a nitro group on either ring is sufficient to prevent the reaction. Since this is most likely due to incompatibility of the nitro function with the reaction conditions, additional evidence was sought from isomeric compounds with methoxy and fluoro substituents, both of which were compatible with the reaction conditions. Thus the 6-fluoro compound 44 in which ortho-metalation is impossible was treated with 2.2 equiv n-BuLi to give the expected rearrangement product 45, isolated after p-toluenesulfonic acid-mediated cyclization as the 7-fluoro-3-phenylphthalide (27%), together with the n-butyl compound 47 resulting from nucleophilic aromatic substitution in low yield (Scheme 15). Methoxy substituents in either the 4- or 5-position were also compatible with the rearrangement and 48 reacted to form 49, isolated as the phthalide 50 while 51 reacted via 52 to give the phthalide product 53 in moderate yield. In contrast to this, the 5-fluoro compound 54 (Scheme 16) underwent decomposition under the normal rearrangement conditions, perhaps due to intervention of an aryne process, while the 3,5-dimethyl-4-benzyloxy compound 55 in which the supposed spiro anion intermediate is sterically disfavored, was recovered largely unchanged.

Scheme 14. Nitro and Dimethylamino Substituted Systems.

Scheme 14

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Scheme 15. Rearrangement with 4-, 5-, or 6-Substituents.

Scheme 15

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Scheme 16. Further Mechanistic Probes Examined.

Scheme 16

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To further probe the mechanism, the 4-trimethylsilyl compound 56 was prepared and was found to undergo rearrangement readily with n-BuLi to afford the alcohol 57. Finally, compounds 58 and 59 in which the benzyloxy group of 21a and 29a is replaced by the isomeric phenoxymethyl group were prepared, and these were also found to readily undergo the rearrangement under the normal conditions, giving, respectively, 22a and 30a.

Although there have been a good number of mechanistic studies on the [1,2]-Wittig rearrangement, some early suggestions involving the intermediacy of arynes and carbonyl compounds were later disproven.20 The most recent and detailed mechanistic study on aryl benzyl ethers employing both experimental and theoretical methods,21 quite clearly points to two major mechanistic possibilities: an anionic mechanism via a spiro-epoxide intermediate that is the normal route for neutral and electron-poor aryl rings, and a radical dissociation/recombination route that is more likely to be important for electron-rich aryl systems. In our system, we envisage initial amide NH deprotonation and ortho-metalation in each case before the third equivalent of n-BuLi deprotonates the benzyl group. The resulting intermediates 60, 62, and 64 can each cyclize to the spiro epoxides implicated in the Wittig rearrangement (Scheme 17) but, while 61 and 65 are be stabilized by the negative charge being on nitrogen, this is not possible for 63 derived from the meta compound thus explaining the lower yields obtained in that case.

The recent mechanistic study21 was focused on substituent effects on the aryl ring rather than the benzyl ring, and substituent effects on the benzyl ring do not seem to have been examined in detail until now. Overall our results on the three isomeric benzyloxybenzamide systems show that a single N-butylbenzamide group on the aryl ring is sufficient to facilitate the rearrangement of ortho and para benzyloxy systems, presumably via the anionic spiro-epoxide intermediates. The meta system is slightly less prone to rearrangement presumably reflecting the reduced capacity for delocalization of the negative charge to a meta disposed electron-withdrawing amide. In all three series, the reaction proceeds with a wide range of both electron-donating and electron-withdrawing benzyl substituents. Only nitro compounds were uniformly unsuccessful due to the incompatibility of that group with butyllithium. The fact that the silyl compound 56 rearranges much more rapidly than benzyl phenyl ether is consistent with the anionic mechanism in that case where the stabilizing effect of silicon upon the α-anion is key. For the isomeric phenoxymethyl compounds 58 and 59 where the spiro-epoxide intermediate cannot be stabilized, the amide group nevertheless promotes the reaction perhaps by favoring the benzylic deprotonation, but the rearrangement must necessarily proceed by the radical route in these cases.

The fact that 48 gives a substantially lower yield than the isomer 51 implies that the rearrangement is discouraged by the presence of a second inductively electron-withdrawing (but mesomerically electron-donating) group in the para position to the rearranging group. The occurrence of the rearrangement for 42a and 42c, which also have an inductively electron-withdrawing group para to the reaction site, can perhaps be taken to indicate that the electron-donating mesomeric effect outweighs the inductive effect in these cases.

Finally, we examined briefly whether the process could be extended from the ethers to the corresponding sulfides or amines since both thia- and aza-[1,2]-Wittig rearrangements are known.22,23 The 2-benzylthio-N-butylbenzamide 66 was readily prepared, but upon treatment with butyllithium, it underwent dehydrative cyclization to afford the 3-aminobenzothiophene 67 in moderate yield, in a reaction analogous to the formation of 20 from 18 (Scheme 18). In an attempt to suppress this process, the more bulky tert-butylbenzamide 68 was prepared, but it was recovered unreacted from BuLi treatment as was the 2-(benzylmethylamino) analogue 69.

Scheme 18. Attempted Extension to thia- and aza-Analogues.

Scheme 18

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Experimental Section

1H and 13C NMR spectra were recorded in CDCl3 unless otherwise stated with internal TMS as reference. IR spectra were recorded using the ATR technique. HRMS measurements were made either using ESI with TOF analyzer or NSI with an ion trap analyzer.

The following procedures are illustrative; full experimental procedures and characterization data are given in the Supporting Information.

2-(Benzyloxy)-N-butylbenzamide 21a

A solution of 2-(benzyloxy)benzoyl chloride13 (10.85 g, 44.0 mmol) in toluene (60 mL) was added dropwise to a stirred 0 °C solution of n-butylamine (12.1 mL, 8.95 g, 0.122 mol) in toluene (60 mL). Once the addition was complete, the reaction mixture was allowed to warm to rt for 1 h before being poured into water and washed with 2 M NaOH and brine. The organic layer was dried and evaporated to afford, after recrystallization (EtOAc/hexane), 21a (9.34 g, 75%) as colorless crystals, mp 52–54 °C; IR 3380, 1648, 1599, 1558, 1292, 1238, 1164, 1101, 1005, 865, 752, 700 cm–1; 1H NMR (500 MHz) δ 8.25 (dd, J = 7.8, 1.8 Hz,1H, ArH), 7.88 (br s, 1H, NH), 7.47–7.38 (m, 6H, ArH and Ph), 7.12–7.08 (m, 1H, ArH), 7.06 (d, J = 8.5 Hz, 1H, ArH), 5.15 (s, 2H, OCH2), 3.34 (td, J = 7.0, 5.5 Hz, 2H, NCH2), 1.35–1.29 (m, 2H, NCH2CH2), 1.19–1.11 (m, 2H, CH2CH3), 0.80 (t, J = 7.3 Hz, 3 H, CH3); 13C NMR (75 MHz) δ 164.9(C), 156.8(C), 135.5(C), 132.5 (CH), 132.4 (CH), 128.9 (2CH), 128.8 (CH), 128.2 (2CH), 122.0(C), 121.6 (CH), 112.4 (CH), 71.4 (OCH2), 39.4 (NCH2), 31.2 (CH2), 20.0 (CH2), and 13.7 (CH3); HRMS (ESI+) m/z [M + Na+] calcd for C18H21NaNO2 306.1465, found 306.1455.

N-Butyl-2-(hydroxy(phenyl)methyl)benzamide 22a, Anthraquinone 24a and 3-Phenylphthalide 23a

Under a nitrogen atmosphere, n-butyllithium (2.6 mL, 6.50 mmol) was added dropwise to a stirred solution of 2-(benzyloxy)-N-butylbenzamide 21a (0.5678 g, 2.00 mmol) in dry THF (20 mL). After stirring at rt for 2 h, the reaction mixture was quenched by addition of sat. aq. NH4Cl and extracted with Et2O (×3). The combined organic layers were washed with 2 M NaOH and water before being dried and evaporated to give 22a as a pale yellow oil: IR 3296, 3064, 2931, 1635, 1540, 1450, 1303, 1228, 1104, 1024, 757, 699 cm–1; 1H NMR (500 MHz) δ 7.38 (t, J = 7.3 Hz, 2H, ArH), 7.29–7.17 (m, 7H, ArH and Ph), 6.31 (t, J = 5.3 Hz, 1H, NH), 5.79 (s, 1H, CHOH), 3.21–3.14 (m, 1H, NCH2), 3.12–3.05 (m, 1H, NCH2), 1.29–1.23 (m, 2H, NCH2CH2), 1.22–1.15 (m, 2H, CH2CH3), 0.85 (t, J = 7.0 Hz, 3H, CH3); 13C NMR (125 MHz) δ 170.8(C), 143.1(C), 142.7(C), 135.8(C), 130.6 (CH), 129.9 (CH), 127.74 (CH), 127.71 (2CH), 127.69 (CH), 126.7 (CH), 126.2 (2CH), 74.9 (CHOH), 39.7 (NCH2), 31.1 (CH2), 19.9 (CH2), 13.6 (CH3); HRMS (ESI+) m/z [M + Na+] calcd for C18H21NaNO2 306.1465, found 306.1456.

On standing at rt in EtOAc solution for 2–3 months, an intramolecular cyclization occurred to give, after purification by column chromatography (SiO2, Et2O/hexane 2:3), at Rf 0.80, 24a (17.5 mg, 4%) as yellow needles, mp 275–279 °C (lit.24 275 °C); 1H NMR (500 MHz) δ 8.34–8.30 (m, 4 H, ArH), 7.83–7.79 (m, 4 H, ArH). The 1H NMR spectral data were in accordance with those previously reported.25

This was followed by a second fraction to give, at Rf 0.55, 23a (0.3350 g, 80%) as tan-colored crystals, mp 113–116 °C (lit.26 115.5 °C); 1H NMR (500 MHz) δ 7.96 (d, J = 7.5 Hz, 1H, ArH), 7.65 (td, J = 7.5, 1.0 Hz, 1H, ArH), 7.55 (t, J = 7.5 Hz, 1H, ArH), 7.39–7.36 (m, 3H, ArH), 7.33 (dd, J = 7.8, 0.8 Hz, 1H, ArH), 7.29–7.26 (m, 2H, ArH), 6.41 (s, 1H, CHPh). The 1H NMR spectral data were in accordance with those previously reported.27

Alternatively, the following literature procedure28 may be employed: A mixture of N-butyl-2-(hydroxy(phenyl)methyl)benzamide 22a (prepared as above from 1.14 g 21a, assuming 4.02 mmol) and p-toluenesulfonic acid monohydrate (1.55 g, 8.15 mmol) in toluene (80 mL) was heated at reflux for 1 h. After cooling to rt, the reaction mixture was washed with water (50 mL), 2 M NaOH (50 mL), and brine (50 mL) before being dried and evaporated. The crude residue was purified by column chromatography (SiO2, gradient elution, Et2O/hexane 1:4 to Et2O) to give 23a (0.76 g, 90%) as tan-colored crystals.

N-Butyl-4-hydroxybenzamide 28

A mixture of methyl 4-hydroxybenzoate (30.43 g, 0.20 mol) and n-butylamine (100 mL, 74.00 g, 1.01 mol) was heated at reflux for 4 d before being concentrated in vacuo. The residue was acidified to pH 1 by the addition of 2 M HCl and extracted with Et2O (3 × 100 mL). The combined organic layers were washed with water (100 mL) before being dried and evaporated. The crude residue was recrystallized (EtOAc/PhMe) to give 28 (28.01 g, 72%) as colorless crystals, mp 118–120 °C (lit.29 118.5–119.5 °C); 1H NMR (500 MHz) δ 7.95 (br s, 1H, OH), 7.62 (d, J = 8.8 Hz, 2H, 2,6-H), 6.86 (d, J = 8.8 Hz, 2H, 3,5-H), 6.17 (t, J = 5.5 Hz, 1H, NH), 3.44 (td, J = 7.0, 5.5 Hz, 2H, NCH2), 1.62–1.56 (m, 2H, NCH2CH2), 1.44–1.36 (m, 2H, CH2CH3), 0.94 (t, J = 7.3 Hz, 3H, CH3). The 1H NMR spectral data were in accordance with those previously reported.30

4-(Benzyloxy)-N-butylbenzamide 29a

N-Butyl-4-hydroxybenzamide 28 (3.87 g, 20.0 mmol) was added to a stirred suspension of sodium hydride (60% in mineral oil, prewashed with hexane, 0.82 g, 20.5 mmol) in DMF (20 mL), and the mixture was stirred at rt for 15 min before benzyl bromide (2.4 mL, 3.45 g, 20.2 mmol) was added. After stirring for 18 h at rt, the reaction mixture was poured into water and extracted with CH2Cl2 followed by Et2O (×3). The combined organic layers were washed with brine (×5) and 2 M NaOH before being dried and evaporated. Recrystallization of the residue (EtOAc/hexane) gave 29a (4.68 g, 82%) as colorless crystals, mp 126–128 °C; (lit.31 119.1–119.7 °C); 1H NMR (500 MHz) δ 7.72 (d, J = 8.8 Hz, 2H, 2,6-H), 7.44–7.38 (m, 4H, Ph), 7.35–7.32 (m, 1H, Ph), 6.99 (d, J = 8.8 Hz, 2H, 3,5-H), 6.03 (t, J = 5.5 Hz, 1H, NH), 5.11 (s, 2H, OCH2), 3.44 (td, J = 7.3, 5.5 Hz, 2H, NCH2), 1.62–1.56 (m, 2H, NCH2CH2), 1.45–1.37 (m, 2H, CH2CH3), and 0.95 (t, J = 7.3 Hz, 3H, CH3). The 1H NMR spectral data were in accordance with those previously reported.31

N-Butyl-4-(hydroxy(phenyl)methyl)benzamide 30a

Under a nitrogen atmosphere, n-butyllithium (2.5 M in hexane, 6.6 mL, 16.5 mmol) was added dropwise to a stirred solution of 4-(benzyloxy)-N-butylbenzamide 29a (1.41 g, 4.98 mmol) in dry THF (50 mL). After stirring at rt for 2 h, the reaction mixture was quenched by addition of sat. aq. NH4Cl and extracted with Et2O (×3). The combined organic layers were washed with 2 M NaOH and water before being dried and evaporated. Purification of the residue by column chromatography (SiO2, gradient elution, Et2O/hexane 7:3 to Et2O) and subsequent recrystallization (EtOAc/hexane) gave 30a (1.11 g, 79%) as colorless crystals, mp 113–114 °C; IR 3432, 3337, 2953, 2926, 1616, 1542, 1448, 1303, 1228, 1045, 736, 694 cm–1; 1H NMR (400 MHz) δ 7.67 (d, J = 8.2 Hz, 2H, ArH), 7.41 (d, J = 8.2 Hz, 2H, ArH), 7.36–7.30 (m, 4H, Ph), 7.28–7.24 (m, 1H, Ph), 6.14 (t, J = 5.6 Hz, 1H, NH), 5.85 (s, 1H, CHOH), 3.41 (td, J = 7.2, 5.6 Hz, 2H, NCH2), 2.76 (d, J = 3.2 Hz, 1H, OH), 1.61–1.53 (m, 2H, NCH2CH2), 1.43–1.34 (m, 2H, CH2CH3), 0.94 (t, J = 7.4 Hz, 3H, CH3); 13C NMR (125 MHz) δ 167.3(C), 147.1(C), 143.4(C), 133.8(C), 128.6 (2CH), 127.8 (CH), 126.9 (2CH), 126.6 (2CH), 126.5 (2CH), 75.7 (CHOH), 39.8 (NCH2), 31.7 (CH2), 20.1 (CH2), 13.8 (CH3); HRMS (NSI+) m/z [M + H+] calcd for C18H22NO2 284.1645, found 284.1644.

3-(Benzyloxy)-N-butylbenzamide 37a

To a stirred solution of 3-(benzyloxy)benzoyl chloride32 (6.82 g, 27.6 mmol) in CH2Cl2 (100 mL) at 0 °C, Et3N (3.85 mL, 27.6 mmol) was added dropwise. The solution was stirred for 5 min, and then n-butylamine (2.73 mL, 27.6 mmol) was added dropwise and the mixture stirred at rt for 18 h. The reaction mixture was poured into H2O, extracted (×3) with CH2Cl2, and the combined organic fractions were dried over MgSO4 and concentrated to afford, after recrystallization (EtOH) 37a (5.80 g, 74%) as off-white crystals, mp 83–86 °C; IR 3298, 3229, 2961, 1626, 1603, 1580,1553, 1016, 698 cm–1; 1H NMR (400 MHz) δ 7.47–7.38 (m, 5H, ArH), 7.38–7.32 (m, 2H, ArH), 7.32–7.28 (m, 1H, ArH), 7.09 (ddd, J = 7.8, 2.6, 1.5 Hz, 1H, ArH), 6.07 (br s, 1H, NH), 5.11 (s, 2H, OCH2), 3.45 (td, J = 7.1, 5.7 Hz, 2H, NHCH2), 1.65–1.53 (m, 2H, NHCH2CH2), 1.51–1.30 (m, 2H, CH2CH3), 0.96 (t, J = 7.3 Hz, 3H, CH2CH3); 13C NMR (100 MHz) δ 167.2(C), 158.9(C), 136.5(C), 136.4(C), 129.6 (CH), 128.6 (CH), 128.1 (CH), 127.5 (CH), 118.8 (CH), 118.1 (CH), 113.3 (CH), 70.1 (OCH2), 39.8 (NHCH2), 31.7 (CH2), 20.1 (CH2), 13.8 (CH3); HRMS (ESI+) m/z [M + H+] calcd for C18H22NO2 284.1651, found 284.1636.

N-Butyl-3-(hydroxy(phenyl)methyl)benzamide 38a

Under a nitrogen atmosphere, n-butyllithium (2.5 M in hexane, 2.64 mL, 6.60 mmol) was added dropwise to a stirred solution of 3-(benzyloxy)-N-butylbenzamide 37a (567 mg, 2.0 mmol) in dry THF (20 mL). After stirring at rt for 2 h, the reaction mixture was quenched by addition of sat. aq. NH4Cl and extracted with Et2O (×3). The combined organic layers were dried and evaporated. Purification of the residue by column chromatography (gradient elution, Et2O/hexane 1:1 to Et2O/hexane 7:3) gave 38a (298 mg, 53%) as colorless crystals, mp 97–100 °C; IR 3298, 3229, 2961, 2932, 2857, 1626, 1553, 1418, 1327, 1016, 746, 698 cm–1; 1H NMR (400 MHz) δ 7.75 (t, J = 1.8 Hz, 1H, ArH), 7.57 (dt, J = 7.7, 1.5 Hz, 1H, ArH), 7.42–7.35 (m, 1H, ArH), 7.31–7.24 (m, 5H, ArH), 7.24–7.21 (m, 1H, ArH) 6.43 (t, J = 5.7 Hz, 1H, NH), 5.74 (s, 1H, CHOH), 3.71 (s, 1H, CHOH), 3.31 (td, J = 7.2, 5.7 Hz, 2H, NHCH2), 1.54–1.45 (m, 2H, NHCH2CH2), 1.39–1.27 (m, 2H, CH2CH3), 0.90 (t, J = 7.3 Hz, 3H, CH2CH3); 13C NMR (100 MHz) δ 167.6(C), 144.5(C), 143.5(C), 134.7(C), 129.5 (CH), 128.5 (CH), 128.4 (2CH), 127.5 (CH), 126.5 (2CH), 125.9 (CH), 124.7 (CH), 75.6 (CHOH), 39.8 (NHCH2), 31.5 (CH2), 20.1 (CH2), 13.7 (CH3); HRMS (ESI+) m/z [M + H+] calcd for C18H22NO2 284.1651, found 284.1637.

Acknowledgments

We dedicate this paper to the memory of Victor Snieckus (1937–2020) and Peter Beak (1936–2021). We thank EPSRC (UK) for a DTA studentship to A.D.H. (Grant EP/L505079/1), EPSRC (UK), and CRITICAT Centre for Doctoral Training for a studentship to R.A.I. (Grant code: EP/L016419/1) and the EPSRC UK National Mass Spectrometry Facility at Swansea University.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.joc.1c03160.

  • Experimental procedures, characterization data, NMR spectra of all newly synthesized compounds, and X-ray crystallographic details (PDF)

Accession Codes

CCDC 2105490–2105493 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_request@ccdc.cam.ac.uk, or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

Author Contributions

The manuscript was written through the contributions of all authors. A.D.H. and R.A.I. contributed equally to the synthetic work, and A.M.Z.S. performed the crystallography. All authors have given approval to the final version of the manuscript.

The authors declare no competing financial interest.

Supplementary Material

jo1c03160_si_001.pdf (12.8MB, pdf)

References

  1. a Gschwend H. W.; Rodriguez H. R. Heteroatom-Facilitated Lithiations. Org. React. 1979, 26, 1–360. 10.1002/0471264180.or026.01. [DOI] [Google Scholar]; b Beak P.; Snieckus V. Directed Lithiation of Aromatic Tertiary Amides: An Evolving Synthetic Methodology for Polysubstituted Aromatics. Acc. Chem. Res. 1982, 15, 306–312. 10.1021/ar00082a002. [DOI] [Google Scholar]; c Reuman M.; Meyers A. I. The Synthetic Utility of Oxazolines in Aromatic Substitution. Tetrahedron 1985, 41, 837–860. 10.1016/S0040-4020(01)96401-4. [DOI] [Google Scholar]; d Snieckus V. Directed Ortho Metalation. Tertiary Amide and O-Carbamate Directors in Synthetic Strategies for Polysubstituted Aromatics. Chem. Rev. 1990, 90, 879–933. 10.1021/cr00104a001. [DOI] [Google Scholar]; e Matsui S.; Uejima A.; Suzukia Y.; Tanaka K. Asymmetric Synthesis of Optically Active Phthalides via ortho-Lithiation and Cyclization of Chiral N-Monosubstituted Benzamides. J. Chem. Soc. Perkin. Trans. 1 1993, 701–704. 10.1039/p19930000701. [DOI] [Google Scholar]; f Nguyen T.-H.; Castanet A.-S.; Mortier J. Directed Ortho-Metalation of Unprotected Benzoic Acids. Methodology and Regioselective Synthesis of Useful Contiguously 3- and 6-Substituted 2-Methoxybenzoic Acid Building Blocks. Org. Lett. 2006, 8, 765–768. 10.1021/ol0530427. [DOI] [PubMed] [Google Scholar]; g Jia B.; Yang Y.; Jin X.; Mao G.; Wang C. Rhenium-Catalyzed Phthalide Synthesis from Benzamides and Aldehydes via C–H Bond Activation. Org. Lett. 2019, 21, 6259–6263. 10.1021/acs.orglett.9b02142. [DOI] [PubMed] [Google Scholar]
  2. a Korvorapun K.; Samanta R. C.; Rogge T.; Ackermann L. Remote C–H Functionalizations by Ruthenium Catalysis. Synthesis 2021, 53, 2911–2934. 10.1055/a-1485-5156. [DOI] [Google Scholar]; b Dey A.; Agasti S.; Maiti D. Palladium catalysed meta-C–H-functionalization reactions. Org. Biomol. Chem. 2016, 14, 5440–5453. 10.1039/C6OB00395H. [DOI] [PubMed] [Google Scholar]; c Mihai M. T.; Genov G. R.; Phipps R. J. Access to the meta position of arenes through transition metal catalysed C–H bond functionalisation: a focus on metals other than palladium. Chem. Soc. Rev. 2018, 47, 149–171. 10.1039/C7CS00637C. [DOI] [PubMed] [Google Scholar]; d Mihai M. T.; Williams B. D.; Phipps R. J. Para-Selective C–H Borylation of Common Arene Building Blocks Enabled by Ion-Pairing with a Bulky Countercation. J. Am. Chem. Soc. 2019, 141, 15477–15482. 10.1021/jacs.9b07267. [DOI] [PMC free article] [PubMed] [Google Scholar]; e Liu L.-Y.; Qiao J. X.; Yeung K.-S.; Ewing W. R.; Yu J.-Q. meta-Selective C–H Arylation of Fluoroarenes and Simple Arenes. Angew. Chem., Int. Ed. 2020, 59, 13831–13835. 10.1002/anie.202002865. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. a Schorigin P. Über die Carbinol-Umlagerung von Benzyläthern. Ber. Dtsch. Chem. Ges. 1924, 57, 1634–1637. 10.1002/cber.19240570878. [DOI] [Google Scholar]; b Wittig G.; Löhmann L. Über die kationotrope Isomerisation gewisser Benzyläther bei Einwirkung von Phenyl-lithium. Liebigs Ann. Chem. 1942, 550, 260–268. 10.1002/jlac.19425500117. [DOI] [Google Scholar]
  4. Wang F.; Wang J.; Zhang Y.; Yang J. The [1,2]- and [1,4]-Wittig rearrangement. Tetrahedron 2020, 76, 130857 10.1016/j.tet.2019.130857. [DOI] [Google Scholar]
  5. Nakano T.; Soeta T.; Endo K.; Inomata K.; Ukaji Y. Stereoselective synthesis of (2Z,4E)-2,4-pentadien-1-ols via sequential 1,4-elimination reaction and [1,2]-Wittig rearrangement starting from (E)-4-alkoxy-2-butenyl benzoates. J. Org. Chem. 2013, 78, 12654–12661. 10.1021/jo402272r. [DOI] [PubMed] [Google Scholar]
  6. a Yang J.; Dudley G. B. [1,2]-Anionic rearrangement of 2-benzyloxypyridine and related pyridyl ethers. J. Org. Chem. 2009, 74, 7998–8000. 10.1021/jo901707x. [DOI] [PubMed] [Google Scholar]; b Yang J.; Dudley G. B. Pyridine-directed organolithium addition to an enol ether. Adv. Synth. Catal. 2010, 352, 3438–3442. 10.1002/adsc.201000495. [DOI] [Google Scholar]
  7. a Barluenga J.; Fañanás F. J.; Sanz R.; Marcos C.; Trabada M. On the reactivity of o-lithiated ethers: tandem anion translocation and Wittig rearrangement. Org. Lett. 2002, 4, 1587–1590. 10.1021/ol0258029. [DOI] [PubMed] [Google Scholar]; b Bertrand M. B.; Wolfe J. P. Tandem Wittig rearrangement/aldol reactions for the synthesis of glycolate aldols. Org. Lett. 2006, 8, 4661–4663. 10.1021/ol062016l. [DOI] [PubMed] [Google Scholar]
  8. a Capriati V.; Florio S.; Ingrosso G.; Granito C.; Troisi L. Stereoselective and competitive [1,2]- and [2,3]-Wittig rearrangements of allyl heteroarylalkyl ethers. Eur. J. Org. Chem. 2002, 2002, 478–484. . [DOI] [Google Scholar]; b Mori-Quiroz L. M.; Maleczka R. E. Jr. Stereoconvergent [1,2]- and [1,4]-Wittig rearrangements of 2-silyl-6-aryl-5,6-dihydropyrans: a tale of steric vs. electronic regiocontrol of divergent pathways. J. Org. Chem. 2015, 80, 1163–1191. 10.1021/jo5026942. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. a Gao G.; Gu F.-L.; Jiang J.-X.; Jiang K.; Sheng C.-Q.; Lai G.-Q.; Xu L.-W. Neighboring lithium-assisted [1,2]-Wittig rearrangement: practical access to diarylmethanol-based 1,4-diols and optically active BINOL derivatives with axial and sp3-central chirality. Chem. – Eur. J. 2011, 17, 2698–2703. 10.1002/chem.201003111. [DOI] [PubMed] [Google Scholar]; b Zheng L.-S.; Jiang K.-Z.; Deng Y.; Bai X.-F.; Gao G.; Gu F.-L.; Xu L.-W. Synthesis of Ar-BINMOL ligands by [1,2]-Wittig rearrangement to probe their catalytic activity in 1,2-addition reactions of aldehydes with Grignard reagents. Eur. J. Org. Chem. 2013, 2013, 748–755. 10.1002/ejoc.201201301. [DOI] [Google Scholar]; c Song T.; Zheng L.-S.; Ye F.; Deng W.-H.; Wei Y.-L.; Jiang K.-Z.; Xu L.-W. Modular synthesis of Ar-BINMOL-Phos for catalytic asymmetric alkynylation of aromatic aldehydes with unexpected reversal of enantioselectivity. Adv. Synth. Catal. 2014, 356, 1708–1718. 10.1002/adsc.201301128. [DOI] [Google Scholar]; d Song T.; Li L.; Zhou W.; Zheng Z.-J.; Deng Y.; Xu Z.; Xu L.-W. Enantioselective copper-catalyzed azide-alkyne click cycloaddition to desymmetrization of maleimide-based bis(alkynes). Chem. – Eur. J. 2015, 21, 554–558. 10.1002/chem.201405420. [DOI] [PubMed] [Google Scholar]; e Wang C.-Y.; Dong C.; Zheng Z.-J.; Xu Z.; Yang K.-F.; Xu L.-W. Construction of an all-substituted pyrrolidine derivative with multiple stereogenic centers and Betti-base-derived γ-amino alcohols by [1,2]-Wittig rearrangement. RSC Adv. 2015, 5, 55819–55824. 10.1039/C5RA09145D. [DOI] [Google Scholar]
  10. Tomooka K.; Yamamoto K.; Nakai T. Enantioselective [1,2] Wittig rearrangement using an external chiral ligand. Angew. Chem., Int. Ed. 1999, 38, 3741–3743. . [DOI] [PubMed] [Google Scholar]
  11. a Tomooka K.; Yamamoto K.; Nakai T. [1,2]-Wittig rearrangement of acetal systems: a highly stereocontrolled conversion of O-glycosides to C-glycosides. J. Am. Chem. Soc. 1996, 118, 3317–3318. 10.1021/ja953933h. [DOI] [Google Scholar]; b Tomooka K.; Yamamoto H.; Nakai T. Stereoselective synthesis of highly functionalized C-glycosides based on acetal [1,2] and [1,4] Wittig rearrangements. Angew. Chem., Int. Ed. 2000, 39, 4500–4502. . [DOI] [PubMed] [Google Scholar]; c Kitagawa O.; Momose S.; Yamada Y.; Shiro M.; Taguchi T. Synthesis of optically active aldol derivatives through chirality transfer type 1,2-Wittig rearrangement of α-alkoxycarboxamides. Tetrahedron Lett. 2001, 42, 4865–4868. 10.1016/S0040-4039(01)00868-1. [DOI] [Google Scholar]
  12. a Velasco R.; Feberero C.; Sanz R. α-Lithiated aryl benzyl ethers: inhibition of [1,2]-Wittig rearrangement and application to the synthesis of benzo[b]furan derivatives. Org. Lett. 2015, 17, 4416–4419. 10.1021/acs.orglett.5b01964. [DOI] [PubMed] [Google Scholar]; b Sedano C.; Velasco R.; Feberero C.; Suárez-Pantiga S.; Sanz R. α-Lithiobenzyloxy as a directed metalation group in ortho-lithiation reactions. Org. Lett. 2020, 22, 6365–6369. 10.1021/acs.orglett.0c02199. [DOI] [PubMed] [Google Scholar]
  13. Joshi G.; Patil R. D.; Adimurthy S. Green bromine: in situ generated catalyst for the selective oxidation of alcohols using H2O2 as a benign oxidant. RSC Adv. 2012, 2, 2235–2239. 10.1039/c2ra20073b. [DOI] [Google Scholar]
  14. Aitken R. A.; Harper A. D.; Slawin A. M. Z. Base-Induced Cyclisation of ortho-Substituted 2-Phenyloxazolines to Give 3-Aminobenzofurans and Related Heterocycles. Synlett 2017, 28, 1738–1742. 10.1055/s-0036-1588503. [DOI] [Google Scholar]
  15. Beak P.; Brown R. A. The Tertiary Amide as an Effective Director of Ortho Lithiation. J. Org. Chem. 1982, 47, 34–46. 10.1021/jo00340a008. [DOI] [Google Scholar]
  16. Worayuthakarn R.; Boonya-udtayan S.; Arom-oon E.; Ploypradith P.; Ruchirawat S.; Thasana N. Synthesis of Unsymmetrical Benzil Licoagrodione. J. Org. Chem. 2008, 73, 7432–7435. 10.1021/jo8013353. [DOI] [PubMed] [Google Scholar]
  17. Kawasaki T.; Kimachi T. Sparteine-Mediated Enantioselective [2,3]-Wittig Rearrangement of Allyl ortho-Substituted Benzyl Prenyl Ethers. Tetrahedron 1999, 55, 6847–6862. 10.1016/S0040-4020(99)00338-5. [DOI] [Google Scholar]
  18. We are grateful to a reviewer for suggesting that the extra equivalent of butyllithium may be required not for ortho metalation, but rather for either coordination to the amide oxygen or to form a bimetallic complex required for the rearrangement. We are unable to exclude these possibilities.
  19. a Tiffeneau M. Mecanisme des transpositions phényliques chez les iodhydrines aromatiques. Bull. Soc. Chim. Fr. 1907, 4, 1205–1220. [Google Scholar]; b Meisenheimer J.; Link J. Über die Verschiebung in der Allyl-Gruppe. 3. Mitteilung über Substitution und Addition. Liebigs Ann. Chem. 1930, 479, 211–277. 10.1002/jlac.19304790114. [DOI] [Google Scholar]; c Zheng H.-X.; Xiao Z.-F.; Yao C.-Z.; Li Q.-Q.; Ning X.-S.; Kang Y.-B.; Tang Y. Transition-Metal-Free Self-Hydrogen-Transferring Allylic Isomerization. Org. Lett. 2015, 17, 6102–6105. 10.1021/acs.orglett.5b03124. [DOI] [PubMed] [Google Scholar]; d Martinez-Erro S.; Sanz-Marco A.; Bermejo Gómez A.; Vázquez-Romero A.; Ahlquist M. S. G.; Martín-Matute B. Base-Catalyzed Stereospecific Isomerization of Electron-Deficient Allylic Alcohols and Ethers through Ion-Pairing. J. Am. Chem. Soc. 2016, 138, 13408–13414. 10.1021/jacs.6b08350. [DOI] [PubMed] [Google Scholar]
  20. a Lansbury P. T.; Pattison V. A. The Wittig Rearrangement of the Benzyl Ethers of Cyclobutanol and Cyclopropylcarbinol. J. Am. Chem. Soc. 1962, 84, 4295–4298. 10.1021/ja00881a020. [DOI] [Google Scholar]; b Lansbury P. T.; Pattison V. A.; Sidler J. D.; Bieber J. B. Mechanistic Aspects of the Rearrangement and Elimination Reactions of α-Metalated Benzyl Alkyl Ethers. J. Am. Chem. Soc. 1966, 88, 78–84. 10.1021/ja00953a016. [DOI] [Google Scholar]; c Schäfer H.; Schöllkopf U.; Walter D. Wanderungstendenz von Alkylgruppen bei der Wittig-Umlagerung. Tetrahedron Lett. 1968, 9, 2809–2814. 10.1016/S0040-4039(00)75637-1. [DOI] [Google Scholar]; d Eisch J. J.; Kovacs C. A.; Rhee S.-G. Rearrangements of organometallic compounds X. The mechanism of 1,2-aryl migration in the Wittig rearrangement of α-metallated benzyl aryl ethers. J. Organomet. Chem. 1974, 65, 289–301. 10.1016/S0022-328X(00)82263-9. [DOI] [Google Scholar]; e Rautenstrauch V.; Buchi G.; Wuest H. Vinyl Migration in Wittig Rearrangements. J. Am. Chem. Soc. 1974, 96, 2576–2580. 10.1021/ja00815a042. [DOI] [Google Scholar]; f Strunk S.; Schlosser M. Wittig Rearrangement of Lithiated Allyl Aryl Ethers: A Mechanistic Study. Eur. J. Org. Chem. 2006, 2006, 4393–4397. 10.1002/ejoc.200600304. [DOI] [Google Scholar]
  21. Velasco R.; Silva López C.; Nieto Faza O.; Sanz R. Exploring the Reactivity of α-Lithiated Aryl Benzyl Ethers: Inhibition of the [1,2]-Wittig Rearrangement and the Mechanistic Proposal Revisited. Chem. – Eur. J. 2016, 22, 15058–15068. 10.1002/chem.201602254. [DOI] [PubMed] [Google Scholar]
  22. Biellmann J. F.; Schmitt J. L. Solvation and rearrangement of a carbanion. Tetrahedron Lett. 1973, 14, 4615–4618. 10.1016/S0040-4039(01)87291-9. [DOI] [Google Scholar]
  23. Eisch J. J.; Kovacs C. A. The π-orbital overlap requirement in 1,2-anionic rearrangements. J. Organomet. Chem. 1971, 30, C97–C100. 10.1016/S0022-328X(00)87510-5. [DOI] [Google Scholar]
  24. Kekulé A.; Franchimont A. Ueber das Benzophenonchlorid und die Bildung von Anthrachinon bei der Darstellung von Benzophenon. Ber. Dtsch. Chem. Ges. 1872, 5, 908–910. 10.1002/cber.18720050292. [DOI] [Google Scholar]
  25. Barton D. H. R.; Hui R. A. H. F.; Ley S. V. Oxidation of benzylic hydrocarbons with benzeneseleninic anhydride and related reactions. J. Chem. Soc., Perkin. Trans. 1 1982, 2179–2185. 10.1039/p19820002179. [DOI] [Google Scholar]
  26. Mermod E.; Simonis H. Ueber einige Phthalide und Mekonine. Ber. Dtsch. Chem. Ges. 1908, 41, 982–985. 10.1002/cber.190804101191. [DOI] [Google Scholar]
  27. Weeks D. P.; Cella J. Preparation of 3-arylphthalides by the Clemmensen reduction of 2-aroylbenzoic acids. J. Org. Chem. 1969, 34, 3713. 10.1021/jo01263a138. [DOI] [Google Scholar]
  28. Kawasaki T.; Kimachi T. Sparteine-mediated Enantioselective [2,3]-Wittig Rearrangement of Allyl ortho-Substituted Benzyl Ethers and ortho-Substituted Benzyl Prenyl Ethers. Tetrahedron 1999, 55, 6847–6862. 10.1016/S0040-4020(99)00338-5. [DOI] [Google Scholar]
  29. Abramovitz A. S.; Massey V. Purification of intact old yellow enzyme using an affinity matrix for the sole chromatographic step. J. Biol. Chem. 1976, 251, 5321–5326. 10.1016/S0021-9258(17)33164-2. [DOI] [PubMed] [Google Scholar]
  30. Mamidi N.; Manna D. Zn(OTf)2-Promoted Chemoselective Esterification of Hydroxyl Group Bearing Carboxylic Acids. J. Org. Chem. 2013, 78, 2386–2396. 10.1021/jo302502r. [DOI] [PubMed] [Google Scholar]
  31. Kajitani T.; Kohmoto S.; Yamamoto M.; Kishikawa K. Liquid crystalline amides: linear arrangement of rod-like molecules by lateral intermolecular hydrogen bonding and molecular shape effect. J. Mater. Chem. 2004, 14, 3449–3456. 10.1039/b408672d. [DOI] [Google Scholar]
  32. Myllymäki M.; Castillo-Melendez J.; Koskinen A.; Minkkilä A.; Saario S.; Nevalainen T.; Järvinen T.; Poso A.; Salo-Ahen O.. Heterocyclic phenyl carbamates as novel FAAH-inhibitors. PCT Int. Appl.WO, 129129 A1, 2008.

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