Organocatalytic selective benzoylation of alcohols with trichloromethyl phenyl ketone: inverse selectivity in benzoylation of alcohols containing phenol or aromatic amine functionality

Tetrahedron 68 (2012) 9068e9075

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Organocatalytic selective benzoylation of alcohols with trichloromethyl phenyl ketone: inverse selectivity in benzoylation of alcohols containing phenol or aromatic amine functionality Ram N. Ram *, Vineet Kumar Soni, Dharmendra Kumar Gupta Department of Chemistry, Indian Institute of Technology, Delhi, Hauz Khas, New Delhi 110016, India

a r t i c l e i n f o

a b s t r a c t

Article history: Received 18 June 2012 Received in revised form 14 August 2012 Accepted 17 August 2012 Available online 23 August 2012

Trichloromethyl phenyl ketone benzoylates primary and secondary aliphatic alcoholic groups in compounds also containing a phenolic group in the presence of 2e10 mol % of PMDETA organocatalyst at room temperature in high yields and excellent selectivity. It also shows the potential to selectively benzoylate primary alcoholic groups of aminoarylalkanols and primary-secondary diols as well as primary amino group of alkyl amines in the presence of aryl amines under similar conditions. A rationale for the selectivity and efficiency of the reaction has been provided. Ó 2012 Elsevier Ltd. All rights reserved.

Keywords: Selective O-benzoylation Inverse selectivity Phenolic alcohols Aminobenzyl alcohols PMDETA-catalyzed Organocatalyst Trichloromethyl phenyl ketone

1. Introduction Benzoylation of alcoholic groups is a common occurrence in chemistry. Some familiar applications of this reaction are in the synthesis of natural1 and synthetic2 benzoate esters, protection of alcoholic groups in multi-step synthesis,3 modification of physical and spectroscopic properties of compounds in analysis and structure determination,4 and molecular recognition.5 Benzoylation invokes special consideration for selective protection of a hydroxy group owing to the better hydrolytic/nucleophilic stability of the benzoate and its lower susceptibility to rearrange by migration to another neighboring hydroxy or nucleophilic group than acetate and most other aliphatic ester protecting groups.3a,6 Usually benzoylation of the hydroxy group is performed with benzoyl chloride or benzoic anhydride in the presence of a stoichiometric amount or more of a base resulting in the formation of a considerable amount of undesired chemical waste. Moreover, due to the high reactivity of these benzoylating agents, selectivity between different types of hydroxy groups is generally not satisfactory. Benzoyl chloride is also lachrymatory and is inconvenient to handle and store.

* Corresponding author. Tel.: þ91 11 26591508; fax: þ91 11 26582037; e-mail address: [email protected] (R.N. Ram). 0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tet.2012.08.051

Therefore, several catalytic methods have been reported for selective benzoylation of a hydroxy group. Most of these reports, however, focus on selective acetylation and deal with direct selectivity exploiting the higher nucleophilicity of a hydroxy group conferred by steric or electronic effects, for example, selective benzoylation of a primary alcoholic group in the presence of a sterically more hindered secondary alcoholic group.7 Accordingly, more nucleophilic phenolate anions derived from phenolic alcohols in mildly basic media7a,8 and amino groups in amino alcohols7a,8d,9 could be selectively benzoylated. However, the inverse selectivity, that is, selective benzoylation of an alcoholic group in the presence of a phenolic or an amino group is scarcely reported. It has been realized for a long time that this type of inverse selectivity could be observed under acidic conditions due to the suppressed ionization of the phenolic group or protonation of the amino group.7a Thus, phenolic alcohols could be benzoylated at the alcoholic group by the classical acid-catalyzed Fischer esterification with benzoic acid usually with complete selectivity. Selective O-acylation of aliphatic amino alcohols is a recognized problem and requires even more strongly acidic conditions for complete protonation of the amino group or prior hydrochloride salt formation, yet seldom yields satisfactory results.7a,10 The acidity is further compounded by the liberated HCl from the acylating agent acyl chloride. While these acidic acylations may be acceptable for the preparation of simple starting materials, they are of little use in multi-step synthesis

R.N. Ram et al. / Tetrahedron 68 (2012) 9068e9075

involving molecules containing acid sensitive protecting or other groups. The problem is arguably more severe for alcohols containing an amino group linked to an aromatic ring due to not so favorable acidebase equilibria. Nevertheless, a few milder Lewis acid-catalyzed methods have been reported for selective benzoylation of an alcoholic group in the presence of a phenolic group, such as Bz2O/Sc(OTf)3,8c Bz2O/Bi(OTf)3,11 vinyl benzoate/ (ClBu2Sn)2O,12 and PhCOCl/LiClO4.13 However, exceptions are also known and the selectivity appears to depend on the nature of the Lewis acid catalyst.14 Recently, Oshima and co-workers15 benzoylated aliphatic amino alcohols at the alcoholic group by a tetranuclear zinc cluster Zn4(OCOCF3)6O-catalyzed transesterfication with PhCO2Me with remarkable chemo-selectivity without any detectable mono-benzoylation at the amino group and with the formation of only 7e18% of ester amide dibenzoylated products. However, metal catalysis in general is less desirable than the greener organocatalysis.16 Incidentally, a few rather non-classical benzoylating agents were found to benzoylate the alcoholic groups of phenolic alcohols8d,9b,17 under neutral conditions or, curiously, on catalysis with a tertiary base with varying degree of selectivity. The primary hydroxy groups of the nucleosides deoxyadenosine and deoxyguanosine were also benzoylated selectively in the presence of the amino groups of the base moieties.18,19 Phenolic alcohols may also be mono-acylated at the alcoholic group by Mitsunobu reaction with aromatic acids.20 However, a common problem with the non-classical benzoylating agents, besides lower degree of selectivity, is that they are not commercially available, need to be freshly prepared from the very benzoyl chloride8d,9b,18 or benzoic acid19 at the time of use and also that these as well as Mitsunobu reaction leave considerable amount of organic material after the reaction to be separated from the benzoylated product. Remarkably, selective O-benzoylation of 3amino-5-bromobenzyl alcohol has been reported to occur with benzoic anhydride in the presence of threefold excess of Et3N and DMAP catalyst in CH2Cl2 in 83% yield.21 However, it raises the environmental concern as mentioned earlier. Lipase-catalyzed chemoselective benzoylation of the alcoholic groups of a few phenolic alcohols with vinyl benzoate2d and that of adenosine with O-benzoylacetoxime22 has also been reported. However, the scope of the lipase-catalyzed reactions might be limited, as the efficiency and selectivity of lipase-catalyzed acylations are known to depend on the source of the lipase as well as on the structure of the acylating agent and substrate.6a,b,22,23 Further, most of these reported methods for benzoylation with inverse selectivity also have one or more of the following limitations: less than excellent selectivity,8c,17 more so in the case of secondary alcohols,8d,11 and yields,8d,10b,13,20b anhydrous reaction conditions,8c,d,9b,18,19,22 inert atmosphere,15,22 relatively high temperatures,8d,9b,10c,11,12,20a expensive,8c toxic12 or large amounts10c,13 of catalyst, potential risk to acid-sensitive groups,8b,c,12,13,24 such as TBDMS, use of excess reagent and its removal,2d,8c,11,12,18,19,22 etc. Besides, all these methods use significant amount of a solvent. Indeed realizing O-benzoylation with inverse selectivity under mild and green conditions is not a trivial task and requires ingenuity, enzyme’s dexterity, or serendipity, or protectionedeprotection methodology as the last resort,7a,10b,25 or in the case of phenolic alcohols, dibenzoylation followed by selective debenzoylation of the aryl ester.26 A trichloroacetyl group has been used as an ester or amide group equivalent through haloform cleavage with an alcohol or amine in the presence of a base.27 The reaction has been found to be useful for introducing an ester or amide group on reactive heteroaromatic rings28 or in other sensitive molecules such as enol ethers and enamines29 by electrophilic trichloroacetylation followed by haloform cleavage and has also been used during total syntheses.28feh,29a,c,30 The possibility of trichloromethyl phenyl ketone as

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a benzoylating agent for alcohols in the presence of a catalytic amount of Et3N at 25  C has been briefly reported.31 This is an attractive method for benzoylation owing to formation of the neutral, volatile, and easily removable by-product chloroform. However, the method has not received much attention probably due to its little known selectivity profile. Some years back, we observed that chloral could be used for selective formylation of alcoholic group in phenolic alcohols by stirring at room temperature in acetone in the presence of K2CO3.32 However, this reaction failed in the case of oand p-hydroxybenzyl alcohols furnishing mixtures of unidentifiable products, presumably through base-promoted elimination in the formylated products to quinone methides under the reaction conditions.33 It was envisaged that the selective acylation might be successful under mildly basic conditions at lower temperatures and by changing the formylation to benzoylation. Accordingly, we now wish to report successful selective benzoylation of phenolic alcohols with commercially available (SigmaeAldrichCPR, etc.) or easily prepared34 trichloromethyl phenyl ketone at ambient temperatures catalyzed by a small amount (2 mol %) of an organocatalyst N,N,N0 ,N00 ,N00 -pentamethyldiethylenetriamine (PMDETA), which also displays a wide range of selectivity, including inverse selectivity in benzoylation of alcohols containing an aromatic amine functionality. 2. Results and discussion Several base catalysts (NaOR,27b,28a,b,d,i,29b,30a,b,d,f,g NaH,28f,30c K2CO3,27c,28c,i KOH,28g NaHCO3,29a Et3N,27c,28e,i,29c,31 DMAP28h,30e) have been reported for haloform cleavage of trichloromethyl ketones in different solvents (MeOH, MeOH/CH2Cl2, MeOH/THF, THF, DMF, MeCN, CHCl3, toluene) at temperatures ranging from 0  C to room temperatures to heating in a sealed tube28e and reaction times varying from few minutes to several hours. Different reported reaction temperatures and/or times for the same catalyst such as Et3N28e,i,29c,31 and DMAP28h,30e have added to the confusion in selection of a suitable catalyst for investigating selective benzoylation with trichloromethyl phenyl ketone. Therefore, it was considered necessary to first identify a suitable catalyst, which functioned efficiently under mild conditions in benzoylation with trichloromethyl phenyl ketone. Accordingly, the reported and some new commercially available organic bases were evaluated for the catalysis. Inorganic bases, such as alkoxide and K2CO3 were not considered due to their high basicity or our earlier experience.32 Thus, a mixture of trichloromethyl phenyl ketone 1, methanol, and the organic base catalyst (1:1.2:0.02 mol ratio) was stirred at room temperature (20e25  C) until the reaction was completed as indicated by TLC monitoring. The product methyl benzoate was isolated by flash column chromatography. The results are shown in Table 1. It was observed that of all the tertiary bases examined, Table 1 Base-catalyzed benzoylation of methanol with trichloromethyl phenyl ketone 1 in the presence of different catalystsa

PhCOCCl3 + MeOH 1

catalyst

PhCOOMe

Entry no.

Catalyst

Catalyst (mol %)

Time

PhCOOMe yield (%)

1 2 3 4 5 6 7

Et3N DBU DMAP TMEDA PMDETA 2,20 -Bipyridine 2,20 -Bipyridineb

2 2 2 2 2 120 120

6h 2.5 h 3h 6h 10 min 24 h 6h

90 90 92 89 95 No reaction No reaction

a Reactions were performed with 1 (2 mmol) and methanol (2.4 mmol) at 20e25  C without a solvent. b In THF (5 mL) and MeOH (1 mL) at reflux temperature.

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PMDETA was the most efficient. The reaction was complete even with 2 mol % of the catalyst in 10 min at room temperature affording methyl benzoate in 95% isolated yield. The formation of chloroform was detected by 1H NMR spectroscopy. Therefore, this catalyst was used for further investigation. Next, the reaction of 1 was performed with 1 equiv of several other alcohols using 2 mol % of PMDETA as catalyst at room temperature (20e25  C) without any solvent. Inert atmosphere or dry conditions were not necessary. The benzoates were isolated by flash column chromatography. The results are shown in Table 2. The reaction was found to be quite general for benzoylation of primary alcohols. Though the reaction time was considerably increased (2.5e18 h) in the case of higher Table 2 PMDETA-catalyzed benzoylation of different alcohols with trichloromethyl phenyl ketone 1a Entry no.

Alcohol

Time (h)

Benzoate yield (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

Ethanol Propanol Allyl alcohol Benzyl alcohol n-Butanol 1-Octanol 1-Nonanol Geraniol 2-Chloroethanolb trans-Hex-2-en-1-ol But-2-yn-1-ol Pent-2-yn-1-ol Cinnamyl alcohol 2,3-Epoxycinnamyl alcohol m-(tert-Butyldimethylsilyloxy) benzyl alcohol p-Acetoxybenzyl alcohol 2-Propanolc Cyclohexanolc tert-Butyl alcohold Phenold

2.5 12 10 8 12 14 15 8 16 12 6 6 10 12 12

95 94 92 96 92 92 94 91 90 93 96 96 96 91 92

18 48 48 24 24

93 82 89 No reaction No reaction

16 17 18 19 20

a Reactions were performed with 1, alcohol/phenol (2 mmol each), and PMDETA (0.04 mmol, 2 mol %) at 20e25  C without a solvent. b With 5 mol % of PMDETA. c With 10 mol % of PMDETA. d With 50 mol % of PMDETA and alcohol/phenol as solvent (5 mL) under reflux or heating at 60  C, respectively.

primary alcohols, the yields of the benzoates were consistently high. Functional groups like carbonecarbon double and triple bonds, epoxide, TBDMS ether, and aryl acetate ester were not disturbed. Secondary alcohols, such as 2-propanol and cyclohexanol (entries 17 and 18) were found to be less reactive and required higher amount of the catalyst (10 mol %) and longer reaction time (48 h) for the reaction to complete. tert-Butyl alcohol and phenol reacted not at all even when 50 mol % of the catalyst was used and the reaction mixture was heated in excess (5 mL) of the hydroxy compound to reflux or at 60  C, respectively, for 24 h. The resistance of phenol to benzoylation strongly suggested that aliphatic alcohols may be selectively benzoylated in the presence of phenols. Therefore, a few competition experiments were performed on mixtures of aliphatic alcohols and phenols with 1 equiv of 1 as shown in Table 3. It was observed that even with 2.5-fold excess (5 mol %) of the catalyst, the alcohols were exclusively benzoylated. No aryl benzoates were detected in the reaction mixture and the phenols were recovered unchanged. Benzoylation of a mixture of benzyl alcohol and aniline (1:1 mol ratio) with 1 under similar conditions also occurred with inverse selectivity. However, it required 1.2 equiv of 1 for complete disappearance of benzyl alcohol due to formation of a small amount of benzanilide along with the major product benzyl benzoate. The reaction was complete in much shorter time (2 h) with only 2 mol % of PMDETA to afford a mixture of benzyl benzoate and benzanilide in 5:1 ratio

Table 3 PMDETA-catalyzed selective benzoylation of benzyl alcohol and its derivatives in the presence of phenols/aniline with trichloromethyl phenyl ketone 1a

OH + R

OCOPh

PhCOCCl3 1

X

+

PMDETA (2-5 mol%)

R 2

X

R 3

R 2

Entry no.

R

X

Time (h)

Isolated yield of 3 (%)

Recovered phenol/ aniline 2 (%)

1 2 3 4 5 6

H Me OMe Cl NO2 H

OH OH OH OH OH NH2

6 6 4 6 36 2

95 93 94 92 66 92 (14)c

91 91 90 91 89 (17)b 72

a Reactions were performed with alcohol, phenol and 1 (2 mmol each) and PMDETA (0.1 mmol, 5 mol %) at 20e25  C without a solvent. Acetonitrile (1 mL) was used as solvent where the alcohol or phenol was solid (entries 2, 4, and 5). b Yield of recovered alcohol in parenthesis. Trichloromethyl phenyl ketone 1 was also recovered in 15% yield. c With 1.2 equiv of 1 and 2 mol % of PMDETA. Yield of benzanilide in parenthesis.

as determined by 1H NMR of the crude mixture, thus showing considerable preference for benzoylation of alcoholic group in the presence of aromatic amino group. Separation by column chromatography afforded these products in 92 and 14% isolated yields, respectively, along with 72% of the unreacted aniline. It is noteworthy that Zucco and co-workers35 observed selective N-benzoylation of ethanol amine by the same reagent. In view of their report and our observation, it was expected that 1 may also benzoylate alkyl amines selectively in the presence of aryl amines. The selectivity was actually more satisfying than anticipated because the reaction of a mixture of benzyl amine and aniline with 1 equiv of 1 in the presence 2 mol % of PMDETA furnished N-benzylbenzamide in 95% isolated yield as the only benzoylated product along with the recovered aniline (89%) (Scheme 1). The competition experiment with a 1:1 mixture of cyclohexanol and phenol showed that secondary alcohols can also be selectively benzoylated in the presence of phenols under similar conditions with higher amount of the catalyst (10 mol %) and longer reaction time.

NH2

NH2

+

OH

OH +

1/ PMDETA (2 mol%) 20-25 °C, 30 min 1/ PMDETA (10 mol%) 20-25 °C, 48 h

NHCOPh

NH2

+ 95%

89%

OCOPh

OH +

88%

89%

Scheme 1. Some other competition experiments.

These results were supplemented by highly efficient selective benzoylation of several phenolic alcohols and m- and p-aminobenzyl alcohols with 1 in the presence of 2 mol % of PMDETA (Table 4). As expected, phenolic alcohols were selectively benzoylated at the alcoholic group. The selectivity was almost perfect. No aryl esters or alkyl aryl diesters were detected in the reaction mixture by 1H NMR spectroscopy. The phenolic diol given at entry 12 in Table 4 yielded the dibenzoate 4l exclusively even with 2 equiv of 1, showing strong preference for benzoylation of the alcoholic group. The sensitive o- and p-hydroxybenzylic primary and secondary alcohols (Table 4, entries 2, 3, 5, and 6) were selectively benzoylated at the benzylic alcoholic group in high yields. However, m- and

R.N. Ram et al. / Tetrahedron 68 (2012) 9068e9075

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Table 4 PMDETA-catalyzed selective benzoylation of phenolic alcohols and aminobenzyl alcohols with trichloromethyl phenyl ketone 1a Entry no.

Phenolic/amino alcohol

Time (h)

Product(s) (4, 5)

OH

OCOPh 16

1

OH

HO OH

4

OCOPh OH 4b

14

OH

3

14

OCOPh OH 4e

72b

OH

HO

OH MeO

12

OH

8

OH

OH OMe

OH

HO

10

11

12

OH HO

OH HO

HO

OH

12

OH

9

MeO

OH

12

12

HO

4j

HO

4k

PhOCO

30

OCOPh

NH2

a b c d

NH2

2

91

H2N

+

5a

OCOPh 5b

93

OCOPh

94

OCOPh

91

OCOPh OH

OH

92

4i

2

H2N

OCOPh 4g

OCOPh OMe 4h

HO

OH

14

86

OCOPh

12

OH

13

84

OCOPh 4f

60b

HO 7

86

4d

OH

6

87

OCOPh

48b

OH OH

92

OCOPh 4c

HO

OH

5

95

4a

OH

OH OH

2

Yield (%)

+

92c

4l

OCOPh 78 (14)d

NHCOPh

PhOCHN

5'a

OCOPh 5'b

76 (13)d

Reactions were performed with phenolic alcohol or aminobenzyl alcohol and 1 (2 mmol each) and PMDETA (0.04 mmol, 2 mol %) in acetonitrile (1 mL) at 20e25  C. With 10 mol % of PMDETA. With 4 mmol (2 equiv) of 1 and 0.04 mmol (2 mol %) of PMDETA in ethyl acetate (5 mL). Yield of O,N-dibenzoylated product in parenthesis. The reaction was performed with 1.2 equiv of 1.

p-aminobenzyl alcohols (Table 4, entries 13 and 14) yielded Obenzoylated and N,O-dibenzoylated products in 5:1 ratio in each case as determined by 1H NMR spectra of the crude reaction mixture. No N-mono-benzoylation was detected. Chemical separation by washing with dil HCl afforded the major O-benzoylated products in 78% and 76% yields, respectively, comparable to that obtained from the reported methods but having other limitations as

mentioned earlier.19,21 The dibenzoylated products were obtained in 14% and 13% yields, respectively. Though the selectivity in the case of aminobenzyl alcohols is lower, it may be considered appreciable in view of the difficulty level of the task and in the absence of a greener and better known method. The lower reactivity of secondary alcohols (Table 2, entries 17 and 18) prompted us to briefly evaluate the reaction for selective

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benzoylation of primary alcoholic group in the presence of a secondary one. Thus, treatment of 1-phenylethane-1,2-diol with 1 equiv of 1 in acetonitrile in the presence of 2 mol % of PMDETA at 20e25  C for 14 h led to mono-benzoylation at the primary hydroxy group exclusively in 92% yield. All the products were identified by IR, 1H NMR, 13C NMR spectroscopy and comparison with the reported data available in the literature. The structures of the new compounds were also supported by HRMS. Regarding the mechanism of the reaction, a few observations are worth mentioning. (i) Benzoylation of m-hydroxybenzyl alcohol with 1 in the presence of 2 mol % of any of the catalysts Et3N, TMEDA or DMAP did not proceed to completion in any case even after 48 h. However, 1H NMR spectra of the reaction mixtures at different stages of the reaction revealed formation of the alkyl ester exclusively as the product. No aryl ester or alkyl aryl diester could be detected. Thus, the observed selectivity was not due to the catalyst, but was an inherent property of the benzoylating reagentesubstrate system. (ii) Nome and co-workers27d studied EtNH2-catalyzed haloform cleavage of 1 with alcohols and suggested a mechanism involving initial reversible formation of hemiacetal tetrahedral intermediate followed by its slow cleavage to the benzoate ester product in the rate determining step, which was assisted by deprotonation of the hydroxy group of the hemiacetal intermediate with EtNH2. In the absence of the catalyst, the reaction did not proceed beyond the tetrahedral intermediate stage. The hemiacetal could not be isolated due to its reversibility to the starting materials. In view of these observations, it appears that the interplay of the steric hindrance of the bulky CCl3 group and its relatively poorer nucleofugality, the nucleophilicity and steric environment of the attacking nucleophile, and the reversibility of the tetrahedral intermediate could be the reason for the selectivity observed in the present investigation. Thus, the formation of the tetrahedral intermediate by attack through a phenolic group or phenolate ion could arguably be highly reversible due to considerably higher nucleofugality of the phenolate ion than that of the trichloromethyl anion. This might not be the case when the alcoholic group acted as the nucleophile due to the higher basicity and lower nucleofugality of the alkoxide, thus leading to the formation of the alkyl benzoate through the haloform cleavage in the forward direction. Though Yamada and co-workers8d suggested that higher nucleophilicity of the alcoholic group than phenolic group under neutral conditions was the reason for selective benzoylation of the alcoholic group of phenolic alcohols with twisted amides, this might not be the reason for the selectivity observed in the present case because the reaction conditions would not be considered to be neutral. The primary hydroxy group in aminobenzyl alcohols and 1phenylethane-1,2-diol is sterically less hindered thus getting preferentially engaged in the formation of the tetrahedral intermediate. However, due to considerably higher nucleophilicity of the amino group than the hydroxy group in the aminobenzyl alcohols, benzoylation at the more hindered amino group could not be completely suppressed. The amino group of benzyl amine has the double advantage of being more nucleophilic and less hindered than that of aniline, thus getting benzoylated with overwhelming preference over the amino group of aniline. The observed order of efficiency of the base catalysts (Table 1) is PMDETA (pKa 9.1)>DBU (pKa 12)>DMAP (pKa 9.7)>TMEDA (pKa 8.97), Et3N (pKa 10.8), which is not in order of their base strength, contrary to the expectation on the basis of rate determining basepromoted cleavage of the tetrahedral intermediate. However, if the number of basic sites present in the catalyst and the basicity of the catalyst both are considered in that order of importance, the observed order of catalyst efficiency could be rationalized. A similar observation has been made earlier during a study on kinetics of polyurethane formation in reaction of diethyleneglycol with 2,4-

toluenediisocyanate catalyzed by several tertiary bases.36 In this reaction, the higher efficiency of PMDETA catalyst was rationalized in terms of its multipoint activating interaction through all the three nitrogen atoms with the reactants along the reaction pathway. It is likely that in the present case also PMDETA is playing a similar role. Thus, the high efficiency of PMDETA catalyst in the present benzoylation reactions might be attributed to involvement of probably a halogen bond-assisted assembly of the reactants and the catalyst during the reaction as indicated in Scheme 2, providing the benefits of an intramolecular reaction. A trichloromethyl group is expected to be a good halogen bond donor particularly to the basic nitrogen atoms due to synergistic electron withdrawing effect of the three chlorine atoms.37 The role of halogen bonding in solid state is well known and there is a growing realization that it may assume considerable significance in condensed media as well.37

Ph O O R Cl Cl Cl H Me2N

N

NMe2

Me

proton shifts

Ph OR O Cl Cl Cl H Me2N

N

NMe2

Me

Scheme 2. Halogen bond-assisted catalysis by PMDETA.

3. Conclusion In the presence of a small amount of an inexpensive organocatalyst PMDETA, trichloromethyl phenyl ketone benzoylates alcohols selectively. The reaction displays a wide range of selectivity. Primary as well as secondary alcoholic groups of phenolic alcohols are almost chemospecifically benzoylated in high yields. Selective mono-benzoylation of primary alcoholic group in aminoarylalkanols and primary-secondary diols may also be realized. Primary alkyl amines may be selectively benzoylated in the presence of primary aryl amines with excellent selectivity. The reaction occurs under mild conditions not requiring anhydrous conditions or inert atmosphere. Several sensitive groups, such as carbonecarbon double and triple bonds, epoxide, TBDMS ether, and aryl acetate ester are not disturbed. Only stoichiometric amount of the alcohol is enough for the reaction to proceed with adequate rate at ambient temperatures. The reaction occurs under solvent free conditions in the case of liquid alcohols and only a minimal amount of a solvent just enough to allow stirring is required in the case of solid substrates. The work up procedure is simple due to the formation of the neutral volatile by-product chloroform. It complements effectively and rather supersedes the reported acidcatalyzed methods for benzoylation with inverse selectivity in some respects. The present green reaction is therefore a useful versatile method for selective benzoylation of alcohols. Involvement of a halogen bond-assisted assembly of the substrate, reagent, and catalyst has been proposed as the possible reason for the high efficiency of the reaction. 4. Experimental section 4.1. General remarks IR spectra were recorded on NICOLET 6700 FT-IR spectrometer by taking solid samples as KBr pellets and liquids as thin films on KBr discs. NMR spectra were recorded on Bruker Spectrospin DPX 300 MHz FT NMR spectrometer in CDCl3 with TMS as internal standard. DEPT spectra were routinely recorded to identify different types of carbons. High-resolution mass spectra were recorded on a Bruker, micrOTOF-QII mass spectrometer using electron spray

R.N. Ram et al. / Tetrahedron 68 (2012) 9068e9075

ionization (ESI) in positive ion mode. Melting points were determined on a Melt-Temp apparatus by taking the samples in a glass capillary sealed at one end and are uncorrected. The progress of the reaction was monitored by TLC using a glass plate coated with a TLC grade silica gel. Iodine was used for visualizing the spots. Rf values were determined by performing thin layer chromatography on Merck DC-Alufolien silica gel 60WF254s thin aluminum precoated plates using 30% (v/v) EtOAc in n-hexane as the developing solvent. Column chromatography was performed using flash column chromatography techniques. Silica gel (60e120 mesh) was used as the stationary phase and n-hexane, n-hexane/ethyl acetate mixtures (9e7:1e3 v/v) and chloroform were used as the mobile phase. Trichloromethyl phenyl ketone34 was prepared by the reported method. PMDETA was purchased from SigmaeAldrich and was used as received. 4.2. PMDETA-catalyzed benzoylation of alcohols with trichloromethyl phenyl ketone (1) General procedure: In a 25 mL round bottom flask, trichloromethyl phenyl ketone (0.447 g, 2 mmol), alcohol (2 mmol; 0.077 g, 2.4 mmol in the case of methanol), and PMDETA (0.007 g, 0.04 mmol; 0.035 g, 0.2 mmol in case of secondary alcohols) were taken without any solvent. The flask was stoppered and the mixture was stirred at room temperature (20e25  C) on a magnetic stirrer. The progress of the reaction was monitored by TLC. After the completion of the reaction (10 min to 48 h), the crude reaction mixture was purified by flash column chromatography using n-hexane or ethyl acetate (5e10% v/v) in n-hexane as the solvent for elution to furnish the benzoate esters (Table 2) in 82e96% yield. 4.3. Competition experiments: PMDETA-catalyzed selective benzoylation of benzyl alcohols in the presence of phenols/ aniline with trichloromethyl phenyl ketone (1) General procedure: In a 25 mL round bottom flask were placed benzyl alcohol or substituted benzyl alcohol (2 mmol), the corresponding phenol or aniline (2 mmol), trichloromethyl phenyl ketone (0.447 g, 2 mmol; 0.536 g, 2.4 mmol in the case of aniline), and PMDETA (0.017 g, 0.1 mmol; 0.007 g, 0.04 mmol in case of aniline). Acetonitrile (1 mL) was additionally taken in the case of any solid reactant for smooth stirring. The flask was stoppered and the reaction mixture was stirred at room temperature (20e25  C) on a magnetic stirrer. The progress of the reaction was monitored by TLC. After the completion of the reaction (2e36 h), the crude reaction mixture was purified by flash column chromatography using n-hexane/EtOAc (9:1 v/v) as the solvent for elution to obtain benzyl benzoates 3 in 66e95% yield. Further elution with chloroform afforded recovered phenols 2 (89e91%) or aniline (72%). 4.4. Competition experiment: PMDETA-catalyzed selective benzoylation of benzyl amine in the presence of aniline with trichloromethyl phenyl ketone (1) A solution of benzyl amine (0.214 g, 2 mmol), aniline (0.186 g, 2 mmol), trichloromethyl phenyl ketone (0.447 g, 2 mmol), and PMDETA (0.007 g, 0.04 mmol) in acetonitrile (1 mL) was stirred in a stoppered flask at room temperature (20e25  C) on a magnetic stirrer. The progress of the reaction was monitored by TLC. After the completion of the reaction (30 min), the crude reaction mixture was diluted with 50 mL of EtOAc and washed with 1 N HCl (430 mL). The organic layer was dried (anhyd Na2SO4), filtered, and evaporated under reduced pressure to yield N-benzylbenzamide (0.401 g, 95% yield). The aqueous washings were combined and basified with excess saturated Na2CO3 solution. The basified solution was extracted with EtOAc (50 mL), dried (anhyd Na2SO4),

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and filtered. Evaporation of the solvent under reduced pressure afforded aniline (0.166 g, 89% yield).

4.5. PMDETA-catalyzed selective benzoylation of phenolic alcohols with trichloromethyl phenyl ketone (1) General procedure: Trichloromethyl phenyl ketone (0.447 g, 2 mmol), phenolic alcohol (2 mmol), and PMDETA (0.007 g, 0.04 mmol; 0.035 g, 0.2 mmol in case of entries 4e6) were taken in a 25 mL round bottom flask. To this heterogeneous mixture, acetonitrile (1 mL) was added, the flask was stoppered and the resulting viscous solution was stirred at room temperature (20e25  C) on a magnetic stirrer. The progress of the reaction was monitored by TLC. After the completion of the reaction (12e60 h), the crude reaction mixture was purified by flash column chromatography using n-hexane/EtOAc (7:3 v/v) as the solvent for elution to provide the phenolic alkyl benzoates 4aek in 84e95% yields. The products 4a,26b 4b,38 4c,20a 4i,12 4j,39 4k,40 and 5b41 are known in the literature. 4.5.1. 1-(3-Hydroxyphenyl)ethyl benzoate (4d). Colorless flakes, mp 62  C (n-hexane/CHCl3), 0.416 g, 86% yield; Rf 0.52 (n-hexane/ EtOAc, 7:3 v/v); dH (300 MHz, CDCl3): 8.08 (d, J¼7.2 Hz, 2H, AreH), 7.56 (t, J¼7.5 Hz, 1H, AreH), 7.44 (t, J¼7.5 Hz, 2H, AreH), 7.23 (t, J¼7.8 Hz, 1H, AreH), 7.0 (d, J¼7.5 Hz, 1H, AreH), 6.92 (s, 1H, AreH), 6.76 (dd, J¼8.1 and 1.5 Hz, 1H, AreH), 6.08 (q, J¼6.6 Hz, 1H, ArCH), 5.09 (s, 1H, ArOH), 1.65 (d, J¼6.6 Hz, 3H, CH3) ppm; dC (75.5 MHz, CDCl3): 166.3, 156.0, 143.4, 133.1, 130.2, 129.8, 129.6, 128.4, 118.0, 114.9, 113.0, 73.0, 22.3 ppm; IR (neat): nmax 3405 (br m), 1695(s), 1596(m), 1454(m), 1317(m), 1277(s), 1120(m), 1064(m), 865(m) cm1; HRMS m/z calcd for [C15H14O3þNa]þ: 265.0835, found: 265.0834. 4.5.2. 1-(2-Hydroxyphenyl)ethyl benzoate (4e). White needles, mp 101  C (n-hexane/EtOAc); 0.406 g, 84% yield; Rf 0.54 (n-hexane/ EtOAc, 7:3 v/v); dH (300 MHz, CDCl3): 8.05 (d, J¼7.5 Hz, 2H, AreH), 7.63 (s, 1H, ArOH), 7.57 (t, J¼7.5 Hz, 1H, AreH), 7.41e7.46 (m, 3H, AreH), 7.24 (t, J¼7.5 Hz, 1H, AreH), 6.94e6.98 (m, 2H, AreH), 6.29 (q, J¼6.6 Hz, 1H, ArCH), 1.78 (d, J¼6.6 Hz, 3H, CH3) ppm; dC (75.5 MHz, CDCl3): 167.8, 154.4, 133.4, 130.1, 129.8, 129.5, 128.4, 127.0, 126.6, 120.9, 118.0, 68.5, 19.9 ppm; IR (KBr): nmax 3358(br s), 1693(s), 1602(m), 1451(m), 1289(s), 1123(m), 1052(m), 749(m), 710(m) cm1; HRMS m/z calcd for [C15H14O3þNa]þ: 265.0835, found: 265.0836. 4.5.3. 1-(4-Hydroxyphenyl)ethyl benzoate (4f). Colorless flakes, mp 65  C (n-hexane/CHCl3), 0.415 g, 86% yield; Rf 0.48 (n-hexane/ EtOAc, 7:3 v/v); dH (300 MHz, CDCl3): 8.06 (d, J¼7.2 Hz, 2H, AreH), 7.54 (t, J¼7.2 Hz, 1H, AreH), 7.42 (t, J¼7.2 Hz, 2H, AreH), 7.30 (d, J¼8.4 Hz, 2H, AreH), 6.80 (d, J¼8.4 Hz, 2H, AreH), 6.07 (q, J¼6.6 Hz, 1H, ArCH), 5.94 (s, 1H, ArOH), 1.64 (d, J¼6.6 Hz, 3H, CH3) ppm; dC (75.5 MHz, CDCl3): 166.3, 155.5, 133.5, 133.0, 130.4, 129.6, 128.3, 127.7, 115.3, 73.0, 22.2 ppm; IR (neat): nmax 3399(br m), 1693(s), 1609(m), 1517(s), 1450(m), 1328(m), 1275(s), 1174(m), 1119(m), 1060(m), 832(m), 713(m) cm1; HRMS m/z calcd for [C15H14O3þNa]þ: 265.0835, found: 265.0837. 4.5.4. 4-Hydroxy-3-methoxybenzyl benzoate (4g). Colorless liquid, 0.475 g, 92% yield; Rf 0.49 (n-hexane/EtOAc, 7:3 v/v); dH (300 MHz, CDCl3): 8.06 (d, J¼7.5 Hz, 2H, AreH), 7.55 (t, J¼7.5 Hz, 1H, AreH), 7.42 (t, J¼7.5 Hz, 2H, AreH), 6.91e7.0 (m, 3H, AreH), 5.69 (s, 1H, ArOH), 5.28 (s, 2H, ArCH2), 3.90 (s, 3H, OCH3) ppm; dC (75.5 MHz, CDCl3): 166.5, 146.5, 145.8, 132.9, 130.1, 129.6, 128.3, 127.8, 122.0, 114.4, 111.3, 66.9, 55.9 ppm; IR (neat): nmax 3432(br m), 1714(s), 1606(m), 1517(s), 1458(s), 1374(m), 1273(s), 1159(s), 1114(m),

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1031(m), 714(m) cm1; HRMS m/z calcd for [C15H14O4þNa]þ: 281.0784, found: 281.0784. 4.5.5. 2-Hydroxy-3-methoxybenzyl benzoate (4h). Colorless liquid, 0.470 g, 91% yield; Rf 0.41 (n-hexane/EtOAc, 7:3 v/v); 1H NMR (300 MHz, CDCl3): dH 8.07 (d, J¼7.5 Hz, 2H, AreH), 7.53 (t, J¼7.5 Hz, 1H, AreH), 7.40 (t, J¼7.5 Hz, 2H, AreH), 7.01 (t, J¼7.8 Hz, 1H, AreH), 6.85 (d, J¼5.1 Hz, 2H, AreH), 6.22 (s, 1H, ArOH), 5.44 (s, 2H, ArCH2), 3.87 (s, 3H, OCH3) ppm; dC (75.5 MHz, CDCl3): 166.8, 146.7, 144.2, 132.9, 130.1, 129.7, 128.2, 122.1, 121.8, 119.5, 110.9, 61.9, 56.0 ppm; IR (neat): nmax 3368(br s), 3062(m), 3015(m), 2964(m), 2935(m), 2838(m), 1704(s), 1606(m), 1489(s), 1444(s), 1375(m), 1350(m), 1280(s), 1179(m), 1109(m), 1079(s), 926(m), 781(m), 709(s) cm1; HRMS m/z calcd for [C15H14O4þNa]þ: 281.0784, found: 281.0780. 4.5.6. p-Hydroxycinnamyl benzoate (4k).40 White needles, mp 77  C (n-hexane/EtOAc); 0.463 g, 92% yield; Rf 0.51 (n-hexane/ EtOAc, 7:3 v/v); dH (300 MHz, CDCl3): 8.08 (d, J¼7.5 Hz, 2H, AreH), 7.57 (t, J¼7.5 Hz, 1H, AreH), 7.45 (t, J¼7.5 Hz, 2H, AreH), 7.30 (d, 8.7 Hz, 2H, AreH), 6.8 (d, 8.7 Hz, 2H, AreH), 6.68 (d, 15.9 Hz, 1H, ArCH]CH), 6.26 (td, 15.9, 6.6 Hz, 1H, ArCH]CH), 6.21 (s, 1H, ArOH), 4.96 (d, 6.6 Hz, 2H, ]CHCH2) ppm; dC (75.5 MHz, CDCl3): 166.6, 155.7, 134.1, 133.0, 130.2, 129.6, 129.0, 128.4, 128.1, 120.8, 115.5, 65.9 ppm; IR (KBr): nmax 3369(br s), 1704(s), 1606(m), 1513(m), 1321(m), 1272(s), 1226(s), 1173(m), 1120(m), 968(m), 933(m), 851(m), 710(m) cm1.

3343(m), 1710(s), 1634(m), 1594(m), 1495(m), 1454(m), 1281(s), 1122(m), 1072(m), 774(m), 711(s), 684(m) cm1; HRMS m/z calcd for [C14H13NO2þNa]þ: 250.0838, found: 250.0839. 4.6.2. 3-Benzamidobenzyl benzoate (50 a). White needles, mp 82  C (n-hexane/CHCl3); 0.092 g, 14% yield; Rf 0.39 (n-hexane/EtOAc, 7:3 v/v); dH (300 MHz, CDCl3): 8.07 (d, J¼7.8 Hz, 2H, AreH), 8.06 (s, 1H, ArNH), 7.86 (d, J¼7.2 Hz, 2H, AreH), 7.73 (s, 1H, AreH), 7.67 (d, J¼7.8 Hz, 1H, AreH), 7.34e7.57 (m, 7H, AreH), 7.23 (t, J¼7.5 Hz, 1H, AreH), 5.34 (s, 2H, ArCH2) ppm; dC (75.5 MHz, CDCl3): 166.4, 165.9, 138.2, 137.0, 134.8, 133.1, 131.9, 129.9, 129.7, 129.3, 128.7, 128.4, 127.0, 124.1, 120.1, 119.8, 66.4 ppm; IR (KBr): nmax 3348(m), 1719(s), 1664(s), 1609(m), 1538(s), 1489(m), 1450(m), 1368(m), 1317(m), HRMS m/z calcd for 1276(s), 1114(m), 713(s) cm1; [C21H17NO3þNa]þ: 354.1101, found: 354.1092. 4.6.3. 4-Aminobenzyl benzoate (5b).41 Colorless flakes, mp 45  C (n-hexane/EtOAc); 0.344 g, 76% yield; Rf 0.37 (n-hexane/EtOAc, 7:3 v/v); dH (300 MHz, CDCl3): 8.04 (d, J¼7.5 Hz, 2H, AreH), 7.50 (t, J¼7.5 Hz, 1H, AreH), 7.38 (t, J¼7.5 Hz, 2H, AreH), 7.23 (d, J¼8.4 Hz, 2H, AreH), 6.64 (d, J¼8.4 Hz, 2H, AreH), 5.22 (s, 2H, ArCH2), 3.73 (s, 2H, ArNH2) ppm; dC (75.5 MHz, CDCl3): 166.5, 146.6, 132.7, 130.2, 130.0, 129.5, 128.2, 125.5, 114.8, 66.8 ppm; IR (KBr): nmax 3443(w, sh), 3375(m), 1710(s), 1618(m), 1520(m), 1318(m), 1272(s), 1177(m), 1110(m), 822(m), 713(m) cm1.

4.5.7. (3-Benzoyloxymethyl-2-hydroxy-5-methyl)benzyl benzoate (4l). Colorless liquid, 0.692 g, 92%; Rf 0.54 (n-hexane/EtOAc, 7:3 v/v); dH (300 MHz, CDCl3): 8.56 (s, 1H, ArOH), 8.06 (d, J¼7.5 Hz, 4H, AreH), 7.53 (t, J¼7.5 Hz, 2H, AreH), 7.40 (t, J¼7.5 Hz, 4H, AreH), 7.20 (s, 2H, AreH), 5.39 (s, 4H, ArCH2), 2.28 (s, 3H, CH3) ppm; dC (75.5 MHz, CDCl3): 167.8, 151.9, 133.2, 132.6, 129.8, 129.6, 129.4, 128.3, 123.2, 63.1, 20.3 ppm; IR (neat): nmax 3267(br m), 1718(s), 1688(s), 1487(m), 1454(m), 1376(m), 1275(s), 1111(s), 713(s) cm1; HRMS m/z calcd for [C23H20O5þNa]þ: 399.1203, found: 399.1191.

4.6.4. 4-Benzamidobenzyl benzoate (50 b). White needles, mp 86  C (n-hexane/CHCl3); 0.086 g, 13% yield; Rf 0.41 (n-hexane-EtOAc, 7:3 v/v); dH (300 MHz, CDCl3): 8.06 (d, J¼7.8 Hz, 2H, AreH), 8.05 (s, 1H, ArNH), 7.86 (d, J¼7.2 Hz, 2H, AreH), 7.67 (d, J¼8.4 Hz, 2H, AreH), 7.40e7.58 (m, 8H, AreH), 5.33 (s, 2H, ArCH2) ppm; dC (75.5 MHz, CDCl3): 166.5, 165.8, 138, 134.7, 133.0, 132.0, 131.9, 130.0, 129.6, 129.2, 128.7, 128.3, 127.0, 120.3, 66.3 ppm; IR (KBr): nmax 3342(m), 1719(s), 1653(s), 1600(m), 1518(s), 1409(m), 1316(m), 1279(s), 1114(m), 826(m), 711(m) cm1; HRMS m/z calcd for [C21H17NO3þNa]þ: 354.1101, found: 354.1102.

4.6. PMDETA-catalyzed selective benzoylation of 3- and 4aminobenzyl alcohols with trichloromethyl phenyl ketone (1)

4.7. PMDETA-catalyzed selective mono-benzoylation of 1phenylethane-1,2-diol with trichloromethyl phenyl ketone (1)

General procedure: In a 25 mL round bottom flask, trichloromethyl phenyl ketone (0.536 g, 2.4 mmol), 3- or 4aminobenzyl alcohol (2 mmol), and PMDETA (0.007 g, 0.04 mmol) were taken. To this heterogeneous mixture, acetonitrile (1 mL) was added and the solution was stirred at room temperature (20e25  C) on a magnetic stirrer. The progress of the reaction was monitored by TLC. After the completion of the reaction (2 h), the crude reaction mixture was diluted with 50 mL of Et2O/EtOAc (1:1 v/v) mixture and washed with 1 N HCl (430 mL). The organic layer was dried (anhyd Na2SO4), filtered, and evaporated under reduced pressure to yield m- or p- benzimidobenzyl benzoate in 14 or 13% yield, respectively. The aqueous washings were combined and basified with excess saturated Na2CO3 solution. The basified solution was extracted with EtOAc (50 mL), the organic layer was washed with brine (30 mL), dried (anhyd Na2SO4), and filtered. Evaporation of the solvent under reduced pressure afforded pure 3- or 4aminobenzyl benzoate in 78 or 76% yield, respectively.

To a mixture of trichloromethyl phenyl ketone (0.447 g, 2 mmol), 1-phenylethane-1,2-diol (0.276 g, 2 mmol), and PMDETA (0.007 g, 0.04 mmol) was added acetonitrile (1 mL) and the viscous solution was stirred in a stoppered 25 mL flask at room temperature (20e25  C) on a magnetic stirrer. The progress of the reaction was monitored by TLC. After the completion of the reaction (14 h), the crude reaction mixture was purified by flash column chromatography using n-hexane/EtOAc (9:1 v/v) as the solvent for elution to furnish 2-hydroxy-2-phenylethyl benzoate42 (0.446 g, 92%).

4.6.1. 3-Aminobenzyl benzoate (5a). Colorless flakes, mp 46  C (n-hexane/EtOAc); 0.354 g, 78% yield; Rf 0.38 (n-hexane/EtOAc, 7:3 v/v); dH (300 MHz, CDCl3): 8.09 (d, J¼7.5 Hz, 2H, AreH), 7.56 (t, J¼7.5 Hz, 1H, AreH), 7.44 (t, J¼7.5 Hz, 2H, AreH), 7.17 (t, J¼7.2 Hz, 1H, AreH), 6.84 (d, J¼7.5 Hz, 1H, AreH), 6.77(s, 1H, AreH), 6.67 (d, J¼7.5 Hz, 1H, Are), 5.28 (s, 2H, ArCH2), 3.72 (s, 2H, ArNH2) ppm; dC (75.5 MHz, CDCl3): 166.3, 146.6, 137.0, 132.9, 130.0, 129.5, 129.4, 128.2, 117.9, 114.7, 114.4, 66.6 ppm; IR (KBr): nmax 3426(m),

Acknowledgements We are thankful to the University Grant Commission, New Delhi and the Council of Scientific Research, New Delhi for research fellowships to V.K.S. and D.K.G., respectively. References and notes 1. (a) Santos, V. A. F. F. M.; Regasini, L. O.; Nogueira, C. R.; Passerini, G. D.; Martinez, I.; Bolzani, V. S.; Graminha, M. A. S.; Cicarelli, R. M. B.; Furlan, M. J. Nat. Prod. 2012, 75, 991e995; (b) Harrar, K.; Reiser, O. Chem. Commun. 2012, 3457e3459; (c) Ramesh, P.; Meshram, H. M. Tetrahedron Lett. 2011, 52, 2443e2445; (d) Ogawa, Y.; Oku, H.; Iwaoka, E.; Iinuma, M.; Ishiguro, K. J. Nat. nard, D.; Gue ritte-Voegelein, F.; Potier, P. Acc. Prod. 2006, 69, 1215e1217; (e) Gue Chem. Res. 1993, 26, 160e167; (f) Schlessinger, R. H.; Lopes, A. J. Org. Chem. 1981, 46, 5252e5253. 2. (a) Manach, C. L.; Baron, A.; Guillot, R.; Vauzeilles, B.; Beau, J.-M. Tetrahedron rez, T.; Fern Lett. 2011, 52, 1462e1465; (b) Rodríguez-Pe andez, S.; Martínez-

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