Tetrahedron Letters 53 (2012) 5131–5135

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Tetrahedron Letters

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Synthesis of diarylmethanes via a Friedel–Crafts benzylation using arenesand benzyl alcohols in the presence of triphenylphosphine ditriflate

Mohammad Mehdi Khodaei ⇑, Ehsan NazariDepartment of Organic Chemistry and Nanoscience & Nanotechnology Research Center (NNRC), Razi University, Kermanshah 67149, Iran

a r t i c l e i n f o

Article history:Received 14 May 2012Revised 26 June 2012Accepted 11 July 2012Available online 20 July 2012

Keywords:ArenesBenzylationElectrophilic aromatic substitutionMitsunobu reactionPhosphorus

0040-4039/$ - see front matter � 2012 Elsevier Ltd. Ahttp://dx.doi.org/10.1016/j.tetlet.2012.07.051

⇑ Corresponding author.E-mail address: mmkhoda@razi.ac.ir (M.M. Khoda

a b s t r a c t

Triphenylphosphine ditriflate (TPPD) was found to be an efficient promoter for the Friedel–Crafts benzy-lation of arenes with benzyl alcohols in CH2Cl2 at room temperature. The good yields, the 1:1 molar ratioof arene and benzyl alcohol, the benzylation of chlorobenzene as a nonactivated aromatic compound atroom temperature, and no by-product formation are the main advantages of this procedure.

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Friedel–Crafts (FC) benzylation is one of the fundamental meth-ods in organic synthesis for the preparation of a wide variety ofdiarylalkanes, which are very useful intermediates in petrochemi-cals, cosmetics, dyes, pharmaceuticals, and many other chemicalindustries.1 FC benzylation with benzyl alcohols2 has attractedattention since benzyl alcohols are more preferable than otherbenzylating reagents. The use of benzyl alcohol instead of benzylchloride in this reaction is an ecofriendly process.1 Benzyl alcoholsare also superior to benzyl acetates3 and styrene derivatives,4 sincemodified substrates are not involved and benzyl alcohols are moreeasily available.

Despite the tremendous success of the published methodsapplying benzyl alcohols, some drawbacks still remain. For exam-ple, the use of a large amount of aromatic compound, not only asthe substrate, but also as the reaction medium, reflux conditionsor high temperatures, long reaction times, the use of rare and expen-sive metal catalysts, and the formation of dibenzyl ether (DBE) as aby-product remain problematic. Therefore, to minimize theseproblems, the development of new methodologies is desirable.

Trifluoromethanesulfonic anhydride (Tf2O) is commerciallyavailable and known for its utility for the conversion of an OHgroup into an OTf leaving group.5 Although Tf2O is expensive, ithas been widely used as a powerful promoter in different organicreactions.6

Tf2O reacts exothermically with Ph3PO in CH2Cl2 to give a whiteprecipitate of the corresponding triphenylphosphine ditriflate

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ei).

(TPPD) or diphosphonium triflate (DPT).7 These salts, commonlycalled Hendrickson’s reagents, were shown to be powerful dehy-drating agents and promoters, and promising reagents for some or-ganic reactions.7,8 In comparison with DPT, however, the potentialof TPPD as a promoter has been less developed.

As part of our ongoing efforts to develop FC reactions,9 we re-port an efficient protocol in which TPPD (produced by addition ofTf2O to Ph3PO with the same equivalents at 0 �C to room tempera-ture) has been used as a promoter for the FC benzylation of areneswith benzyl alcohols in CH2Cl2 at room temperature (Scheme 1).

To optimize the reaction conditions, mesitylene (1 mmol) andbenzyl alcohol (1 mmol), as model substrates, were reacted inthe presence of 1, 1.2, and 1.4 mmol of TPPD in 1 mL of CH2Cl2 atroom temperature. The best result was obtained by carrying outthe reaction with a 1:1:1.2 molar ratio of arene, alcohol, and TPPDfor 0.5 h. When 1.4 mmol of TPPD was used, the results did notshow any noticeable differences with respect to the yield and reac-tion time. A control experiment conducted without Ph3PO showedthat the reaction did not take place, and the mesitylene remainedunreacted at the end of the reaction.

In order to study the scope and limitations of this procedure,several arenes were reacted with various benzyl alcohols accordingto the optimized reaction conditions, and the results are presentedin Table 1. The reaction of mesitylene with 4-chloro- and 4-nitro-benzyl alcohol afforded the corresponding diarylmethanes in 87%and 75% yields, respectively (Table 1, entries 2 and 3). In addition,the three isomers of xylene were treated under the same condi-tions. Except for the case of p-xylene, the other isomers affordedmixtures of two products (Table 1, entries 6–8). According to these

HR1

+ HO

R3

R2

PPh

PhPh

OTf

TPPD

CH2Cl2, 0 oC to rt

R3R1

R2

R1 = H, Me, n-Bu, i-Pr, Et, ClR2 = H, Cl, NO2

R3 = H, Me

TfO

Scheme 1. TPPD-Promoted benzylation of arenes.

Table 1TPPD-Promoted benzylation of arenes with primary benzyl alcohols

HO

R

R = H, Cl, NO2

ArH +

Entry ArH R Major product

1

Me

MeMe

H

Me

Me Me

2 Cl

Me

Me Me Cl

3 NO2

Me

Me Me NO2

4

Me

Me

H

Me

Me

5 Cl

Me

MeCl

6

Me

Me

H

Me

Me

7Me

MeH

Me

Me

8 ClMe

Me

Cl

9

Me

H Me

10 ClMe Cl

11

i-Pr

H i-Pr

12

n-Bu

H n-Bu

5132 M. M. Khodaei, E. Nazari / Tetrahedron Letters 53 (2012) 5131–5135

results, applying different benzyl alcohols did not have a noticeableimpact on the selectivity and the yields, while in the case of reac-tion time, benzyl alcohol reacted faster than 4-chlorobenzylalcohol.

The reactivity of mono-substituted arenes such as toluene, cu-mene and n-butyl benzene was examined. The reaction of toluenewith benzyl alcohol and 4-chlorobenzyl alcohol afforded a mixtureof ortho and para isomers in 84% and 80% yields, and the p:o ratioswere 58:42 and 54:46, ‘respectively’ (Table 1, entries 9 and 10). Inthe cases of cumene and n-butyl benzene, the para selectivity couldbe improved (Table 1, entries 11 and 12). The reactions of 1- and 2-methylnaphthalenes with benzyl alcohol produced mixtures of

Ar

R

TPPD

Time (h) Yielda (%) Selectivityb (%) Ref.

0.5 90 100 10

1 87 100 2 g

5 75 100 11

1 79 100 12

1.5 80 100 13

0.5 83 76:24c 10

0.5 80 62:38d 12

1 78 60:40e 3b

0.5 84 58:42f 12

1 80 54:46f 14

0.5 82 66:34f 15

0.5 83 60:40f 16

Table 1 (continued)

Entry ArH R Major product Time (h) Yielda (%) Selectivityb (%) Ref.

13

Cl

H Cl 2g 64 69:31f 15

14 S Cl

S

Cl

0.08 75 57:43h 13

15

OH

H — 0.5 — — —

16

NH2

H — 0.5 — — —

a Isolated yield.b Regioselectivity was determined by 1H NMR spectroscopy and by comparison with literature data.c 2-Benzyl-1,3-dimethylbenzene was obtained as the minor product.d 3-Benzyl-1,2-dimethylbenzene was obtained as the minor product.e 3-(4-Chlorobenzyl)-1,2-dimethylbenzene was obtained as the minor product.f Ratio = para:ortho.g 3 mmol of chlorobenzene was used.h 3-(4-Chlorobenzyl)-thiophene was obtained as the minor product.

Table 2TPPD-Benzylation of arenes with 1-phenylethanol

HO ArArH +

Me MeTPPD

Entry ArH Major product Time (h) Yield (%)a Selectivityb (%) Ref.

1

Me

MeMe Me

MeMe

Me

0.5 88 100 17

2

Me

Me

MeMe

Me

1 81 100 12

3 Me

Me

Me

MeMe

1 79 100 2f

4

Me

Me Me

MeMe

1 80 100 18

5

Me Me

Me

0.5 87 91:9c 12

6

Et Me

Et

0.5 85 93:7c 19

7

i-Pr Me

i-Pr

0.5 84 100 20

8 S

S

Me

0.08 68 50:50d 2f

(continued on next page)

M. M. Khodaei, E. Nazari / Tetrahedron Letters 53 (2012) 5131–5135 5133

Table 2 (continued)

Entry ArH Major product Time (h) Yield (%)a Selectivityb (%) Ref.

9

OH

— 0.5 — — –

10

NH2

— 0.5 — — —

a Isolated yield.b Regioselectivity was determined by 1H NMR spectroscopy and by comparison with literature data.c Ratio = para:ortho.d Mixture of 2- and 3-isomers.

Scheme 2. Proposed reaction mechanism.

Table 3The results of recycling experiments of Ph3PO in the FC benzylation of mesitylenewith benzyl alcohol

Cycle Recovered Ph3PO (%) Yielda (%)

1 87 902 84 863 83 864 81 85

a Isolated yield of the desired diarylmethane.

5134 M. M. Khodaei, E. Nazari / Tetrahedron Letters 53 (2012) 5131–5135

products that were difficult to separate; after laborious separation,we did not achieve acceptable yields of the corresponding diary-lmethanes. It is noted that chlorobenzene as a nonactivated aro-matic compound could be benzylated with benzyl alcohol underthe reported reaction conditions (Table 1, entry 13). To our knowl-edge, there are no reports on the benzylation of chlorobenzenewith benzyl alcohols at room temperature. The reaction of benzo-nitrile with benzyl alcohol did not yield the desired diarylmethane,instead the product was N-benzyl-benzamide; this observation isin accordance with the Ritter reaction,21 producing amides fromnitriles and alcohols.

Thiophene, as a representative heterocyclic compound, reactedwith 4-chlorobenzyl alcohol under the described conditions and amixture of 2- and 3-benzylated isomers was obtained in 75% yield(Table 1, entry 14).

The reactions of aromatic compounds with heteroatom func-tional groups were also investigated under the present reactionconditions. Unfortunately, the reactions of phenol and aniline (Ta-ble 1, entries 15 and 16), and N,N-dimethylaniline were accompa-nied with the formation of several by-products, and efforts toobtain the corresponding diarylmethanes were not successful.Similarly, benzoic acid and methyl benzoate did not react underthe present conditions. It appears that this protocol does not workwith compounds having active and nucleophilic heteroatoms dueto the presence of the positively charged phosphorus of TPPD.

It should be noted that in all cases, the formation of dibenzylether (DBE) was not detected. This indicates that the benzyl alco-hols were efficiently trapped with TPPD, and therefore did not re-act with each other to produce DBE.

In the other part of this work, we utilized 1-phenylethanol as abenzylating reagent for the FC benzylation of a variety of arenes inCH2Cl2 at room temperature, and the results are summarized in Ta-ble 2. The molar ratio of arene to 1-phenylethanol to TPPD (1:1:1.2)was found to be optimum. In contrast to the reactions of ortho andmeta xylenes with primary benzyl alcohols, the above xylenes re-acted regiospecifically with 1-phenylethanol and produced onlyone product (Table 2, entries 3 and 4). The reaction of toluene un-der the same conditions gave a mixture of ortho and para isomersin 87% yield in which the desired p-isomer was obtained in 91%along with 9% of the o-isomer (Table 2, entry 5). When ethyl ben-zene was reacted with 1-phenylethanol in the presence of TPPD,the corresponding diarylethanes were produced in 85% yield witha para:ortho ratio of 93:7. Interestingly, the FC benzylation ofcumene occurred with the complete p-selectivity (Table 2, entry7). Again, the reactions of 1- and 2-methylnaphthalenes wereaccompanied by the formation of several by-products, and thecorresponding diarylethanes were not obtained. Unfortunately, inthe case of chlorobenzene, we did not obtain the desired product.However, thiophene yielded a mixture of 2- and 3-substitutedisomers in an equal ratio. Attempted reactions of phenol, aniline,

N,N-dimethylaniline, benzoic acid and methyl benzoate wereunsuccessful under the present conditions. Similar to benzyl alco-hols, 1-phenylethanol did not afford the corresponding ether dur-ing the reaction.

A proposed reaction mechanism is outlined in Scheme 2. Nucle-ophilic attack of Ph3PO on Tf2O leads to TPPD in which the phos-phonium cation is ready to accept a nucleophilic alcohol and thetriflate leaving group is ready to exit. Subsequent replacement oftriflate with the oxygen of the benzyl alcohol produces intermedi-ate 1. Next, nucleophilic attack of the arene on intermediate 1 leadsto elimination of Ph3PO and yields the desired diarylalkane.

The above mechanism is presented according to the Mitsunobu-type reaction mechanism in which the nucleophile attacks viaSN2.22 In order to test this mechanism, we used R-(+)-1-phenyleth-anol for the benzylation of mesitylene. It was found that the ob-tained corresponding diarylmethane was optically active withnegative optical rotation.

Based on the proposed mechanism shown in Scheme 2, Ph3POwould be recoverable at the end of the reaction. We investigatedthis and found that Ph3PO could be recovered and successfully recy-cled and reused four times (Table 3). It is noteworthy that after eachcycle, Ph3PO was not modified and did not require reactivation.

Accordingly, we surmised that Ph3PO could be used in catalyticamount, and therefore we utilized 10 mol % of Ph3PO and 1.2 mmol

M. M. Khodaei, E. Nazari / Tetrahedron Letters 53 (2012) 5131–5135 5135

of Tf2O for the benzylation of mesitylene (1 mmol) with benzylalcohol (1 mmol), however, the results did not show significantbenzylation of mesitylene. It seems that the excess amount ofTf2O leads to an unwanted reaction with benzyl alcohol. Therefore,using the same equivalents of Tf2O and Ph3PO is necessary for thesuccess of this type of FC benzylation.

In summary, TPPD is an extremely efficient promoter for theFC-benzylation of a variety of arenes. The good yields, use of a1:1 molar ratio of arene and benzyl alcohol, mild reaction condi-tions, metal-free conditions, room temperature reactions,23 andno formation of by-products such as DBE are the main advantagesof the described method.

Acknowledgments

We thank Razi University for generous financial support of thiswork and Mr. Mehdi Sheikh-Arabi for his constructive help.

Supplementary data

Supplementary data associated with this article can be found, inthe online version, at http://dx.doi.org/10.1016/j.tetlet.2012.07.051.

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23. General procedure for the benzylation of arenes: To a solution of Ph3PO (0.33 g,1.2 mmol) in CH2Cl2 (1 mL), Tf2O (0.2 mL, 1.2 mmol) was added at 0 �C and thesolution was stirred for 15 min at room temperature. Then, arene (1 mmol) andbenzyl alcohol (1 mmol) were added to the reaction mixture and the mixturewas stirred for the appropriate time shown in Tables 1 and 2. Upon completionof the reaction, the organic solvent was evaporated and the crude product waspurified by column chromatography using n-hexane as eluent to give thediarylmethane. In the case of 4-nitrobenzyl alcohol, EtOAc/n-hexane (1:9) wasused as the eluent.