Synthesis of diarylmethanes via a Friedel-Crafts benzylation using arenes and benzyl alcohols in the presence of triphenylphosphine ditriflate

Article abstract of DOI:10.1016/j.tetlet.2012.07.051

Triphenylphosphine ditriflate (TPPD) was found to be an efficient promoter for the Friedel-Crafts benzylation of arenes with benzyl alcohols in CH ₂Cl₂ at room temperature. The good yields, the 1:1 molar ratio of arene and benzyl alcohol, the benzylation of chlorobenzene as a nonactivated aromatic compound at room temperature, and no by-product formation are the main advantages of this procedure.

Full text of DOI:10.1016/j.tetlet.2012.07.051

Tetrahedron Letters 53 (2012) 5131–5135
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of diarylmethanes via a Friedel–Crafts benzylation using arenes
and benzyl alcohols in the presence of triphenylphosphine ditriflate
⇑
Mohammad Mehdi Khodaei , Ehsan Nazari
Department 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
a b s t r a c t
Article history:
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 ratio
of arene and benzyl alcohol, the benzylation of chlorobenzene as a nonactivated aromatic compound at
room temperature, and no by-product formation are the main advantages of this procedure.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 14 May 2012
Revised 26 June 2012
Accepted 11 July 2012
Available online 20 July 2012
Keywords:
Arenes
Benzylation
Electrophilic aromatic substitution
Mitsunobu reaction
Phosphorus
Friedel–Crafts (FC) benzylation is one of the fundamental meth-
ods in organic synthesis for the preparation of a wide variety of
diarylalkanes, which are very useful intermediates in petrochemi-
cals, cosmetics, dyes, pharmaceuticals, and many other chemical
industries.1 FC benzylation with benzyl alcohols2 has attracted
attention since benzyl alcohols are more preferable than other
benzylating reagents. The use of benzyl alcohol instead of benzyl
chloride in this reaction is an ecofriendly process.1 Benzyl alcohols
are also superior to benzyl acetates3 and styrene derivatives,4 since
modified substrates are not involved and benzyl alcohols are more
easily available.
Despite the tremendous success of the published methods
applying benzyl alcohols, some drawbacks still remain. For exam-
ple, the use of a large amount of aromatic compound, not only as
the substrate, but also as the reaction medium, reflux conditions
or high temperatures, long reaction times, the use of rare and expen-
sive metal catalysts, and the formation of dibenzyl ether (DBE) as a
by-product remain problematic. Therefore, to minimize these
problems, the development of new methodologies is desirable.
Trifluoromethanesulfonic anhydride (Tf2O) is commercially
available and known for its utility for the conversion of an OH
group into an OTf leaving group.5 Although Tf2O is expensive, it
has been widely used as a powerful promoter in different organic
reactions.6
(TPPD) or diphosphonium triflate (DPT).7 These salts, commonly
called 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 potential
of 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 of
Tf2O to Ph3PO with the same equivalents at 0 °C to room tempera-
ture) has been used as a promoter for the FC benzylation of arenes
with benzyl alcohols in CH2Cl2 at room temperature (Scheme 1).
To optimize the reaction conditions, mesitylene (1 mmol) and
benzyl alcohol (1 mmol), as model substrates, were reacted in
the presence of 1, 1.2, and 1.4 mmol of TPPD in 1 mL of CH2Cl2 at
room temperature. The best result was obtained by carrying out
the reaction with a 1:1:1.2 molar ratio of arene, alcohol, and TPPD
for 0.5 h. When 1.4 mmol of TPPD was used, the results did not
show any noticeable differences with respect to the yield and reac-
tion time. A control experiment conducted without Ph3PO showed
that the reaction did not take place, and the mesitylene remained
unreacted 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 according
to the optimized reaction conditions, and the results are presented
in 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 afforded
mixtures of two products (Table 1, entries 6–8). According to these
Tf2O reacts exothermically with Ph3PO in CH2Cl2 to give a white
precipitate of the corresponding triphenylphosphine ditriflate
⇑
Corresponding author.
E-mail address: mmkhoda@razi.ac.ir (M.M. Khodaei).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.07.051

5132
M. M. Khodaei, E. Nazari / Tetrahedron Letters 53 (2012) 5131–5135
results, applying different benzyl alcohols did not have a noticeable
Ph
Ph P OTf
Ph
impact on the selectivity and the yields, while in the case of reac-
tion time, benzyl alcohol reacted faster than 4-chlorobenzyl
alcohol.
TfO
R3
R3
R1
R1
TPPD
H
HO
The reactivity of mono-substituted arenes such as toluene, cu-
mene and n-butyl benzene was examined. The reaction of toluene
with benzyl alcohol and 4-chlorobenzyl alcohol afforded a mixture
of ortho and para isomers in 84% and 80% yields, and the p:o ratios
were 58:42 and 54:46, ‘respectively’ (Table 1, entries 9 and 10). In
the cases of cumene and n-butyl benzene, the para selectivity could
be improved (Table 1, entries 11 and 12). The reactions of 1- and 2-
methylnaphthalenes with benzyl alcohol produced mixtures of
+
CH2Cl2, 0 oC to rt
R2
R2
R1 = H, Me, n-Bu, i-Pr, Et, Cl
R
2 = H, Cl, NO2
R3 = H, Me
Scheme 1. TPPD-Promoted benzylation of arenes.
Table 1
TPPD-Promoted benzylation of arenes with primary benzyl alcohols
TPPD
HO
Ar
ArH
+
R
R
R = H, Cl, NO2
Entry
1
ArH
R
Major product
Time (h)
0.5
Yielda (%)
90
Selectivityb (%)
100
Ref.
10
Me
Me
H
Me
Me
Me
Me
Me
Me
Me
Me
2
3
Cl
1
5
87
75
100
100
2 g
11
Me
Me
Cl
NO2
NO2
Me
Me
4
H
1
79
100
12
Me
Me
Me
5
6
Cl
H
1.5
0.5
80
83
100
13
10
Cl
Me
Me
Me
76:24c
Me
Me
Me
Me
7
8
H
0.5
1
80
78
62:38d
60:40e
12
3b
Me
Me
Me
Cl
Me
Me
Cl
Cl
Me
9
10
11
H
Cl
H
0.5
1
84
80
82
58:42f
54:46f
66:34f
12
14
15
Me
i-Pr
0.5
i-Pr
n-Bu
12
H
0.5
83
60:40f
16
n-Bu

M. M. Khodaei, E. Nazari / Tetrahedron Letters 53 (2012) 5131–5135
5133
Table 1 (continued)
Entry
ArH
R
Major product
Time (h)
2g
Yielda (%)
64
Selectivityb (%)
69:31f
Ref.
Cl
13
14
H
15
13
Cl
Cl
Cl
0.08
75
57:43h
S
S
OH
15
16
H
H
—
0.5
0.5
—
—
—
—
—
—
NH2
—
a
Isolated yield.
b
Regioselectivity was determined by 1H NMR spectroscopy and by comparison with literature data.
2-Benzyl-1,3-dimethylbenzene was obtained as the minor product.
3-Benzyl-1,2-dimethylbenzene was obtained as the minor product.
3-(4-Chlorobenzyl)-1,2-dimethylbenzene was obtained as the minor product.
Ratio = para:ortho.
c
d
e
f
g
h
3 mmol of chlorobenzene was used.
3-(4-Chlorobenzyl)-thiophene was obtained as the minor product.
Table 2
TPPD-Benzylation of arenes with 1-phenylethanol
Me
Me
TPPD
HO
Ar
ArH
+
Entry
1
ArH
Major product
Time (h)
0.5
Yield (%)a
Selectivityb (%)
100
Ref.
17
Me
Me Me
88
81
Me
Me
Me
Me Me
Me
Me
2
1
100
12
Me
Me
Me
Me
Me Me
Me
Me
3
4
5
6
1
79
80
87
85
100
2f
Me
Me
Me
Me
Et
Me
1
100
18
12
19
Me
Me
0.5
0.5
91:9c
93:7c
Et
Me
i
-Pr
Me
7
8
0.5
84
68
100
20
2f
i-Pr
Me
50:50d
S
0.08
S
(continued on next page)

5134
M. M. Khodaei, E. Nazari / Tetrahedron Letters 53 (2012) 5131–5135
Table 2 (continued)
Entry
ArH
OH
Major product
—
Time (h)
0.5
Yield (%)a
—
Selectivityb (%)
—
Ref.
–
9
NH2
10
—
0.5
—
—
—
a
Isolated yield.
b
Regioselectivity was determined by 1H NMR spectroscopy and by comparison with literature data.
c
Ratio = para:ortho.
Mixture of 2- and 3-isomers.
d
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 under
the reported reaction conditions (Table 1, entry 13). To our knowl-
edge, there are no reports on the benzylation of chlorobenzene
with 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 is
in accordance with the Ritter reaction,21 producing amides from
nitriles and alcohols.
Thiophene, as a representative heterocyclic compound, reacted
with 4-chlorobenzyl alcohol under the described conditions and a
mixture of 2- and 3-benzylated isomers was obtained in 75% yield
(Table 1, entry 14).
Scheme 2. Proposed reaction mechanism.
Table 3
The reactions of aromatic compounds with heteroatom func-
tional groups were also investigated under the present reaction
conditions. 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 to
obtain the corresponding diarylmethanes were not successful.
Similarly, benzoic acid and methyl benzoate did not react under
the present conditions. It appears that this protocol does not work
with compounds having active and nucleophilic heteroatoms due
to the presence of the positively charged phosphorus of TPPD.
It should be noted that in all cases, the formation of dibenzyl
ether (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.
The results of recycling experiments of Ph3PO in the FC benzylation of mesitylene
with benzyl alcohol
Cycle
Recovered Ph3PO (%)
Yielda (%)
1
2
3
4
87
84
83
81
90
86
86
85
a
Isolated yield of the desired diarylmethane.
N,N-dimethylaniline, benzoic acid and methyl benzoate were
unsuccessful under the present conditions. Similar to benzyl alco-
hols, 1-phenylethanol did not afford the corresponding ether dur-
ing the reaction.
In the other part of this work, we utilized 1-phenylethanol as a
benzylating reagent for the FC benzylation of a variety of arenes in
CH2Cl2 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 and
meta xylenes with primary benzyl alcohols, the above xylenes re-
acted regiospecifically with 1-phenylethanol and produced only
one product (Table 2, entries 3 and 4). The reaction of toluene un-
der the same conditions gave a mixture of ortho and para isomers
in 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 with
a para:ortho ratio of 93:7. Interestingly, the FC benzylation of
cumene occurred with the complete p-selectivity (Table 2, entry
7). Again, the reactions of 1- and 2-methylnaphthalenes were
accompanied by the formation of several by-products, and the
corresponding diarylethanes were not obtained. Unfortunately, in
the case of chlorobenzene, we did not obtain the desired product.
However, thiophene yielded a mixture of 2- and 3-substituted
isomers in an equal ratio. Attempted reactions of phenol, aniline,
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 the
triflate leaving group is ready to exit. Subsequent replacement of
triflate with the oxygen of the benzyl alcohol produces intermedi-
ate 1. Next, nucleophilic attack of the arene on intermediate 1 leads
to 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 via
SN2.22 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 with
negative optical rotation.
Based on the proposed mechanism shown in Scheme 2, Ph3PO
would be recoverable at the end of the reaction. We investigated
this and found that Ph3PO could be recovered and successfully recy-
cled and reused four times (Table 3). It is noteworthy that after each
cycle, Ph3PO was not modified and did not require reactivation.
Accordingly, we surmised that Ph3PO could be used in catalytic
amount, and therefore we utilized 10 mol % of Ph3PO and 1.2 mmol

M. M. Khodaei, E. Nazari / Tetrahedron Letters 53 (2012) 5131–5135
5135
1495–1498; (g) Chu, C. M.; Huang, W. J.; Liu, J. T.; Yao, C. F. Tetrahedron Lett.
2007, 48, 6881–6885.
5. Effenberger, F. Angew. Chem. 1980, 92, 147–232.
6. Baraznenok, I. L.; Nenajdenko, V. G.; Balenkova, E. S. Tetrahedron 2000, 56,
3077–3119.
of Tf2O for the benzylation of mesitylene (1 mmol) with benzyl
alcohol (1 mmol), however, the results did not show significant
benzylation of mesitylene. It seems that the excess amount of
Tf2O leads to an unwanted reaction with benzyl alcohol. Therefore,
using the same equivalents of Tf2O and Ph3PO is necessary for the
success of this type of FC benzylation.
In summary, TPPD is an extremely efficient promoter for the
FC-benzylation of a variety of arenes. The good yields, use of a
1:1 molar ratio of arene and benzyl alcohol, mild reaction condi-
tions, metal-free conditions, room temperature reactions,23 and
no formation of by-products such as DBE are the main advantages
of the described method.
7. (a) Hendrickson, J. B.; Schwartzman, S. M. Tetrahedron Lett. 1975, 16, 277–280;
(b) Crich, D.; Dyker, H. Tetrahedron Lett. 1989, 30, 475–476; (c) Aaberg, A.;
Gramstad, T.; Husebye, S. Tetrahedron Lett. 1979, 20, 2263–2264.
8. (a) Hendrickson, J. B.; Hussoin, M. S. J. Org. Chem. 1989, 54, 1144–1149; (b)
Caddick, S.; Wilden, J. D.; Judd, D. B. J. Am. Chem. Soc. 2004, 126, 1024–1025; (c)
Xu, P.; Liu, G.-S.; Xi, J.; Wang, Sh.; Yao, Z.-J. Tetrahedron 2011, 67, 5455–5460;
(d) Xu, M.; Hou, Q.; Wang, Sh. Synthesis 2011, 626–634; (e) Xi, J.; Dong, Q.-L.;
Liu, J. S.; Chen, L.; Yao, Z.-J. Synlett 2010, 1674–1678; (f) Wu, M.; Wang, Sh.
Synthesis 2010, 587–592; (g) You, S.-L.; Kelly, J. W. Tetrahedron 2005, 61, 241–
249; (h) You, S.-L.; Kelly, J. W. Tetrahedron Lett. 2005, 46, 2567–2570; (i) Liang,
Y.; Jiang, X.; Yu, Z.-X. Org. Lett. 2009, 11, 5302–5305; (j) You, S.-L.; Kelly, J. W.
Org. Lett. 2004, 6, 1681–1683; (k) You, S.-L.; Kelly, J. W. J. Org. Chem. 2003, 68,
9506–9509.
9. (a) Salehi, P.; Khodaei, M. M.; Zolfigol, M. A.; Sirouszadeh, S. Bull. Chem. Soc. Jpn.
2003, 76, 1863–1864; (b) Salehi, P.; Khodaei, M. M.; Zolfigol, M. A.; Zeinoldini,
S. Synth. Commun. 2003, 33, 1367–1373; (c) Alizadeh, A.; Khodaei, M. M.;
Nazari, E. Bull. Korean Chem. Soc. 2007, 28, 1854–1856; (d) Khodaei, M. M.;
Alizadeh, A.; Nazari, E. Tetrahedron Lett. 2007, 48, 4199–4202; (e) Alizadeh, A.;
Khodaei, M. M.; Nazari, E. Tetrahedron Lett. 2007, 48, 6805–6808; (f) Bahrami,
K.; Khodaei, M. M.; Shahbazi, F. Chem. Lett. 2008, 38, 844–845; (g) Bahrami, K.;
Khodaei, M. M.; Shahbazi, F. Tetrahedron Lett. 2008, 49, 3931–3934; (h)
Khodaei, M. M.; Nazari, E. Chem. Lett. 2010, 39, 390–391; (i) Khodaei, M. M.;
Nazari, E. J. Iran. Chem. Soc. doi: http://dx.doi.org/10.1007/s13738-011-0062-3.
10. Sarca, V. D.; Laali, K. K. Green Chem. 2006, 8, 615–620.
Acknowledgments
We thank Razi University for generous financial support of this
work and Mr. Mehdi Sheikh-Arabi for his constructive help.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.07.
051.
11. Case, L. C. J. Appl. Polym. Sci. 1964, 8, 533–540.
12. Prades, A.; Corber, R.; Poyatos, M.; Peris, E. Chem. Eur. J. 2009, 15, 4610–4613.
13. Podder, S.; Roy, S. Tetrahedron 2007, 63, 9146–9152.
14. Blackwell, J.; Hickinbottom, W. J. J. Chem. Soc. 1961, 1405–1407.
15. Shrigadi, N. B.; Shinde, A. B.; Shriniwas. D. Samant, S. H. D. Appl. Catal. A: Gen.
2003, 252, 23–35.
16. Zhang, Ch.-Y.; Gao, X. Q.; Zhang, J. H.; Peng, X. J. Chin. Chem. Lett. 2009, 20, 913–
916.
17. Xiao, Y.-P.; Liu, X.-Y.; Che, Ch.-M. J. Organomet. Chem. 2009, 694, 494–501.
18. Sun, G.; Sun, H.; Wang, Zh.; Zhou, M.-M. Synlett 2008, 1098–1100.
19. Gribble, G. W.; Leese, R. M.; Evans, B. E. Synthesis 1977, 172–176.
20. Iwai, Y.; Gilgorich, K. M.; Sigman, M. S. Angew. Chem., Int. Ed. 2008, 120, 3263–
3266.
21. (a) Benson, F. R.; Ritter, J. J. J. Am. Chem. Soc. 1949, 71, 4128–4129; (b) Martinez,
A. G.; Alvarez, R. M.; Vilar, E. T.; Fraile, A. G.; Hanack, M.; Subramanian, L. R.
Tetrahedron Lett. 1989, 30, 581–582.
22. (a) Mitsunobu, O. Synthesis 1981, 1–28; (b) Hughes, D. L. Org. React. 1992, 42,
335–656; (c) Jenkins, I. D.; Mitsunobu, O. In Encyclopaedia of Reagents for
Organic Synthesis, ed. L. A. Paquette, Wiley, 1995, vol. 8, pp. 5379–5390.; (d)
Hughes, D. L. Org. Prep. Proc. Int. 1996, 28, 127–164.
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 the
solution was stirred for 15 min at room temperature. Then, arene (1 mmol) and
benzyl alcohol (1 mmol) were added to the reaction mixture and the mixture
was stirred for the appropriate time shown in Tables 1 and 2. Upon completion
of the reaction, the organic solvent was evaporated and the crude product was
purified by column chromatography using n-hexane as eluent to give the
diarylmethane. In the case of 4-nitrobenzyl alcohol, EtOAc/n-hexane (1:9) was
used as the eluent.
References and notes
1. (a) Olah, G. A. Friedel–Crafts and Related Reactions; Wiley-Interscience: New
York, 1964; (b) Olah, G. A. Friedel–Crafts Chemistry; Wiley: New York, 1973; (c)
Roberts, R. M.; Khalaf, A. A. Friedel-Crafts Alkylation Chemistry; A Century of
Discovery; Marcel Dekker: New York, 1984.
2. (a) De la Cruz, M. H. C.; Da Silva, J. F. C.; Lachter, E. R. Appl. Catal. A: Gen. 2003,
245, 377–382; (b) Smith, K.; El-Hiti, G. A. Curr. Org. Synth. 2004, 1, 253–274; (c)
Yi, W.-B.; Cai, Ch. J. Fluorine Chem. 2005, 126, 831–833; (d) Mantri, K.; Komura,
K.; Kubotal, Y.; Sugi, Y. J. Mol. Catal. A: Chem. 2005, 236, 168–175; (e) Sarca, V.
D.; Laali, K. K. Green Chem. 2006, 8, 615–620; (f) Rueping, M.; Nachtsheim, B. J.;
Ieawsuwan, W. Adv. Synth. Catal. 2006, 348, 1033–1037; (g) Sun, H. B.; Li, B.;
Chen, S. J.; Li, J.; Hua, R. M. Tetrahedron 2007, 63, 10185–10188; (i) Satam, J. R.;
Jayaram, R. V. Catal. Commun. 2008, 9, 1937–1940; (j) Wang, F.; Ueda, W. Chem.
Eur. J. 2009, 15, 742–753.
3. (a) Mertins, K.; Iovel, I.; Kischel, J.; Zapf, A.; Beller, M. Adv. Synth. Catal. 2006,
348, 691–695; (b) Mertins, K.; Iovel, I.; Kischel, J.; Zapf, A.; Beller, M. Angew.
Chem., Int. Ed. 2005, 44, 238–242; (c) Iovel, I.; Mertins, K.; Kischel, J.; Zapf, A.;
Beller, M. Angew. Chem., Int. Ed. 2005, 44, 3913–3917.
4. (a) Choudhury, J.; Podder, S.; Roy, S. J. Am. Chem. Soc. 2005, 127, 6162–6163; (b)
Kischel, J.; Jovel, I.; Mertins, K.; Zapf, A.; Beller, M. Org. Lett. 2006, 8, 19–22; (c)
Reuping, M.; Nachtsheim, B. J.; Scheidt, T. Org. Lett. 2006, 8, 3717–3719; (d)
Sun, H.-B.; Li, B.; Hua, R.; Yin, Y. Eur. J. Org. Chem. 2006, 4231–4236; (e) Podder,
S.; Choudhury, J.; Roy, S. J. Org. Chem. 2007, 72, 3129–3132; (f) Nishibayashi, Y.;
Inada, Y.; Yoshikawa, M.; Hidai, M.; Uemura, S. Angew. Chem., Int. Ed. 2003, 42,