Friedel-Crafts catalysts as assistants in the tritylation of less reactive hydroxyls

Article abstract of DOI:10.1016/j.tetlet.2010.05.144

Less reactive hydroxyls, such as those present in secondary alcohols and in some primary alcohols, phenols and carboxylic acids, were easily tritylated with the homogeneous assistance of equimolar quantities of chlorides of di- and trivalent metals in apr

Full text of DOI:10.1016/j.tetlet.2010.05.144

Tetrahedron Letters 51 (2010) 4113–4116
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Tetrahedron Letters
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Friedel–Crafts catalysts as assistants in the tritylation of less reactive hydroxyls
Roberta Bernini a, Maurizio Maltese b,
*
a Dipartimento di Agrobiologia e Agrochimica, Università degli Studi della Tuscia, Via S. Camillo De Lellis, 01100 Viterbo, Italy
b Dipartimento di Chimica, Università degli Studi ‘La Sapienza’, P.le A. Moro 5, 00185 Rome, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Less reactive hydroxyls, such as those present in secondary alcohols and in some primary alcohols, phenols
and carboxylic acids, were easily tritylated with the homogeneous assistance of equimolar quantities of
chlorides of di- and trivalent metals in aprotic solvents. The metal ions allowed both high concentration
of the effective reagent triphenylmethylcarbenium ion and mobilisation of the hydroxyl proton, thus giv-
ing rise to rapid, room temperature substitution reactions. The experimental conditions were so mild that
other protected groups, such as alkyl- or trityl-protected carboxyls and (9-fluorenylmethoxycarbonyl)- or
trityl-protected amino groups, remained unaffected.
Received 16 March 2010
Revised 27 May 2010
Accepted 28 May 2010
Available online 2 June 2010
Keywords:
Friedel–Crafts catalysts
O-Tritylation
Ó 2010 Elsevier Ltd. All rights reserved.
Trityl ethers
Secondary hydroxyls tritylation
1. Introduction
This reagent is prepared in situ by reaction of TrOH and trimethy-
silyl trifluoromethanesulfonate (TMSOTf) and used in association
The triphenylmethyl (trityl) group is a common protecting
group for hydroxyls, being easily introduced and successively re-
moved by mild acidic treatment.1 It is widely accepted that the
tritylation reaction predominantly consists of an attack by the
triphenylmethylcarbenium ion Tr+ on the nucleophilic substrate
through a SN1 mechanism. The process rate depends on the capabil-
ity of its components to favour the heterolytic cleavage of the Tr–X
bond. With reference to the sole homogeneous methods, when tri-
phenylcarbinol (X = OH) is employed as the reagent, the goal of
increasing Tr+ concentration is achieved by the action of strong
Brønsted acids, for example, H2SO4.2 However, as substrates suffer
as a result of this treatment, milder procedures based on the use
with 2,4,6-collidine17 or by reaction of silver triflate (AgOTf) and
TrCl in the presence of 2,6-di-t-butylpyridine or 1-methyl-2-pyrro-
lidinone.18 O-Tritylation of alcohols, phenols and carboxylic acids
is also achieved by acid-catalysed trans-etherification between
trimethyltrityloxysilane and trimethylsilyl ethers.19 As a further
example of a tritylation procedure for aromatic hydroxyls, phenyl-
trityl ether has been prepared by treatment of phenol with tri-
phenylmethyl pyridones20 and with TrCl in the presence of
DBU.12 In contrast with the described protocols, the most widely
used tritylation method for hydroxyls in carboxylic acids is chiefly
based on the action of trityl bromide on their metal salts21 and of
trityl chloride on their silver22 or cesium salts.23 However, prepara-
tions of N-trityl glycine trityl ester by TrCl/triethylamine (TEA)24
andofsomepertritylatedaminoacidsbyTrBr/TEA25 are also reported.
Recently, we devised a new route to O-tritylation26 using re-
agent mixtures of the type TrCl/MClx (MClx is a Friedel–Crafts cat-
alyst, x = 2, 3),27 where M+x is capable of giving rise to both high
concentrations of triphenylmethylcarbenium ions, by acceptance
of Xꢀ and proton mobilisation on the functional group to be pro-
tected, through coordination of the metal ions themselves and for-
mation of oxonium chlorides (Scheme 1). We reasoned that, in the
presence of a substrate having hydroxyls as the functional groups,
a complex equilibrium should be established in which all the pos-
itively charged ions present, namely H+, Tr+ and M+x, compete for
the donor site to be substituted. The introduction of a proton scav-
enger, such as TEA, should reduce the competition between Tr+ and
M+x only. Thus, the success of tritylation should ultimately depend
on the relative affinity of Tr+ and M+x for the donor atom to be
substituted and on their relative concentrations.
4
of Lewis acids such as B(C6F5)3,3 ZnCl2,3 AlCl3,3 FeCl34,5 and FeClO4
have been suggested. With the same aim, trityl ethers (X = OR,
where R = benzyl, p-methoxybenzyl and prenyl) in the presence
of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) or DDQ/
Mn(OAc)3 have been employed.6,7 Triphenylmethyl chlorides and
bromides (X = Cl, Br) are used in association with an organic base
such as pyridine,8–10 dimethylaminopyridine (DMAP),11 2,4,6-tert-
butyl pyridine,12 2,4,6-collidine13 or 1,8-diazabicyclo[5.4.0]undec-
7-ene (DBU).14
10
13
ꢀ
ꢀ
Tritylating reagents with ionic character (X ¼ ClO4
,
PF6 ,
BF4 15,16) alone or in association with a substituted pyridine have
been employed with the aim of achieving a higher Tr+ concentra-
tion. Trityl triflate (X = OTf) is widely used in hydroxyl tritylation.
ꢀ
* Corresponding author. Tel.: +39 06 49913342; fax: +39 06 490324.
E-mail address: maurizio.maltese@uniroma1.it (M. Maltese).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.05.144

4114
R. Bernini, M. Maltese / Tetrahedron Letters 51 (2010) 4113–4116
TrCl + MClx
a) TrCl, MClx solvent,
OH
OTr
5 min
TrH
+
+
b) TEA, 5 min
1
c) 5% Citric acid buffer,
2
3
O
-
Tr+ [MClx+1
]
pH=5, 5 min
TrOH
+
ROH
R
4
+
+
R
H
O MClx-1Cl-
+
O
TrCl-
H
MClx: ZnCl2,HgCl2, FeCl3, AlCl3
Solvent: CH3CN, CH2Cl2
TEA
Scheme 2. Procedure of tritylation of 2-propanol 1.
ROMClx-1
+
ROTr
+
TEAH+Cl
Scheme 1. Equilibria involved in the metal chloride-assisted O-tritylation.
Table 1
Evaluation of several metal chlorides and their concentration on the tritylation of 2-
propanol 1 in acetonitrile and dichloromethane
Our preliminary experiments on the use of metal chlorides in
assisting O-tritylations with TrCl showed that this procedure was
in fact capable of increasing the reaction rate and that many of
the less reactive hydroxyls reported in the literature, such as those
of secondary alcohols, were susceptible to protection. These data
prompted us towards the development of a protocol for a high rate,
high yield and room temperature tritylation of this type of func-
tionality and the experimental results are reported here.
Entry
MClx
Solvent
2a (yield %)
3a (yield %)
1
2
3
4
5
6
7
8
9
ZnCl2
ZnCl2
HgCl2
HgCl2
FeCl3
FeCl3
AlCl3
AlCl3
CH3CN
CH2Cl2
CH3CN
CH2Cl2
CH3CN
CH2Cl2
CH3CN
CH2Cl2
CH3CN
CH2Cl2
CH3CN
CH2Cl2
50
46
66
—
—
43
—
23
36
32
—
10
14
8
—
77
29
—
—
8
11
26
6
b
2. Procedure and results
ZnCl2
ZnCl2
FeCl3
FeCl3
b
10
11
12
b
The organic solvent for the reaction needed to be a good solvent
for the reagent mixture TrCl/MClx, in order to allow both high Tr+
concentrations and low reaction volumes. Pyridine and its deriva-
tives were excluded in order to avoid any overlap of the catalytic
effect on tritylation, reported in the literature for these bases, with
that of the metal acids we wanted to investigate in the present
work. Our screening process indicated acetonitrile and dichloro-
methane as solvents and HgCl2, ZnCl2, FeCl3 and AlCl3 as metal
chlorides.
As a general procedure, the substrate (1.0 mmol) was intro-
duced into a solution of TrCl (1.0 mmol) and metal chloride
(1.0 mmol) in the chosen solvent (6.0 mL) and the mixture was
kept under magnetic stirring at room temperature for 5 min. Then,
a solution of TEA (1.0 mmol) in the same solvent (2.0 mL) was
added for 5 min. Finally, the reaction was quenched with aqueous
5% citric acid buffer at pH 5 (10.0 mL) and stirred for another 5 min.
In the case of acetonitrile, the organic solvent was then evaporated
under reduced pressure and the resulting suspension was ex-
tracted with diethyl ether. Organic extracts were combined,
washed with water, dried on sodium sulfate and evaporated. In
the case of dichloromethane, the organic solution was directly iso-
lated, dried and evaporated.
b
—
a
Determined by GC–MS analysis of the organic extracts obtained after the
workup.
b
ZnCl2 and FeCl3 at 0.5 mmol.
tries 1 and 2). A better result (yield: 66%) was obtained by using
HgCl2 in acetonitrile (entry 3), whilst the low solubility of this salt
in dichloromethane did not allow the relative solvent effect to be
studied (entry 4). FeCl3 and AlCl3 were inactive concerning the pro-
duction of the trityl ether in acetonitrile (entries 5 and 7), the for-
mer chloride exclusively leading to substrate oxidation in this
solvent. In dichloromethane, in the presence of FeCl3, the desired
product was obtained at a better yield compared to AlCl3 (entry
6 vs entry 8). Finally, in dichloromethane, despite comparable
yields of the produced trityl ether, the amount of TrH was rela-
tively lower for ZnCl2 than for FeCl3 (entry 2 vs entry 6).
With the aim of reducing the quantity of the metal chloride em-
ployed, we investigated reactions on substrate 1 with less than
equimolar concentrations of metal chloride. The results, as illus-
trated in Table 1 by the use of 0.5 mmol of ZnCl2 (entries 9 and
10) and of FeCl3 (entries 11 and 12), indicated that the yield of
the trityl ether formed decreased. The production of TrH followed
the same trend (entries 9–10 vs entries 1–2 and entries 11–12 vs
entries 5–6). We have ascribed this result to the effect produced
on the chloride ion transfer equilibrium by the addition of TEA.
In fact, the base acts as a proton scavenger only if the substrate
hydroxyls release protons at a reasonable rate. Otherwise, its addi-
tion to the reaction mixture reduces the concentration of the metal
ion by complexation, progressively precluding both the chloride
ion transfer mechanism and the catalytic effect on the mobility
of the substrate protons. Furthermore, the base may directly
quench the reactive species Tr+ through N-quaternisation.
Owing to the high Tr+ concentration employed in this proce-
dure, the oxidation of secondary alcohols due to hydride abstrac-
tion should be expected.28–30 The amount of triphenylmethane
(TrH) produced in this reaction is a measure of its importance. This
is the reason why, in order to evaluate how much this competitive
reaction could hamper the tritylation of secondary alcohols by the
present methodology, we used 2-propanol 1, known to be suscep-
tible to oxidation, as a model substrate (Scheme 2).
The yields of 2-trityloxypropane 231 and triphenylmethane 3
are listed in Table 1; the data on triphenylcarbinol 4, resulting from
unreacted TrCl through water workup, have been omitted for the
sake of brevity. Blank reactions performed in the absence of TEA
led to undetectable amounts of trityl ether 2. Analogously, an equi-
molar mixture of TEA, ZnCl2 and TrCl was not able to tritylate sub-
strate 1.
In principle, this hampering effect may be reduced by a slower
addition of TEA, but as we wanted to develop a rapid procedure for
the formation of trityl ethers, we did not pursue this. Since we
wanted to develop an environmentally friendly procedure, we also
attempted to reduce the amount of metal chloride by employing
other bases; however, the use of pyridine, 2,4,6-collidine, DMAP
The use of ZnCl2, in both acetonitrile and dichloromethane, gave
a significant yield of trityl ether 2 (50% and 46%, respectively, en-

R. Bernini, M. Maltese / Tetrahedron Letters 51 (2010) 4113–4116
4115
or DBU, in place of TEA, in the metal-assisted tritylation of 2-pro-
panol 1 did not produce remarkable changes in the yield of 2-trityl-
oxypropane 2 produced.
Alcohols 5, 7 and 9 were chosen on the grounds of their low reactiv-
ity; 1-trityloxy-2-propanol 11 and 1,3-di-trityloxy-2-propanol 13
were investigated to evaluate the role of steric hindrance against
the installation of the voluminous trityl group; and substrates with
functionalities protected by other groups (15, 19, 21 and 25) or the
same trityl group (11, 13, 17, 21 and 23) were included to investi-
gate the stability of previously introduced protections to the
manipulations of the proposed method. Finally, optically active
compounds 19 and 23 were examined to check if the present meth-
od, as compared with other tritylation procedures, affects the enan-
tiomeric purity of the tritylated derivatives (20 and 24).
Despite the moderate yields of 2 obtained in the preliminary
screening, we considered these data promising enough to extend
the procedure to other substrates. The experimental data suggested
the use of HgCl2 in acetonitrile (highest yield of 2 and relatively low
production of 3); however, in view of the demand for efficient, eco-
nomic, reliable and environmentally friendly processes, ZnCl2 was
chosen as the chloride and acetonitrile as the solvent for the O-trity-
lation of several secondary alcohols and some primary alcohols,
carboxylic acids and phenols of low reactivity (listed in Table 2).
In general, the reactions proceeded smoothly for all cases, in good
to excellent yields, within the very short reaction time chosen for
screening. The oxidation reaction of the secondary alcohol function
was observed for cyclohexanol 5, amounting to about 10% of the em-
ployed TrCl, but a satisfactory yield of tritylated compound 632 was
observed (entry 1). In contrast, we did not isolate TrH in the prepa-
ration of compound 87 (entry 2) and 10 (entry 3). In this case, only
the trans-isomer 10 was obtained, as previously observed.14
The success of the tritylation of secondary alcohol groups in
propylene glycol and glycerol trityl derivatives 11 and 13 to pre-
pare compounds 1233 and 1434 indicated a minor role of steric hin-
drance on the final yield of these reactions (entries 4 and 5).
Since in this method, the substrate experiences acidic condi-
tions until the addition of the base is accomplished, O-detritylation
of 11 and 13 (entries 4 and 5), N-detritylation of 17, 21 and 2327
(entries 7, 9 and 10) and trans-esterification of 19 and 21 (entries
8 and 9) could be expected. However, we found no evidence for
such processes and the high yield of reaction for these substrates
confirmed this. In our opinion, the accelerated tritylation rate of
this procedure does not affect the previously protected groups
present in the molecule.
Table 2
Scope of ZnCl2-promoted tritylation of secondary alcohols, phenols and carboxylic
acidsa
Entry
1
Substrate
Product
Yieldb (%)
80
OH
OTr
6
TrO
5
HO
2
72
7
8
OH
OTr
3
4
92c
79
67
9
10
TrO
TrO
OH
OTr
12
11
The N-Fmoc group present in compounds 15 and 2535 (entries 6
and 11) remained unaffected after the present tritylation protocol.
In contrast, when the tritylation of this kind of substrate is per-
formed with procedures based on the use of TrCl in the presence of
a base, the N-Fmoc moieties may suffer deprotection.1 Thus, the
present procedure seems to offer a suitable route for orthogonally
protected substrates of the Fmoc/Tr type.
TrO
OTr
TrO
OTr
5d
OTr
OH
14
13
OH
OTr
NHFmoc
OH
NHFmoc
6
7
83
82
16
15
TrHN
The optical activities of the trityl derivatives 2014 and 2436 (en-
tries 8 and 10) were in agreement with the literature data.
TrHN
OTr
18
17
OH
OTr
H
H
3. Conclusion
8
9
83
92
83
COOEt
COOEt
20
19
In summary, we have developed a new simple and high rate
procedure for preparing trityl ethers and esters under very mild
reaction conditions and easy workup. The reactions are performed
at room temperature, thus preventing or reducing the impact of
secondary reactions and allow the use of non-chlorinated solvents.
The method offers the opportunity of tritylating hydroxyls in the
presence of base-sensitive functions, such as esters or Fmoc-pro-
tected amino groups, and does not give rise to racemisation in ami-
no acid derivatives. Further investigation of the scope of this
methodology is currently underway in our laboratory.
H
NHTr
H NHTr
HO
TrO
TrO
COOMe
COOMe
21
22
H
NHTr
H
NHTr
TrO
10
COOTr
COOH
24
23
H
H
NHFmoc
COOMe
NHFmoc
COOMe
11
80
Acknowledgement
OH
25
OTr
26
The authors are grateful to Dr. M. P. Donzello (Dipartimento di
Chimica, Università degli Studi La Sapienza, Roma) for the elemen-
tal analysis data of the tritylated compounds.
a
Tritylation reactions were performed according to the general procedure
described for the screening experiments (see text).
b
Isolated yield.
Supplementary data
c
Yield based on trans-4-t-butylcyclohexanol present in the commercial product
9 (mixture of cis/trans 33/67).
Reaction performed in dichloromethane as substrate 13 was insoluble in
acetonitrile.
d
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.05.144.

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