The triazolyl analogue of the trityl cation

Article abstract of DOI:10.1016/j.tetlet.2013.05.138

The formation of the tris(3-benzyl-triazol-5-yl)carbenium cation, a heterocyclic analogue of the trityl cation, from tris(3-benzyl-triazol-5-yl) methanol, itself generated by Cu(I)-catalyzed Huisgen reaction of benzyl azide with triethynylmethanol, in the

Full text of DOI:10.1016/j.tetlet.2013.05.138

Accepted Manuscript
The triazolyl analogue of the trityl cation
Mohamed Oukessou, Yves Génisson, Dounia El Arfaoui, Abdeslem Ben-Tama,
El Mestafa El Hadrami, Remi Chauvin
PII:
S0040-4039(13)00929-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.05.138
TETL 43038
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
1 May 2013
19 May 2013
22 May 2013
Please cite this article as: Oukessou, M., Génisson, Y., Arfaoui, D.E., Ben-Tama, A., Hadrami, E.M.E., Chauvin,
R., The triazolyl analogue of the trityl cation, Tetrahedron Letters (2013), doi: http://dx.doi.org/10.1016/j.tetlet.
2013.05.138
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Graphical Abstract
Ph
N
N
OH
N
Nu
C
N
N
N
N
C
N
N
Ph
NuŠE
- E
(CF3CO)2O
CH2Cl2, 0 C
C
N
N
N
N
N
N
N
N
N
Ph
Ph
Ph
Ph
N
N
N
N
N
N
N
N
N
E = H, K, ZnEt
Nu = O-, N-, S-
or C-nucleophile
Ph
Ph
Ph
tris(1,2,3-triazolyl)methanol
Ē trizyl cation Č
10 examples
1

The triazolyl analogue of the trityl cation
Mohamed Oukessou,a,b Yves Génisson,a* Dounia El Arfaoui,a,b Abdeslem Ben-Tama,b
El Mestafa El Hadrami,b Remi Chauvinc,d,a
*
a SPCMIB, UMR CNRS 5068, Université Paul Sabatier, 118 route de Narbonne, 31062
Toulouse Cedex 9, France.
Fax: +33-5-61556011, E-mail: genisson@chimie.ups-tlse.fr
Laboratoire de Chimie Organique Appliquée, Faculté des Sciences et Techniques ,
b
Université Sidi Mohamed Ben Abdallah, Fès, Maroc.
E-mail: elhadrami_mes@yahoo.com, bent_abslam@yahoo.fr
c CNRS, LCC (Laboratoire de Chimie de Coordination), 205 route de Narbonne, BP 44099,
F-31077 Toulouse Cedex 4, France.
Fax: +33 (0)5 61 55 30 03; Tel: +33 (0)5 61 33 31 13; E-mail: chauvin@lcc-toulouse.fr
d Université de Toulouse, UPS, ICT-FR2599, F-31077 Toulouse, France.
Abstract.
The formation of the tris(3-benzyl-triazol-5-yl)carbenium cation, a heterocyclic analogue of
the trityl cation, from tris(3-benzyl-triazol-5-yl)methanol, itself generated by Cu(I)-catalyzed
Huisgen reaction of benzyl azide with triethynylmethanol, in the presence of trifluoroacetic
anhydride is evidenced through a selective SN1 reactivity with various O-, N-, S- and C-
nucleophiles, giving the corresponding triazolylmethane derivatives in moderate to high
yields.
Key-Words.
Carbenium,
Trityl
cation,
Tris(1,2,3-triazolyl)methanol,
Tris(triazolyl)methylium
2

Introduction
By virtue of their steric and electronic stabilization, trivalent triphenylmethyl -or
“trityl”- centers could long be studied under radical,i anionic,ii or cationic state,iii the latter
having to be considered as the stable paradigm.iv Associated to nonbonding anions such as
hexafluorophosphate,v tetrafluoroborate,vi or trifluoroacetate,vii the trityl cation is indeed
currently used as a versatile electrophilic reagent, in particular towards alcohols for the
reversible generation of hindered ethers (alternative to tert-butyl ethers), and towards C–H
hydrides, e.g. in oxidative aromatization of cyclohexene derivatives.viii Beyond this reference
use as an alkoxide or hydride abstractor, the trityl cation has long been reported to react with
other nucleophiles, in a stoichiometric or catalytic manner,ix or even as an initiator of cationic
polymerization.x Chiral related functional triarylcarbenium ions were also used as catalysts
for various organic transformations.xi In spite of an obvious generalization principle (Scheme
1), functional variation of the trityl cation has been however limited to substituted or
ethynylogous versions of the phenyl substituents,xii e.g. with stabilizing anisylxiii or anilinyl
substituents, such as in the classical triarylmethane dyes (with primary uses as pH
indicators),xiv or to trinaphthyl-xv or triazulenyl-methyl analogues.xvi
OH
S
X
C
R
R
R
R
S
C
[]
C
[]
[]
C
C
Ar
X
Ar
X
Ar
S
R
R
X = O, S
Scheme 1. Known structural types of trityl cation derivatives or analogues.
3

Heteroaromatic analogues of trityl salts have been mainly illustrated by trithienyl
representatives,xvii and a few other examples.xviii In the aza-aromatic series, tripyridylmethylxix
and tripyrrolylmethyl cations have been considered as putative or elusive species.18 The
challenge is here resumed in the triazolyl series. The 1,2,3-triazole ring, in particular, is
indeed an ubiquitous “clicking“ motif resulting from Huisgen [2+3] cycloaddition reactions of
alkynes with organic azides,xx and its stability can be related to its weak basicity and strong
aromaticity,xxi which, in the topological scale, turns out to be essentially identical to that of
benzene (Topological Resonance Energy, TRE = 0.274 β vs 0.273 β, where β is the assumed
transferable Hückel resonance integral for C–C bonds).xxii
Results and discussion
Reaction of tris(trimethylsilylethynyl)methanol 1, prepared by a modified version of a
previously described method (see Supplementary data, S.D.),xxiii with three equivalents of
benzyl azide under “Cu-AAC” (copper-mediated alkyne-azide cycloaddition) click-chemistry
conditions afforded the triple Huisgen reaction product tris(1-benzyl-1H-1,2,3-triazol-4-
yl)methanol 2 with simultaneous desilylation of the three terminal carbon atoms (Scheme 2).
Although a slightly different procedure was employed (see S.D.), this alcohol was previously
described by Pericas et al. and reported to act as an efficient ligand for further Cu-AAC
reactions of various terminal alkynes with alkyl- and aryl-azides.xxiv
OH
N
OH
CuSO4
sodium ascorbate
N
N
+ 3 PhCH2N3
N
N
TMS
TMS
Ph
Ph
N
N
EtOH/H2O
TMS
Ph
N
N
1
2
Scheme 2. Cu-ACC access to the tris-N-benzyl derivative of triazolylmethanol.
4

The generation of the corresponding tris(triazolyl)carbenium 3, abreviated below as
the “trizyl” cation for the sake of brevity, was tentatively carried out by treating a solution of
2 in dichloromethane (DCM) with trifluoroacetic anhydride, a treatment that resulted in the
appearance of the same yellow color as that of the trityl cation. Evidences for the formation of
the trizyl cation 3 were sought by trapping experiments consisting in the quenching of the
solution with an excess of various nucleophilic reagents.
Ph
N
N
Nu
N
N
N
N
NuŠH
Ph
(CF3CO)2O
CH2Cl2, 0 C
N
N
2
N
N
N
N
N
N
Ph
Ph
N
N
Ph
N
N
Ph
CF3CO2
3
4 (4a-4j)
Scheme 3. Evidence of the generation of a tris(triazolyl)carbenium by trapping with
nucleophiles.
Upon addition of methanol, the color faded away indeed rapidly, and after treatment
with aqueous NaOH, the methyl ether 4a was obtained in 77 % yield (Scheme 3, Nu = OMe),
thus demonstrating the intermediacy of the trizyl cation 3. It is noteworthy that tritylation of
alcohols usually calls for the use of Ph3CCl as the precursor.xxv In the present case, attempt at
chlorination of 2 with SOCl2 in diethyl ether, or using the reported method for the conversion
of Ph3C–OH to Ph3C–Cl (with acetyl chloride in refluxing toluene),xxvi failed to convert the
alcohol 2. The straightforward use of the alcohol substrate 2 is however benefitial and could
be generalized for the preparation of other ethers by reaction of the transient carbenium 3 with
primary (EtOH), secondary (i-PrOH) and tertiary (t-BuOH) alcohols 4b, 4c and 4d in 68 %,
74 % and 63 % yield, respectively (Table 1).
5

δ13 (2,4)a
δ13 (Ph3C-Nu)b
entry Nu
E
Yield (%)
C
C
2
OH
H
H
H
H
H
H
quant.
77
68.0 (67.1)24a 82.0
4a
4b
4c
4d
4e
4f
4g
4h
4i
OMe
OEt
OiPr
OtBu
tBuNH
100.5
97.8
82.2
89.5
55.5
57.1
78.7
64.3
69.9
42.5
87.0
68
86.5
88.525c
74
63
-
54
-
(R)-NHCHMePh H
75
-
NEt2
H
75
(77.5: calcd)
(73.0: calcd)28
64.330
SC(S)OEt
4-MeO-C6H4
Et
K
75
H
86
4j
ZnEt
48
61.032
Table 1. Reaction of in-situ generated tris(triazolyl)carbenium trifluoroacetate 3 (Scheme 3)
a
with nucleophilic reagents Nu–E (0°C, DCM: see general procedure and S.D. for details).
13C NMR chemical shifts of the triarylated quaternary carbon atom; spectra recorded in
b
CDCl3 solution, at 75 MHz and 293 K. Chemical shifts for the trityl analogues, when
available under the “spectra” rubric from SciFinder (https://scifinder.cas.org/scifinder/).
References are also recalled for the specific cases 4c, 4h-4j.
The conditions were then applied to the trizylation of other nucleophilic heteroatoms.
Primary amines such as t-BuNH2 and (R)-MePhCHNH2 were thus found to afford the
trizylated products 4e (whose analogous trityl derivative is known)xxvii and 4f in 54 % and 75
% yield, respectively. Likewise a secondary amine, Et2NH, gave the corresponding highly
hindered tertiary amine product 4g in 75 % yield. Nevertheless treatment of 3 with a tertiary
amine like NEt3 failed to provide the corresponding quaternary amonium salt.
6

In contrast to the hard oxygen and nitrogen atoms, a soft sulfur atom was also found to
undergo trizylation by 3. Potassium O-ethyl xanthate thus led to the S-trizyl carbonodithioate
4h in 75 % yield. Incidentally, just as the analogous S-trityl xanthate is the precursor of the
trityl radical,xxviii the S-trizyl xanthate 4h could behave as a precursor of the trizyl radical.xxix
Generalization of the SN1 reactivity of 3 to monoatomic nucleophiles was then
investigated with halogen anions. Treatment of solutions of 3 with the soft bromide anion of
[n-Bu4N][Br] was however found unproductive. The same absence of reactivity was observed
with chloride ions of either the poorly soluble [Et4N][Cl] salt or the more soluble [BnEt-
3N][Cl] salt. Finally, no reaction occured with [n-Bu4N][F]. A similar inertness was finally
observed with the hard hydride ion in NaBH4.
In view of generating novel quaternary carbon centers, the reactivity of 3 was finally
envisaged with C nucleophilic centers. An efficient C-C bond formation process was found to
occur with anisole, affording the p-trizylated product in high yield (86 %) and complete
regioselectivity (the o-isomer was not observed). The p-anisylyl-trityl analogue was recently
reported to be prepared by a similar SN1 method from triphenylmethanol.xxx Further attempts
at C-trizylation were envisaged with sp3- and sp-hybridized carbon nucleophiles. In spite of
its illustrated C-nucleophilic reactivity with carbenium centers under Friedel-Crafts
conditions,xxxi bis(trimethylsilyl)acetylene (Me3Si–CC–SiMe3) was found unreactive with the
trizyl cation 3. In contrast, the more reactive ethylide groups of diethylzinc led to the ethyl-
trizyl coupling product in 48 % yield. The analogous trityl-ethyl compound was prepared
from Ph3C-Cl and EtMgBr,xxxii and this direct procedure for C-trizylation from 2 in acidic
medium contrasts with the most used methods for C-tritylation: from isolated trityl salts (e.g.
pre-associated to a PF6 anion),xxxiii more frequently from trityl chloride,32,xxxiv or in a quite
–
original manner from lithium triphenylmethoxide in the presence of FeCl3.xxxv
7

Conclusion
The existence of the trizyl cation 3 has been appraised through its electrophilic
properties towards an illustrative set of nucleophiles, showing both analogy and specificity
with respect to classical tritylation reactions. The scope of chemical applications now
deserves further investigations, in particular from a larger panel of trizyl N-substituents (a
priori accessible thanks to the flexibility of the click chemistry), and with other nucleophiles
and compatible solvents (different from DCM, e.g. for Grignard nucleophiles). Efforts for the
crystallization of pure trizyl salts should also be pursued (attempts hitherto led to the isolation
of tris(triazolyl)methanol 2 only, indicative a high hydrolytic sensitivity of 3). Regarding
comparative physical properties, it is noteworthy that the range of the 13C NMR chemical
shifts of the central quaternary carbon of trizylated compounds is wider (40-100 ppm) than in
the corresponding trityl series (60-90 ppm, Table 1). The optical properties of trizyl cations
with various N- and C-substituents, starting from their absorption and emission spectra,
should also be the topics of further investigations for comparison with those of the trityl
counterpart.14 Finally, biological properties of O-, N-, S- and C-trizyl derivatives, whose three
triazole rings are known for their peptido-mimetic properties, also deserve to be examined by
comparison to the corresponding trityl derivatives.xxxvi
Typical tris(triazolyl)methylation procedure (Scheme 3). To a 0.1 M solution of tris(1-
benzyl-1H-1,2,3-triazol-4-yl)methanol 2 (0.1 g, 0.2 mmol) in DCM (2 mL) at 0°C under a
nitrogen atmosphere, 1.2 equivalents of trifluoroacetic anhydride (0.03 mL, ca 45 mg, 2.1
mmol) are added dropwise. After stirring for 30 min., five equivalents of nucleophile (1
mmol) are added (e. g. 0.04 mL of MeOH), and stirring is continued for another 3 h at 0°C.
The reaction medium is finally treated with aqueous NaOH (1 M), and the medium is
extracted by DCM. The combined organic layers were dried and concentrated under vacuum,
8

and the residue is purified by chromatography on silicagel, using EtOAc/petroleum ether
mixtures as eluting systems, to afford the trizylated product (usually as a pale yellow oil) in
the specific yield given in Table 1.
Supplementary data. Experimental procedures and spectroscopical characterizations of the
previously described compounds 1 and 2,23,24 and of the 10 new compounds 4a-4j.
Acknowledgements. The Hubert Curien program Volubilis (MA/09/207) and the CNRS
International Associated Laboratory (LIA) Laboratoire en Chimie Moléculaire Maroco-
Français (LCMMF) are acknowledged, in particular for funding of the fellowship of M. O.
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