In situ activation of benzyl alcohols with XtalFluor-E: Formation of 1,1-diarylmethanes and 1,1,1-triarylmethanes through Friedel-Crafts benzylation

Article abstract of DOI:10.1039/c4ob02655a

The Friedel-Crafts benzylation of arenes using benzyl alcohols activated in situ with XtalFluor-E is described. A wide range of 1,1-diarylmethanes and 1,1,1-triarylmethanes were prepared under experimentally simple and mild conditions, without the need for a transition metal or a strong Lewis acid. Notably, the reactivity observed demonstrates the potential of XtalFluor-E to induce C-OH bond ionization and S_N1 reactivity of benzylic alcohols. This journal is

Full text of DOI:10.1039/c4ob02655a

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In situ activation of benzyl alcohols with
XtalFluor-E: formation of 1,1-diarylmethanes and
1,1,1-triarylmethanes through Friedel–Crafts
benzylation†
Cite this: Org. Biomol. Chem., 2015,
13, 2243
Received 23rd December 2014,
Accepted 7th January 2015
DOI: 10.1039/c4ob02655a
Justine Desroches, Pier Alexandre Champagne, Yasmine Benhassine and
Jean-François Paquin*
www.rsc.org/obc
The Friedel–Crafts benzylation of arenes using benzyl alcohols be possible to accomplish both steps in the same reaction
activated in situ with XtalFluor-E is described. A wide range of 1,1- vessel, i.e. performing the deoxofluorination in the presence of
diarylmethanes and 1,1,1-triarylmethanes were prepared under the reagent needed for the FCB step (1 → 3, Fig. 1).
experimentally simple and mild conditions, without the need for a
We first probed this idea by performing test reactions using
transition metal or a strong Lewis acid. Notably, the reactivity 4-tert-butylbenzyl alcohol (4) and p-xylene (Table 1). Using
observed demonstrates the potential of XtalFluor-E to induce DAST (diethylaminosulfur trifluoride)5 as the deoxofluorina-
C–OH bond ionization and SN1 reactivity of benzylic alcohols.
tion agent in a CH2Cl2–HFIP (9 : 1) mixture, the 1,1-diaryl-
methane 5 was isolated in a promising 68% yield (entry 1).
When the reaction was performed without HFIP, a slightly
lower yield (entry 2) was obtained. The crude NMR spectra for
both reactions showed traces of the benzyl fluoride (2; R = 4-t-
Bu) supporting our initial hypothesis that the reaction would
proceed through the in situ formation of the benzyl fluoride.
However, this hypothesis conflicted with the results obtained
with XtalFluor-E ([Et2NSF2]BF4), a more thermally stable deoxo-
fluorinating agent.6 Indeed, using a slight excess of XtalFluor-E
(1.1 equiv.) in a CH2Cl2–HFIP (9 : 1) mixture, product 5 was
also obtained, in a quantitative yield (entry 3). As expected
when using XtalFluor-E, a reagent that requires an external
source of fluoride to induce the deoxofluorination reaction,6
no benzylic fluoride could be detected in the crude NMR
spectra of the reaction, thus raising questions concerning the
1,1-Diarylmethanes and 1,1,1-triarylmethanes as well as
related structures represent important cores in medicinal
chemistry and materials sciences.1 While
a number of
approaches exist for their synthesis, the Friedel–Crafts benzyl-
ation (FCB) reaction remains the simplest and the most widely
used one.2 We have recently reported the synthesis of 1,1-di-
arylmethanes (3) using benzylic fluorides (2) as enabled by
hydrogen-bonding (2 → 3, Fig. 1).3 The benzyl fluorides (2)
were generally prepared from the benzyl alcohol (1) through
deoxofluorination (1 step) or a halogenation/substitution
sequence (2 steps). Given the fact that HFIP (1,1,1,3,3,3-hexa-
fluoro-2-propanol), required for the FCB using benzyl fluor-
ides, has a very low nucleophilicity,4 we wondered if it would
Table 1 Selected optimization results
Deoxofluorinating
agent (equiv)
Yielda
(%)
Entry
Solvent
Fig. 1 Previous and current work.
1
2
3
4
5
6
CH2Cl2–HFIP (9 : 1)
CH2Cl2
CH2Cl2–HFIP (9 : 1)
CH2Cl2–HFIP (9 : 1)
CH2Cl2–HFIP (19 : 1)
CH2Cl2
DAST (1.1)
DAST (1.1)
XtalFluor-E (1.1)
XtalFluor-E (1.0)
XtalFluor-E (1.1)
XtalFluor-E (1.1)
68
62
100
89
87
82
Canada Research Chair in Organic and Medicinal Chemistry, CGCC, PROTEO,
Département de chimie, Université Laval, 1045 Avenue de la Médecine,
Pavillon Alexandre-Vachon, Québec, Québec G1V 0A6, Canada.
E-mail: jean-francois.paquin@chm.ulaval.ca; Tel: +1-418-656-2131 ext. 11430
†Electronic supplementary information (ESI) available: Full experimental details
and 1H, 13C, and 19F NMR spectra. See DOI: 10.1039/c4ob02655a
a Isolated yield of 5.
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possible mechanism for the FCB using this activating agent.
Reducing the amount of XtalFluor-E (entry 4), of HFIP (entry 5)
or performing the reaction in CH2Cl2 only (entry 6) all resulted
in reduced yield. XtalFluor-E is a known activating agent for
the SN2 substitution of alcohols,7 yet had never been described
as an effective stand-alone promoter for the SN1 reaction of
benzyl alcohols.
Scheme 1 Self-polymerization of 4 observed for electron-poor arenes.
Herein, we report our results concerning this Friedel–Crafts
benzylation of arenes using in situ activation of benzylic alco-
hols8 or 1,1-diarylmethanols with XtalFluor-E to generate
1,1-diarylmethanes or 1,1,1-triarylmethanes respectively. In
addition, we present evidence that the reaction proceeds
through the in situ formation of an activated alkoxy-N,N-diethyl-
aminodifluorosulfane intermediate. Finally, the reactivity
observed herein demonstrates the potential of XtalFluor-E to
act as an equivalent of triflic anhydride in other transform-
ations where the ionization of a benzylic C–OH bond is
necessary.
Using the optimized conditions (Table 1, entry 3), we investi-
gated the use of various arene nucleophiles using 4-tert-butyl-
benzyl alcohol (4) and the results are shown in Table 2.
Various electron-rich or electron-neutral aromatic compounds9
could be used and the corresponding 1,1-diarylmethanes
could be isolated in good to excellent yield.10,11 Benzene or
slightly deactivated fluorobenzene generated better yields
when used as the co-solvent. More deactivated arenes, such as
chlorobenzene or α,α,α-trifluorotoluene provided only very low
yields (<5%) of the expected product and a polymer corres-
ponding to the self-polymerization of 4 was observed instead
(Scheme 1). Informatively, both acetanilide and phenylacetate
provided moderate to good yield of the corresponding
product.12 This result contrasts drastically with our previous
findings on the Friedel–Crafts of benzyl fluorides where no
conversion was observed with those arenes,3 suggesting that a
different mechanism may be operating.
We next evaluated the reactivity of various benzyl alcohols
under the optimized conditions using p-xylene as the nucleo-
phile (Table 3). Numerous substituents are fully tolerated,
including a phenyl group and halogens. In a few cases,
increasing the amount of XtalFluor-E and/or a longer reaction
time was necessary to obtain full conversion. The presence of a
methoxy group in para position was not tolerated as self-
polymerization was observed. Moving the methoxy in meta
position or replacing it by a less electro-donating substituent,
such as an acetoxy group, allowed the reactions to proceed as
expected. Surprisingly, the presence of a nitro group did not
prevent the reaction as it was the case with benzyl fluorides,3
again pointing toward a different mechanism. The use of
3-pyridinemethanol provided the desired product 27 in low NMR
yield demonstrating that heterocyclic-based alcohols could be
tolerated although further optimization will be necessary.
Finally, using 4-(chloromethyl)benzyl alcohol, a bifunctional
substrate bearing both a benzylic chloride and a benzylic
alcohol, a chemoselective reaction occurred on the hydroxyl
group and 28 was isolated in good yield.
Table 2 Benzylation of 4 with various arenesa,b
We then investigated the reactivity of secondary alcohols.
When 1-phenylethanol derivatives were used under the stan-
dard conditions, the desired products were observed, albeit in
low yields, along with numerous side-products (including
elimination products). In order to avoid any elimination, we
sought to produce 1,1,1-triarylmethanes from 1,1-diarylmetha-
nols, and the results are shown in Table 4. In all cases, the
desired product was obtained in good to excellent yield.
While investigating the FCB using benzylic alcohols, we
noticed a few results that contrasted with those obtained using
benzyl fluorides (vide supra). All of which suggested that the
initial steps in this system may be mechanistically distinct
from our previous work and this was confirmed by examining
the effect of added base. In the Friedel–Crafts reaction of
benzylic fluorides, the presence of base was shown to inhibit
a Isolated yield. b Ratio of regioisomers determined by 1H NMR
analysis with the major regioisomer shown. c Yield estimated by NMR.
d Reaction was run in a benzene–HFIP (9 : 1) mixture at 60 °C for 18 h.
e Reaction was run in a fluorobenzene–HFIP (9 : 1) mixture at 60 °C for
18 h. f Ratio of regioisomers (ortho : meta : para) determined by 1H
NMR analysis with the major regioisomer shown.
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Table 3 Benzylation of various benzyl alcohols with p-xylenea
a Isolated yield. b 2.0 equiv of XtalFluor-E were used. c Reaction time was 48 h. d Reaction time was 24 h. e Decomposition. f Reaction time was
72 h. g Yield estimated by NMR. h Reaction time was 18 h.
Table 4 Synthesis of 1,1,1-triarylmethanesa,b
a Isolated yield. b Ratio of regioisomers (ortho : meta : para) determined
by 1H NMR analysis. cReaction was run in a toluene–HFIP (9 : 1)
mixture.
Scheme 2 Mechanistic hypothesis and reactivity of a benzyl triflate
generated in situ. The BF4− counter-ion has been omitted for clarity.
the reaction through the neutralization of HF, the active cata-
lyst.3 In the present system, addition of 0.1 or 1 equivalent of a alkoxy-N,N-diethylaminodifluorosulfane (33).6,14 Ionization
base (NaHCO3 or 2,6-di(tert-butyl)-4-methylpyridine) had would provide a stabilized benzylic carbocation (34)15 along
limited effect on the reaction and the product was isolated in with diethylaminosulfinyl fluoride (35) after fluoride loss.16
similar yields.13 Based on those experiments and observations, The fact that using deactivated arenes as nucleophiles pro-
our current mechanistic hypothesis is shown in Scheme 2. The vided essentially a product corresponding to the self-polymer-
benzylic alcohol would react with XtalFluor-E to generate an ization of 4 (c.f. Scheme 1) suggests that this ionization step is
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irreversible as opposed to what has been observed by Bode for
the FCB of benzyl hydroxamates in the presence of BF3·Et2O.17
The benzylic carbocation 34 would react with the arene nucleo-
phile (Ar2–H) to produce the 1,1-diarylmethane product.
This proposal is further supported by the fact that, as
shown in Scheme 2, in situ generated benzyl triflate 36, which
bears some structural resemblance with the proposed alkoxy-
N,N-diethylaminodifluorosulfane intermediate 33, reacted in a
similar fashion providing the 1,1-diarylmethane 5 in an un-
optimized 65% isolated yield (89% NMR yield). Finally, while
in this system HFIP is not directly involved in the transformation,
the slight improvements observed in its presence (c.f. Table 1)
suggest that it may nevertheless facilitate the reaction, likely
because of its polar nature and high ionizing power.4
In summary, we have reported the Friedel–Crafts benzy-
lation of arenes using benzyl alcohols, which are activated in situ
with XtalFluor-E. A wide range of 1,1-diarylmethanes and
1,1,1-triarylmethanes can be prepared in moderate to excellent
yields. The reaction proceeds under experimentally simple and
mild conditions, without the need for a transition metal or a
strong Lewis acid. Notably, the reactivity observed herein
demonstrates the potential of XtalFluor-E to induce C–OH
bond ionization and SN1 reactivity of benzyl alcohols.
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This work was supported by the Canada Research Chair
Program, the Natural Sciences and Engineering Research 10 In all cases, the regioisomers could not be separated by
Council of Canada, the Canada Foundation for Innovation, flash chromatography.
FQRNT Centre in Green Chemistry and Catalysis (CGCC) and 11 The pure 1,1-diarylmethanes 6, 13–14 could not be
the Université Laval. We thank OmegaChem for a generous
gift of XtalFluor-E.
obtained during chromatography as they co-eluted with the
excess arene nucleophile.
12 We have no explanation up to now for the unusual ortho
selectivity observed. For a related case, see: S. Sinha,
B. Mandal and S. Chandrasekaran, Tetrahedron Lett., 2000,
41, 9109.
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