Catalytic Friedel–Crafts Reactions of Highly Electronically Deactivated Benzylic Alcohols

Article abstract of DOI:10.1002/anie.201612573

Highly electronically deactivated benzylic alcohols, including those with a CF₃ group adjacent to the OH-bearing carbon, undergo dehydrative Friedel–Crafts reactions upon exposure to catalytic Br?nsted acid in 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) solvent. Titration and kinetic experiments support the involvement of higher order solvent/acid clusters in catalysis.

Full text of DOI:10.1002/anie.201612573

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International Edition: DOI: 10.1002/anie.201612573
German Edition: DOI: 10.1002/ange.201612573
Friedel–Crafts Reactions
Catalytic Friedel–Crafts Reactions of Highly Electronically
Deactivated Benzylic Alcohols
´
Vuk D. Vukovic, Edward Richmond, Elꢀna Wolf, and Joseph Moran*
Abstract: Highly electronically deactivated benzylic alcohols,
including those with a CF3 group adjacent to the OH-bearing
carbon, undergo dehydrative Friedel–Crafts reactions upon
exposure to catalytic Brønsted acid in 1,1,1,3,3,3-hexafluoro-2-
propanol (HFIP) solvent. Titration and kinetic experiments
support the involvement of higher order solvent/acid clusters in
catalysis.
T
he Friedel–Crafts reaction is a transformation of central
importance for the synthesis of industrially relevant arenes
and heteroarenes.[1,2] The classical version requires stoichio-
metric quantities of Lewis acid and uses alkyl halides as
starting materials, which are often generated in a separate
step from alcohol precursors. Variants developed recently by
Bode and Stephan have expanded the scope of the Friedel–
Crafts reaction to include electronically deactivated benzylic
electrophiles through the use of benzylic N-methylhydroxa-
mic acids and fluorides, respectively (Figure 1a).[3] However,
like the classical version, these reactions require additional
steps for substrate preactivation and use stoichiometric
activating agents. The need to improve the step- and atom-
economy of the Friedel–Crafts reaction prompted the ACS
Green Chemistry Pharmaceutical Roundtable to designate the
development of catalytic versions starting directly from
alcohols, which produce water as the only stoichiometric by-
product, as a top priority for green chemistry.[4] Accordingly,
the past years have witnessed numerous reports of Lewis or
Brønsted acid catalyzed Friedel–Crafts reactions of electroni-
cally activated benzylic alcohols,[5–7] but the inability of the
reaction to accommodate electronically deactivated alcohols
remains a striking limitation. For example, the ferrocenium
hexafluoroantimonate boronic acid catalyst developed by
Hall and McCubbin—arguably the most active catalytic
system described to date—reaches its limits at primary
benzylic alcohols bearing modestly deactivating substituents,
and restricts access to highly fluorinated molecules of
potential interest to the pharmaceutical and agrochemical
industries (Figure 1b).[6i] Recently, we observed that hydro-
gen bonding interactions between Brønsted acid catalysts and
cocatalysts or solvents can have profound accelerating effects
and even change the kinetic concentration dependence in
catalytic substitution reactions of alcohols.[8] Herein, we
Figure 1. Friedel–Crafts reactions of highly electronically deactivated
benzylic electrophiles.
report that interactions between Brønsted acid catalysts and
solvents of low nucleophilicity known to form H-bond
clusters, such as hexafluoroisopropanol (HFIP),[9–11] can be
exploited to surpass current limitations of the catalytic
dehydrative Friedel–Crafts reaction by enabling reactivity of
highly electronically deactivated benzylic alcohols; including
those bearing a geminal CF3 group. This new method grants
access to deactivated, often highly fluorinated, diaryl-
methanes and diaryltrifluoroethanes from the corresponding
alcohol in a single catalytic step (Figure 1c). Mechanistic
experiments support the involvement of higher order solvent/
acid clusters and point to an SN1-type mechanism.
Initial experiments targeted Friedel–Crafts reactivity of
m-xylene with alcohol 1a, which was too deactivated for
catalysis by ferrocenium hexafluoroantimonate boronic
acid.[6i] To our delight, the simple conjugate acid,
HSbF6·6H2O, furnished modest yields of 2a under otherwise
identical conditions (Table 1, entry 1). Reactivity was
improved slightly using HFIP exclusively as the solvent
(Table 1, entry 2). TfOH furnished higher yields because of its
´
[*] V. D. Vukovic, Dr. E. Richmond, Dr. E. Wolf, Dr. J. Moran
University of Strasbourg, CNRS, ISIS UMR 7006
67000 Strasbourg (France)
E-mail: moran@unistra.fr
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
http://dx.doi.org/10.1002/anie.201612573.
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Table 1: Optimization of conditions.[a]
Table 2: Scope for deactivated primary benzylic alcohols.[a]
Entry
Catalyst
Solvent
x
Yield[b] [%]
1
2
3
4
5
6
7
8
HSbF6·6H2O
HSbF6·6H2O
TfOH
HFIP/MeNO2 (4:1)
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
CF3CH2OH
(CF3)3COH
MeNO2
THF
5
5
5
5
5
5
5
5
3
3
3
3
3
3
28
39
90
18
90
<1
<1
<1
83
19
69
FeCl3
Bi(OTf)3
HSbF6·6H2O[c]
NaSbF6
TFA
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
9
10
11
12
13
14
<1
<1
<1
Toluene
[a] All experiments were conducted in sealed reaction tubes. [b] Isolated
yields of a mixture of regioisomers after silica gel chromatography. See
Supporting Information for details. [c] Conducted in the presence of
10 mol% Proton Sponge.
superior thermal stability compared to HSbF6·6H2O (Table 1,
entry 3). Other strong Lewis and Brønsted acids were also
effective (Table 1, entries 4–5). The addition of catalytic
quantities of base to the reaction mixture, or the use of
sodium salts or weaker Brønsted acids completely shut down
the reaction (Table 1, entries 6–8). Nucleophile excess could
be reduced to 3 equiv without a large drop in yield (Table 1,
entry 9). Other fluorinated protic solvents were less effective
(Table 1, entries 10–11) and several non-fluorinated common
solvents did not produce a detectable amount of 2a (Table 1,
entries 12–14).
[a] Yields of isolated products after column chromatography over silica.
[b] Performed with 20 mol% TfOH. [c] Combined yield of regioisomers.
See the Supporting Information for more details. [d] Reaction time was
48 h. [e] Performed with 10 mol% HSbF6·6H2O as catalyst, 808C.
[f] Performed with 5 equiv of nucleophile. [g] Performed at 508C, 30 min.
[h] Performed at 508C, 1 h.
A variety of electronically deactivated primary benzylic
alcohols and arene nucleophiles were examined to assess the
scope of the transformation (Table 2). Benzylic alcohols
substituted with single CN, NO2, SF5, and CF3 groups reacted
efficiently (2b–e). Impressively, benzylic alcohols bearing up
to two CF3 groups, two NO2 groups, or up to five fluorine
atoms on the aromatic ring were well-tolerated (2 f–l).
Heteroaromatic nucleophiles were unfortunately not com-
patible with the reaction conditions.[12] Pleasingly, less acti-
vated nucleophiles such as benzene, fluorobenzene, 1-bromo-
2-fluorobenzene, and 1,3-difluorobenzene are tolerated,
albeit in lower yield (2m–p).
Success with highly deactivated benzylic alcohols
prompted us to explore the possibility that carbenium ions
with adjacent electron-withdrawing groups might be gener-
ated and trapped directly from the alcohol in a catalytic
manner. a-Trifluoromethyl cations are synthetically valuable
intermediates but difficult to form from the alcohol with
catalytic turnover because of a high activation barrier.
Consequently, the desired reactivity has previously only
been accessed by stepwise or in situ pre-activation of alcohols
using stoichiometric activating agents, or in concentrated
H2SO4.[13–15] Gratifyingly, our standard conditions provide the
first example of catalytic access to a-trifluoromethyl cations
directly from a-trifluoromethyl benzylic alcohols, as indicated
by direct dehydrative Friedel–Crafts reactions with a range of
nucleophiles (Table 3). This reaction provides an efficient
catalytic route to nonsymmetric fluorinated analogues of the
insecticide DDT, complementing existing routes to symmetric
analogues.[15,16] The parent a-trifluoromethyl benzylic alco-
hol, and analogues thereof bearing an electron-donating
substituent on the aromatic ring, furnished the desired
diarylmethanes in good to excellent yields (3a–i). Naphthyl-
derived alcohols are well-tolerated by the reaction system
(3j–k). Analogues bearing halogens on the aromatic ring
provide the product diarylmethanes in more modest synthetic
yields (3l–n), but nevertheless offer a handle for further
functionalization through metal-catalyzed cross-coupling
reactions.
To evaluate whether factors beyond the appealing bulk
properties of HFIP solvent might be crucial to expanding the
limits of the dehydrative Friedel–Crafts reaction, a solution of
pentafluorobenzyl alcohol (1b) in HFIP was titrated with
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Table 3: Scope of diaryltrifluoroethanes.[a]
Figure 2. 1H NMR titration of a mixture of HFIP (1 equiv) and 1b
(0.050 equiv) with TfOH (C6D6 as external standard). Spectra were
acquired in the presence of the following quantities of TfOH:
a) 0 mol%; b) 0.5 mol%; c) 5 mol%; d) 10 mol%; e) 43 mol%;
f) 110 mol%.
conditions led to a near complete loss of stereochemical
information in the product; this result is consistent with the
intermediacy of a carbenium ion adjacent to the CF3 group
[Eq. (1)].
[a] Yields of isolated products after column chromatography over silica.
[b] Performed with 20 mol% TfOH. [c] Performed with 10 mol% TfOH.
[d] Combined yield of regioisomers. See the Supporting Information for
more details. [e] Reaction performed at 758C.
1
TfOH and monitored by H NMR (Figure 2). In addition to
fast proton exchange between TfOH and the OH proton of
HFIP (Hx and Hy, respectively), an increasingly downfield
shift of the HFIP methine proton (Hz) was observed with
increasing concentrations of TfOH. In contrast, fast proton
exchange was not observed between TfOH and the OH
proton of 1b (Hn); nor was the signal corresponding to the
methylene protons of 1b (Hm) observed to shift during the
titration, indicating that TfOH preferentially donates H-
bonds to HFIP rather than 1b. Mixed ethers resulting from
dehydrative condensation of HFIP and 1b were not observed,
ruling out the possibility that HFIP ethers serve as a reservoir
of benzylic cations.[3a,10e] However, in the absence of arene
nucleophile, ethers resulting from the dehydrative dimeriza-
tion of 1b were observed to form in small quantities when
higher catalyst loadings (> 40 mol% TfOH) were employed.
Initial rate kinetics experiments using benzene as nucleophile
revealed a first order kinetic concentration dependence on
TfOH and a fifth order concentration dependence on HFIP.[17]
Finally, the reaction of (À)-1d with p-xylene under standard
Taken together, the titration, initial rate kinetics and
racemization experiments, and the lack of observation of
a “carbenium reservoir” support an SN1-type mechanism
where HFIP serves to interact with the Brønsted acid to
generate higher order mixed aggregates that are superior (and
thus the kinetically competent) catalytic species for the
ionization of benzylic alcohols. The underappreciated role
of HFIP as an H-bond acceptor[18] with strong Brønsted acids,
and the importance of aggregation, lends mechanistic insight
into the apparently critical inclusion of HFIP in several other
Brønsted acid catalyzed reactions that have been reported
recently.[10,19]
In conclusion, we have described a simple catalytic system
that significantly pushes the boundaries of the dehydrative
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i) L. Chen, X.-P. Yin, C.-H. Wang, J. Zhou, Org. Biomol. Chem.
2014, 12, 6033; j) M. Dryzhakov, E. Richmond, J. Moran,
Synthesis 2016, 935; see also Ref [2d].
Friedel–Crafts reaction to incorporate highly electronically
deactivated benzylic alcohols, including those with a CF3
group adjacent to the OH-bearing carbon. Interactions
between the Brønsted acid and HFIP generates catalytically
active aggregates in which the H-bond accepting ability of
HFIP plays an important role. Further studies are underway
to exploit this operationally simple approach to promote
a wide variety of Brønsted acid catalyzed transformations that
do not otherwise proceed in traditional solvents.
[6] For selected intermolecular examples, see: a) T. Tsuchimoto, K.
Tobita, T. Hiyama, S. Fukuzawa, Synlett 1996, 557; b) T.
Tsuchimoto, K. Tobita, T. Hiyama, S. Fukuzawa, J. Org. Chem.
1997, 62, 6997; c) K. Mertins, I. Iovel, J. Kischel, A. Zapf, M.
Beller, Angew. Chem. Int. Ed. 2005, 44, 238; Angew. Chem. 2005,
117, 242; d) I. Iovel, K. Mertins, J. Kischel, A. Zapf, M. Beller,
Angew. Chem. Int. Ed. 2005, 44, 3913; Angew. Chem. 2005, 117,
3981; e) J. Choudhury, S. Podder, S. Roy, J. Am. Chem. Soc. 2005,
127, 6162; f) P. G. Cozzi, L. Zoli, Angew. Chem. Int. Ed. 2008, 47,
4162; Angew. Chem. 2008, 120, 4230; g) M. Niggemann, M. J.
Meel, Angew. Chem. Int. Ed. 2010, 49, 3684; Angew. Chem. 2010,
122, 3767; h) E. Wolf, E. Richmond, J. Moran, Chem. Sci. 2015, 6,
2501; i) X. Mo, J. Yakiwchuk, J. Danserau, J. A. McCubbin, D. G.
Hall, J. Am. Chem. Soc. 2015, 137, 9694; j) H. Feng, M. Patel, F.
Luo, C. Flach, R. Mendelsohn, E. Garfunkel, H. He, M. Szostak,
J. Am. Chem. Soc. 2015, 137, 14473.
[7] For examples specific to propargylic benzylic alcohols, see: a) Y.
Nishibayashi, Y. Inada, M. Yoshikawa, M. Hidai, S. Uemura,
Angew. Chem. Int. Ed. 2003, 42, 1495; Angew. Chem. 2003, 115,
1533; b) M. Georgy, V. Boucard, J.-M. Campagne, J. Am. Chem.
Soc. 2005, 127, 14180; c) H. Matsuzawa, Y. Miyake, Y. Nishi-
bayashi, Angew. Chem. Int. Ed. 2007, 46, 6488; Angew. Chem.
2007, 119, 6608.
Acknowledgements
This project has received funding from the European
Research Council (ERC) under the European Unionꢀs
Horizon 2020 research and innovation programme (grant
agreement no 639170). Further funding was provided by
grants from LabEx “Chemistry of Complex Systems” and the
Marie Curie Actions FP7-PEOPLE Program (CIG-2012-
326112). V.D.V. and E.W. thank the French government for
MRT fellowships.
[8] M. Dryzhakov, M. Hellal, E. Wolf, F. C. Falk, J. Moran, J. Am.
Chem. Soc. 2015, 137, 9555.
Conflict of interest
[9] a) J.-P. Bꢂguꢂ, D. Bonnet-Delpon, B. Crousse, Synlett 2004, 18;
b) D. Vuluga, J. Legros, B. Crousse, A. M. Z. Slawin, C.
Laurence, P. Nicolet, D. Bonnet-Delpon, J. Org. Chem. 2011,
76, 1126; For the lifetime of dialkylcarbocations in HFIP, see:
c) J. P. Pezacki, D. Shukla, J. Lusztyk, J. Warkentin, J. Am. Chem.
Soc. 1999, 121, 6589.
The authors declare no competing financial interest.
Keywords: alcohols · Brønsted acid catalysis · carbenium ion ·
Friedel–Crafts · hexafluoro-2-propanol
[10] For examples of HFIP-enabled strong Brønsted acid catalyzed
reactions, see: a) A. Saito, M. Takayama, A. Yamazaki, J.
Numaguchi, Y. Hanzama, Tetrahedron 2007, 63, 4039; b) H. F.
Motiwala, Charaschanya, V. W. Day, J. Aubꢂ, J. Org. Chem.
2016, 81, 1593; c) X. Zeng, S. Liu, B. Xu, Org. Lett. 2016, 18,
4770; d) W. Liu, H. Wang, C.-J. Li, Org. Lett. 2016, 18, 2184; e) T.
Kamitanaka, K. Morimoto, K. Tsuboshima, D. Koseki, H.
Takamuro, T. Dohi, Y. Kita, Angew. Chem. Int. Ed. 2016, 55,
15535; Angew. Chem. 2016, 128, 15764.
[11] For examples of Friedel–Crafts and related reactions that are
promoted or assisted by fluorinated alcohol solvents, see: a) M.
Hofmann, N. Hampel, T. Kanzian, H. Mayr, Angew. Chem. Int.
Ed. 2004, 43, 5402; Angew. Chem. 2004, 116, 5518; b) M. Willot,
J. Chen, J. Zhu, Synlett 2009, 577; c) G.-X. Li, J. Qu, Chem.
Commun. 2010, 46, 2653; d) D. Petruzziello, A. Gualandi, S.
Grilli, P. G. Cozzi, Eur. J. Org. Chem. 2012, 6697; e) P. Trillo, A.
Baeza, C. Najera, J. Org. Chem. 2012, 77, 7344; f) J. Xiao, K.
Zhao, T. P. Loh, Chem. Commun. 2012, 48, 3548; g) F.-Z. Zhang,
Y. Tian, G.-X. Li, J. Qu, J. Org. Chem. 2015, 80, 1107; h) N.
Weisner, M. G. Khaledi, Green Chem. 2016, 18, 681; i) R. H.
Vekariya, J. Aubꢂ, Org. Lett. 2016, 18, 3534.
[12] Heterocyclic nucleophiles, including 2-methylfuran and 2-meth-
ylthiophene, decomposed under the reaction conditions. More
surprisingly, the use of methoxybenzene derivatives resulted in
no reaction and returned unchanged starting materials.
[13] For a review, see: X. Creary, Chem. Rev. 1991, 91, 1625.
[14] For generation of a-trifluoromethyl cations from tosylates,
triflates, bromides, and p-nitrobenzoates, see: a) A. D. Allen,
I. C. Ambridge, C. Che, H. Michael, R. J. Muir, T. T. Tidwell, J.
Am. Chem. Soc. 1983, 105, 2343; b) A. D. Allen, R. Girdhir,
M. P. Jansen, J. D. Mayo, T. T. Tidwell, J. Org. Chem. 1986, 51,
1324; c) J. P. Richard, J. Am. Chem. Soc. 1986, 108, 6819; d) J. P.
Richard, J. Chem. Soc. Chem. Commun. 1987, 1768; e) J. P.
[1] C. Friedel, J. M. Crafts, C. R. Hebd. Seances Acad. Sci. 1877, 84,
1450.
[2] For reviews, see: a) C. C. Price, Org. React. 1946, 3, 1; b) R. M.
Roberts, A. A. Khalaf, Friedel – Crafts Alkylation Chemistry: A
Century of Discovery, Marcel Dekker, New York, 1984; c) S. C.
Eyley, Compr. Org. Synth. 1991, 2, 707; d) M. Rueping, B. J.
Nachtsheim, Beilstein J. Org. Chem. 2010, 6, 6.
[3] a) G. Schꢁfer, J. W. Bode, Angew. Chem. Int. Ed. 2011, 50, 10913;
Angew. Chem. 2011, 123, 11105; b) J. Zhu, M. Pꢂrez, D. W.
Stephan, Angew. Chem. Int. Ed. 2016, 55, 8448; Angew. Chem.
2016, 128, 8588. For related methods for non-highly deactivated
benzylic fluorides, see: c) P. A. Champagne, Y. Benhassine, J.
Desroches, J.-F. Paquin, Angew. Chem. Int. Ed. 2014, 53, 13835;
Angew. Chem. 2014, 126, 14055; d) R. Hemelaere, P. A. Cham-
pagne, J. Desroches, J.-F. Paquin, J. Fluorine Chem. 2016, 190, 1.
[4] D. J. C. Constable, P. J. Dunn, J. D. Hayler, G. R. Humphrey,
J. J. L. Leazer, R. J. Linderman, K. Lorenz, J. Manley, B. A.
Pearlman, A. Wells, A. Zaks, T. Y. Zhang, Green Chem. 2007, 9,
411.
[5] For reviews covering the direct dehydrative Friedel–Crafts
reactions of alcohols, see: a) M. Bandini, M. Tragni, Org.
Biomol. Chem. 2009, 7, 1501; b) P. G. Cozzi, F. Benfatti,
Angew. Chem. Int. Ed. 2010, 49, 256; Angew. Chem. 2010, 122,
264; c) M. Bandini, Angew. Chem. Int. Ed. 2011, 50, 994; Angew.
Chem. 2011, 123, 1026; d) E. Emer, R. Sinisi, M. G. Capdevila,
D. Petruzziello, F. De Vincentiis, P. G. Cozzi, Eur. J. Org. Chem.
2011, 647; e) B. Sundararaju, M. Achard, C. Bruneau, Chem. Soc.
Rev. 2012, 41, 4467; f) R. Kumar, E. V. Van der Eycken, Chem.
Soc. Rev. 2013, 42, 1121; g) R. R. Naredla, D. A. Klumpp, Chem.
Rev. 2013, 113, 6905; h) A. Baeza, N. Carmen, Synthesis 2014, 25;
4
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Richard, J. Am. Chem. Soc. 1989, 111, 1455; f) J. P. Richard,
Tetrahedron Lett. 1989, 30, 23; g) J. Kwong-Chip, T. T. Tidwell,
Tetrahedron Lett. 1989, 30, 1319.
b) A. Berkessel, J. A. Adrio, D. Hꢃttenhain, J. M. Neudçrfl, J.
Am. Chem. Soc. 2006, 128, 8421.
À
[18] For HFIP as an H-bond acceptor with the N H bond of
piperidine, see: J.-F. Berrien, M. Ourꢂvitch, G. Morgant, N. E.
Ghermani, B. Crousse, D. Bonnet-Delpon, J. Fluorine Chem.
2007, 128, 839.
[15] E. D. Bergmann, Z. Pelchowicz, A. Shani, Isr. J. Chem. 1963, 1,
129.
[16] For a route to symmetric fluoro analogues of DDT from
fluorinated hemiacetals, see: G. K. S. Prakash, F. Paknia, T.
Matthew, G. Mloston, J. P. Joschek, G. A. Olah, Org. Lett. 2011,
13, 4128.
[19] Previously, only the H-bond donating role of HFIP was discussed
with regard to its accelerating effect on Brønsted acid catalyzed
reactions (Ref [10d]).
[17] Pentane was employed as an inert cosolvent and the kinetic
order in HFIP changed across concentration regimes. See
Supporting Information for details. For an example of higher
order kinetic dependence on HFIP in olefin epoxidation, see:
a) A. Berkessel, J. A. Adrio, Adv. Synth. Catal. 2004, 346, 275;
Manuscript received: December 27, 2016
Final Article published: && &&, &&&&
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Communications
Friedel–Crafts Reactions
´
V. D. Vukovic, E. Richmond, E. Wolf,
J. Moran*
&&&& — &&&&
Catalytic Friedel–Crafts Reactions of
Highly Electronically Deactivated Benzylic
Alcohols
More than a solvent: The use of the
fluorinated solvent 1,1,1,3,3,3-hexafluoro-
2-propanol (HFIP) and a catalytic amount
of a strong Brønsted acid enables dehy-
drative Friedel–Crafts reactions of highly
deactivated benzylic alcohols. Mixed
aggregates of acid and HFIP are likely to
be involved in the catalysis.
6
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