Oxidative para- Triflation of acetanilides

Article abstract of DOI:10.1021/ol400604e

Direct triflation of acetanilide derivatives with silver triflate has been accomplished under mild iodine(III)-mediated oxidative conditions. The reaction shows excellent regioselectivity for the para position and tolerates a range of ortho and meta substituents on the aromatic ring. This method is also compatible with the preparation of arylnonaflates in synthetically useful yields.

Full text of DOI:10.1021/ol400604e

ORGANIC
LETTERS
2013
Vol. 15, No. 7
1764–1767
Oxidative para-Triflation of Acetanilides
ꢀ
Amelie Pialat, Benoıt Liegault,* and Marc Taillefer*
ꢀ
ˆ
Institut Charles Gerhardt, UMR-CNRS 5253, AM2N
0ꢀ
ENSCM, 8 rue de l ecole normale, 34296 Montpellier Cedex 5, France
benoit.liegault@enscm.fr
Received March 6, 2013
ABSTRACT
Direct triflation of acetanilide derivatives with silver triflate has been accomplished under mild iodine(III)-mediated oxidative conditions.
The reaction shows excellent regioselectivity for the para position and tolerates a range of ortho and meta substituents on the aromatic ring. This
method is also compatible with the preparation of arylnonaflates in synthetically useful yields.
Aryltriflates (or aryltrifluoromethanesulfonates) consti-
tute a family of very versatile reagents that can notably
be used as electrophilic coupling partners in transition
metal-catalyzed cross-coupling reactions.1 They offer an
alternative to other (pseudo)halide derivatives, while dif-
fering not only by their synthetic accessibility but also by
their reactivity,1a,2,3 which can sometimes be essential for
their successful transformation into more elaborated
products.4 Moreover, aryltriflates bearing a trimethylsilyl
group at the ortho position are the most convenient aryne
precursors.5 Also, a recent study has shown that the
aryltriflate moiety has the ability to improve the biological
activity of some medicinal compounds.6
The preparation of aryltriflates almost exclusively relies
on the use of phenols and a source of electrophilic triflate,
typically the highly moisture sensitive triflic anhydride,
or for better selectivity, practical but expensive N-phenyl-
triflimide (Scheme 1).2,7 Furthermore, the preparation
of highly substituted substrates can sometimes be seriously
challenging, due to the lengthy/difficult access to the starting
phenol derivatives.
(1) (a) For reviews on transition metal-catalyzed coupling reactions
involving aryltriflates, see: (a) Hartwig, J. F. Angew. Chem., Int. Ed.
ꢀ
1998, 37, 2046–2067. (b) Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.;
Scheme 1. Synthesis of para-Amido Aryltriflates using Electro-
philic and Nucleophilic Triflate Sources
Lemaire, M. Chem. Rev. 2002, 102, 1359–1470. (c) Metal-Catalyzed
Cross-Coupling Reactions; de Meijere, A., Diederich, F., Eds.; Wiley-VCH:
New York, 2004.
(2) For reviews on the preparation and applications of aryltriflates,
see: (a) Stang, P. J.; Hanack, M.; Subramanian, L. R. Synthesis 1982, 85–
126. (b) Ritter, K. Synthesis 1993, 735–762.
(3) Aryltriflates have been shown to react preferentially over bro-
mides and chlorides in palladium-catalyzed cross-coupling reactions,
see: (a) Ikawa, T.; Barder, T. E.; Biscoe, M. R.; Buchwald, S. L. J. Am.
Chem. Soc. 2007, 129, 13001–13007. However, this trend seems to be
inverted when using boronic acids as coupling partners; see: (b) Espino,
G.; Kurbangalieva, A.; Brown, J. M. Chem. Commun. 2007, 1742–1744
and references therein.
(4) For a representative example where only aryltriflates (as opposed
to other aryl (pseudo)halides) are efficient coupling partners, see:
Watson, D. A.; Su, M.; Teverovskiy, G.; Zhang, Y.; Garcıa-Fortanet,
´
J.; Kinzel, T.; Buchwald, S. L. Science 2009, 325, 1661–1664.
(5) Due to its mild reaction conditions, Kobayashi’s method for the
generation of aryne intermediates from o-(trimethysilyl)aryltriflates is
the most attractive to date. For recent reviews, see: (a) Bhunia, A.; Yetra,
A. R.; Biju, A. T. Chem. Soc. Rev. 2012, 41, 3140–3152. (b) Tadross,
P. M.; Stoltz, B. M. Chem. Rev. 2012, 112, 3550–3577. (c) Dubrovskiy,
A. V.; Markina, N. A.; Larock, R. C. Org. Biomol. Chem. 2013, 11, 191–
218.
Oxidative aromatic umpolung reactions represent a class
ofveryuseful processes, which have notably been exploited
(6) Moriconi, A.; Bigogno, C.; Bianchini, G.; Caligiuri, A.; Resconi,
A.; Dondio, M. G.; D’Anniballe, G.; Allegretti, M. ACS Med. Chem.
Lett. 2011, 2, 768–773.
r
10.1021/ol400604e
Published on Web 03/27/2013
2013 American Chemical Society

in the area of phenol dearomatization.8 Toward this goal,
hypervalent iodine reagents have emerged as the reagents
of choice due to their ease of handling, their low toxicity
and their commercial availability.8b,9 These strategies
also provide interesting opportunities for the nucleophilic
functionalization, with subsequent rearomatization, of
electron-rich arenes. In this context, the use of aniline
derivatives has remained scarce.10,11
AgOTf (1.2 equiv) in the presence of BTI in DCE at 20 °C
over 1 h (Table 1, entry 10).12 Running the reaction
with a Lewis acid as an additive (Table 1, entry 11)13 or in
fluorinated solvents, such as hexafluoro-iso-propanol
(Table 1, entry 12)10a,c,e did not improve the yields.
Table 1. Optimization of Reaction Conditionsa
Herein we describe the iodine(III)-mediated para-
functionalization of acetanilides employing triflates as
nucleophiles (Scheme 1). Under mild reaction conditions,
the use of easy-to-handle reagents allows a direct access
to a range of functionalized aryltriflates in moderate to
good yields. As well, this method has been extended to the
preparation of arylnonaflates.
entry triflate (x equiv)
I(III)
solvent time (h)
yieldb
1d Cu(OTf)2 (0.1 equiv) PhI(OAc)2
CHCl3
CHCl3
CHCl3
CHCl3
24
4
4
4
4
1
1
1
1
1
1
1
7% (4%)c
54%
This reactivity was initially discovered during our
studies on the development of copper-catalyzed anilide
functionalization reactions. Under conditions employing
acetanilide 1a, 10 mol % of Cu(OTf)2 and 1.5 equiv of
PhI(OAc)2 (DIB) in CHCl3 at 60 °C, trace amounts of
aryltriflate 2a were isolated (Table 1, entry 1). Based on
this intriguing result, a reaction employing an excess
of copper(II) triflate at room temperature for 4 h was
attempted. Product 2a was obtained in a moderate,
but promising, yield of 54% (Table 1, entry 2). Several
parameters were then evaluated in order to optimize
the reaction conditions, including the triflate source, the
iodine(III) oxidant, the nitrogen-protecting group and the
solvent. A general trend first emerged in which combina-
tions of either DIB in CHCl3 or PhI(OCOCF3)2 (BTI) in
dichloroethane gave the best results. The triflate source
was found to play a crucial role for the desired reactivity.
Whereas Cu(OTf)2, Zn(OTf)2, Fe(OTf)2 and Ce(OTf)3
offered moderate yields (and low reproducibility in some
cases), CuOTf (as its toluene complex form), NaOTf
and KOTf were found to be much less efficient (Table 1,
entries 2ꢀ5 vs entries 6ꢀ8). Finally, aryltriflate 2a was
obtained in 66% isolated yield from acetanilide 1a and
2
3
4
5
6
7
8
9
Cu(OTf)2 (2.0 equiv) PhI(OAc)2
Zn(OTf)2 (2.0 equiv) PhI(OAc)2
Fe(OTf)2 (2.0 equiv) PhI(OAc)2
49%
45%
Ce(OTf)3 (2.0 equiv) PhI(OCOCF3)2 DCE
CuOTff (2.0 equiv) PhI(OAc)2
CHCl3
(1.2 equiv) PhI(OCOCF3)2 DCE
(1.2 equiv) PhI(OCOCF3)2 DCE
52%
11%
NaOTf
KOTf
7%
4%
AgOTf
(2.0 equiv) PhI(OAc)2
CHCl3
60% (58%)c
70% (66%)c
26%
10 AgOTf
11e AgOTf
12 AgOTf
(1.2 equiv) PhI(OCOCF3)2 DCE
(1.2 equiv) PhI(OCOCF3)2 DCE
(1.2 equiv) PhI(OCOCF3)2 HFIP
trace
a Reactions performed on 0.25 mmol scale. b Determined by 19F NMR
analysis of the crude reaction mixture, in methanol-d4, using 4,40-difluoro-
benzophenone as an internal standard. c Isolated yield. d Reaction
performed at 60 °C. e BF3 OEt2 (1.2 equiv) was used as an additive.
3
f (CuOTf)2 toluene complex.
3
The scope of the iodine(III)-mediated oxidative para-
triflation was next investigated with diversely substituted
acetanilides (Scheme 2). Aryltriflates bearing halides 2bꢀe
and 2kꢀn, trifluoromethyl 2f and carbonyl-derived func-
tional groups 2g, 2m and 2n, at the ortho or meta position,
were prepared in yields ranging from 45% for 2f to 84%
for 2e. A small increase in temperature (from 20 to 50 °C)
was sometimes necessary to obtain complete conversions,
probably due to electronic/steric factors. Valuable amido-
substituted aryne precursor5 2o could be isolated in
a modest 41% yield, which remains synthetically useful
when compared to lengthy traditional methods for its
preparation (typically 5ꢀ6 steps from commercially avail-
able o-halophenol).14 The presence of electron-neutral
or -donating alkyl or methoxy groups on the aromatic
ring proved tobe morechallenging, owing totheformation
of unidentified oxidative byproducts. Indeed, 3-methyl
and 2-methyl aryltriflates 2h and 2p were obtained in
28 and 26% yield, respectively. Running the reaction
at ꢀ20 °C or with slow addition of anilide 1h still led to
full consumption of the starting material but was not more
(7) For representative examples of electrophilic triflation of phenol
derivatives, see: (a) Comins, D. L.; Dehghani, A. Tetrahedron Lett. 1992,
33, 6299–6302. (b) Baraznenok, I. L.; Nenajdenko, V. G.; Balenkova,
E. S. Tetrahedron 2000, 56, 3077–3119. (c) Frantz, D. E.; Weaver, D. G.;
Carey, J. P.; Kress, M. H.; Dolling, U. H. Org. Lett. 2002, 4, 4717–4718.
(d) Bengtson, A.; Hallberg, A.; Larhed, M. Org. Lett. 2002, 4, 1231–
1233.
(8) For reviews on oxidative dearomatization reactions, see: (a)
ꢀ
Quideau, S.; Pouysegu, L.; Deffieux, D. Synlett 2008, 66, 467–495. (b)
ꢀ
Pouysegu, L.; Deffieux, D.; Quideau, S. Tetrahedron 2010, 66, 2235–
2261. (c) Roche, S. P.; Porco, J. A., Jr. Angew. Chem., Int. Ed. 2011, 50,
4068–4093.
(9) For reviews on hypervalent iodine chemistry, see; (a) Zhdankin,
V. V.; Stang, P. J. Chem. Rev. 2008, 108, 5299–5358. (b) Zhdankin, V. V.
ARKIVOC 2009, 1–62.
(10) For iodine(III)-mediated nucleophilic aromatic functionaliza-
tion of anilide derivatives, see: (a) Itoh, N.; Sakamoto, T.; Miyazawa, E.;
Kikugawa, Y. J. Org. Chem. 2002, 67, 7424–7428. (b) Karade, N. N.;
Tiwari, G. B.; Huple, D. B.; Siddiqui, T. A. J. J. Chem. Res. 2006, 366–
(12) AgOTf and BTI are affordable and easy-to-handle solids that
can be stored in a desiccator and weighed to air without precaution.
(13) It has been proposed that BF3 OEt2 can activate BTI by means
of coordination to the trifluoroacetoxy ligand; see: Dohi, T.; Ito, M.;
Morimoto, K.; Iwata, M.; Kita, Y. Angew. Chem., Int. Ed. 2008, 47,
1301–1304. See also reference 10d.
ꢀ
368. (c) Jean, A.; Cantat, J.; Berard, D.; Bouchu, D.; Canesi, S. Org.
Lett. 2007, 9, 2553–2556. (d) Liu, H.; Wang, X.; Gu, Y. Org. Biomol.
Chem. 2011, 9, 1614–1620. (e) Samanta, R.; Lategahn, J.; Antonchick,
3
ꢀ
A. P. Chem. Commun. 2012, 48, 3194–3196. (f) Jacquemot, G.; Menard,
M.-A.; L’Homme, C.; Canesi, S. Chem. Sci. 2013, 4, 1287–1292.
(11) During the preparation of this manuscript, the para-fluorination
of N-pivaloyl anilines was also reported; see: Tian, T.; Zhong, W.-H.;
Meng, S.; Meng, X.-B.; Li, Z.-J. J. Org. Chem. 2013, 78, 728–732.
(14) Brown, N.; Luo, D.; Velde, D. V.; Yang, S.; Brassfield, A.;
Buszek, K. R. Tetrahedron Lett. 2009, 50, 63–65.
Org. Lett., Vol. 15, No. 7, 2013
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reactions.1 This aspect can conveniently be circumvented
with the use of analogous arylnonaflates, less prone to
“OꢀSO2” cleavage.15,16 Fortunately, easily prepared and
bench-stable AgONf17 also showed good activity under
our optimized conditions and allowed us to synthesize
arylnonaflates 3a, 3e, 3l and 3r in moderate to good yields
(Scheme 3).
Scheme 2. Oxidative para-Triflation of Acetanilidesa,b
Scheme 3. Oxidative para-Nonaflation of Acetanilidesa,b
a Reactions performed on 0.5 mmol scale. b Isolated yield.
Although acetanilide starting materials 1 were found
to give the best results under the reaction conditions, other
N-protected anilines were also tested. Gratifyingly, aryltri-
flates 5aꢀc, with N-pivaloyl, -benzoyl and -benzyloxycar-
bonyl groups could be prepared, albeit in lower yields
(30ꢀ60%) than withthecorrespondingN-acetyl derivative
2a (Scheme 4). Importantly, a lone electron-withdrawing
substituent on the nitrogen atom is required. Indeed,
aniline 4d and N-methyl aniline 4e led to complete decom-
position, while N-methyl-N-acetyl aniline 4f was found to
be unreactive under the reaction conditions.
a Reactions performed on 0.5 mmol scale. b Isolated yield. c Reaction
performed on 5 mmol scale. d 20 °C. e 50 °C. f ꢀ20 °C.
Scheme 4. Oxidative para-Triflation of N-Substituted Anilinesa,b
successful. Following the same trend, product 2q was only
detected in trace amounts. Nevertheless, replacing the
methyl group on the oxygen atom by an acetyl entirely
restored the reactivity, providing aryltriflate 2r in 64%
yield. Of note, a reaction on a larger scale (5 mmol) was
realized and led to product 2a in 56% yield.
All aryltriflates described in Scheme 2 were found to
be bench stable and could be purified by standard silica gel
chromatography. However, product stability can some-
times be more problematic under harsher, basic condi-
tions, sometimes required in further functionalization
reactions such as transition metal-catalyzed coupling
a Reactions performed on 0.5 mmol scale. b Isolated yield. c Conditions
from Table 1 Entry 4 were used (DIB in CHCl3). d Complete decomposi-
tion of the starting material. e No reaction.
(15) For a review on the use of nonaflates in transition metal-
€
catalyzed couplings, see: Hogermeier, J.; Reissig, H.-U. Adv. Synth.
Catal. 2009, 351, 2747–2763.
(16) For recent applications of arylnonaflates, see: (a) Fors, B. P.;
Buchwald, S. L. J. Am. Chem. Soc. 2009, 131, 12898–12899. (b) Monzon,
G.; Knochel, P. Synlett 2010, 304–308. (c) Barluenga, J.; Florentino, L.;
From a mechanistic point of view, several scenarios
can be envisaged and preliminary experiments have been
ꢀ
Aznar, F.; Valdes, C. Org. Lett. 2011, 13, 510–513. (d) Ikawa, T.;
Nishiyama, T.; Nosaki, T.; Takagi, A.; Akai, S. Org. Lett. 2011, 13,
1730–1733. (e) Shekhar, S.; Dunn, T. B.; Kotecki, B. J.; Montavon,
D. K.; Cullen, S. C. J. Org. Chem. 2011, 76, 4552–4563. (f) Manabe, K.;
Kimura, T. Org. Lett. 2013, 15, 374–377.
€
(17) Hashmi, A. S.; Hengst, T.; Lothschutz, C.; Rominger, F. Adv.
Synth. Catal. 2010, 352, 1315–1337.
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Org. Lett., Vol. 15, No. 7, 2013

performed to gain some insight. First, a radical pathway
can most likely be ruled out since running the reaction
in the presence of radical scavengers, such as TEMPO or
1,1-diphenylethylene, only resulted in slightly decreased
product yields.18 As highlighted (Table 1, entry 12), the use
of hexafluoro-iso-propanol (HFIP) as the reaction solvent
has a dramatic effect on the reaction outcome. Not only
does it inhibit the formation of the desired aryltriflate
product, but it also favors the generation of diarylamide
byproduct 6, isolated in 21% yield (Scheme 5).10a,e Addi-
tionally, under optimized reaction conditions, no para-
amidophenol byproduct (arising from a potential compe-
titive nucleophilic attack of a trifluoroacetate moiety in the
reaction media) could be detected, in contrast to some
other similar processes.10,11
Scheme 6. Proposed Associative and Dissociative Mechanisms
Scheme 5. Isolation of Diarylamide Byproduct 6
high reactivity of silver triflate over alkaline triflates could
potentially be rationalized with the HSAB theory. Agþ
may “soften” the TfOꢀ anion, therefore faciliting its inter-
action with the soft anilide electrophile.22 As well, hard
Naþ or Kþ and TfOꢀ ions would be poorly dissociated in
the reaction media. Experimentally, we found that the
addition of AgNO3 or crown ethers to reactions conducted
with NaOTf or KOTf partially reestablished the reactivity
(13 and 19% with AgNO3, and 45 and 40% with 15-C-5
and 18-C-6, respectively).
In summary, we have developed an original and prac-
tical protocol for the iodine(III)-mediated oxidative para-
triflation of acetanilides under mild reaction conditions,
providing a range of substituted aryltriflates in moderate
to good yields and excellent regioselectivity. Replacement of
easy-to-handle AgOTf by AgONf as the nucleophile ex-
tended the method to the synthesis of several arylnonaflates.
Preliminary mechanistic studies suggest that an associative
pathway is probably operative. Further extensions of this
methodology are currently under investigation.
On the basis of the above remarks and literature
precedent,8b,9,10 we propose the following mechanism
(Scheme 6). Intermediate A is first generated by reaction
of anilide 1a with the electrophilic iodine(III) center. Next,
nucleophilic attack of the triflate ion occurs on the most
sterically accessible, electrophilic position, with concomi-
tant departure of iodobenzene and the (trifluoro)acetate
counterion. This associative bimolecular process, normally
favored in poorly polarizable solvents (such as CHCl3 and
DCE),19 would subsequently be followed by a deprotona-
tion/rearomatization step and produce aryltriflate 2a.20
Alternatively, HFIP would promote a dissociative pathway
in which free iodobenzene would react with the highly
electrophilic nitrenium species B and generate diarylamide 6.
The role of the metallic counterion is not clearly under-
stood at this stage. However, the differences in solubility
of the various triflate salts reported in Table 1 cannot
account for the yield discrepancies. Indeed, a rapid survey
showed that their solubilities are in the 1ꢀ6 mg.mLꢀ1
range (in CHCl3 or DCE), with NaOTf and KOTf being
the least and the most soluble, respectively.21 Finally, the
Acknowledgment. We thank the CNRS, ENSCM and
MENRT for a PhD grant (A.P.). Drs. Sophie Rousseaux,
Baptiste Lecachey and Eric Leclerc are also kindly
acknowledged for insightful discussions and critical read-
ing of this manuscript.
Supporting Information Available. Experimental pro-
cedures, characterization data and NMR spectra for all
new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
(18) (a) Cho, S. H.; Yoon, J.; Chang, S. J. Am. Chem. Soc. 2011, 133,
5996–6005. (b) Antonchick, A. P.; Samanta, R.; Kulikov, K.; Lategahn,
J. Angew. Chem., Int. Ed. 2011, 50, 8605–8608.
(19) For a similar observation, see: Dohi, T.; Maruyama, A.; Takenaga,
N.; Senami, K.; Minamitsuji, Y.; Fujioka, H.; Caemmerer, S. B.; Kita, Y.
Angew. Chem., Int. Ed. 2008, 47, 3787–3790.
(20) A ligand-coupling mechanism, involving a (4-amido-cyclo-
hexadienyl)(phenyl)-λ3-iodanyl triflate intermediate, can also not be
excluded. In such a process, the Agþ cation would facilitate the reductive
elimination step. However, the use of freshly prepared PhI(OTf)2 proved
to be unsuccessful. We thank a reviewer for pointing out this mechanistic
pathway.
(21) See Supporting Information for details.
(22) The role of Agþ as a soft counterion was recently demonstrated
in the trifluoromethylation-iodination of arynes; see: Zeng, Y.; Zhang,
L.; Zhao, Y.; Ni, C.; Zhao, J.; Hu, J. J. Am. Chem. Soc. 2013, 135, 2955–
2958.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 7, 2013
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