Reactions of triflate esters and triflamides with an organic neutral super-electron-donor

Article abstract of DOI:10.1039/c2ob25116g

The bis-pyridinylidene 13 converts aliphatic and aryl triflate esters to the corresponding alcohols and phenols respectively, using DMF as solvent, generally in excellent yields. While the deprotection of aryl triflates has been seen with other reagents and by more than one mechanism, the deprotection of alkyl triflates is a new reaction. Studies with ¹⁸O labelled DMF indicate that the C-O bond stays intact and hence it is the S-O bond that cleaves, underlining that the cleavage results from the extraordinary electron donor capability of 13. Trifluoromethanesulfonamides are converted to the parent amines in like manner, representing the first cleavage of such substrates by a ground-state organic reducing reagent.

Full text of DOI:10.1039/c2ob25116g

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COMMUNICATION
Reactions of triflate esters and triflamides with an organic neutral
super-electron-donor†‡
Phillip I. Jolly, Nadia Fleary-Roberts, Steven O’Sullivan, Eswararao Doni, Shengze Zhou and
John A. Murphy*
Received 15th January 2012, Accepted 20th February 2012
DOI: 10.1039/c2ob25116g
with some C–O cleavage;5c and solvolysis of particular aryl
The bis-pyridinylidene 13 converts aliphatic and aryl triflate
esters to the corresponding alcohols and phenols respectively,
using DMF as solvent, generally in excellent yields. While the
deprotection of aryl triflates has been seen with other
reagents and by more than one mechanism, the deprotection
of alkyl triflates is a new reaction. Studies with 18O labelled
DMF indicate that the C–O bond stays intact and hence it is
the S–O bond that cleaves, underlining that the cleavage
results from the extraordinary electron donor capability of
13. Trifluoromethanesulfonamides are converted to the
parent amines in like manner, representing the first cleavage
of such substrates by a ground-state organic reducing
reagent.
triflates in trifluoroethanol with K2CO35d gives C–O cleavage.6
In contrast, alkyl triflates are excellent alkylating agents even
towards mild nucleophiles, undergoing facile displacement of
triflate anion (C–O bond cleavage). Alkyl triflates are such sensi-
tive electrophiles that their deprotection to their parent aliphatic
alcohols (S–O bond cleavage) has never been reported. This con-
trasts with alkyl tosylates, for example, which have been reduced
to their parent alcohols.6a,b,d,e,g,i,k Reductive cleavage of triflates
was reported by Yus et al.4b,c and affected both alkyl and aryl
triflate esters, but with very divergent outcomes. For example,
the NiCl2–Li-arene (cat.) combination (using 4,4-di-tert-butyl-
biphenyl, DTBB, as arene) generated alkane 2 and alkene 4 from
respective alkyl and enol triflates 1 and 3, completely removing
the triflate group in the process (Scheme 1). It is notable that no
S–O bond cleavage was observed for alkyl triflates. However
less selectivity between C–O and S–O σ-bond scission was
observed when the reaction was applied to aryl triflates 5 and 6,
with mixtures of deoxygenated arenes and phenols 7–10 being
afforded.
The triflyl group makes important contributions in organic chem-
istry, due to its strong electron-withdrawing effect. Aryl and
alkyl triflamides act as protected and activated forms of aryl and
alkyl amines respectively, and have been particularly useful for
the preparation of secondary amines via the mono-alkylation of
primary triflamides.1 Deprotection of the product secondary
triflamides to the parent amine (S–N bond cleavage) is required
at the end of the synthetic sequence and reduction by LiAlH4 is
one successful approach to this deprotection,2 while Red-Al
cleaves primary and secondary triflamides.2 Aryl triflate esters
find extensive use in metal-mediated cross-coupling reactions,3
and in this regard they differ from other aryl sulfonate esters. In
addition, aryl triflates4a have also been used to modulate the
reactivity of aryl rings towards electrophiles at key stages during
synthetic sequences; once this role has been fulfilled, their
removal (C–O cleavage)4 to form arenes or deprotection (S–O
bond cleavage) to form their parent phenols is required; depro-
tection of aryl triflates has been accomplished with a number of
reagents,5 such as Et4NOH,5a LiAlH4;5b electrochemical
reduction affords mainly deprotection (S–O cleavage), together
We have recently developed a series of neutral, organic,
ground-state super-electron-donor (SED) reducing reagents
11–137,8 as a novel type of reagent, and so we are keen to
WestCHEM, Department of Pure and Applied Chemistry, University of
Strathclyde, 295 Cathedral Street, Glasgow, G1 1XL, UK. E-mail:
john.murphy@stratch.ac.uk
†This article is part of the Organic & Biomolecular Chemistry 10th
Anniversary issue.
‡Electronic supplementary information (ESI) available. See DOI:
10.1039/c2ob25116g
Scheme 1 Cleavage of triflates
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Scheme 2 Reactivity of SED reagents 11–13.
understand the scope of their reactivity. This Communication
now reports their reactions with triflate esters and triflamides.
These electron donors have already shown themselves to
perform many reactions that had never previously been achieved
with neutral organic electron donors. For example, efficient
single electron transfer (SET) from bisbenzimidazolylidene 11
[E1 = −0.82 V; E2 = −0.76 V vs. SCE in DMF]8d,e,g to
Scheme 3 Cleavage of triflates with donor 13.
1/2
1/2
unactivated aryl iodides (e.g. 14) and to alkyl iodides, generated
the corresponding aryl or alkyl radicals7a that were trapped by
alkenes affording cyclic products, such as 15, in high yield
(Scheme 2). The more powerful donor 12,7b [E1/2 (DMF) =
−1.20 V vs. SCE], was the first neutral organic ground-state mol-
ecule to generate aryl anions from aryl iodides via double elec-
tron transfer. Schoenebeck et al. further demonstrated its
reductive capabilities with cleavage of activated arenesulfones
e.g. 16–17 and also of activated arenesulfonamides in good to
excellent yields.7c The novel structure 13, easily prepared from
4-DMAP,7d [13, oxidation potential E1/2 (DMF) = −1.18 V vs.
SCE7d] has very similar reactivity to 12. It has successfully gen-
erated aryl anions from aryl iodides in excellent yield, as seen in
the cyclisation of substrate 18 to indanone 19. It also cleaves
activated sulfones,7d and mediates the N–O and C–O σ-bond
cleavage, respectively, of Weinreb amides7f and acyloin derivati-
ves.7h Compounds 12 and 13 are the strongest neutral ground-
state organic electron donors known, but 13 has a distinct advan-
tage compared to 12 as its synthesis is so easy, and so we were
keen to explore the reactivity of 13, in particular, with triflates
and triflamides.
alternative reaction that might be expected, where compound 13
acts as a nucleophile towards the excellent electrophiles 21–23,
rather than as an electron donor, would also lead to an aromatic
product, 29, and yet this outcome is not seen. This reflects
exceptional prowess of compound 13 as an electron donor. We
propose that the generic triflate 30 receives an electron from the
donor 13. The resulting radical–anion 31, undergoes very easy
fragmentation9 to afford a radical and anion pair. DFT (6-31G*)
calculations on the radical–anion of 21 show the SOMO deloca-
lized on the sulfonate unit; the radical anion shows a stretched
S–O bond (2.39 Å) and with the departing oxygen atom as the
negative end of that dipole (see ESI† file). Hence, in generic
terms, radical 32 + anion 33 are preferred over radical 35 +
anion 34, as the initial products of the fragmentation. A second
electron transfer should occur very rapidly in the highly reducing
medium from donor 13 or 27, converting the radical in either of
these radical–anion pairs, into the corresponding anion so that
the pair of anions 33 and 34 finally results.7c Acidification
should then afford the requisite alcohol together with trifluoro-
methanesulfinic acid.
Initial investigations were carried out with donor 13 and
primary aliphatic triflates 21–23 (Scheme 3). Under mild reac-
tion conditions using 1.5 equivalents of donor 13 in anhydrous
DMF at room temperature, triflates 21–23 afforded the corre-
sponding alcohols 24–26 cleanly and in excellent yield
(85–93%). These reactions are noteworthy. The driving force for
donor 13 to donate electrons derives from the aromaticity of its
oxidised products, radical–cation 27 and dication 28, as well as
from the ability of nitrogen to delocalise the positive charge. The
In principle, the formation of the alcohol 36 could occur by
other routes that were considered. Thus the observed alcohols
might have arisen from attack on the triflate substrates 30 by
DMF as nucleophile to give an imidate salt, 37, that would
hydrolyse to the alcohol 36 on aqueous work-up, or that could
be reduced by the donor 13 to the aminol ether 39; in turn, this
could be hydrolysed to the alcohol 36 on work-up. In these
DMF-mediated routes, the important point is that the oxygen
atom of DMF, shown in red in Scheme 3, ends up incorporated
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Scheme 4 Aryl triflate cleavage outcomes.
Scheme 5 Reactivity of substrates 45 and 47.
into the alcohol product. To address the possible involvement of
DMF as a nucleophile, DMF labelled with 18O (13% enrich-
ment) was prepared, and the reaction of triflate 21 with the donor
was repeated in this labelled DMF. This afforded alcohol 24
without incorporation of 18O, thereby ruling out this DMF-
mediated route to explain the alcohol formation. These exper-
iments support the cleavage of the alkyl triflates by reductive
electron transfer.
Extending our studies beyond alkyl triflates, reagent 13 was
found to be equally good at cleaving aryl triflate 40 to form
phenol 41 in 89% yield (Scheme 4). In this case with an aryl
triflate, the cleavage could be consistent with either a mechanism
involving attack by 13 as a nucleophile at the sulfonyl sulfur of
40, or with an electron transfer mechanism, as with the aliphatic
substrates 21–23. Given the strong preference for 13 to react as
an electron donor rather than as a nucleophile in reactions with
21–23, we suggest a similar pathway with the aryl triflates.
The electron transfer pathway predicts formation of triflinate
anion 34, and so we probed for this anion, arising from cleavage
of substrate 40. To this end, the cleavage of aryl triflate 40 was
repeated with subsequent addition of four equivalents of benzyl
bromide. After workup, purification by silica column and recrys-
tallisation, pure benzyltriflone 44 (91%) was isolated. This does
not prove that the electron transfer mechanism operated on the
aryl triflates, however, as the nucleophilic pathway would have
produced sulfone 42 as an intermediate. This would be likely to
fragment to disalt 43, where trifluoromethansulfinate is a
counter-ion to the nitrogen heterocycle. Hence addition of
benzyl bromide would again be expected to afford the sulfone
44.
Further substrates 45 and 47 were easily prepared from reac-
tion of triflic anhydride with corresponding phenols.10 Triflate
45 showed selective cleavage of the triflate S–O bond; interest-
ingly, the alkene was isomerised to the styrene 46 during the
reaction. We have previously seen the electron donors behaving
as bases, presumably protonating on the central CvC bond to
afford an aromatic product 50, and this example highlights their
basicity. The contrast with the aliphatic triflate substrates, which
do not act as proton donors to 13 (no elimination to alkenes was
Scheme 6 Cleavage of trifluoromethanesulfonamides.
observed) is notable. We have not determined the relative
sequence of alkene isomerisation and triflate cleavage from 45.
The reduction potentials of PhOTf and PhBr11 as individual
compounds are almost identical, Ered = −2.70 V vs. SCE for
PhBr, and −2.63 V for PhOTf, and so it was of interest to
explore the relative reactivity of these two closely matched elec-
trophores in p-bromophenyl triflate 47. DFT (6-31G*) calcu-
lations show the SOMO orbital dispersed over the whole
BrC6H4OSO2 unit (see ESI† file) although principally on the
C–Br bond. In the event, p-bromophenyl triflate 47 was reacted
with 1.5 equivalents of donor 13 at room temperature and
afforded p-bromophenol, 48, exclusively and in excellent yield
(84%), demonstrating the selective cleavage of triflate over
bromide functional group (Scheme 5). In looking for evidence of
reductive outcome from the experiment, we again looked for the
presence of the trifluoromethansulfinate anion in a repeat exper-
iment (Scheme 5). The experiment was worked-up following
stirring with benzyl bromide and afforded the benzyl ether 49
(88%) and the sulfone 44 (59%).
Finally, two examples of triflamides, 51 and 53, were investi-
gated (Scheme 6). Although they do not react appreciably at
room temperatures, when the reaction was conducted at 100 °C
and for 12 hours, cleavage was observed to afford amines 52
(53%) and 54 (40%). Reduction of triflamides is of course, a
much more difficult task than reduction of triflate esters, and it is
remarkable that this degree of cleavage is observed with a
neutral organic ground-state reagent.
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6 Additional methods have been reported for deprotection of aryl and alkyl
tosylates and tosylamides: (a) M. Sridhar, B. A. Kumar and R. Narender,
Tetrahedron Lett., 1998, 39, 2847–2850; (b) T. Ankner and
G. Hilmersson, Org. Lett., 2009, 11, 503–506; (c) E. R. Civitello and
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B. Goldstein, J. Org. Chem., 1956, 21, 479; (e) W. D. Closson, P. Wriede
and S. Bank, J. Am. Chem. Soc., 1966, 88, 1581–1583; (f) S. Ji, L.
B. Gortler, A. Waring, A. Battisti, S. Bank, W. D. Closson and P. Wriede,
J. Am. Chem. Soc., 1967, 89, 5311–5312; (g) W. Oppolzer, H. Bienaymé
and A. Genevois-Borella, J. Am. Chem. Soc., 1991, 113, 9660–9661;
(h) D. I. Weisblat, B. J. Magerlein and D. R. Myers, J. Am. Chem. Soc.,
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1949, S178–S181; ( j) E. Vellemae, O. Lebedev and U. Maeorg, Tetrahe-
dron Lett., 2007, 49, 1373–1375; (k) G. Sabitha, S. Abraham, B.
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In summary, cleavage of aliphatic triflates by reaction with
endiamine 13 affords the corresponding alcohols under mild
reaction conditions cleanly and in excellent yield, the first time
that this has been achieved for any reagent. The reaction of aryl
triflates also gave excellent yields of S–O bond cleavage and no
evidence of alternative routes such as C–O bond cleavage that is
seen with some other reducing systems.4,5c The by-product is
trifluoromethanesulfinate, as seen in conversion to a sulfone on
reaction with benzyl bromide; the sulfinate is not subject to the
further reduction seen in some other reducing systems.6b Finally,
the first examples of cleavage of triflamides with the neutral
organic reagents are reported; this reaction needs more vigorous
conditions than for cleavage of triflate esters.
7 (a) J. A. Murphy, T. A. Khan, S. Z. Zhou, D. W. Thomson and
M. Mahesh, Angew. Chem., Int. Ed., 2005, 44, 1356–1360; (b) J.
A. Murphy, S. Z. Zhou, D. W. Thomson, F. Schoenebeck, M. Mohan, S.
R. Park, T. Tuttle and L. E. A. Berlouis, Angew. Chem., Int. Ed., 2007,
46, 5178–5183; (c) F. Schoenebeck, J. A. Murphy, S. Z. Zhou,
Y. Uenoyama, Y. Miclo and T. Tuttle, J. Am. Chem. Soc., 2007, 129,
13368–13369; (d) J. A. Murphy, J. Garnier, S. R. Park, F. Schoenebeck,
S. Z. Zhou and A. T. Turner, Org. Lett., 2008, 10, 1227–1230;
(e) J. Garnier, J. A. Murphy, S. Z. Zhou and A. T. Turner, Synlett, 2008,
2127–2131; (f) S. P. Y. Cutulic, J. A. Murphy, H. Farwaha, S. Z. Zhou
and E. Chrystal, Synlett, 2008, 2132–2136; (g) J. A. Murphy,
F. Schoenebeck, N. J. Findlay, D. W. Thomson, S. Z. Zhou and
J. Garnier, J. Am. Chem. Soc., 2009, 131, 6475–6479;
(h) S. P. Y. Cutulic, N. J. Findlay, S. Z. Zhou, E. Chrystal and J.
A. Murphy, J. Org. Chem., 2009, 74, 8713–8718; (i) J. Garnier, A.
R. Kennedy, L. E. A. Berlouis, A. T. Turner and J. A. Murphy, Beilstein
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8 For prior work on imidazole-derived electron donors, see:
(a) J. Bourson, Bull. Soc. Chim. Fr., 1971, 3541; (b) S. Hünig,
D. Scheutzow, H. Schlaf and H. Quast, Justus Liebigs Ann. Chem.,
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Acknowledgements
We thank EPSRC for funding and EPSRC National Mass Spec-
trometry Service Centre, Swansea, for mass spectra.
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