Super-electron donors: Bis-pyridinylidene formation by base treatment of pyridinium salts

Article abstract of DOI:10.1021/ol800134g

Deprotonation of bispyridinium salt 7b affords bispyridinylidene 10, a very powerful neutral organic two-electron donor [E_1/2 (DMF) = -1.13 V vs Ag/AgCI/KCI (sat)], presumably via the pyridinylidene 8. Donor 10 reduces aryl iodides and bromides to aryl anions in excellent yield and also reductively cleaves selected phenylalkylsulfones very efficiently.

Full text of DOI:10.1021/ol800134g

ORGANIC
LETTERS
2008
Vol. 10, No. 6
1227-1230
Super-Electron Donors:
Bis-pyridinylidene Formation by Base
Treatment of Pyridinium Salts
John A. Murphy,*,† Jean Garnier,† Stuart R. Park,† Franziska Schoenebeck,†
Sheng-ze Zhou,† and Andrew T. Turner‡
WestCHEM, Department of Pure and Applied Chemistry, UniVersity of
Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, United Kingdom, and
UM4 Main Lb Block Process R&D, AstraZeneca, Hurdsfield Industrial Estate,
Macclesfield SK10 2NA, United Kingdom
John.Murphy@strath.ac.uk
Received January 19, 2008
ABSTRACT
Deprotonation of bispyridinium salt 7b affords bispyridinylidene 10, a very powerful neutral organic two-electron donor [E1 (DMF)
)
/
2
−1.13 V vs Ag/AgCl/KCl (sat)], presumably via the pyridinylidene 8. Donor 10 reduces aryl iodides and bromides to aryl anions in excellent
yield and also reductively cleaves selected phenylalkylsulfones very efficiently.
Metal-based reducing agents dominate the field of electron-
transfer reactions, particularly for thermodynamically difficult
reductions such as Birch reductions,1 acyloin condensa-
tions,2,3 and reductions of aryl halides.4 We recently ques-
tioned whether difficult reductions could alternatively be
achieved by simple but powerful neutral organic electron
donors, working under mild conditions in the ground state.
If such reducing agents could be prepared, they could have
significant attractions for use in synthetic chemistry in terms
of selectivity, tolerance of other functional groups, tunability,
ease of attachment to solid supports, and ease of regeneration.
With this in mind, we recently showed that compound 1
is the first neutral ground-state organic donor (super-electron
donor, S.E.D.) to succeed in converting iodoarenes to aryl
radicals by electron transfer.4 More recently, we showed5
that the more powerful donor 36 is the first S.E.D. to convert
haloarenes to aryl anions, following transfer of two electrons.
Donor 3 undergoes reversible oxidation to 4 and then 5 at
† University of Strathclyde.
‡ AstraZeneca.
(1) (a) Hook, J. M.; Mander, L. N. Nat. Prod. Rep. 1986, 3, 35-85. (b)
Donohoe, T. J.; Garg, R.; Stevenson, C. A. Tetrahedron: Asymmetry 1996,
7, 317-344.
(2) Finley, K. T. Chem. ReV. 1964, 64, 573-589.
(3) Ru¨hlmann, K. Synthesis 1971, 236-253.
(4) Murphy, J. A.; Khan, T. A.; Zhou, S.-Z.; Thomson, D. W.; Mohan,
M. Angew. Chem., Int. Ed. 2005, 44, 1356-1360.
(5) Murphy, J. A.; Zhou, S.-Z.; Thomson, D. W.; Schoenebeck, F.;
Mohan, M.; Park, S. R.; Tuttle, T.; Berlouis, L. E. A. Angew. Chem., Int.
Ed. 2007, 46, 5178-5183.
10.1021/ol800134g CCC: $40.75
© 2008 American Chemical Society
Published on Web 02/21/2008

much more negative potentials than 1 [For 3, E1/2 (DMF) )
-1.11 V vs Ag/AgCl/KCl (sat)] (Scheme 1).7
to afford a benzylic anion, rather than from the 2-position
of the ring. Such exocyclic deprotonations have literature
precedent.9 However, selective base-induced proton exchange
in the 2-position of pyridinium salts has been shown under
some conditions.10 To make the proposed electron donor as
electron-rich as possible, dimethylamino analogue 10 was
selected for synthesis. This molecule has the advantage of
four nitrogen atoms, each of which adds electron density to
the π-system.
Scheme 1. Strong Donors 1 and 3, Their Formation, and Their
Reactivity
Diiodide 7b was easily prepared from reaction of the easily
available and economical 4-dimethylaminopyridine11 with
1,3-diiodopropane. The crucial questions were (i) whether
7b could be selectively deprotonated to afford a carbene 8
and (ii) whether such a carbene would undergo nucleophilic
attack on the adjacent pyridinium ring, ultimately leading
to 10. (In this regard, our attempts to prepare 13 by
deprotonation of bisimidazolium salt 12 had failed,12,13
whereas deprotonation of 2 to form 3 had proceeded in
high yield.5 Clearly, in that case, the presence of two
trimethylene bridges had been necessary to create the reactive
alkene.)
To test our case, 7b was now treated with NaH in liquid
ammonia. Evaporation of the ammonia, followed by extrac-
tion with diethyl ether and solvent removal,5 afforded air-
sensitive bispyridinylidene 10 (83%) as a purple solid. 13C
Although 3 is an excellent electron donor, development
of more powerful bisimidazolylidene electron donors related
to 3 would be nontrivial. To avoid isomeric mixtures of
imidazole-derived donors, and thereby develop donors that
can be precisely characterized, symmetrical 4,5-disubstituted
imidazoles would be needed as synthetic precursors. How-
ever, the available range of such imidazoles is limited, and
so the attractions of developing the bisimidazolylidene
nucleus recede.
Accordingly, we set out to find alternatives to imidazoles
as the basis of S.E.D. reagents that would be capable of
reducing aryl halides and other difficult substrates; this paper
announces our success in developing a new structural motif
for that purpose through the same convenient deprotonation
route routinely used for the preparation of bisimida-
zolylidenes and used above in the preparation of donor 3
from 2.5
1
NMR and H NMR spectra supported its structural assign-
ment with the central alkene carbons resonating at δ 116
ppm. It was further characterized by reaction with iodine to
afford the diiodide 11. Here, the NCH2 protons show
nonequivalence, and their diastereotopic nature must reflect
the nonplanarity of the positively charged ring systems as
the two rings twist to avoid interaction. This is analogous to
the dication derived from 14 but entirely different to the
essentially planar dication 5 derived from 3.5
Electrochemical characterization of 10 showed a single
reversible two-electron peak at E1/2 (DMF) ) -1.13 V vs
Ag/AgCl/KCl (sat), and hence this molecule is as strong a
donor as compound 3. However, whereas cyclic voltammetry
of compound 3 showed two electron-transfer steps at almost
identical potentials (a shoulder appears on the peak in both
oxidative and reductive mode, implying that the loss of its
second electron is only slightly more difficult than its first),
compound 10 showed a clean, single two-electron peak,
indicating that the loss of the second electron occurs at
essentially the same potential as the first, under the conditions
of the experiment (see Figure 1).14
Our primary focus was on pyridine-based structures. In
principle, bispyridinylidene 68 might be formed through
deprotonation of a bridged bispyridinium salt 7a. However,
the 2-position of pyridinium salts will be less acidic than
the 2-position of imidazolium salts, and it was very possible
that deprotonation would occur from the trimethylene bridge,
(6) Literature measurements of the redox potentials of the bromide
salt analogous to 3, E1/2 (MeCN)7a ) -1.18 V and -1.37 V (ir) vs.
S.C.E., where “ir” represents an irreversible step; E1/2 (DMF)7a
)
-1.20 V vs. S.C.E.; and E1/2 (MeCN)7b ) -1.12 V and -1.28 V (ir) vs
S.C.E.].
(9) (a) King, L. C.; Brownell, W. L. J. Am. Chem. Soc. 1950, 72, 2507-
2508. (b) Katritzky, A. R.; Chermprapai, A.; Patel, R. C.; Tarraga-Tomas,
A. J. Org. Chem. 1982, 47, 492-497. (c) Kro¨hnke, F. Angew. Chem., Int.
Ed. Engl. 1963, 2, 225-238.
(10) (a) Obaid, A. Y.; Soliman, M. S. Spectrochim. Acta 1990, 46A,
1779-1791. (b) Kawazoe, Y.; Ohnishi, M.; Yoshioka, Y. Chem. Pharm.
Bull. 1964, 12, 1384-1386.
(11) Spivey, A. C.; Arseniyadis, S. Angew. Chem., Int. Ed. 2004, 43,
5436-5441.
(12) Thomson, D. W. Ph.D. thesis, Universirty of Strathclyde, 2005.
(13) The delicate balance between tetrazaalkenes and imidazolylidene
precursors is seen in ref 7c. (See also Hahn, F. E.; Wittenbecher, L.; Le
Van, D.; Fro¨hlich, R. Angew. Chem., Int. Ed. 2000, 39, 541-544).
(14) For a discussion of 2-electron transfer, see: Evans, D. H.; Hu, K.
J. Chem. Soc., Fraraday Trans. 1996, 92, 3983-3990.
(7) (a) Ames, J. R.; Houghtaling, M. A.; Terrian, D. L.; Mitchell,
T. A. Can. J. Chem. 1997, 75, 28-36. (b) Thummel, R. P.; Goulle,
V.; Chen, B. J. Org. Chem. 1989, 54, 3057-3061. (c) Taton, T. A.; Chen,
P. Angew. Chem., Int. Ed. Engl. 1996, 35, 1011-1013. (d) Hu¨nig, S.;
Sheutzov, D.; Schlaf, H. Justus Liebigs Ann. Chem. 1972, 765, 126-
132.
(8) Alternative routes to bis-2-pyridinylidenes are known through reduc-
tion of pyridine-borane complexes and of 2,2-bipy salts: (a) Koester, R.;
Bellut, H.; Ziegler, E. Angew. Chem. 1967, 79, 241-242. (b) Kuck, M. A.;
Urry, G. J. Am. Chem. Soc. 1966, 88, 426-431. (c) Maeda, K.; Matsuyama,
Y.; Isozaki, K.; Yamada, S.; Mori, Y. J. Chem. Soc., Perkin Trans. 2 1996,
121-126. (d) Hu¨nig, S.; Gross, J. Tetrahedron Lett. 1968, 9, 2599-
2604.
1228
Org. Lett., Vol. 10, No. 6, 2008

remaining pyridinium salt would afford 9, and this would
be followed by deprotonation to give 10.
Since the formation of 10 proceeded efficiently, it follows
that carbene formation in this system is facile under these
conditions. The ease of formation of carbenes from depro-
tonation of “unactivated” pyridinium salts has rarely been
previously recognized; however, metal-bound pyridinylidines
featuring a strategically placed extra functional group to
activate the precursor pyridinium salt for proton removal have
been formed in this way.16-18
We then explored the reactivity of donor 10 in dehaloge-
nation reactions (Scheme 3). Aryl iodide 14 and 9-bromoan-
Figure 1. Cyclic voltammogram of donor 10.
Scheme 3. Reduction of Organic Substrates by Donor 10
Bispyridinylidene 10 is the first bis-2-pyridinylidene to
be reported by this deprotonation route.8 The formation of
10 must feature initial deprotonation in the 2-position of
pyridinium salt 7b to form pyridinylidene 8 (Scheme 2).
Scheme 2. Formation and Reaction of Bispyridinylidene 10
thracene 17 were reduced at room temperature (92% and
96% yields of 16 and 18, respectively), whereas reduction
of bromide 15 at 100 °C afforded 16 in 82% yield. These
outcomes compare very favorably with the best current
results with a neutral organic electron donor, namely 3.5
It is likely that these reductions proceed via aryl anion
intermediates. Some evidence for this was found when donor
10 was reacted with the hindered iodide 19. Clean reduction
to 20 (95%) was effected at room temperature. When the
reaction was repeated, this time with D2O present in the
reaction from the start, a mixture of 20 and the deuterated
analogue 21 (1:4) was produced (94%). This regiospecific
formation of the C-D bond is consistent with an aryl anion
Assuming that the pathway to bispyridinylidene 10 is
analogous to that seen in the formation of bisimida-
zolylidenes,15 then subsequent nucleophilic attack on the
(16) Owen, J. S.; Labinger, J. A.; Bercaw, J. E. J. Am. Chem. Soc. 2004,
(15) For mechanistic discussion of dimerisation of N-heterocyclic car-
benes, see: (a) Alder, R. W.; Chaker, L.; Paolini, F. V. P. Chem. Commun.
2004, 2172-2173. (b) Alder, R. W.; Blake, M. E.; Chaker, L.; Harvey, J.
N.; Paolini, F. V. P.; Schu¨tz, J. Angew. Chem., Int. Ed. 2004, 43, 5896-
5911.
126, 8247-8255.
(17) Piro, N. A.; Owen, J. S.; Bercaw, J. E. Polyhedron 2004, 23, 2797-
2804.
(18) Albrecht, M.; Stoeckli-Evans, H. Chem. Commun. 2005, 4705-
4707.
Org. Lett., Vol. 10, No. 6, 2008
1229

intermediate, but the experiment is also important in dem-
onstrating the mildness of the reaction conditions, with aryl
anion formation occurring in the presence of D2O. To look
for further evidence of aryl anion intermediates, donor 10
was then reacted with iodoester 22. We have recently shown5
that conversion of 22 and related substrates to cyclic ketones
(here 23) identifies the presence of aryl anions (as opposed
to aryl radicals) as reaction intermediates. Here, the ketone
23 was formed together with the ester 25 as an inseparable
mixture. Hydrolysis of the ester in the mixture afforded ke-
tone 23 in an excellent 83% yield as well as acid 24 (8%).
This shows that at least 83% yield of aryl anions was pro-
duced during the reaction that formed the indanone, and this
is higher than any previous generation of aryl anions by
donor 3.
reductions, and substrates such as 26-28 are routinely
reduced with sodium metal.19
The bipyridinylidene, 10, therefore proves to be a very
strong electron donor. The preparation of 10 features the
deprotonation of an “unactivated” pyridinium salt to form
an N-heterocyclic carbene as an intermediate. The efficient
preparation of donor 10 from 4-DMAP in two steps makes
this the most conveniently prepared S.E.D. to date. The ease
of deprotonation of the unactivated pyridinium salt 7b opens
the door not only to widespread studies on new S.E.D.s
derived from deprotonation of pyridinium salts but also to
the wider use of pyridinium-derived carbenes in chemistry.
Acknowledgment. We thank EPSRC, WestCHEM, and
AstraZeneca for funding and the EPSRC National Mass
Spectrometry Service for mass spectra.
Finally, to give the donor 10 a very severe test, three
sulfones 26-28 were reacted with 10. Reductive cleavage
in excellent yield (96-99%) was seen in each case. Reduc-
tion of sulfones is among the most difficult of organic
Supporting Information Available: Experimental details
and spectral data for compounds. This material is available
free of charge via the Internet at http://pubs.acs.org
(19) Najera, C.; Jus, M. Tetrahedron 1999, 55, 10547-10658.
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