Amidine dications as superelectrophiles

Article abstract of DOI:10.1021/ja908191k

2-Dimethylalkylammonium pyridinium and 2-dimethylalkylammonium pyrimidinium ditriflate salts are very powerful methylating agents toward phosphorus (triphenylphosphine) and nitrogen (triethylamine) nucleophiles. In competition experiments with triethylamine as nucleophile, these N-methyl disalts are more reactive methylating agents than dimethyl sulfate. Reaction of the pyridinium dications with water as an oxygen nucleophile leads to attack at the 2-position of the heteroaromatic ring and displacement of an ammonium group; 2-hydroxypyridinium compounds are formed in the first instance, which are easily converted to 2-pyridones. Extending the scope of the reactions, a tricationic 2,6-bis(dimethylalkylammonium) pyridinium salt has also been prepared and characterized and its reactivity as a methylating agent assessed in comparison with that of the dications.

Full text of DOI:10.1021/ja908191k

Published on Web 11/16/2009
Amidine Dications as Superelectrophiles
Michael J. Corr, Mark D. Roydhouse, Kirsty F. Gibson, Sheng-ze Zhou,
Alan R. Kennedy, and John A. Murphy*
WestCHEM, Department of Pure and Applied Chemistry, UniVersity of Strathclyde,
295 Cathedral Street, Glasgow G1 1XL, United Kingdom
Received September 26, 2009; E-mail: John.Murphy@strath.ac.uk
Abstract: 2-Dimethylalkylammonium pyridinium and 2-dimethylalkylammonium pyrimidinium ditriflate salts
are very powerful methylating agents toward phosphorus (triphenylphosphine) and nitrogen (triethylamine)
nucleophiles. In competition experiments with triethylamine as nucleophile, these N-methyl disalts are more
reactive methylating agents than dimethyl sulfate. Reaction of the pyridinium dications with water as an
oxygen nucleophile leads to attack at the 2-position of the heteroaromatic ring and displacement of an
ammonium group; 2-hydroxypyridinium compounds are formed in the first instance, which are easily
converted to 2-pyridones. Extending the scope of the reactions, a tricationic 2,6-bis(dimethylalkylammo-
nium)pyridinium salt has also been prepared and characterized and its reactivity as a methylating agent
assessed in comparison with that of the dications.
Introduction
solvents seemed remote. However, in 1995, Berkessel and
Thauer6 made the revolutionary proposal that superelectrophilic
The development of superacids as non-nucleophilic solvents
allowed detailed studies of highly reactive acidic and electro-
philic organic dications and polycations. For example, the teams
of Olah1 and Hogeveen2 studied the remarkable properties of
such superelectrophilic3 dicationic species as 1-3 (Scheme 1).
The reactivity of such superelectrophiles also led to novel
intermolecular chemistry as exemplified by the reaction of acetyl
cation 5 with 2-methylpropane 7.4,5 In the absence of superacid,
no reaction was observed, whereas in superacid (HF-BF3),
hydride transfer occurred from the 2-methylpropane 7 to afford
tert-butyl cation 9 and protonated acetaldehyde 10. The
enhanced reactivity was ascribed to added activation of the
acetyl cation 5 by the superacid. At one extreme, this could
feature protonation to afford the dication 6, whereas a less
extreme activation could arise through hydrogen bonding
(protosolvation) enhancing the polarization of the carbonyl
group, represented by 6′. The unstable species 6 and/or 6′ were
neither isolated nor detected spectroscopically, but were inferred
from the unusual chemistry that was observed.
activation might be present in the active site of the N5,N10-
methylenetetrahydromethanopterin dehydrogenase enzyme.7,8
This was proposed to explain the reactivity of the substrate,
methenyltetrahydromethanopterin 11, toward H2 in the hydro-
genase enzyme, affording methylenetetrahydromethanopterin 14
as product (Scheme 2). At the time of the proposal, it was
thought that the enzyme contained no functional metal, and
hence that activation of substrate 11 to form a stronger
electrophile, the unprecedented amidine dication 12 or 13, by
protonation6 at a reactive site on the enzyme would rationalize
the formal delivery of hydride from H2. Such a protonation
would remove the very strong resonance stabilization present
in amidinium salt 11, leading to exceptionally high reactivity
for 12 and 13. (As with the activation of the acetyl cation 6,
hydrogen-bonding of the additional proton to 11 would represent
a less extreme activation than full protonation.) Whereas it is
now recognized that an iron atom is situated in the active site,8
the role of the metal ion has not yet been fully elucidated, and
the original activation proposed by Berkessel and Thauer still
stands. This reaction is currently the subject of energetic
investigation.9
Whatever their stability in superacids, the possibility of
formation or detection of such reactive species in more routine
In organic chemistry, some dications, e.g. pyrimidinium
dication 15, have been isolated,10 but they are less reactive than
the superelectrophilic amidine dications discussed above. Alky-
lation of 16 to form 15 requires no sacrifice of mesomeric
(1) (a) Olah, G. A.; Grant, J. L.; Spear, R. J.; Bollinger, M.; Serianz, A.;
Sipos, G. J. Am. Chem. Soc. 1976, 98, 2501–2507. (b) Prakash, G. K.;
Krishnamurthy, V. V.; Herges, R.; Bau, R.; Yuan, H.; Olah, G. A.;
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6091.
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(3) Superelectrophiles bear more than a single positive charge and are
considerably more reactive than their monocationic precursors: (a)
Olah, G. A.; Klumpp, D. A. Superelectrophiles and Their Chemistry;
Wiley-Interscience: NJ, 2008. (b) Olah, G. A.; Klumpp, D. A. Acc.
Chem. Res. 2004, 37, 211–220. (c) Olah, G. A. Angew. Chem., Int.
Ed. Engl. 1993, 32, 767–788.
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2247–2250.
(7) Also known as iron-sulfur cluster-free [Fe]-hydrogenase or H2-
forming methylenetetrahydromethanopterin dehydrogenase (Hmd):
Zirngibl, C.; Hedderich, R.; Thauer, R. K. FEBS Lett. 1990, 261, 112-
116.
(4) Brouwer, D. M.; Kiffen, A. A. Recl. TraV. Chim. Pays-Bas 1973, 92,
689–697.
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Thauer, R. K.; Shima, S. J. Biol. Chem. 2006, 281, 30804–30813. (b)
Vogt, S.; Lyon, E. J.; Shima, S.; Thauer, R. K. J. Biol. Inorg. Chem.
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9
17980 J. AM. CHEM. SOC. 2009, 131, 17980–17985
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Amidine Dications as Superelectrophiles
A R T I C L E S
Scheme 1. Superelectrophiles in superacid
Scheme 2. Dication superelectrophiles
stabilization, and hence, de-ethylation of 15 does not have the
added driving force seen for the amidine dications.
salt 19 and moncationic pyridinium salt 20 was very marked,
with product 20 being completely unreactive under the hydro-
genation conditions. The reactivity of disalt 19 supports the high
reactivity proposed by Berkessel and Thauer for their putative
disalt intermediates 12 and 13. (Dications 12 and 13 should be
even more reactive toward H2 than 19 since addition of hydrogen
to 19 very likely causes temporary loss of aromaticity in forming
a dihydropyridinium intermediate that then collapses to 20,
whereas addition of hydrogen to 12 and 13 would cause no
loss of aromaticity.)
Recently, dications such as 17 have been suggested as
intermediates in a number of organic synthetic reactions,11 but
isolation of these species has not been reported, and character-
ization data are sparse.12 One tricationic salt, 18, has been
isolated;13 but its reactivity has not been described. However,
it is clear that the chemistry of organic dications is now of
significant interest.
We recently announced the isolation and characterization of
the first amidine dications 19 and 21 and the highly reactive
reduction of 19 with H2 to afford 20.9f The difference in
reactivity toward hydrogen gas between dicationic pyridinium
This article now describes the clues that set us on the path to
the preparation and isolation of these dications, the reactivity
of such dications toward phosphorus-, nitrogen- and oxygen-
(10) (a) Curphey, T. J. J. Am. Chem. Soc. 1965, 87, 2063–2064. (b)
Curphey, T. J.; Prasad, K. S. J. Org. Chem. 1972, 37, 2259–2266. (c)
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V.; Saper, J. J. Chem. Soc. 1948, 1389–1392. (j) Baldamus, J.; Cole,
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Klaucke, W.; Warkentin, E.; Thauer, R. K.; Ermler, U. Science 2008,
321, 572–575. (b) Hiromoto, T.; Ataka, K.; Pilak, O.; Vogt, S.; Stagni,
M. S.; Meyer-Klaucke, W.; Warkentin, E.; Thauer, R. K.; Shima, S.;
Ermler, U. FEBS Lett. 2009, 583, 585–590. (c) Obrist, B. V.; Chen,
D.; Ahrens, A.; Schuenemann, V.; Scopelliti, R.; Hu, X. Inorg. Chem.
2009, 48, 3514–3516. (d) Royer, A. M.; Rauchfuss, T. B.; Gray, D. L.
Organometallics 2009, 28, 3618–3620. (e) Yang, X.; Hall, M. B.
J. Am. Chem. Soc. 2009, 131, 10901–10908. (f) Corr, M. J.; Gibson,
K. F.; Kennedy, A. R.; Murphy, J. A. J. Am. Chem. Soc. 2009, 131,
9174–9175. (g) Heinekey, D. M. J. Organomet. Chem. 2009, 694,
2671–2680. (h) Hiromoto, T.; Warkentin, E.; Moll, J.; Ermler, U.;
Shima, S. Angew. Chem., Int. Ed. 2009, 48, 6457–6460.
9
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A R T I C L E S
Corr et al.
Scheme 3. Electron Donors: Approaches to 27 Produce a Curious Result
nucleophiles, and the preparation and reactivity of a salt
containing a related trication.
substituents in these positions. This compound was to be
prepared by reaction of 2-dimethylaminopyridine (2-DMAP) 28
with 1,3-diiodopropane 29 (Scheme 3). Instead of the expected
26, three products were formed, 30-32. (Compounds 30 and
31 were isolated from this mixture (in 77% and 39% yield,
respectively, based on 29 as limiting reagent—see Supporting
Information), while 32 was inferred by comparison of the NMR
of the mixture with the analogous triflate salt 39, shown in Scheme
5.) Salts 31 and 32 arose by methylation of 2-DMAP 28, and 30
featured incorporation of the 1,3-diiodopropane and loss of a methyl
group. In principle 30 could have arisen by demethylation of
intermediate monocations 33 or 35 by the pathways shown
(Scheme 4). (We envisage that the demethylation step is promoted
by DMAP 28. Alternatively, demethylation could be triggered by
iodide ion; this would result in formation of iodomethane, which
on reaction with DMAP 28 would afford salts 31 and 32.)
Experience of pyridinium salt reactivity15 suggests that such
an easy demethylation would be surprising under these condi-
tions, and thus, we proposed that a much more electrophilic
species might be in play, i.e. the unprecedented disalt 37.9f
Barbieri and co-workers showed that in 2-DMAP 28, unlike
in 4-DMAP, the dimethylamino group is out of the plane of
the ring.16 In turn, this suggests imperfect overlap between the
exocyclic N lone pair and the ring π-system; as a result it is
not surprising that 2-DMAP undergoes preferential alkylation
on the exocyclic nitrogen.16 Hence, the favored sequence of
events leading to 30 goes through ammonium salt 35 and
amidine dication salt 37. To see whether salt 37 could be
prepared, isolated, and characterized, the above experiment was
repeated, but the diiodide 29 was replaced by propane-1,3-
ditriflate, and the conditions were changed to avoid an excess
of 28 being in the reaction at any time. This afforded the
ditriflate salt 19 as reported earlier.9f Similarly, the disalt 21
was prepared from reaction of 2-dimethylaminopyrimidine with
propane-1,3-ditriflate, and both dication salts 19 and 21 were
characterized by single-crystal X-ray structure determinations
and spectroscopic means.9f
Results and discussion
Recent studies14 had allowed us to prepare very strong neutral
organic electron donors 22-24 (Scheme 3). These compounds,
in their ground-state, reduce aryl halides to the corresponding
aryl radicals or aryl anions by transfer of one or two electrons,
respectively. In doing so, radical cations and dications that show
extensive stabilization by the nitrogen atoms are formed from
these donors. Among these donors, the most conveniently
prepared was the 4-dimethylaminopyridine-derived compound
24 and we were keen to investigate the effect of yet more
powerful analogues that featured additional substitution on this
bipyridine scaffold. Such donors might be prepared by adding
to the electron density of 24 with additional appropriately placed
electron-releasing substituents, e.g. 25.
As a prelude to preparing 25, we sought to prepare 26 as a
precursor to 27 to estimate the effect of the dimethylamino
(11) (a) Banwell, M. G.; Bissett, B. D.; Busato, S.; Cowden, C. J.; Hockless,
D. C. R.; Holman, J. W.; Read, R. W.; Wu, A. W. J. Chem. Soc.,
Chem. Commun. 1995, 2551–2553. (b) Charette, A. B.; Chua, P.
Tetrahedron Lett. 1997, 38, 8499–8502. (c) Charette, A. B.; Chua, P.
Synlett 1998, 163–165. (d) Charette, A. B.; Chua, P. J. Org. Chem.
1998, 63, 908–909. (e) Charette, A. B.; Chua, P. Tetrahedron Lett.
1998, 39, 245–248. (f) Yokohama, A.; Ohwada, T.; Shudo, K. J. Org.
Chem. 1999, 64, 611–617. (g) Charette, A. B.; Grenon, M. Can.
J. Chem. 2001, 79, 1694–1703. (h) Charette, A. B.; Mathieu, S.;
Martel, J. Org. Lett. 2005, 7, 5401–5404. (i) Movassaghi, M.; Hill,
M. D. J. Am. Chem. Soc. 2006, 128, 14254–14255. (j) Movassaghi,
M.; Hill, M. D. J. Am. Chem. Soc. 2006, 128, 4592–4593. (k)
Movassaghi, M.; Hill, M. D.; Ahmad, O. K. J. Am. Chem. Soc. 2007,
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Org. Chem. 2009, 74, 1341–1344.
1
(12) A H NMR spectrum and a 19F NMR spectrum were consistent with
a two-component mixture containing 17.11g
(13) Weiss, R.; Roth, R. Synthesis 1987, 870–873.
(14) (a) Murphy, J. A.; Khan, T. A.; Zhou, S.-Z.; Thomson, D. W.; Mahesh,
M. Angew. Chem., Int. Ed. 2005, 44, 1356–1360. (b) Murphy, J. A.;
Zhou, S.-Z.; Thomson, D. W.; Schoenebeck, F.; Mahesh, M.; Park,
S. R.; Tuttle, T.; Berlouis, L. E. A. Angew. Chem., Int. Ed. 2007, 46,
5178–5183. (c) Schoenebeck, F.; Murphy, J. A.; Zhou, S.-Z.; Ue-
noyama, Y.; Miclo, Y.; Tuttle, T. J. Am. Chem. Soc. 2007, 129, 13368–
13369. (d) Murphy, J. A.; Garnier, J.; Park, S. R.; Schoenebeck, F.;
Zhou, S.-Z.; Turner, A. T. Org. Lett. 2008, 10, 1227–1230. (e) Garnier,
J.; Murphy, J. A.; Zhou, S.-Z.; Turner, A. T. Synlett 2008, 14, 2127–
2131. (f) Cutulic, S. P. Y.; Murphy, J. A.; Farwaha, H.; Zhou, S.-Z.;
Chrystal, E. Synlett 2008, 2132–2136. (g) Murphy, J. A.; Schoenebeck,
F.; Findlay, N. J.; Thomson, D. W.; Zhou, S.-Z.; Garnier, J. J. Am.
Chem. Soc. 2009, 131, 6475–6479.
The reactivity of ditriflate salt 19 was now investigated
(Scheme 5). In particular we were keen to compare its reactivity
(15) (a) Murphy, J. A.; Sherburn, M. S. Tetrahedron 1991, 47, 4077–4088.
(b) Murphy, J. A.; Sherburn, M. S. Tetrahedron Lett. 1990, 31, 3495–
3496. (c) Murphy, J. A.; Sherburn, M. S. Tetrahedron Lett. 1990, 31,
1625–1628.
(16) Barbieri, G.; Benassi, R.; Grandi, R.; Pagoni, U. M.; Taddie, F. Org.
Magn. Reson. 1979, 12, 159–162.
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Amidine Dications as Superelectrophiles
A R T I C L E S
Scheme 4
Scheme 5
Table 1. Results of Methylation of Triphenylphosphine 40
fast methylation at r.t. upon treatment with disalt 19 (Scheme
6). Using cyclooctatetraene 46 as an internal nonreacting NMR
standard, the quantities of each methylating reagent before and
after the addition of triethylamine 42 in each competition
40
recovered/%
salt recovered
(38 or 39)/%
yield
41/%
entry
salt
solvent
T/°C
1
2
3
4
5
6
19
19
38
38
39
39
PhCl
CH3CN
PhCl
CH3CN
PhCl
CH3CN
reflux
r.t.
reflux
r.t.
reflux
r.t.
-
-
N.A.
N.A.
29
98
67
95
97
52
-
-
-
1
experiment were determined by H NMR analysis (Table 2).
29
(It was recognized that slow reaction occurs between the disalt
19 and the CD3CN solventshence, the need for an inert
standard, cyclooctatetraene 46.)
96
100
90
84
As can be seen from the results, disalt 19 is a far more
powerful methylating reagent than iodomethane (Table 2, entry
1), with 100% of the iodomethane being present 5 min after
the addition of 42. Disalt 19 even shows slightly higher reactivity
than dimethyl sulfate (Table 2, entry 2), with 47% and 41% of
19 and dimethyl sulfate being consumed respectively (i.e., 53%
and 59% remaining at the end of the experiment). In the case
of methyl trifluoromethanesulfonate (entry 3), the high reactivity
of this potent methylating reagent is shown, with virtually no
demethylation of disalt 19 observed.
To test the methylating ability of disalt 21, the competitive
methylation of triethylamine 42 with dimethyl sulfate was exam-
ined. The results (entry 4) show that pyrimidine disalt 21 is indeed
a stronger methylating reagent than dimethyl sulfate with 23% and
70% of the methylating reagents remaining, respectively, after
treatment with one equivalent of triethylamine 42.
with monocationic counterparts, 38 and 39. All three salts were
separately reacted with triphenylphosphine 40 as a nucleophile
in both chlorobenzene at reflux and acetonitrile at r.t. In
chlorobenzene the salts were reacted at reflux temperature to
ensure solubility. The results (Table 1) show that disalt 19 shows
the highest reactivity, methylating triphenylphosphine 40 in
almost quantitative yield in both solvents (entries 1-2). Mono-
cation salt 38 exhibited some reactivity, showing 52% methy-
lation of 40 after 18 h in chlorobenzene (Table 1, entry 3) but
showing no reaction with 40 when acetonitrile was the solvent
(entry 4). In contrast, monocation 39 showed no reaction with
40 in either solvent (entries 5-6).
To determine the power of disalt 19 as a methylating reagent
toward nitrogen nucleophiles, in comparison to the commercially
available methylating reagents iodomethane, dimethyl sulfate,
and methyl trifluoromethanesulfonate, each individual methy-
lating reagent and disalt 19 were reacted in a 1:1 competition
reaction. Equimolar solutions of 19 (1 equiv) and each separate
commercial methylating reagent (1 equiv) were treated with
triethylamine 42 (1 equiv), which was found to undergo very
These compounds are the most reactive substrates known for
transfer of a methyl group from an sp3 nitrogen. Such transfers
are very important in biology17 in the formation of methionine
52 from homocysteine 51 (Scheme 7). The methyl group is
(17) Matthews, R. G. Acc. Chem. Res. 2001, 34, 681–689.
9
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A R T I C L E S
Corr et al.
Scheme 6. Reaction of Disalts with Triethylamine 42, with Water, and with NaOH
Table 2. Competitive Methylation Study of Triethylamine 42 with
from dicationic and monocationic derivatives of 53 and will
report on this in due course.
Disalts 19, 21 and 61 at 27 °C in CD3CN
amount remaininga/%
Returning to the reactivity of disalt 19, its reactions with water
and also with sodium hydroxide were next examined. With water,
conversion into hydroxypyridinium disalt 47 occurred cleanly
(Scheme 6), and this disalt was fully characterized, including a
single crystal X-ray structure determination. The compound is quite
reactive, and over a period of several days in CD3CN, or instantly
upon the addition of d6-DMSO, hydroxypyridinium salt 47 was
converted to pyridone salt 48. This was shown by an upfield shift
in the ring protons and corresponding ring carbon signals.
Comparison of the NMR spectra of pyridone salt 48 and 1-meth-
ylpyridone22 show very similar values for the relevant signals in
the 1H NMR and 13C NMR spectra.
Reaction of 2-DMAP disalt 19 with saturated sodium
hydroxide solution led to the formation of pyridone 49. The
absence of the protonated nitrogen of 48 is shown by the upfield
shift in the methyl and methylene protons of 49 compared to
48. Pyridone 49 shows methylene protons at δH (d6-DMSO)
1.79, 2.34, and 3.88 ppm compared to 2.04, 3.05, and 3.93 ppm
for pyridone 48. The methyl protons in 49 appear as a singlet
at δH (d6-DMSO) 2.24 ppm and as a doublet at δH (d6-DMSO)
2.78 ppm J(H,H) ) 5.0 Hz for pyridone salt 48. Conversion of
pyridone salt 48 to pyridone 49 was simply achieved by treating
the former with base (Scheme 6).
methylating
reagent (MR)
entry
disalt used
disalt
MR
1
2
3
4
5
19
19
19
21
64
MeI
0b
53b
94b
23f
100c
59d
0e
Me2SO4
MeOTf
Me2SO4
Me2SO4
70d
-
53g
a All proton signal integrations were taken relative to
1,3,5,7-cyclooctatetraene at δH 5.77 ppm. All experiments were carried
out in CD3CN. b Proton signal for Me groups at δH 3.84 ppm used.
c Proton signal for Me group at δH 2.09 ppm used. d Proton signal for
Me groups at δH 3.94 ppm used. e Proton signal for Me group at δH
4.27 ppm used. f Proton signal for Me groups at δH 3.85 ppm used.
g Proton signal for ArH groups at δH 7.30 ppm used.
transferred from the tertiary amine N5-methyltetrahydroflate (N5-
MeTHF, 53) and extensive discussion has taken place on the
possible mechanism of the reaction. In the MetE enzyme, where
the transfer takes place directly to homocysteine, the currently
accepted proposal17 is that the N5-protonated ammonium salt
55 is the actual substrate for this transfer. Dicationic electrophiles
have never been proposed as intermediates in that reaction,18
but would a dication be a reasonable intermediate? It is known
that tetrahydrofolates are easily oxidized structures,19 and recent
cyclic voltammetry studies on the closely related tetrahydro-
biopterin 58,19 have shown a single two-electron wave in a
reversible oxidation, implying that the second electron is
transferred as easily or more easily than the first. If N5-MeTHF,
53, transfers two electrons, then it forms a dication 56. Such a
highly reactive electrophile could be an excellent substrate for
methyl transfer, and since the transfer of a methyl group from
N5-MeTHF is widely viewed as a reaction with a problematic
mechanism17 (in terms of the likely degree of reactivity of 55),
then (along with the hydrogenase proposal of Berkessel and
Thauer), this could be another example where superelectrophiles
have a key role to play in enzyme reactions.20 We are now
scrutinizing the relative ease of transfer of the methyl group
Hydrolysis of 21 also occurred very readily (in undried d6-
DMSO) and led to hydroxypyrimidinium salt 50 as shown
(20) This begs the question of how the proposed oxidation would occur. It is
known that no external co-factor (that could be reduced, to balance the
oxidation of the N5-MeTHF) is involved. Within a protein, a disulfide
might fit this role, but the published structure of the MetE enzyme, with
both homocysteine and N5-MeTHF loaded, shows no disulfides. However,
the preparation of the samples of the enzyme for X-ray crystallography
involves treating the enzyme with Zn2+ but also with tris(2-carboxyeth-
yl)phosphine or dithiothreitol (DTT),21 reagents that are specifically
designed to break disulfide bonds. When prepared in the absence of such
reductants, a disulfide is seen in the protein structure.21a
(21) (a) Pejchal, R.; Ludwig, M. L. PLoS Biology 2005, 3, 254–265. (b)
Ferrer, J.-L.; Ravanel, S.; Robert, M.; Dumas, R. J. Biol. Chem. 2004,
279, 44235–44238.
(22) 1-Methyl-2-pyridone: 1H NMR (CDCl3) δ 3.54 (s, 3H; CH3), 6.17
(ddd, J(H, H) ) 8.1, 6.6, 1.4 Hz, 1H, H-5), 6.54 (dd, J(H, H) ) 9.7,
1.4 Hz, 1H, H-3), 7.34 (ddd, J(H, H) ) 9.7, 6.6, 2.2 Hz, 1H, H-4),
7.35 (dd, J(H, H) ) 8.1, 2.2 Hz, 1H, H-6); 13C NMR (CDCl3) δ 34.7
(CH3), 105.8 (CH), 120.2 (CH), 138.8 (CH), 139.7 (CH), 162.9 (CO);
Shiina, I.; Kawakita, Y. Tetrahedron Lett. 2003, 44, 1951–1955.
(18) For earlier chemical modelling, and discussion of mechanistic pos-
sibilities, including oxidation, see: Hilhorst, E.; Chen, T. B. R. A.;
Iskander, A. S.; Pandit, U. K. Tetrahedron 1994, 50, 7837–7848.
(19) Hoke, K. R.; Crane, B. R. Nitric Oxide 2009, 20, 79–87.
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17984 J. AM. CHEM. SOC. VOL. 131, NO. 49, 2009

Amidine Dications as Superelectrophiles
A R T I C L E S
Scheme 7
Scheme 8. Synthesis of Trication Salt 64
1
(Scheme 6). The H NMR spectrum of 50 shows aromatic
Salt 64 was subjected to the methylation competition reaction
with dimethyl sulfate as carried out previously. The results showed
that trication 64 had approximately the same reactivity as dimethyl
sulfate (Table 2, entry 5). The enhanced electrophilicity expected
from a tricationic electrophile is balanced in this case by the
electron-releasing effect of the p-dimethylamino group.
signals at δH (d6-DMSO) 6.91 and 8.83 ppm, further downfield
than expected for that of a pyridone-type species.22 The 13C
NMR spectrum shows the signal for the quaternary carbon in
the ring at δC (d6-DMSO) 149.6 ppm, further upfield than
expected if a pyrimidone had formed.
The amidine disalts 19 and 21 are the first amidine dication
salts to be isolated, characterized and studied, which on
dealkylation, afford resonance-stabilized amidinium salts. To
develop this chemistry, we sought to prepare a salt that
incorporates a trication. For this, 2,4,6-tris(dimethylamino)py-
ridine 61 was prepared23 from the known 2,6-diiodo-4-dim-
ethylaminopyridine 59,24 and tritriflate 63 was prepared from
pentane-1,3,5-triol 62 (Scheme 8). Reaction of pyridine 61 with
1,3,5-tritriflate 63 in the presence of diethyl ether led to
formation of trisalt 64 (43%). Full characterization of trisalt 64,
including X-ray crystal structure determination, confirmed that
the structure was indeed as shown.
In summary, we have reported the methylating ability of dication
salts 19 and 21. Both salts show methylating power stronger than
that of dimethyl sulfate. Trication salt 64 has also been synthesized
and shows decreased methylating ability compared to dication salts
19 and 21, influenced by the p-dimethylamino group.
Acknowledgment. We thank the EPSRC for funding and the
EPSRC National Mass Spectrometry Service for spectra. We thank
Callum Scullion for helpful discussions.
Supporting Information Available: Experimental procedures
1
as well as H and 13C NMR spectra of compounds and CIF
files for 47 and 64. This material is available free of charge via
the Internet at http://pubs.acs.org.
(23) Shafir, A.; Buchwald, S. L. J. Am. Chem. Soc. 2006, 128, 8742–8743.
(24) Aucagne, V.; Berna´, J.; Crowley, J. D.; Goldup, S. M.; Ha¨nni, K. D.;
Leigh, D. A.; Lusby, P. J.; Ronaldson, V. E.; Slawin, A. M. Z.; Viterisi,
A.; Walker, D. B. J. Am. Chem. Soc. 2007, 129, 11950–11963.
JA908191K
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