Thermally generated phenylcarbenium ions: acid-free and self-quenching Friedel-Crafts reactions

Article abstract of DOI:10.1016/j.tetlet.2007.09.116

2-Benzyloxy-1-methylpyridinium triflate (1) serves as a stable precursor to a phenylcarbenium species as evidenced by its reactivity in Friedel-Crafts alkylations with electron-rich arenes.

Full text of DOI:10.1016/j.tetlet.2007.09.116

Available online at www.sciencedirect.com
Tetrahedron Letters 48 (2007) 8097–8100
Thermally generated phenylcarbenium ions: acid-free and
self-quenching Friedel–Crafts reactions
Philip A. Albiniak and Gregory B. Dudley*
Department of Chemistry and Biochemistry, Florida State University, Tallahassee, FL 32306-4390, USA
Received 24 August 2007; revised 7 September 2007; accepted 18 September 2007
Available online 21 September 2007
Abstract—2-Benzyloxy-1-methylpyridinium triflate (1) serves as a stable precursor to a phenylcarbenium species as evidenced by its
reactivity in Friedel–Crafts alkylations with electron-rich arenes.
Ó 2007 Elsevier Ltd. All rights reserved.
The recognized importance of carbocations in organic
chemistry1 dates back to when Ingold and Hughes first
described them as intermediates in the SN1 reaction.2,3
Carbocations play a crucial role in many important
reactions including Friedel–Crafts alkylations (e.g.,
Scheme 1) and acylations,4 Prins reactions,5 pinacol
rearrangements,6 Nazarov cyclizations,7 Ritter reac-
tions,8 Mukaiyama aldol couplings,9 and others.
olefins, and alkyl halides using strong activators like
Lewis or protic acids.15 Olah contributed significantly
to this field with his development of ‘superacid’ sol-
vents,16 which make it possible to prepare free carbo-
cations that are too reactive to exist in less acidic
media.17 In general, however, the need for acidic media
limits the range of functional groups that are compatible
with traditional methods for generating reactive carbe-
nium species.
Carbocations are frequently used to facilitate key steps
in natural products synthesis. For example, Johnson’s
synthesis of progesterone features an elegant cascade
cation–p cyclization to assemble the steroid core.10,11
Modern synthetic approaches to the ‘ladder’ polycyclic
polyethers focus on conceptually related cascade
cation–epoxide cyclizations.12–14 Such studies require
means of generating cation initiators to trigger cycliza-
tion under conditions that is compatible with the rest
of the molecule.
Alternatively, newer methods involving thermal decom-
position of N-alkyl, N-nitrosamides18 or photolysis of
diazonium salts19–21 circumvent the need for strong acid
activators, but these methods require the use of danger-
ous or unstable starting materials. Furthermore, the
reaction of a cation with a neutral arene nucleophile
generates a strongly acidic by-product (e.g., HAlCl4,
Scheme 1).
ROH, MgO, Δ
OR
ð1Þ
O
N
For synthetic purposes, carbenium ions (trivalent carbo-
cations) are typically generated from aldehydes, alcohols,
PhCF3
Me
OTf
1
Our group recently reported the synthesis of benzyl
ethers via thermolysis of 2-benzyloxy-1-methylpyridini-
um triflate (1)22 in the presence of alcohols (Eq. 1).23
We postulated an SN1-type mechanism proceeding
through a phenylcarbenium triflate salt.
toluene
AlCl3
Cl
CH2
Bn
nitromethane
HCl•AlCl3
Aryl–H, Δ
Aryl
Scheme 1. Lewis acid-promoted carbocation formation with accom-
panying Friedel–Crafts alkylation.4
ð2Þ
O
N
PhCF3
Me
OTf
1
*
Given the broader importance of generating reactive
intermediates under neutral conditions, our new study
Corresponding author. Tel.: +1 850 644 2333; fax: +1 850 644
8281; e-mail: gdudley@chem.fsu.edu
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.09.116

8098
P. A. Albiniak, G. B. Dudley / Tetrahedron Letters 48 (2007) 8097–8100
The mechanistic rationale is outlined in Scheme 2:
Δ
CH2
thermolysis of 1 was expected to release the benzyl elec-
trophile transiently along with pyridone 2. Then, the
reaction of an arene substrate with phenylcarbenium
would furnish 4. The strong acid by-product (in this
case, triflic acid) would be buffered by pyridone 2
through the formation of 5. Note that the hydroxypyrid-
inium species (5) is 10 or more orders of magnitude less
acidic than triflic acid: pKa (TfOH) = ꢀ10 to ꢀ15,26
whereas pKa (5) = 0.30.27
O
N
O
N
Me
Me
OTf
OTf
1
2
H
H
ED
3
ED
O
N
Me
O
OTf
80 ºC, 1d
2
H
ED
+
N
Electron-rich arenes such as anisole or 1,3-dimethoxy-
benzene efficiently trapped the putative phenylcar-
benium species to provide the corresponding
diarylmethanes in excellent yields (Table 1), whether
the reaction is conducted neat or in an inert aromatic
solvent (cf. entry 2). As indicated in entry 2, productive
Friedel–Crafts reactions occur even under non-acidic con-
ditions (i.e., buffered with magnesium oxide). Less acti-
vated arene substrates provided more modest yields
(entries 5–8).
Me
OTf
4
5•OTf
Scheme 2. Proposed mechanism of the Friedel–Crafts reaction of 1
with electron-rich arenes.
aims to determine if 1 indeed serves as a stable, pre-acti-
vated source of phenylcarbenium by exploring Friedel–
Crafts benzylation reactions24 under conditions that
do not involve the addition of acid or other activating
agent (Eq. 2).
Interestingly, the reaction between 1 and N,N-dimethyl-
aniline took a different course: one of the methyl groups
was replaced with a benzyl group to yield N-benzyl, N-
methylaniline (entry 9).28 We draw an analogy between
the N-methyl!benzyl exchange that we observed (entry
Herein we report data and observations on the thermol-
ysis of 1 in the presence of various arenes, which in most
cases afforded characterizable Friedel–Crafts-type
products.25
Table 1. Reaction of 1 with electron-rich arenes25
5–10 equiv. 3
ED
O
N
80 ºC, 24 h
Me
OTf
1
4
Entry
1
Arene 5
Isolated products
Yielda (ratio)b
100 (12:88)
OMe
OMe
OMe
Bn
:
Bn
OMe
OMe
OMe
OMe
OMe
:
OMe
2
3
4
5
6
7
93, 94c, 90d (65:35)
Bn
Bn
Bn
57
Bn
:
:
72 (38:62)
72 (33:67)
43
Bn
Bn
Bn
Br
Br
Br
N
N
Bn
65
a Yields refer to isolated product judged to be >95% pure by 1H NMR spectroscopy. All compounds provided characterization data in accord with
the literature reports.
b Regioisomer ratios estimated by 1H NMR.31
c Magnesium oxide (MgO, 1.0 equiv) added as the terminal acid scavenger.
d Reaction conducted in trifluorotoluene (PhCF3, 1.0 mL/mmol of 1) as solvent; MgO (1.0 equiv) added as the terminal acid scavenger.

P. A. Albiniak, G. B. Dudley / Tetrahedron Letters 48 (2007) 8097–8100
8099
Mori, Y.; Yamashita, Y.; Kobayashi, S. J. Am. Chem.
Soc. 2004, 126, 9192.
10. Johnson, W. S. Acc. Chem. Res. 1968, 1, 1.
11. Johnson, W. S.; Gravesto, M.; McCarry, B. E. J. Am.
Chem. Soc. 1971, 93, 4332.
9) and the O-methyl!benzyl exchange detailed by
Speranza and co-workers.29 Other labs have reported
similar but less dramatic observations of heteroatom
substitution products under conventional Friedel–Crafts
conditions.30
12. Vilotijevic, I.; Jamison, T. F. Science 2007, 317, 1189, and
references cited therein.
Based on these results, we conclude that a reactive ben-
zyl electrophile is generated upon mild thermal activa-
tion (ca. 80 °C) of 1. Benzyloxypyridinium triflate 1 is
unique among phenylcarbenium precursors: it is neutral,
pre-activated, stable at room temperature, and can be
stored and handled without special precautions. The
reactive electrophilic species is produced alongside N-
methyl-pyridone (2), which can act as an acid scavenger
(2!5) to moderate the acidity of the reaction.
13. Valentine, J. C.; McDonald, F. E. Synlett 2006, 1816.
14. Zakarian, A.; Batch, A.; Holton, R. A. J. Am. Chem. Soc.
2003, 125, 7822.
15. Mayr, H.; Kempf, B.; Ofial, A. R. Acc. Chem. Res. 2003,
36, 66.
16. Olah, G. A.; Suryaprakash, G. K.; Sommer, J. Science
1979, 206, 13.
17. Olah, G. A.; McIntyre, J. S.; Bastien, I. J.; Tolgyesi, W. S.;
Baker, E. B.; Evans, J. C. J. Am. Chem. Soc. 1964, 86,
1360.
18. Darbeau, R. W.; White, E. H. J. Org. Chem. 2000, 65,
1121.
19. Fagnoni, M.; Albini, A. Acc. Chem. Res. 2005, 38, 713.
20. Milanesi, S.; Fagnoni, M.; Albini, A. J. Org. Chem. 2005,
70, 603.
In summary, 2-benzyloxy-1-methylpyridinium triflate
(1) decomposes upon heating to release a phenylcar-
benium species, as evidenced by its efficient Friedel–Crafts
alkylations of electron-rich arenes.32 These reactions do
not require strong Lewis or protic acids, in contrast to
the classical conditions for Friedel–Crafts reactions,
and can even be conducted in the presence of hetero-
geneous base (MgO). Stable species that produce carbo-
cations under mild, neutral conditions contribute to the
study of reactive intermediates in organic chemistry and
their potential applications in synthesis.
21. Gasper, S. M.; Devadoss, C.; Schuster, G. B. J. Am.
Chem. Soc. 1995, 117, 5206.
22. (a) 2-Benzyloxy-1-methylpyridinium triflate [26189-59-3] is
licensed, manufactured, and distributed non-exclusively by
Sigma–Aldrich Chemical Co., catalog #679674; see:
Dudley, G. B. Compounds and methods of arylmethyl-
ation (benzylation) as protection for alcohol groups. U.S.
Patent Appl. 11/399,300, 2006; (b) ChemFiles 2007, 7, 3.
23. (a) Poon, K. W. C.; Albiniak, P. A.; Dudley, G. B. Org.
Synth. 2007, 84, 295; (b) Poon, K. W. C.; Dudley, G. B. J.
Org. Chem. 2006, 71, 3923; (c) Poon, K. W. C.; House, S.
E.; Dudley, G. B. Synlett 2005, 3142; For the synthesis of
PMB ethers, see: (d) Nwoye, E. O.; Dudley, G. B. Chem.
Commun. 2007, 1436.
24. Zhang, J. J.; Schmidt, R. R. Synlett 2006, 1729.
25. General procedure: An oven-dried vial with magnetic stir-
bar was charged with arene 3 (5–10 mol equiv) and
pyridinium triflate 1 (0.5 mmol, 1 mol equiv). The vial
was heated at 80 °C for 24 h. The reaction mixture was
diluted with 49:1 hexanes/EtOAc (10 mL) and filtered over
a bed of Celite. Solvent and excess arene were removed in
vacuo to yield the diarylmethane product. When neces-
sary, the product was further purified by silica gel
chromatography. All compounds were judged to be
>95% pure by 1H NMR spectroscopy and provided
characterization data in accord with the literature reports.
26. Triflic acid is one of the most acidic monoprotic acids
known and readily protonates sulfuric acid. (a) Howells,
R. D.; McCown, J. D. Chem. Rev. 1965, 77, 69; (b)
Senning, A. Chem. Rev. 1965, 65, 385; (c) Stang, P. J.;
White, M. R. Aldrichim. Acta 1983, 16, 15.
Acknowledgments
This research was supported by the James and Ester
King Biomedical Research Program, Florida Depart-
ment of Health, an award from Research Corporation,
and by the FSU Department of Chemistry and
Biochemistry.
References and notes
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28. Analytical data: H NMR (300 MHz, CDCl3) d 7.31–7.02
(m, 7H), 6.74–6.57 (m, 3H), 4.45 (s, 2H), 2.93 (s, 3H). 13
C
NMR (75 MHz, CDCl3) d 149.7, 139.0, 129.1, 128.5,
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3
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3
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Mechanism, 4th ed.; Kluwer Academic/Plenum: New
York, 2000, pp 551–583.
31. Friedel–Crafts alkylations of electron-rich arenes are
thought to have early transition states with little r-bond
character between the electrophile and arene. Therefore,
the o/p selectivity is generally modest. Less activated arene
substrates react through later transition states, which
usually translate to higher para-selectivity (cf. entries 2
and 6). For further discussion, see: (a) March, J.; Smith,
M. B. Advanced Organic Chemistry: Reactions, Mecha-
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32. With respect to our earlier reports on the use of 1 as a
neutral reagent for the synthesis of benzyl ethers,23a,b note
that the formation of benzyl ether takes precedence over
Friedel–Crafts chemistry.
2.0 equiv 1, MgO
80 ºC, PhCF3
OH
OBn
MeO
MeO
OMe
OMe
9
10
primary product