A ceric ammonium nitrate N-dearylation of N-p-anisylazoles applied to pyrazole, triazole, tetrazole, and pentazole rings: Release of parent azoles. Generation of unstable pentazole, HN5/N5-, in solution

Article abstract of DOI:10.1021/jo702423z

(Chemical Equation Presented) The reaction of cerium(IV) ammonium nitrate (CAN) with a range of N-(p-anisyl)azoles in acetonitrile or methanol solvents leads to N-dearylation releasing the parent NH-azole and p-benzoquinone in comparable yields. The scope and limitations of the reaction are explored. It was successful with 1-(p-anisyl)pyrazoles, 2-(p-anisyl)-1,2,3-triazoles, 2-(p-anisyl)-2H-tetrazoles, and 1-(p-anisyl)pentazole. The dearylation renders the p-anisyl group as a potentially useful N-protecting group in azole chemistry. The azole released in solution from 1-(p-anisyl)pentazole is unstable HN₅, the long-sought parent pentazolic acid. p-Anisylpentazole samples were synthesized with combinations of one, two, and three ¹⁵N atoms at all positions of the pentazole ring. The unstable HN ₅/N₅^- produced at -40°C did not build up in the solution but degraded to azide ion and nitrogen gas with a short lifetime. The ¹⁵N-labeling of the N₃^- ion obtained from all samples proved unequivocally that it came from the degradation of HN ₅ (tautomeric forms) and/or its anion N₅^- in the solution.

Full text of DOI:10.1021/jo702423z

A Ceric Ammonium Nitrate N-Dearylation of N-p-Anisylazoles
Applied to Pyrazole, Triazole, Tetrazole, and Pentazole Rings:
Release of Parent Azoles. Generation of Unstable Pentazole,
-
HN5/N5 , in Solution
Richard N. Butler,*,† John M. Hanniffy,† John C. Stephens,† and Luke A. Burke‡
Chemistry Department, National UniVersity of Ireland, Galway, Ireland, and Chemistry Department,
Rutgers UniVersity, Camden, New Jersey 08102
r.debuitleir@nuigalway.ie
ReceiVed NoVember 10, 2007
The reaction of cerium(IV) ammonium nitrate (CAN) with a range of N-(p-anisyl)azoles in acetonitrile
or methanol solvents leads to N-dearylation releasing the parent NH-azole and p-benzoquinone in
comparable yields. The scope and limitations of the reaction are explored. It was successful with 1-(p-
anisyl)pyrazoles, 2-(p-anisyl)-1,2,3-triazoles, 2-(p-anisyl)-2H-tetrazoles, and 1-(p-anisyl)pentazole. The
dearylation renders the p-anisyl group as a potentially useful N-protecting group in azole chemistry. The
azole released in solution from 1-(p-anisyl)pentazole is unstable HN5, the long-sought parent pentazolic
acid. p-Anisylpentazole samples were synthesized with combinations of one, two, and three 15N atoms
at all positions of the pentazole ring. The unstable HN5/N5- produced at -40 °C did not build up in the
solution but degraded to azide ion and nitrogen gas with a short lifetime. The 15N-labeling of the N3- ion
obtained from all samples proved unequivocally that it came from the degradation of HN5 (tautomeric
-
forms) and/or its anion N5 in the solution.
Introduction
The strong aryl-oxygen and aryl-nitrogen bonds are difficult
to cleave. The ubiquitous alkyl-oxygen cleavage of alkyl aryl
ethers with hydrogen iodide is the basis of the classical Zeisel
methoxy analysis1 for estimating the number of methoxy groups
bound to aryl rings. Because of our interest in seeking a mild
method of breaking aryl-nitrogen bonds in N-arylazoles, with
a view to applying it to arylpentazoles, some years ago we were
attracted to the reaction (eq 1) reported by Jacob et al.2 which
clearly involved an aryl-oxygen bond cleavage by cerium(IV)
ammonium nitrate (CAN).
Since the report by Jacob et al.,2 the CAN dearylation has
been developed as a deprotecting reaction for many p-anisy-
lamino-type systems including azetidines,3 p-anisylamines,4 and
amino acid precursors.5,6 It has not been applied to aromatic
(3) Kronenthal, D. R.; Han, C. Y.; Taylor, M. K. J. Org. Chem. 1982,
47, 2765-2768.
† National University of Ireland.
(4) De Lamo Marin, S.; Martens, T.; Mioskowski, C.; Royer, J. J. Org.
Chem. 2005, 70, 10592-10595.
‡ Rutgers University.
(1) (a) Zeisel, S. Monatsh. Chem. 1885, 6, 989-997. (b) Perkin, W. H.
J. Chem. Soc. Trans. 1903, 83, 1357-1371. (c) McMurry, J. Organic
Chemistry, 5th ed.; Brooks/Cole: New York, 1999; p 738.
(2) Jacob, P., III; Callery, P. S.; Shulgin, A. T.; Castagnoli, N., Jr. J.
Org. Chem. 1976, 41, 3627-3629.
(5) Verkade, J. M. M.; van Hemert, L. J. C.; Quaedflieg, P. J. L. M.;
Alsters, P. L.; van Delft, F. L.; Rutjes, F. P. J. T. Tetrahedron Lett. 2006,
47, 8109-8113 and references therein.
(6) Hata, S.; Iguchi, M.; Iwasawa, T.; Yamada, K.; Tomioka, K. Org.
Lett. 2004, 6, 1721-1723.
10.1021/jo702423z CCC: $40.75 © 2008 American Chemical Society
Published on Web 01/17/2008
1354
J. Org. Chem. 2008, 73, 1354-1364

Ceric Ammonium Nitrate N-Dearylation of N-p-Anisylazoles
TABLE 1. CAN Dearylations of N-p-Anisylpyrazoles (Scheme 1)
substrate
conditions
solvent
Me Me CAN (3.0 equiv) MeCN/H2O (4.75:1 v/v)
products
entry compd
R1
R2
reagent
T (°C) time (h)
yield (%)
mp (°C)
yield (%)
1
2
3
4
5
6
7
8
1a
1b
1b
1c
1c
1c
1c
1c
rt
rt
1
1
2a
2b
2b
2c
2c
2c
2c
2c
47
30
30
57
70
40
52
43
107-108a
201-202b
3
3
3
3
3
3
3
3
41
30
53
53
76
48
57
71
Ph
Ph
Ph
Ph
CAN (3.0 equiv) MeCN/H2O (4.75:1 v/v)
CAN (3.0 equiv) MeCN/H2O (4.75:1 v/v)
CAN (3.0 equiv) MeCN/H2O (4.75:1 v/v)
CAN (3.0 equiv) MeCN/H2O (4.75:1 v/v)
CAN (3.0 equiv) MeOH:H2O (10:1 v/v)
CAN (3.0 equiv) MeOH/H2O (4:1 v/v)
CAN (3.0 equiv) MeCN/CH2Cl2/H2O (5:5:1 v/v)
-10
rt
72
1
Me Ph
Me Ph
Me Ph
Me Ph
Me Ph
124-125c
-10
-40
rt
72
168
1
rt
1
a Lit.15 mp 107-109 °C. b Lit.16 mp 201 °C. c Lit.17 mp 125-126 °C.
TABLE 2. CAN Dearylations of N-p-Anisyl-1,2,3-triazoles and -tetrazoles
substrate
conditions
products
yield
(%)
yield
(%)
entry
compd
R
reagent
solvent
T (°C)
time
mp (°C)
1
2
3
4
5
6
7
8
9
4a
4a
4a
4a
4a
4a
4a
4b
4c
6a
6b
H
H
H
H
H
H
H
Me
OMe
H
CAN (2.7 eq.)
CAN (5.0 eq.)
CAN (2.7 eq.)
CAN (2.7 eq.)
CAN (2.7 eq.)
Ce(OH)4 (2.7 eq.), HCl
CAS (2.1 eq.), HCl
CAN (2.7 eq.)
CAN (2.7 eq.)
CAN (3.0 eq.)
CAN (3.0 eq.)
MeCN/H2O (10:1 v/v)
MeCN/H2O (10:1 v/v)
MeCN/H2O (10:1 v/v)
MeCN/H2O (20:1 v/v)
MeCN/CH2Cl2/H2O (10:10:1 v/v)
MeCN/H2O (10:1 v/v)
MeOH/H2O (6:1 v/v)
MeCN/H2O (10:1 v/v)
MeCN/H2O (10:1 v/v)
MeCN/H2O (10.8:1 v/v)
MeCN/H2O (8.8:1 v/v)
rt
rt
-10
-40
rt
rt
rt
rt
24 h
5a
5a
5a
5a
5a
5a
5a
5b
5c
7a
7b
44a
36c
67d
15e
52f
11
130-131b
3
39
37
46
15
69
4 days
7 days
7 days
24 h
6 days
24 h
24 h
24 h
142 h
105 h
3
3
3
3
19
52g
20h
15
156-157
169-170
216-217j
252-253m
3
3
3
3
55
29
15k
6k
rt
10
11
rti
rtl
Me
6
a 2-(3′-Nitro-4′-methoxyphenyl)-4,5-diphenyl-1,2,3-triazole (7%) also obtained. b Lit.19 mp 134-135 °C. c 2-(3′-Nitro-4′-methoxyphenyl)-4,5-diphenyl-
1,2,3-triazole (17%) also obtained. d 2-(3′-Nitro-4′-methoxyphenyl)-4,5-diphenyl-1,2,3-triazole (4%) also obtained. e No nitrated products encountered. f 2-
(3′-Nitro-4′-methoxyphenyl)-4,5-diphenyl-1,2,3-triazole (13%) also obtained. g 2-(3′-Nitro-4′-methoxyphenyl)-4,5-di(p-tolyl)-1,2,3-triazole (8%) also obtained.
h No 2-(3′-nitro-4′-methoxyphenyl)-4,5-di(p-anisyl)-1,2,3-triazole could be isolated. i Reaction initiated at -10 °C (4 h), temperature then raised to 0 °C (45
h), rt (45 h), 40 °C (28 h), and 60 °C (20 h). j Lit.20 mp 215-216 °C. k Estimated yield from 1H NMR analysis. l Reaction initiated at -10 °C (4 h),
temperature then raised to 0 °C (6 h), rt (19 h), 40 °C (19 h), 60 °C (57 h). m Lit.21 mp 252 °C.
azole molecules. In 2003, we made a preliminary report7 of the
NH-azole along with p-benzoquinone. The yields of p-benzo-
quinone were generally comparable to the yields of the
regenerated parent NH-azoles (apart from a few cases of workup
difficulties where some p-benzoquinone can be lost), and the
presence of p-benzoquinone, detectable by TLC, was an easy
indicator of the successful dearylation. In these reactions, a clear
solution of the N-p-anisyl azole in acetonitrile or methanol was
treated dropwise with a 2.7-3 M quantity of CAN, dissolved
in water, and stirred at the temperature indicated for the time
shown in the tables. The product solution was distributed
between dichloromethane and water and the residue from the
dichloromethane extract was chromatographed through a column
of silica gel to give the products shown in Tables 1 and 2. In
each case, the parent N-H azole was identified by comparison
of its IR and proton and carbon-13 NMR spectra with authentic
samples and also by mixture melting points.
(i) N-p-Anisylpyrazoles (Table 1). The results for the CAN
dearylations of a number of N-p-anisylpyrazoles under a range
of conditions are shown in Scheme 1 and Table 1. The overall
solvent is the final composition arising from the dropwise
addition of the aqueous CAN solution into the solution of the
starting pyrazole in the organic solvent. Good results were
obtained at ambient temperature, but better results were at lower
temperatures (Table 1, entries 3, 5, and 6). Compound 2a was
rearylated back to 1a in 80% yield by using p-anisylboronic
acid following a protocol similar to that of Lam et al.14 (Scheme
1).
successful application of CAN dearylation to N-p-anisylpyra-
+ 8
zoles and p-anisylpentazole following the discovery of N5
.
Having reviewed pentazole chemistry,9 we have reported on
the mechanisms of the formation10 of the pentazole ring and its
thermal degradation,11 as well as basicity and protonation.12
Herein we describe fully our work on the N-dearylation of N-p-
anisylazoles including p-anisylpentazole. Our preliminary report7
on pyrazoles and pentazoles in 2003 drew a challenge,13 part
of which was correct, and we will respond to that also herein.
Results and Discussion
Part I: C,N-Azoles. When the prospective CAN dearylation
for N-p-anisylazoles was attempted with N-p-anisylpyrazoles,
2-N-p-anisyl-1,2,3-triazoles, and 2-N-p-anisyl-1,2,3,4-tetrazoles,
an N-dearylation was achieved which regenerated the parent
(7) Butler, R. N.; Stephens, J. C.; Burke, L. A. Chem. Commun. 2003,
1016-1017.
(8) Christe, K. O.; Wilson, W. W.; Sheehy, J. A.; Boatz, J. A. Angew.
Chem., Int. Ed. 1999, 38, 2004-2009.
(9) Butler, R. N. Pentazoles. In ComprehensiVe Heterocyclic Chemistry
II; Katritzky, A. R., Rees, C. W., Scriven, E. F., Eds.; Elsevier Science:
New York, 1996; Vol. 4, pp 897-904.
(10) Butler, R. N.; Fox, A.; Collier, S.; Burke, L. A. J. Chem. Soc., Perkin
Trans. 2 1998, 2243-2247.
(11) Butler, R. N.; Collier, S.; Fleming, A. F. M. J. Chem. Soc., Perkin
Trans. 2 1996, 801-803.
(12) Butler, R. N.; Stephens, J. C.; Hanniffy, J. M. Tetrahedron Lett.
2004, 45, 1977-1979.
(13) Schroer, T.; Haiges, R.; Schneider, S.; Christe, K. O. Chem.
Commun. 2005, 1607-1609.
(14) Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Winters, M.
P.; Chan, D. M. T.; Combs, A. Tetrahedron Lett. 1998, 39, 2941-2944.
J. Org. Chem, Vol. 73, No. 4, 2008 1355

Butler et al.
SCHEME 1. CAN Dearylation and Reanisylation of 1-N-p-Anisylpyrazoles
a Isolated yield at ambient temperature.
SCHEME 2. CAN Dearylation and One-Pot Dearylation-Alkylation of 2-N-(p-Anisyl)-4,5-diaryl-1,2,3-triazoles (Ar )
p-RC6H4-)
b
a Lit.18 mp 61-63 °C. Lit.18 mp 129-130 °C.
SCHEME 3.
tetrazoles
CAN Dearylations of 2-N-(p-Anisyl)-5-aryl-
CAN procedure. The detrimental effects of the low pH, due to
HNO3, in CAN dearylations of p-anisylamines has led to the
development of alternative nonmetallic oxidative organic N-
dearylating agents including trichloroisocyanuric acid (TCCA).5
When attempted dearylation reactions were carried out with the
triazole 4a using TCCA, tetracyanoethylene (TCNE) and 2,3-
dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), no dearylations
occurred and no traces of p-benzoquinone or the parent NH-
1,2,3-triazoles were detected. The presence of nitric acid in the
CAN dearylation medium resulted in some competitive nitration
of the 2-N-p-anisyl ring of the 1,2,3-triazole substrates (Scheme
2, Table 2, footnotes). This was reduced by using lower
temperatures for the dearylation reaction (Table 2, entry 2 versus
entries 3 and 4).
(ii) 2-N-p-anisyl-1,2,3-triazoles and -1,2,3,4-tetrazoles (Table
2). The N-dearylation reaction was successful with 2-p-anisyl-
1,2,3-triazoles and -tetrazoles. The results for reactions of CAN
with some 2-p-anisyl-4,5-diaryl-1,2,3-triazoles 4 and 2-p-anisyl-
5-aryltetrazoles 6 are shown in Schemes 2 and 3 and Table 2.
The growing presence of p-benzoquinone in the solution again
indicated the progress of N-dearylation. Control reactions with
the substrate 4a in which quantities of p-benzoquinone were
added to the triazole solution prior to the dropwise addition of
the CAN solution showed no detrimental effect on the yield of
5a regenerated. In order to assess any effects of the presence
of HNO3 in the CAN reaction other CeIV salts such as the sulfate
(CAS) and hydroxide (both with necessary added HCl) were
also examined (Table 2, entries 6, 7). Both gave low yields of
parent NH-1,2,3-triazole 5a. No p-benzoquinone was detected
in these reactions and overall they were less effective than the
4,5-Diphenyl-1,2,3-triazole 5a has previously been synthe-
sized in 37% yield from the reaction of potassium tert-butoxide
with benzaldehyde azine by Grundon and Khan.19 Samples of
(15) Butler, R. N.; Scott, F. L.; Scott, R. D. J. Chem. Soc. C 1970, 2510-
2512.
(16) Simon, D.; Lafont, O.; Farnoux, C. C.; Miocque, M. J. Heterocycl.
Chem. 1985, 22, 1551-1557.
(17) Grandi, R.; Messerotti, W.; Pagnoni, U. M.; Trave, R. J. Org. Chem.
1977, 42, 1352-1355.
1356 J. Org. Chem., Vol. 73, No. 4, 2008

Ceric Ammonium Nitrate N-Dearylation of N-p-Anisylazoles
SCHEME 4. Proposed Mechanism of Azole N-Dearylation
compound 5a from the dearylation reaction were identical to
samples prepared by this method.19 The dearylation route is
somewhat more convenient since 2-N-p-anisyl-1,2,3-triazoles
5 are readily available from benzil bis-p-methoxyphenylhydra-
zones.22 In the CAN reaction with the substrate 4c, 2,4,5-tri-
(p-anisyl)-1,2,3-triazole, only the 2-N-p-anisyl group was oxi-
datively removed, and the C-p-anisyl groups at the triazole
positions 4- and 5- were not affected. The 2-p-anisyl-5-
aryltetrazoles 6 were dearylated by CAN giving low yields of
5-aryltetrazoles 7 along with comparable quantities of p-
benzoquinone (Table 2, Scheme 3).
(iii) One-Pot N-Dearylation-Methylation Protocol. The
2-p-anisyl-1,2,3-triazole substrate was explored further as a
model system. A one-pot dearylation-methylation protocol was
developed (Scheme 2), which involved raising the pH of the
completed CAN dearylation reaction mixture to 10 with KOH
followed by introduction of the super alkylating Meerwein
reagent trimethyloxonium tetrafluoroborate. This allowed a one-
pot conversion of an N-arylazole to an N-methylazole in
reasonable yields (Scheme 2). The 2- and 1-methyl-1,2,3-triazole
isomers 8 and 9 were identical with authentic samples. The in
situ methylation of the regenerated 5a was also carried out on
the acidic CAN dearylation solution, without basification to pH
10. In this case, the yields of the N-methyl isomers 8 (3%) and
9 (7%) were significantly lower and reversed in relative magni-
tude. These trends were also observed in separate independent
methylations of compound 5a distinct from those carried out
in situ on 5a regenerated by CAN dearylation of 4a.
(iv) Mechanism, Limitations, and Selectivity of CAN Azole
N-Dearylations. The CAN dearylation process renders the
p-anisyl substituent as a potential aryl protecting group in the
chemistry of N-arylpyrazoles and 2-aryl-1,2,3-triazoles and
-tetrazoles. Since many triazole and tetrazole derivatives display
biological activity, a reviewer has pointed out that the reaction
may prove useful for deprotecting N-aryl-bearing products of
click reactions. In this context, we feel that the use of the sulfate
salt CAS merits further exploration in order to avoid the nitric
acid environment which may be detrimental to some structures
linked by click reactions. The reaction was not effective with
N-p-anisylimidazoles, N-p-anisyl-1,2,4-triazoles, and 1-p-anisyl-
1,2,3-triazoles. For a range of these cases studied, no benzo-
quinone was produced and the parent N-H azole was not
regenerated. Ce(IV) is a one-electron oxidizing agent, and by
analogy with the proposed literature mechanism2,3,23-25 for the
oxidation of alkyl aryl ethers to p-benzoquinone, we expect that
successive one-electron oxidations give rise to the dicationic
species 10 which undergoes hydrolytic degradation to the parent
N-H azole and p-benzoquinone (Scheme 4).
Theoretical calculations26 suggest that the species 10 is
-
considerably stabilized by ion-pairing, and when the two NO3
anions are included above and below the plane of the benzene
ring in B3LYP/3-611+G(d) geometry optimizations for X,Y,
Z ) N the bond lengths resemble much more a neutral aromatic
system than a quinone structure.26 The benzene 1- and 4-carbons
remain positive enough to still favor nucleophilic H2O addition
which facilitates the separation of the aromatic rings.
The N-p-anisylazoles which have been dearylated have
characteristically weak basicities possessing basic pKa values
(pKa of conjugate acid) less than 0.5. Thus, 1-phenylpyrazole
has a basic pKa of 0.43, while 1-phenylimidazole has basic pKa
5.1.27 In the triazole series, the N-substituted derivatives for
which basic pKa values are available, such as 1- and 4-methyl-
1,2,4-triazoles, display pKa values of 3.2 and 3.4, respectively,
while 1-methyl-1,2,3-triazole has a basic pKa of 1.23.27 Only
the 2-substituted 1,2,3-triazoles are well-known as exceptionally
weak bases, with the pKa for 2-methyl-1,2,3-triazole being as
low as -3.25.27 The reported N-aryl- and N-alkyltetrazoles have
low basic pKa values in the range -1.96 to -3.25.27 In
agreement with the mechanism of Scheme 4, only azoles which
are unprotonated in the strongly acidic conditions of aqueous
CAN solutions are expected to be oxidized by CeIV. For 4-p-
anisyl-1,2,4-triazole, the CAN solution in CD3OD-D2O showed
deshielding of the 3-CH/5-CH proton from δ 8.9 to 9.6 as
expected for protonation of the molecule. The results suggest
that the reaction is limited to substrates with basic pKa values
lower than ca. 0.5 because of prior protonation, which then
requires oxidative electron extraction from a cation. Arylpen-
tazoles are exceptionally weak bases.28-31 A basic pKa value
of -8.9 has been theoretically estimated for 1-methylpenta-
zole.30,31 Arylpentazoles are not protonated by trifluoroacetic
acid but in the superacid, chlorosulfonic acid, p-anisylpentazole
was fully protonated at N-3 (rather than the ethereal oxygen)
and this pentazole derivative has a basic pKa of ca. -8.12 Hence,
(24) Nair, V.; Balagopal, L.; Rajan, R.; Mathew, J. Acc. Chem. Res. 2004,
37, 21-30.
(25) Fetter, J.; Keskeny, E.; Czuppon, T.; Lempert, K.; Kajta´r-Peredy,
M.; Tama´s, J. J. Chem. Soc., Perkin Trans. 1 1992, 3061-3067.
(26) Burke, L. A.; Butler, R. N.; Stephens, J. C. J. Chem. Soc.. Perkin
Trans. 2 2001, 1679-1684.
(27) Catala´n, J.; Abboud, J.-L. M.; Elguero, J. In AdVances in Hetero-
cyclic Chemistry; Katritzky, A. R., Ed.; Academic Press: New York 1987;
Vol. 41, pp 187-274.
(28) Mo´, O.; de Paz, J. L. G.; Ya´n˜ez, M. J. Phys. Chem. 1986, 90, 5597-
5604.
(29) Jano, I. J. Phys. Chem. 1991, 95, 7694-7699.
(30) Claramunt, R. M.; Sanz, D.; Boyer, G.; Catala´n, J.; de Paz, J. L.
G.; Elguero, J. Magn. Reson. Chem. 1993, 31, 791-800.
(31) Catala´n, J.; de Paz, J. L. G.; Ya´n˜ez, M.; Elguero, J. Chem. Scr.
1984, 24, 84-91.
(18) Gilchrist, T. L.; Gymer, G. E.; Rees, C. W. J. Chem. Soc.. Perkin
Trans. 1 1975, 1-8.
(19) Grundon, M. F.; Khan, E. A. J. Chem. Soc., Perkin Trans. 1 1988,
2917-2919.
(20) Demko, Z. P.; Sharpless, K. B. J. Org. Chem. 2001, 66, 7945-
7950.
(21) Butler, R. N.; Garvin, V. C. J. Chem. Soc., Perkin Trans. 1 1981,
390-393.
(22) Butler, R. N.; O’Shea, D. F. Heterocycles 1994, 37, 571-584.
(23) Molander, G. A. Chem. ReV. 1992, 92, 29-68.
J. Org. Chem, Vol. 73, No. 4, 2008 1357

Butler et al.
1-p-anisylpentazole should be a good candidate for CAN
dearylation. The results in Table 1 (entry 6) and Table 2 (entry
4) confirmed that CAN dearylations are successful at -40 °C,
well below the thermal degradation temperature of arylpenta-
zoles.
character of the M-N compared to group I and II counterions.
(However, adding Zn2+ ion was discontinued as it proved
ineffective.) Subsequent theoretical work45 showed that the
presence of counterions such as Fe2+ changes the nature of the
ground state Fe2+‚2N5 complex from a singlet to a quintet,
-
-
lowering the barrier to N5 decomposition. Interestingly, a
Part II: Pentazoles. The arylpentazole system, ArN5, was
discovered by Huisgen and Ugi32 in Munich and Clusius and
Hu¨rzeler33 in Zurich. Its dimensions,34 spectral effects,35 basicity,
and protonation site12 place the pentazole ring firmly as the
highest nitrogen member of the azoles. A potentially viable route
to HN5 of ozonolytic degradation of the aryl ring was attempted
by Ugi36 and recently repeated with necessary gentler more
controlled conditions by Kaszynski and co-workers.37 However,
while no indication of HN5 was found, compelling theoretical
studies in 1992 by Bartlett’s group38 determined activation
barriers for the decomposition pathways for HN5 and predicted
computational study by the Klapo¨tke group46 has predicted
methyl pentazole, MeN5, to be among the most stable pentazole
derivatives, and this prompted our development of the one-pot
dearylation-methylation protocol for N-p-anisylazoles (part I).
Methylation of N5-, if possible, would be a prime route to
MeN5.
(i) p-Anisylazide: 15N Signal Intensities and Control
Reactions with CAN. In a linear chain of three nitrogen atoms
(-N3) containing one 15N atom the intensity of the 15N NMR
signal of the central 15N atom (which will be doubly bound to
two 14N atoms) will be much stronger than either of the terminal
15N atoms (which will be doubly bound to only one 14N atom)
due to more efficient relaxation of the central 15N atom.47 In
the Supporting Information (S5), we show the natural abundance
15N NMR spectrum of p-anisylazide, where the central 15Nâ
signal at -134.3 ppm is much more intense than that of Nγ
(-146.1 ppm) or NR (-290.0 ppm) as expected.
-
that both it and its pentazolate anion N5 should be viable
entities under appropriate conditions.
Schleyer et al.39 and Nguyen et al.40 have theoretically
illustrated that the most stable all-nitrogen systems, after N2,
are pentazolic units and that HN5 and N5- should be comparable
in aromaticity to furan and pyrrole. Two groups41,42 have
-
detected N5 in the gas phase from high-energy mass spectro-
metric degradation of aryl pentazoles. A theoretical assessment
of the acidity of HN5 concluded that it may be a stronger acid
than HNO3,43 and hence, if generated in an aqueous nitrate salt
environment it could form a metallic salt. A range of theoretical
studies26,44 have suggested that metallic salts of N5- should be
stable entities. But which metal cations should be chosen? The
low-temperature solution chemistry of pentazoles is difficult and
not suitable for a wide variety approach. Following our own
theoretical assessment26 of the relative stability of pentazole
counterions, we initially chose Zn2+ due to the higher covalent
Since arylpentazole samples may contain various levels of
aryl azide impurities, it was necessary to examine the reactions
of p-anisylazide with CAN to (a) eliminate any possible reaction
of CAN with arylazide impurity and (b) ensure that the reaction
of CAN with p-anisylpentazole did not begin with pentazole
ring destruction to p-anisylazide. This was confirmed by proton
NMR spectra of the products from the reaction of CAN with
p-anisylazide at -40 °C showing a very weak signal for
p-benzoquinone (maximum isolated yield 5-6%) as against the
comparable NMR spectra from the reaction of CAN with
p-anisylpentazole at -40 °C, showing a much stronger p-
benzoquinone signal (maximum isolated yield 34%) (S6).
The reaction of CAN with p-anisylazide is more rapid than
with the pentazole, and pentazole samples containing a signifi-
cant arylazide impurity will show no reaction with CAN because
the arylazide will consume much of the CAN reagent. With
such cases it is necessary to introduce a second charge of CAN
to achieve the pentazole dearylation and this procedure may
also be used to clean up a poor pentazole sample. One of the
early products of the reaction of CAN with p-anisylazide at
(32) (a) Huisgen, R. The Pentazole Story. In The AdVenture Playground
of Mechanisms and NoVel Reactions, Profiles, Pathways and Dreams;
Seeman, J. I., Series Ed.; American Chemical Society: Washington D.C.,
1994; pp 79-82. (b) Huisgen, R.; Ugi, I. Angew. Chem. 1956, 68, 705-
706. (c) Huisgen, R.; Ugi, I. Chem. Ber. 1957, 90, 2914-2927.
(33) (a) Clusius, K.; Hurzeler, H. HelV. Chim. Acta 1954, 37, 798-804.
(b) Ugi, I.; Huisgen, R.; Clusius, K.; Vecchi, M. Angew. Chem. 1956, 68,
753-754.
(34) For crystal structures, cf. (a) Wallis, J. D.; Dunitz, J. D. J. Chem.
Soc., Chem. Commun. 1983, 910-911. (b) Biesemeier, F.; Mu¨ller, U.;
Massa, W. Z. Anorg. Allg. Chem. 2002, 628, 1933-1934.
(35) UV: Ugi, I.; Perlinger, H.; Behringer, L. Chem. Ber. 1958, 91, 2324.
1H NMR: cf. refs 9 and 11.
(36) Ugi, I. Angew. Chem. 1961, 73, 172.
(37) Benin, V.; Kaszynski, P.; Radziszewski, J. G. J. Org. Chem. 2002,
67, 1354-1358.
(38) (a) Ferris, K. F.; Bartlett, R. J. J. Am. Chem. Soc. 1992, 114, 8302-
8303. (b) Fau, S.; Wilson, K. J.; Bartlett, R. J. J. Phys. Chem. A 2002, 106,
4639-4644. (c) Perera, S. A.; Bartlett, R. J. Chem. Phys. Lett. 1999, 314,
381-387. (d) Bartlett, R. J. Chem. Ind. 2000, 140-143.
(39) (a) Glukhovtsev, M. N.; Jiao, H.; Schleyer, P. v. R. Inorg. Chem.
1996, 35, 7124-7133. (b) Glukhovtsev, M. N.; Schleyer, P. v. R.; Maerker,
C. J. Phys. Chem. 1993, 97, 8200-8206.
(40) Nguyen, M. T.; Ha, T.-K. Chem. Ber. 1996, 129, 1157-1159.
(41) Ostmark, H.; Wallin, S.; Brinck, T.; Carlqvist, P.; Claridge, R.;
Hedlund, E.; Yudina, L. Chem. Phys. Lett. 2003, 379, 539-546; see also
ref 25 therein.
(42) Vij, A.; Pavlovich, J. G.; Wilson, W. W.; Vij, V.; Christe, K. O.
Angew. Chem., Int. Ed. 2002, 41, 3051-3054.
(43) Chen, C. Int. J. Quantum Chem. 2000, 80, 27-37.
(44) (a) Zhao, J. F.; Li, N.; Li, Q. S. Theor. Chem. Acc. 2003, 110, 10-
18. (b) Lein, M.; Frunzke, J.; Timoshkin, A.; Frenking, G. Chem. Eur. J.
2001, 7, 4155-4163. (c) Gagliardi, L.; Pyykko¨, P. J. Phys. Chem. A 2002,
106, 4690-4694. (d) Kobrsi, I.; Zheng, W.; Knox, J. E.; Heeg, M. J.;
Schlegel, H. B.; Winter, C. H. Inorg. Chem. 2006, 45, 8700-8710. (e)
Nguyen, M. T.; McGinn, M. A.; Hegarty, A. F.; Elguero, J. Polyhedron
1985, 4, 1721-1726.
-40 °C is N3-. In these solutions, the 15N NMR shifts of N3
-
15
are
N
,-281 ( 2 ppm and 15Nâ, -144 ( 3 ppm. In the 15N
R,γ
-
NMR spectrum of fully labeled 15N3 (Na15N3) in CD3OD-
D2O, the shifts are 15NR,γ -280 to -281 ppm (d) and 15Nâ -131
ppm (t) (with Nâ again more intense than the combined NR,γ
signal) (S7). When this fully labeled N3- is added to the product
solution from CAN dearylation of the pyrazole 1c (Table 1)
(after first adding unlabeled N3- to consume any remaining CeIV
since azide ion is oxidized by CeIV above 0 °C), the 15N NMR
spectrum now shows three Nâ signals for the labeled azide ion,
at -129.4 ppm (t) (uncomplexed 15N3-), -132 ppm, and -143
ppm (S8). The latter signals are from metal complexed azide
ions. The presence of azide ion in three different environments
is further confirmed by three separate signals also for the NR,γ
atoms of the azide ion between -290 and -293 ppm. Each of
(45) Burke, L. A.; Fazen, P. J. Chem. Commun. 2004, 1082-1083.
(46) Hammerl, A.; Klapo¨tke, T. M.; Schwerdtfeger, P. Chem. Eur. J.
2003, 9, 5511-5519.
(47) A review: Mason, J. Chem. ReV. 1981, 81, 205-227; cf. p 207.
1358 J. Org. Chem., Vol. 73, No. 4, 2008

Ceric Ammonium Nitrate N-Dearylation of N-p-Anisylazoles
SCHEME 5. Preparation of 15N-Labeled p-Anisyl Pentazoles (Ar ) p-MeOC6H4)
these is a doublet split by the azide ion Nâ (Supporting
Information, S8). The strongest signals are from uncomplexed
the NR,γ signal for a single label may be lost in the baseline,
but its splitting effect on the adjacent strong Nâ signal is readily
detected.
-
15N3 where NR and Nγ are identical. The appearance of the
azide ion 15Nâ signal at ca. -143 ppm is probably due to CeIII
complexation. The 15N NMR signal of Nâ for the azide ion
formed by decomposition of HN5/N5-, produced by CAN
dearylation of p-anisylpentazole, appears at the same chemical
shift, 144 ( 3 ppm. The spectra (Supporting Information, S8)
also illustrate a feature of the metal complexed azide ions in
these solutions where despite 15N labels at both NR and Nγ sites
the combined terminal NR,γ signal is exceptionally weak relative
to that of Nâ, possibly due to CeIII complexation. In such cases
(ii) CAN Dearylation of p-Anisylpentazole: Generation
of HN5/N5- in Solution. A suite of 15N-labeled pentazoles was
prepared (Scheme 5). The series 14A + 14B, 15, and 16 carry
a single 15N atom located at each position of the pentazole ring,
namely N-1, N-2, and N-3. The series 17A + 17B, 18, and
19A + 19B contain two 15N atoms in each pentazole molecule
(Scheme 5, nos. 4-6). The compounds 20A + 20B contain
three 15N atoms in each pentazole ring. The reactions of each
of these with CAN were examined. Those molecules with more
J. Org. Chem, Vol. 73, No. 4, 2008 1359

Butler et al.
SCHEME 6. CAN Dearylation of Singly 15N-Labeled p-Anisylpentazoles
than one 15N atom allow splitting effects as well as chemical
shifts to be used for analysis. In preparing these pentazoles,
inorganic nitrite salts were avoided where possible and isoamyl
nitrite was used as the preferred diazotization reagent, as in our
preliminary report.7 It was found that the level of p-anisyl azide
impurity present in pentazoles prepared by using inorganic nitrite
salts in the diazotization step was often unacceptably high, and
a second impurity, 1,3-di-p-anisyltriazene, was also present in
significant quantity. (Separate reactions of CAN with the diaryl
triazene produced aryl diazonium ion). The only case where
these impurities could not be fully avoided was for reaction
no. 2 (Scheme 5) in which the 15N label was placed exclusively
at the pentazole N-2 in compound 15. However, this problem
was somewhat alleviated in cases 5 and 7 by in situ generation
of 15N-labeled isoamyl nitrite, and for case 6 the triazene and
most of the aryl azide was removed by cleaning using CAN
(see the Supporting Information). The label was placed exclu-
sively at the pentazole N-1 in compound 16, by using 15N-
labeled p-anisidine. This was synthesized by nitrating chlo-
robenzene with H15NO3, carrying out an SNAr displacement of
chloride with MeO- on the isolated p-ClC6H415NO2 isomer, and
subsequently reducing the nitro group. This synthesis was
experimentally not trivial. In the preliminary account of this
work7 the pentazole substrate used was a 1:1 mixture of 14A
and 14B which was reacted with one charge of CAN. The
spectra obtained are in the literature.7 In Scheme 5, reaction 1,
CD3OD at -40 °C was treated by dropwise addition of a cooled
solution of CAN in D2O with stirring and the mixture stirred at
-40 °C for several days p-benzoquinone was produced (Sup-
porting Information, S6). NMR samples were withdrawn and
15N NMR spectra were measured at -40 °C and again at
-20 °C. This work was described in the preliminary com-
munication.7 The spectra, which have been published,7 showed
the presence of NO3- (correctly reassigned by Schroer et al.13),
unreacted 14, and a mixture of azide ions labeled at NR/γ and
Nâ, 15NRdNdN- and Nd15NâdN-. The signal for NR,γ-labeled
N3- was at -281 ( 2 ppm and that for Nâ-labeled N3- was at
-144 ( 3 ppm (Scheme 6). These results showed that N5- had
been present in the solution. Schroer et al.,13 however, disputed
that these signals were from azide ion labeled at NR/γ and Nâ
but significantly acknowledged that if they were azide signals
they would constitute strong evidence for the formation of an
-
intermediate N5 anion in which all nitrogens had become
equivalent. They interpreted the signal at -283 ppm as NR of
singly labeled azide anion impurity carried invisibly through
all of the 15N NMR spectra from the pentazole synthesis but
reappearing in the last spectrum from the CAN reaction. The
signal at -147 ppm was ascribed to Nγ of p-anisyl azide (from
decomposition of compound 14A + 14B) but in which Nâ of
the p-anisyl azide was not visible because its signal was too
weak. However, the natural abundance 15N NMR spectrum of
p-anisyl azide shows the supposedly invisible Nâ signal to be
the mechanism11,32 of the reaction of N3 with aryldiazonium
much more intense than that of Nγ. Schroer et al.13 show a 15
N
-
ion is summarized. When mono-15N-labeled azide anion is used
the 15N label at the terminal position of the azide anion is
focused heavily into the γ-position of the main p-anisyl azide
product. This is the arylazide impurity which will contaminate
the arylpentazole. The 15N label can only make its way into the
â-position of p-anisyl azide via thermal degradation of the
pentazole which is a minor part of the overall reaction of an
aryl diazonium salt with azide ion.11,32
NMR spectrum of p-anisyl azide where the signal for Nγ is twice
as intense as Nâ from a sample which is claimed to have equal
labels at Nâ and Nγ. However, the spectrum shown by Schroer
et al.13 is a sample of the aryl azide heavily contaminated with
compound 13 (Scheme 5, reaction 1) in which the 15N label
has been bonded exclusively at Nγ, a consequence of the
mechanism of the reaction. Compound 13 is the main product
of the reaction of aryl diazonium ions with terminally 15N-
labeled azide ion.11,32 If the sample of the arylpentazole used
to produce aryl azide is contaminated by the aryl azide 13 false
(a) Pentazole Samples with One 15N Atom (Scheme 6).
When a solution of the pentazole 14A + 14B (Scheme 5) in
1360 J. Org. Chem., Vol. 73, No. 4, 2008

Ceric Ammonium Nitrate N-Dearylation of N-p-Anisylazoles
SCHEME 7. Expected Azide Anion 15N Multiplicities and Intensities from Di-15N-Labeled Pentazoles (Ar ) p-MeOC6H4-)
relative intensities will be observed for the Nâ and Nγ signals,
with Nγ appearing much more intense.
at positions 1 and 3 and at positions 1 and 2, as in structures
17A + 17B and 18 (Scheme 7), the azide anion expected from
-
degradation of HN5/N5 will have a combination of special
The issue was further resolved by placing a single 15N label
at the N-1 and N-2 pentazole positions as in structures 15 and
16. When these singly 15N-labeled pentazoles 15 and 16 were
similarly treated with CAN the results obtained were the same
as those for 14, namely p-benzoquinone and metal-complexed
15N-labeled azide ions with a strong label at the important Nâ
position were produced (Scheme 6, reactions 2 and 3) (Sup-
porting Information, S9-S10). The azide ion had the same
chemical shifts as those from reaction 1, Scheme 6. Raising
the temperature of the reaction to -20 °C, or introducing a
second charge of CAN, increased the intensity of the azide ion
signals and significantly reduced the amount of unreacted
pentazole (spectra in the Supporting Information). No 15N-
labeled azide ion was used in the synthesis of the starting
pentazoles 15 and 16, and neither of these can decompose to a
15Nγ-labeled arylazide. These results show that ceric ammonium
nitrate has dearylated p-anisylpentazole just as it did the other
azoles in part I. The reaction has produced p-benzoquinone and
intensities and splitting patterns for the 15N-labeled Nâ and NR,γ
positions as illustrated in Scheme 7. The key central 15Nâ signal
of the azide ion at 144 ( 3 ppm is particularly significant. From
the equimolar mixture 17A + 17B it will be an overlapping
-
strong singlet (c + e) and a weaker doublet (c′ + d′). For N5
from substrate 18 the azide anion Nâ signal will be a strong
doublet (c′ + d′, Scheme 7). Both of these expectations were
borne out in the 15Nâ signal at -144 ( 3 ppm which appears
in the solutions from the separate dearylations of substrates 17A
+ 17B and 18 with CAN at -40 °C (Supporting Information,
S11-S12). The strong singlet azide ion Nâ signal (Supporting
Information, S11) is particularly significant. It can only arise
-
-
for N3 from HN5 or N5 since the only possible aryl azides
from fragmentation of 17A + 17B are Ar-15NdNâd15N and
Ar-15Nd15NâdN, neither of which can produce azide anion
with an 15Nâ singlet signal. The expected strong doublet azide
ion Nâ signal (split by a single 15N labeled NR,γ) is also obtained
-
from degradation of HN5/N5 generated by dearylation of
-
-
pentazole 18 (c′, d′, Scheme 7) (S12). The sample of HN5/N5
HN5/N5 in which a single 15N label at any position in the
produced from dearylation of the p-anisyl pentazoles 19A +
19B (with different initial labels) will have the same distribution
of 15N labels as that from 17A + 17B (Scheme 7). As expected
the azide ion produced from its degradation again showed the
15Nâ signal as a strong singlet overlapping a weaker doublet
(Supporting Information, S13). These results combined with
those of the singly labeled pentazoles above are unequivocal.
starting pentazole has been scrambled to produce 15N-labeled
azide ion with 15N atoms at NR/γ and Nâ as shown in reactions
1-3, Scheme 6. Because of the difficulties already mentioned
concerning the synthesis of the N-2-labeled pentazole 15, S10
(Supporting Information) also shows the presence of â-labeled
aryldiazonium ion [Ar-N+t15N] from CAN degradation of the
diaryltriazene contaminant.
-
They confirm the formation of N3 by degradation of HN5/
(b) Pentazole Samples with Two 15N Atoms (Scheme 7).
When the starting arylpentazole contains two 15N labels located
N5- in these solutions. The azide anion NR,γ signals, which are
much weaker than Nâ, also have significant characteristics. In
J. Org. Chem, Vol. 73, No. 4, 2008 1361

Butler et al.
some cases, the weak azide ion NR,γ signal itself is not visible
in the low-temperature 15N spectra above the level of noise; its
presence is confirmed by its splitting effect on the Nâ signal in
expected for HN5/N5-, from -20 to 50 ppm. The results were
the same in the presence and absence of Zn2+ ions. Extensive
attempts were also made to trap HN5/N5- by in situ methylation
of a number of 15N-labeled samples for both the normal acidic
and basified solutions from CAN dearylations using the
procedures established with the triazole 5a. Calculated 15N NMR
shifts have been published46 for methyl pentazole and if a second
pentazole molecule had appeared in these solutions its set of
signals would have been easily detected in the NMR spectra.
However, methyl pentazole was not detected. Hence, we
conclude that the species HN5/N5- is unstable and did not build
up in the solutions even at -40 °C. If it is ever to be directly
detected or isolated it will need to be specially stabilized.
-
cases where the decomposition of N5 can give an azide ion
with two 15N labels, at both NR,γ and Nâ, as in S12(Supporting
Information). Samples of 20A + 20B were treated with CAN
at -40 °C, and recording of 15N NMR spectra was started within
20 min of the CAN addition, examined every 500 scans (49
min) for up to 14 h, and accumulated accordingly (Supporting
Information, S57-S62). The weak NR,γ signal at -280 ppm
began to appear after 2000 scans, and as it grew it displayed
the expected doublet character split by 15Nâ. Since the azide
ion used for the synthesis of 20A + 20B contained only a single
terminal 15NR atom, the doublet NR,γ signal for the azide ion
from 20A + 20B again shows that it now possesses an 15Nâ
Experimental Section
-
atom and that it came from degradation of N5 and is not a
Details of instrumentation used and all spectral figures are in
the Supporting Information.
leftover from the synthesis of 20A + 20B. In this case, the azide
Nâ signal is a multiplet of overlapping doublets and triplets.
N-Dearylations of C-N Azoles. Representative Procedure for
the Dearylation of N-p-Anisylpyrazoles: CAN Dearylation of
1a (Table 1, Entry 1). A solution of 1a (0.27 g, 1.33 mmol) in
MeCN (19 mL) was treated dropwise with an aqueous solution (4
mL) of CAN (2.19 g, 3.99 mmol) and stirred at ambient temperature
for 1 h. The reaction mixture was then diluted with water (30 mL)
and the MeCN removed under reduced pressure. The remaining
aqueous solution was extracted with CH2Cl2 (4 × 20 mL). The
combined organic extracts were washed with saturated aqueous
NaHCO3 solution (4 × 20 mL) and dried over MgSO4, and the
solvent was removed under reduced pressure. The residue (in 3
mL of CH2Cl2), was placed on a column of silica gel (230-400
mesh ASTM) and eluted with a gradient mixture of petroleum spirit
(bp 40-60 °C)-CH2Cl2 (1:0 to 0:1 v/v using a 5% v/v changing
gradient) to give 3 (0.06 g, 41%) and with a gradient mixture of
CH2Cl2-Et2O (1:0 to 0:1 v/v using a 2.5% v/v changing gradient)
followed by Et2O-MeOH (1:0 to 19:1 v/v) to give 2a (0.06 g,
47%). Compound 2a: mp 107-108 °C (from petroleum spirit (bp
80-100 °C)) (lit.15 mp 107-109 °C); 1H NMR (400 MHz, CDCl3)
(iii) p-Benzoquinone. p-Benzoquinone was produced in the
CAN reactions carried out with the pentazole samples, as for
the other azoles. It could be observed in low-temperature proton
NMR spectra for both unlabeled and 15N-labeled pentazole
samples (Supporting Information, S13). It was isolated by
partitioning the CAN solution between dichloromethane and
water, evaporation of the dichloromethane extract and chro-
matographic separation of the residue on a silica gel column.
The p-benzoquinone could also be sublimed out of the dichlo-
romethane residue onto a cold finger. Because of the large
number of p-benzoquinone isolations, a rapid proton NMR
estimation method was developed from a plot of standard
p-benzoquinone-methyl iodide mixtures in CD2Cl2 whereby a
proton NMR spectrum of a CD2Cl2 extract containing a known
quantity of added MeI gave an estimated % yield of p-
benzoquinone (Supporting Information, S47-S49). All yields
quoted are isolated values unless specifically designated as
estimated. Both methods were in agreement within experimental
error. The yields of p-benzoquinone from the CAN dearylation
of p-MeOC6H4N5 were 23-34%. By analogy with the other
azoles this implied that a comparable quantity of HN5 should
have been produced alongside. Schroer et al.13 state that there
was no reaction between CAN and p-anisylpentazole and no
“evidence of N5-, N3- or benzoquinone” formation “under the
reported conditions”, but the conditions used were quite different
to our reported conditions7 and the reaction could not have been
observed (Supporting Information, S49).
δ 2.31 (s, 6H, CH3), 5.81 (s, 1H, 4-CH), 12.18 (br s, 1H, NH); 13
C
NMR (CDCl3) δ 12.3 (3-CH3/5-CH3) 104.0 (C-4), 144.3 (C-3/C-
5); IR (mull, cm-1) νmax 3108 (NH), 1595 (CdN). Anal. Calcd for
C5H8N2: C, 62.5; H, 8.4; N, 29.1. Found: C, 62.3; H, 8.7; N, 29.0.
Compound 3: mp 109-110 °C (from petroleum spirit (bp 40-
60 °C) (lit.2 mp 111.5-112.5 °C); 1H NMR (400 MHz, CDCl3) δ
6.78 (4H, s); 13C NMR (100 MHz, CDCl3) δ 136.6 (C-2/C-3/C-
5/C-6), 187.3 (C-1/C-4).
Representative Procedure for the Dearylation of 2-N-p-
Anisyl-1,2,3-triazoles: CAN Dearylation of 4a (Table 2, Entry
1). A solution of 4a (0.40 g, 1.2 mmol) in MeCN (18 mL) was
treated dropwise with an aqueous solution (1.8 mL) of CAN (1.75
g, 3.2 mmol) and stirred at ambient temperature for 24 h. The
reaction mixture was diluted with water (10 mL) and the MeCN
removed under reduced pressure. The aqueous solution remaining
was extracted with CH2Cl2 (4 × 10 mL). The combined extracts
were dried over MgSO4, and the solvent was removed under
reduced pressure. The residue (in 3 mL of CH2Cl2) was placed on
a column of silica gel (230-400 mesh ASTM) and eluted with a
gradient mixture of petroleum spirit (bp 40-60 °C)-CH2Cl2 (9:1
to 0:1 v/v using a 5% v/v changing gradient) followed by CH2-
Cl2-Et2O (1:0 to 4:1 v/v using a 2.5% v/v changing gradient). The
products eluted from the column were isolated in the following
order: 2-(3′-nitro-4′-methoxyphenyl)-4,5-diphenyl-1,2,3-triazole
(0.03 g, 7%); 3 (0.05 g, 39%); 5a (0.12 g, 44%). Compound 5a:
mp 130-131 °C (from toluene) (lit.19 mp 134-135 °C); 1H NMR
(400 MHz, CDCl3) δ 7.31-7.33 (m, 6H, Hm, Hp, phenyl), 7.52-
7.54 (m, 4H, Ho, phenyl), 13.97 (s, 1H, NH); 13C NMR (100 MHz,
CDCl3) δ 130.0, 128.2, 128.6, 128.5 (C-1′, C-2′, C-3′, C-4′
respectively, phenyl rings), 142.3 (C-4/C-5); IR (mull, cm-1) νmax
3065 (NH), 1584 (CdN). Anal. Calcd for C14H11N3: C, 76.0; H,
(iv) Search for N5-. In the preliminary communication,7 we
reported a 15N signal at -10 ( 2 ppm which agreed with the
-
expected position for N5 with one 15N atom. This signal can
appear anywhere between -5 and -17 ppm as seen in the wider
range of spectra herein, and its variability combined with an
intensity comparable to the signals obtained from 15N labeled
samples proved misleading. The reassignment of the signal as
-
-
a natural abundance NO3 by Schroer et al.13 means that N5
has not been directly seen. One purpose of putting three 15N
atoms into the aryl pentazoles 20A + 20B was to increase the
-
intensity of the possible signal from HN5/N5 where each
molecule would have three equivalent 15N atoms. Samples of
20A + 20B were treated with CAN at -40 °C as described.
Recording of 15N NMR spectra was started within 20 min of
the CAN addition, and spectra were examined and accumulated
every 500 scans (49 min) for up to 14 h (Supporting Information,
S57-S62), but no signals were detected anywhere in the range
1362 J. Org. Chem., Vol. 73, No. 4, 2008

Ceric Ammonium Nitrate N-Dearylation of N-p-Anisylazoles
5.0; N, 19.0. Found: C, 76.1; H, 4.6; N, 19.0. 2-(3′-Nitro-4′-
methoxyphenyl)-4,5-diphenyl-1,2,3-triazole: mp 176-178 °C (from
Synthesis and Dearylation of N-p-Anisylpentazoles (Schemes
5 and 6). Unstable p-anisylpentazole samples, unlike the stable
lower azole samples, cannot be stored and weighed for separate
dearylation reactions. Hence, all pentazole samples, once prepared
and isolated at -40 °C, were immediately reacted with CAN.
Representative Procedure for the Synthesis of Arylpentazoles.
Synthesis of Unlabeled 1-(p-Anisyl)pentazole. A solution of
p-anisidine (1.61 g, 13.1 mmol) in MeOH (8.2 mL) at 0-2 °C was
treated dropwise with concd HCl (2.1 mL) followed by isoamyl
nitrite (1.9 mL, 1.66 g, 14.2 mmol). The mixture was allowed to
stand for 20 min at 0-2 °C and then diluted with a MeOH-H2O
mixture (1:1 v/v) (22.4 mL) and covered with a layer of petroleum
spirit (bp 40-60 °C) (120 mL). The mixture was cooled to
-35 °C, and a cooled solution of sodium azide (0.85 g, 13.1 mmol)
in MeOH-H2O (3:2 v/v) (6.95 mL) was injected into the lower,
aqueous layer. A solid mixture of products separated and was
isolated by filtration through a sintered glass funnel with a cooling
jacket at -40 °C. The solid was repeatedly washed with a MeOH-
H2O mixture (3:2 v/v), cooled below -55 °C, to give 1-(p-anisyl)-
pentazole containing a small quantity of p-anisyl azide impurity
(max 12-16% by 1H NMR): 1H NMR (400 MHz, CD3OD-CD2-
Cl2 (1:1 v/v), -40 °C) δ 3.96 (s, 3H, OCH3), 7.22-7.25 (d, 2H,
Hm, AA′BB′, NC6H4OCH3-p, AA′BB′ JAB 9.1 Hz), 8.15-8.17 (d,
2H, Ho, AA′BB′, NC6H4OCH3-p); 13C NMR (100 MHz, CDCl3,
-40 °C) δ 56.1 (OCH3), 126.7, 122.6, 115.3, 161.4 (C-1′, C-2′,
C-3′, C-4′ respectively, NC6H4OCH3-p).
1
CH2Cl2-hexane 2:1 v/v); H NMR (400 MHz, CDCl3) δ 4.03 (s,
3H, OCH3), 7.20-7.22 (d, 1H, J6′-5′ 9.0 Hz, 5′-CH of 3′-NO2-4′-
OCH3C6H3-), 7.40-7.41 (m, 6H, phenyl), 7.62-7.63 (m, 4H,
phenyl), 8.33-8.36 (dd, 1H, J6′-5′ 9.0 Hz, J6′-2′ 3.0 Hz, 6′-CH of
3′-NO2-4′-OCH3C6H3-), 8.67-8.68 (d, 1H, 2′-CH of 3′-NO2-4′-
OCH3C6H3-); 13C NMR (100 MHz, CDCl3) δ 56.9 (OCH3), 132.7,
116.2, 139.7, 151.8, 114.2, 123.7 (C-1′, C-2′, C-3′, C-4′, C-5′,
C-6′ respectively, 3′-NO2-4′-OCH3C6H3-), 146.5 (C-4/C-5), 128.4,
128.7, 128.9 (phenyls), 130.3 (C-1′, phenyl). Anal. Calcd for
C21H16N4O3: C, 67.7; H, 4.3; N, 15.1. Found: C, 67.3; H, 4.3; N,
15.4.
Representative Procedure for the Dearylation of 2-N-p-
Anisyl-1,2,3,4-tetrazoles: CAN Dearylation of 6a (Table 2,
Entry 10). A suspension of 6a (0.20 g, 0.79 mmol) in MeCN (27
mL) at -10 °C was treated dropwise with an aqueous solution (2.5
mL) of CAN (1.30 g, 2.37 mmol) and stirred at this temperature
for 4 h. The temperature was raised to 0 °C for 45 h, then to ambient
temperature for 45 h, 40 °C for 28 h, and finally 60 °C for 20 h.
The reaction mixture was diluted with MeCN (30 mL) and brought
to pH 10 using 0.1 M aqueous NaOH. The precipitate was filtered
and washed with water (10 mL). The combined filtrate and water
washings were extracted with Et2O (3 × 30 mL) and the aqueous
layer acidified to pH 3.5 with concd HCl. The acidified aqueous
layer was extracted with CH2Cl2 (4 × 20 mL). The combined
organic extracts were dried over MgSO4 and evaporated under
reduced pressure to give 7a (0.017 g, 15%). Further workup resulted
in the isolation of unreacted starting material and gums. Compound
7a: mp 216-217 °C (from EtOH) (lit.20 mp 215-216 °C); 1H NMR
(400 MHz, CD3OD) δ 7.57-7.59 (m, 3H, Hm,p, 5-CC6H5), 8.01-
8.30 (m, 2H, Ho, 5-CC6H5); 13C NMR (100 MHz, CD3OD) δ 125.4,
132.7, 130.6, 128.3 (C-1′, C-2′, C-3′, C-4′, respectively, 5-C-C6H5),
157.5 (tetrazole C-5); IR (mull, cm-1) νmax 3141 (NH), 1613
(CdN). Anal. Calcd for C7H6N4: C, 57.5; H, 4.1; N, 38.3. Found:
C, 57.5; H, 4.0; N, 38.1.
15N-Labeled 1-(p-anisyl)pentazole samples 14A + 14B, 15, 16,
17A + 17B, 18, 19A + 19B and 20A + 20B were prepared in a
similar manner using 15N-labeled p-anisidine to introduce an isotope
label at N-1, 15N-labeled sodium nitrite to introduce an isotope label
at N-2, terminally 15N-labeled sodium azide to introduce an isotope
label at N-2 or N-3, and combinations of these for the di- and tri-
15N-labeled pentazole samples (experimental details in the Sup-
porting Information).
CAN Dearylation of Unlabeled 1-(p-Anisyl)pentazole. Isola-
tion of p-Benzoquinone 3. 1-(p-Anisyl)pentazole (1.09 mmol, see
below) was dissolved in MeOH (32 mL) at -40 °C in a jacketed
reaction flask. The solution was treated dropwise with a cooled
aqueous solution (4.2 mL) of CAN (4.93 g, 9.0 mmol). The reaction
mixture was allowed to stir for 6 days at -40 °C, followed by
warming to ambient temperature, dilution with water (30 mL), and
extraction with CH2Cl2 (5 × 20 mL). The combined extracts were
dried over MgSO4 and evaporated under reduced pressure. The
residue (in 5 mL of CH2Cl2) was placed on a column of silica gel
(230-400 mesh ASTM) and eluted using a gradient mixture of
petroleum spirit (bp 40-60 °C)-CH2Cl2 (1:0 to 0:1 v/v) to give 3
(0.04 g, 34%).
One-Pot Dearylation-Alkylation of 4a: Basic Conditions. A
solution of 4a (1.00 g, 3.05 mmol) in MeOH (45 mL) was treated
dropwise with an aqueous solution (4.5 mL) of CAN (4.74 g, 8.65
mmol) and stirred at ambient temperature for 24 h. The reaction
mixture was then adjusted to pH 10 with dropwise addition of a
solution of KOH in MeOH. Trimethyloxonium tetrafluoroborate
(2.26 g, 15.28 mmol) was added, and the mixture was stirred for a
further 24 h at ambient temperature. The reaction mixture was then
diluted with water (40 mL) and the MeOH evaporated under
reduced pressure. The resulting aqueous mixture was extracted with
CH2Cl2 (4 × 20 mL). The combined organic extracts were dried
over MgSO4 and evaporated under reduced pressure, and the residue
(in 8 mL CH2Cl2) was placed on a column of silica gel (230-400
mesh ASTM) and eluted using a gradient mixture of petroleum
spirit (bp 40-60 °C)-CH2Cl2 (1:0 to 0:1 v/v using a 5% v/v
changing gradient), followed by a gradient mixture of CH2Cl2-
Et2O (1:0 to 3:2 v/v using a 2.5% v/v changing gradient) to give 8
(0.25 g, 35%) and 9 (0.08 g, 11%). Compound 8: mp 65-66 °C
To precisely estimate the molar amount of 1-(p-anisyl)pentazole
present as starting material, the above procedure was repeated to
the point where the solution of the pentazole in MeOH at -40 °C
was prepared. This solution was allowed to warm to ambient tem-
perature, and evaporated under reduced pressure, giving a residue
of p-anisylazide (0.19 g, 1.27 mmol). The original 1-(p-anisyl)-
1
pentazole was shown by H NMR to contain 14% p-anisylazide;
the molar amount of pentazole present was therefore estimated to
1
(from petroleum spirit (bp 40-60 °C)) (lit.18 mp 60-61 °C); H
be 1.09 mmol, giving a yield of p-benzoquinone of 34%. In repeated
1
NMR (400 MHz, CDCl3) δ 4.26 (s, 3H, CH3), 7.34-7.36 (m, 6H,
isolations and H NMR estimations of p-benzoquinone from such
H
m,p, phenyl), 7.53-7.55 (m, 4H, Ho, phenyl); 13C NMR (100 MHz,
reactions the yield of 3 ranged from 23 to 34%. Compound 3 was
also directly detected in these solutions at -40 °C by proton NMR
before its isolation (Supporting Information, S6 and S13).
CDCl3) δ41.8 (CH3), 131.1 (C-1′, phenyl), 128.3, 128.4 (C-2′/C-
3′, phenyl), 128.7 (C-4′, phenyl), 144.6 (C-4/C-5, triazole). Anal.
Calcd for C15H13N3: C, 76.6; H, 5.6; N, 17.9. Found: C, 76.5; H,
5.8; N, 17.6. Compound 9: mp 128-129 °C (from EtOAc-
petroleum spirit (bp 40-60 °C)) (lit.18 mp 129-130 °C); 1H NMR
(400 MHz, CDCl3) δ 3.92 (s, 3H, CH3), 7.24-7.34 (m, 5H, phenyl),
7.49-7.55 (m, 5H, phenyl); 13C NMR (100 MHz, CDCl3) δ 35.4
(CH3), 131.0, 128.0, 129.8, 127.8, 127.0, 128.7, 129.5, 129.9
(phenyl), 134.2 (C-5, triazole), 144.4 (C-4, triazole). Anal. Calcd
for C15H13N3: C, 76.6; H, 5.6; N, 17.9. Found: C, 76.5; H, 5.7; N,
18.0.
CAN Dearylation of 16 (Scheme 6, Reaction 3). A sample of
16 prepared as described was dissolved in CD3OD (2.5 mL) at
-40 °C and treated dropwise with a solution of Zn(NO3)2‚6H2O
(0.32 g, 1.08 mmol) in D2O (0.125 mL), followed by a solution of
CAN (0.59 g, 1.08 mmol) in D2O (0.50 mL). The reaction mixture
was stirred at -40 °C for 24 h. A sample was then withdrawn and
1
1
analyzed by H and 15N NMR at -41 °C. The H NMR signals
(400 MHz, CD3OD-D2O (4:1 v/v), -41 °C) included: δ 3.84 (s,
OCH3, 16), 6.73 (3), 7.16-7.19 (d, Ho, AA′BB′ spectrum, 16),
J. Org. Chem, Vol. 73, No. 4, 2008 1363

Butler et al.
8.04-8.06 (d, Hm, AA′BB′ spectrum, 16); 15N NMR (40 MHz,
CD3OD-D2O (4:1 v/v), -41 °C, 6.892 scans) δ -7.1 (NO3-),
-80.2 (N-1, 16), (-140.3)-(-147.3) (15Nâ, azide ion) (Supporting
Information, S9). Repetition of the procedure without addition of
Zn(NO3)2‚6H2O gave the same results.
Acknowledgment. This paper is dedicated to the memory
of Professor Charles W. Rees. J.M.H. acknowledges the
financial support of the Government of Ireland through the Irish
Research Council for Science, Engineering and Technology
(IRCSET). L.A.B. acknowledges the National Science Founda-
tion for a computer equipment grant (MRI 9871088).
CAN Dearylation of 15 (Scheme 6, Reaction 2). A sample of
15 prepared as described was dissolved in CD3OD (4.0 mL) at
-40 °C and treated dropwise with a cooled solution of CAN (1.23
g, 2.24 mmol) in D2O (1.0 mL). A sample was withdrawn from
the reaction after ca. 5 min and analyzed by 15N NMR (40 MHz,
CD3OD-D2O (4:1 v/v), -41 °C, 1,160 scans). Signals attributable
Supporting Information Available: Key figures directly
mentioned in the text (S5-S13); synthetic details for all substrates
and products not included in Experimental Section (S14-S26);
further experimental procedures for azole dearylations (S27-S32);
further experimental details for anisylation and alkylation of parent
azoles (S32-S33); experimental procedures for substrates giving
unsuccessful dearylation reactions (S34-S38); detailed experimental
procedures for synthesis of labeled pentazole samples (S39-S44);
further experimental procedures for dearylation of labeled pentazole
samples (S45-S46); details of NMR quantification of p-benzo-
quinone yields (S47-S49); additional 15N NMR spectra for
pentazole dearylation reactions (S50-S62); NMR spectra for
previously unknown compounds 4b,c and 5b,c (S63-S70). This
material is available free of charge via the Internet at http://pubs.
acs.org.
-
to NO3 (-12.3 ppm), remaining 15 (-23.3 ppm), N-2-labeled
p-anisyldiazonium ion (-56.3 ppm), N-2-labeled p-anisylazide
(-133.7 ppm), and Nâ-labeled azide ion ((-143.2)-(-143.6) ppm)
were visible.
The reaction mixture was allowed to stir at -40 °C for 3 days,
after which time a further sample was withdrawn and analyzed by
1
NMR at -41 °C. The H NMR spectrum (400 MHz, CD3OD-
D2O (4:1 v/v), -41 °C) shows a significant peak attributable to 3
(δ 6.76 ppm). The 15N NMR spectrum (40 MHz, CD3OD-D2O
-
(4:1 v/v), -37.4 °C, 3758 scans) shows peaks attributable to NO3
(-16.6 ppm), remaining 15 (-23.2 ppm), N-2-labeled p-anisyl-
diazonium ion (-56.4 ppm), N-2-labeled p-anisylazide (-133.8
ppm), and Nâ-labeled azide ion ((-143.0)-(-143.6) ppm) (Sup-
porting Information, S10).
JO702423Z
1364 J. Org. Chem., Vol. 73, No. 4, 2008