Rearrangements of N-heterocyclic carbenes of pyrazole to 4-aminoquinolines and benzoquinolines

Article abstract of DOI:10.1002/ejoc.201000507

1-Phenyl-substituted pyrazolium salts, formed by quaternization of pyrazoles with benzyl halides or long-chain alkyl halides, deprotonate to pyrazol-3-ylidenes that undergo a sequence of ring-opening, ring-closure, and tautomerization to new substituted 4

Full text of DOI:10.1002/ejoc.201000507

FULL PAPER
DOI: 10.1002/ejoc.201000507
Rearrangements of N-Heterocyclic Carbenes of Pyrazole to 4-Aminoquinolines
and Benzoquinolines
Andrij Dreger,[a] Rafael Cisneros Camuña,[a] Niels Münster,[a] Tibor András Rokob,[b]
Imre Pápai,[b] and Andreas Schmidt*[a]
Keywords: Carbenes / Nitrogen heterocycles / Density functional calculations / Reaction mechanisms / Sigmatropic
rearrangement / Malaria
1-Phenyl-substituted pyrazolium salts, formed by quaterni-
zation of pyrazoles with benzyl halides or long-chain alkyl
halides, deprotonate to pyrazol-3-ylidenes that undergo a se-
quence of ring-opening, ring-closure, and tautomerization to
new substituted 4-aminoquinolines. Similarly, 1-naphthyl-
substituted pyrazolium-3-carboxylates decarboxylate on
heating in toluene to give benzoquinolines in excellent yields
by an analogous reaction pathway. DFT calculations indicate
that the ring transformation proceeds through a sequence of
intramolecular elimination, imine inversion and 6π-electrocy-
clization steps.
which displays catalytic activities in Suzuki–Miyaura and
Mizoroki–Heck reactions.[22] This species has recently been
described as a cyclic allene, such as 5, possessing electron-
donating groups in positions 3 and 5 of the pyrazole
ring.[23] The zwitterionic structure 5Ј has been discussed as
an alternative representation of this compound.[24]
Introduction
The advance of N-heterocyclic carbenes (NHC) has be-
come one of the most significant developments in modern
organic chemistry.[1] The first complexes of imidazolin-2-
ylidenes were prepared and isolated as early as 1968 by
Öfele and Wanzlick,[2] and, shortly later, Lappert and co-
workers described metal complexes of imidazolidin-2-ylid-
enes.[3] The isolation of stable N-heterocyclic carbenes by
Arduengo et al. in 1991,[4] however, initiated intensive in-
vestigations into the physical properties,[5] coordination
chemistry,[6] and catalytic properties.[7] N-Heterocyclic carb-
enes have now emerged as a class of ligands with outstand-
ing properties, largely due to their performance in metal-
catalyzed reactions such as cross-couplings[8] and second-
generation olefin metathesis.[9] In addition, they play impor-
tant roles in organocatalysis.[10] In contrast to N-heterocy-
clic carbenes of imidazole,[4] imidazoline,[11] triazole,[12] and
benzimidazoline,[12,13] hitherto, less interest has focused on
N-heterocyclic carbenes of pyrazole[14] and indazole.[15] Pyr-
azol-3-ylidene 1 was described as a rhodium complex 2 in
1997,[16] and was identified spectroscopically and by trap-
ping reactions[17] (Scheme 1). In addition, catalytic activities
of Iridium,[18] Ruthenium[19] and palladium complexes[20]
Scheme 1. N-Heterocyclic carbenes of pyrazole.
Recently, we described the initial results of a new re-
have been examined. Structure 4 represents a palladium arrangement of pyrazol-3-ylidenes 1 (R = Ph or substituted
complex of the remote N-heterocyclic carbene 3 (rNHC[21]), phenyl rings), generated in situ either by thermal decarbox-
ylation of pyrazolium-3-carboxylates or by deprotonation
of pyrazolium salts, to new 4-aminoquinolines.[25] Such
[a] Clausthal University of Technology, Institute of Organic
Chemistry,
compounds are of great interest in Malaria research as they
represent new substitution patterns and related structures
of chloroquine, amodiaquine, and other anti-malarials. In-
deed, some new derivatives of 4-aminoquinolines have
proven to be highly active,[26] including ring-annelated sys-
tems.[27] Simplified, the mechanism of this new rearrange-
Leibnizstrasse 6, 38678 Clausthal-Zellerfeld, Germany
Fax: +49-5323-722858
E-mail: schmidt@ioc.tu-clausthal.de
[b] Chemical Research Center of HAS,
Pusztaszeri út 59-67, 1025 Budapest, Hungary
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000507.
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Rearrangements of N-Heterocyclic Carbenes
ment can be formulated as shown in Scheme 2: The N-het-
erocyclic carbene A, which is generated in situ, undergoes
ring-cleavage to an intermediate that can be represented by
two canonical formulae, B and C. Ring-closure of this inter-
mediate to D requires an unsubstituted 2-position of the
phenyl ring in the 1-position of the starting material. Inter-
mediate D tautomerizes to 4-aminoquinoline 7. The ring-
closure can be regarded either as electrophilic aromatic sub-
stitution from B, or as a 6π-electrocyclization of the non-
polar structure C. No experimental evidence has been avail-
able to establish the nature of this ring closure.
Scheme 3. Synthesis of 4-aminoquinolines.
Next, we became interested in the synthesis of enlarged
ring systems. We therefore started a sequence of reactions
with the condensation of 1-naphthyl hydrazine and the 2,4-
dioxoester 10 to give pyrazole ester 11, which proceeded in
53% yield. Its isomeric species was easily separated by col-
umn chromatography in 9% yield. Methylation, followed by
ester cleavage gave the pyrazolium betaine 12 in excellent
yield (98%) as a stable yellow solid. On heating in toluene,
rearrangement to the benzo[h]quinolin-4-amine 13 occurred
in 93% yield (Scheme 4).
Scheme 2. Rearrangement of pyrazolium-3-carboxylates to 4-ami-
noquinolines via N-heterocyclic carbenes of pyrazole.
Our first results revealed that this metal-free thermal re-
action, which requires no special handling, allows the syn-
thesis of a broad variety of substituted 4-aminoquinolines,
among these: bis-, tris-, tetrakis-, and pentakis-substituted
derivatives.[25] The scope and limitations of this approach
are, however, not yet known.
Scheme 4.
An analogous series of reactions was performed starting
from 2-naphthyl hydrazine, which was subsequently con-
verted into the pyrazole betaine 14 (Scheme 5). Only one
In a continuation of our interest in N-heterocyclic carb-
enes in synthesis[28] and catalysis,[29] and in view of the great
pharmacological interest in new 4-aminoquinolines and re-
lated ring systems, we present here new suitable starting ma-
terials for this reaction. DFT calculations offer valuable in-
sights into the mechanism of this new rearrangement.
Results and Discussion
One unsubstituted ortho-position of the phenyl substitu-
ent in position 1 of the starting pyrazolium-3-carboxylate
is the conditio sine qua non of the thermal decarboxylation/
rearrangement sequence to 4-aminoquinolines. Thus, the bi-
phenyl-substituted pyrazolium-3-carboxylate 8, which is a
new representative of the class of pseudo-cross-conjugated
heterocyclic mesomeric betaines (PPCMB), gives 8-phenyl-
quinolin-4-amine 9 in 83% yield on heating in toluene
(Scheme 3).
Scheme 5. Regioselective rearrangement to benzo[f]quinolin-1-
amine.
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A. Schmidt et al.
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product was formed by rearrangement in 77% yield:
benzo[f]quinoline-1-amine 15. No traces of the isomeric
benzo[g]quinolin-4-amine 16 were isolated. Scheme 6 shows
some diagnostic NMR results, which were obtained by a
series of NOESY, HMBC, and HSQC NMR measurements
for unambiguous peak assignments. Thus, in agreement
with structure 15, 10-H couples to C-10b as shown, and the
resonance frequency of 10-H is shifted downfield as pre-
dicted. On the other hand, no coupling is observed between
5-H and C-4 as would be present in the hypothetical struc-
ture 16.
Scheme 6. Diagnostic NMR results.
Scheme 7. Rearrangements starting from pyrazolium salts.
Only a very few pieces of information on pyrazolium
salts are available in the literature. We therefore started a (∆G = +18.1 kcal/mol); however, the equilibrium between 6
series of reactions as follows: Ester cleavage of the pyrazole and A + CO2 is shifted towards A if carbon dioxide is re-
esters 17 and 18 followed by decarboxylation in quinoline moved from the solution, which is the case under the ap-
gave the pyrazoles 19 and 20, respectively, in very good plied reaction conditions.
yields (Scheme 7). According to a modified literature pro-
For the initial step of the reaction, we also considered
cedure,[30] pyrazole 19 was treated with benzyl bromide un- the possibility of N–N cleavage before or along with the
der microwave conditions to give the benzyl-substituted CO2 extrusion; the latter pathway would correspond to a
pyrazolium salt 21a in good yield. We next tried to qua- Grob-type fragmentation. Our attempts to find transition
ternize 19 and 20 with long-chain aliphatic residues. Thus, states for these pathways were unsuccessful, which corrobo-
substitution starting from iodooctane was accomplished on rates the idea that carbene A is indeed an intermediate in
heating to 140 °C over a period of 11 h to give the salt 21b the overall process.
in 58% yield. The reaction with iododecane, however, re-
The results of our computations for the further steps
quired a longer reaction time, a higher temperature and from A towards product 7 are summarized in Figure 1 in
gave a considerably lower yield of the desired pyrazolium the form of a solvent-phase free energy diagram. The N–N
salt 21c. Because thermal conditions failed, microwave irra- bond of A can be cleaved via the low-lying transition state
diation was then applied to quaternize pyrazole 20 with TSN–N, producing the E isomer of intermediate C. The cis–
iodohexadecane to give 21d; the yield, however, was low. trans isomerism barrier arises due to the π-bonds in C caus-
Rearrangements of 21a–d to the new 4-aminoquinolines ing restricted rotation around the C=N moiety.[31] Subse-
22a–d (Scheme 7) were accomplished by mixing potassium quent cyclization can only proceed from the Z-C isomer, an
tert-butoxide with the corresponding pyrazolium salts, and inversion of the imine nitrogen is therefore required
adding these mixtures to boiling anhydrous toluene. In spite (TSC=N). Starting from Z-C, two different transition states
of only moderate yields for the rearrangement, this ap- for C–C bond formation can be identified (TSC–C,E and
proach enabled the synthesis of 4-aminoquinolines pos- TSC–C,Z, Figure 2). The two pathways correspond to attack
sessing benzyl or long-chain alkyl groups at the amino on two different atoms of the phenyl group, and lead to two
group.
cyclized products (E-D and Z-D) differing in the resulting
To obtain further insights into the mechanism of these configuration of a C=N bond, which was initially part of
rearrangements, we carried out quantum chemical calcula- the azaallenic system. Interestingly, the higher-lying transi-
tions for the reaction pathway depicted in Scheme 2.
tion state leads to the lower-lying product.
Starting from 6, the C–C bond was found to be cleaved
A proton transfer, which was not investigated in detail,
directly in a single step to yield A + CO2. This process is may ultimately convert E-D and Z-D into 7, with a large
endergonic and occurs without any kinetic barrier (i.e., the gain in free energy and loss of stereochemical information.
reverse reaction of A + CO2 to 6 is barrierless). The pre-
Beyond revealing the reaction pathway, our calculations
dicted endergonicity for the CO2 dissociation is fairly large provided the possibility of a deeper understanding of the
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Rearrangements of N-Heterocyclic Carbenes
Figure 1. Calculated solvent-phase Gibbs free energy profile for the conversion of A into 7. Atom numbering used in text is indicated.
Figure 2. Geometries of the ring-closing transition states TSC–C,E
and TSC–C,Z
.
Figure 3. Reorganization of σ (top) and π (bottom) electrons of A
upon ring opening. Curved lines and dots indicate bonding and
nonbonding pairs according to one of the high-weight resonance
forms.
mechanism through an analysis of the structural and elec-
tronic properties. Starting on the reactant side of this re-
arrangement process, a simple heterolytic C–C bond break-
ing in 6 initiates the reaction. The resulting carbene A has
The resulting open-chain π-system in C can be repre-
a five-membered ring with almost planar ring atoms (the sented as azaallene–imine (C) or nitrilium–enamide (B)
smallest sum of angles is 354.1° at N1), which indicates a type resonance forms (see Scheme 2). As mentioned in the
significant degree of cyclic π-delocalization, i.e., a high con- introduction, the two different forms imply two different
tribution of the zwitterionic resonance forms.
mechanistic scenarios for the ring-closing step via TSC–C
A remarkable feature of the ring-opening reaction of A is (electrocyclization and electrophilic aromatic substitution
that the C3–N2–Me angle first significantly increases, then for C and B, respectively). To discriminate between these
decreases again along the reaction route (A: 126.5°, TSN–N
:
extremes or characterize the situation as an intermediate
134.2°, maximum along the intrinsic reaction coordinate: between them, we inspected the computed geometry of C
ca. 139°, E-C: 125.2°). This observation might be rational- (Figure 4). The calculated bond lengths suggest a markedly
ized if one considers the reorganization of electrons, as larger contribution from the nonpolar, azaallene–imine
shown in Figure 3.
The N–N σ-bond is cleaved upon interaction with the through a 6 (or 10) electron electrocyclization.
carbene lone pair, in a process resembling the second step In an attempt to confirm the above descriptions of π-
structure; the ring closure is thus expected to proceed
of a unimolecular elimination with a conjugate base (E1cB). system transformations, we calculated nucleus independent
The 5-orbital, 6-electron cyclic π-system undergoes a sim- chemical shift (NICS)[32,33] values above the breaking and
ple, smooth cleavage to an open-chain structure. The two forming rings[34,35] along the reaction pathway.[36] Ring cur-
participating orbitals on N2 allow this atom to continu- rents in aromatic systems cause magnetic shielding above
ously keep a significant degree of bonding both in the σ and below the ring, which is manifested in significantly
and in the π systems, which provides a rationale for the low negative NICS values; no such effect is expected for nonaro-
barrier. The widening angle around the TS comes about matic rings.[33]
as a consequence of the rehybridization that takes place to
maintain efficient overlap between the two systems.
The computed curve for the ring-opening of A via
TSN–N shows a continuous decrease in π-aromaticity that is
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A. Schmidt et al.
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Experimental Section
General: Compounds 17 and 19 were prepared as described be-
1
fore.[25] The H and 13C NMR spectra were recorded with Bruker
Avance DPX 200 (200 MHz), Avance 400 (400 MHz), or Avance
III (600 MHz) spectrometers and samples were analyzed in [D6]-
DMSO, D2O, or CDCl3 at 200, 400, or 600 MHz, respectively. The
chemical shifts are reported in ppm relative to internal tetramethyl-
silane (δ = 0.00 ppm) or HDO (δ = 4.65 ppm). Multiplicities are
described by the following abbreviations: s = singlet, d = doublet,
t = triplet, m = multiplet; br. = broad. Peak assignments were ac-
complished by analyzing the results of HMBC-, HSQC-NMR and
HH-NOESY measurements. FTIR spectra were obtained with a
Bruker Vektor 22 in the range of 400 to 4000 cm–1 (2.5% pellets in
KBr). The GC–MS spectra (EI) were recorded either with a Varian
320 GC-MS, or with a Varian GC3900 with a SAT2100T mass
spectrometer. The ESI mass spectra were measured with an Agilent
LCMSD Series HP1100 with APIES. Samples were sprayed from
methanol at 0 V fragmentor voltage unless otherwise noted. Melt-
ing points were determined with a Boëtius melting apparatus.
Yields are not optimized.
Figure 4. Computed geometry of intermediate E-C. Calculated
bond lengths (Å) of some model compounds formally correspond-
ing to parts of resonance structures B and C are also given for
comparison. Similar results were obtained for Z-C.
consistent with a gradual cyclic to acyclic transition (Fig-
ure 5). In contrast, results for both C–C bond forming path-
ways show a characteristic minimum near the TS in the
NICS versus reaction coordinate plot. Symmetry-allowed
pericyclic reactions are known to possess aromatic transi-
tion states[37] yielding such minima;[33,36,38] the present ring-
1-(Biphenyl-2-yl)-2,5-dimethylpyrazolium-3-carboxylate (8): A sam-
ple of ethyl 2,4-dioxopentanoate (1.020 g, 6.45 mmol) was dissolved
in ethanol (10 mL), treated with (biphenyl-2-yl)hydrazine (1.188 g,
6.45 mmol), and heated for 1 h at reflux temperature. The solvent
was then distilled off in vacuo and the resulting residue was purified
closing reaction can thus be concluded to exhibit a signifi- by chromatography (petroleum ether/ethyl acetate, 3:1) to give ethyl
1-(biphenyl-2-yl)-5-methylpyrazole-3-carboxylate (44%, 0.860 g) as
an orange oil. Its isomer (18%, 0.347 g) was also isolated. 1H NMR
(400 MHz, 21 °C, CDCl3, TMS): δ = 7.46–7.55 (m, 4 H, HBp),
7.23–7.27 (m, 3 H, HBp), 7.08–7.11 (m, 2 H, HBp), 6.49 (s, 1 H,
4-H), 4.42 (q, J = 7.1 Hz, 2 H, CH3CH2O), 1.67 (s, 3 H, 5-CH3),
1.41 (t, J = 7.1 Hz, 3 H, CH3CH2O) ppm. 13C NMR (100 MHz,
21 °C, CDCl3, TMS): δ = 162.8, 143.7, 141.7, 139.1, 137.8, 136.8,
130.5, 129.9, 128.9, 128.5, 128.4, 128.3, 127.6, 108.3, 60.9, 14.5,
cant degree of pericyclic character.
11.2 ppm. IR (NaCl): ν = 1732, 1717, 1485, 1432, 1374, 1228, 1152,
˜
1107, 1029, 777, 739, 702 cm–1. HRMS (ESI): calcd. for
C19H19N2O2 [M + H]+ 307.1447; found 307.1443. A sample of this
ester (0.784 g, 2.56 mmol) was dissolved in xylene (10 mL) contain-
ing one drop of nitrobenzene, and treated with dimethyl sulfate
(0.24 mL, 2.56 mmol). After heating at reflux temperature for 2 h
and cooling to room temp., the solvent was distilled off in vacuo.
The residue was dissolved in 50% sulfuric acid (15 mL) and heated
at reflux temperature over a period of 7 h, then neutralized with
NaOH, evaporated to dryness, and extracted with EtOH
(6 ϫ 10 mL). The solvent was then distilled off and the residue was
purified by chromatography (MeOH) to give a beige solid (91%,
0.677 g); m.p. 133 °C (dec.). 1H NMR (400 MHz, 21 °C, [D6]-
DMSO): δ = 7.87–7.90 (m, 2 H, HBp), 7.75–7.78 (m, 2 H, HBp),
7.38–7.40 (m, 3 H, HBp), 7.08–7.10 (m, 2 H, HBp), 6.74 (s, 1 H,
4-H), 3.96 (s, 3 H, 2-CH3), 2.05 (s, 3 H, 5-CH3) ppm. 13C NMR
(100 MHz, 21 °C, [D6]DMSO): δ = 156.9, 147.4, 145.9, 140.5,
135.9, 133.1, 131.8, 130.3, 129.7, 129.0, 128.6, 128.2, 127.8, 108.8,
Figure 5. NICS values as a function of the intrinsic reaction coordi-
nate for ring-opening via TSN–N and ring-closing reactions via
TSC–C,E and TSC–C,Z
.
Conclusions
In summary, we have investigated the scope and limita-
tions of a new rearrangement of N-heterocyclic carbenes of
pyrazole generated in situ, to 4-aminoquinolines and benzo-
quinolines. The mechanism of the ring transformation was
elucidated by calculating the reaction pathway and analyz-
ing the computed geometric, electronic, and magnetic prop-
erties. The ring-opening step was found to be an intra-
molecular E1cB-like elimination, whereas the ring-closure
proceeds through a pericyclic reaction; the overall pathway
also involves an imine nitrogen inversion.
35.4, 11.8 ppm. IR (KBr): ν = 3479, 1661, 1646, 1481, 1438, 1330,
˜
836, 793, 752, 704 cm–1. HRMS (ESI): calcd. for C18H17N2O2 [M
+ H]+ 293.1290; found 293.1290.
N,2-Dimethyl-8-phenylquinolin-4-amine (9): A sample of betaine 8
(205 mg, 0.7 mmol) was suspended in toluene (4 mL) and heated
at reflux temperature for 1 h. The solvent was then distilled off in
vacuo and the residue was purified by chromatography (MeOH/
EtOAc, 1:1). Compound 9 was obtained as a yellow solid (83%,
0.145 g); m.p. 223–224 °C. 1H NMR (600 MHz, 21 °C, CDCl3,
TMS): δ = 8.14 (dd, J = 8.4, 1.3 Hz, 1 H, HQu), 7.62–7.64 (m, 2
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Rearrangements of N-Heterocyclic Carbenes
H, HPh), 7.54 (dd, J = 7.0, 1.3 Hz, 1 H, HQu), 7.39–7.43 (m, 3 H,
HQu, HPh), 7.32–7.35 (m, 2 H, HPh, HN), 6.33 (s, 1 H, 3-H), 2.89
(d, J = 4.2 Hz, 3 H, H3CN), 2.41 (s, 3 H, 2-CH3) ppm. 13C NMR
(150 MHz, 21 °C, CDCl3, TMS): δ = 158.6, 151.8, 145.4, 140.9,
139.3, 131.1, 130.3, 127.9, 127.0, 123.4, 121.5, 118.3, 98.3, 29.9,
117.0, 113.2, 100.5, 30.1, 25.8 ppm. IR (KBr): ν = 3394, 1623, 1596,
˜
1565, 1540, 1448, 1360, 1288, 1145, 1078, 818, 797, 756, 717 cm–1.
HRMS (ESI): calcd. for C15H15N2 [M + H]+ 223.1235; found
223.1235.
2,5-Dimethyl-1-(naphthalen-2-yl)pyrazolium-3-carboxylate (14): A
sample of ethyl 2,4-dioxopentanoate (0.593 g, 3.75 mmol) was dis-
solved in ethanol (10 mL), treated with naphthalen-2-ylhydrazine
(0.593 g, 3.75 mmol), and heated for 1 h at reflux temperature. The
solvent was then distilled off in vacuo and the resulting residue was
purified by chromatography (petroleum ether/ethyl acetate, 3:1) to
give ethyl 5-methyl-1-(naphthalen-2-yl)pyrazole-3-carboxylate
(60%, 0.630 g) as a brown solid. Its isomer (26%, 0.271 g) was also
isolated; m.p. 77–78 °C. 1H NMR (400 MHz, 21 °C, CDCl3, TMS):
δ = 7.87–7.95 (m, 4 H, HNp), 7.53–7.60 (m, 3 H, HNp), 6.78 (d, J
= 0.8 Hz, 1 H, 4-H), 4.43 (q, J = 7.2 Hz, 2 H, CH3CH2O), 2.38 (d,
J = 0.8 Hz, 3 H, 5-CH3), 1.41 (t, J = 7.2 Hz, 3 H, CH3CH2O) ppm.
13C NMR (100 MHz, 21 °C, CDCl3, TMS): δ = 162.7, 144.1, 140.8,
136.6, 133.0, 132.8, 129.2, 128.2, 127.9, 127.1, 127.0, 124.0, 123.4,
109.4, 61.0, 14.4, 12.5 ppm. ESI-MS: m/z (%) = 281.1 (100) [M +
26.0 ppm. IR (KBr): ν = 3399, 1597, 1543, 1443, 1387, 1364, 1242,
˜
1217, 1189, 1118, 1016, 813, 759, 702 cm–1. HRMS (ESI): calcd.
for C17H17N2 [M + H]+ 249.1392; found 249.1392.
Ethyl 5-Methyl-1-(naphthalen-1-yl)pyrazole-3-carboxylate (11): A
sample of ethyl 2,4-dioxopentanoate (1.237 g, 7.82 mmol) was dis-
solved in ethanol (10 mL), treated with naphthalen-1-ylhydrazine
(1.237 g, 7.82 mmol), and heated for 1 h at reflux temperature. The
solvent was then distilled off in vacuo and the resulting residue was
purified by chromatography (petroleum ether/ethyl acetate, 3:1) to
give a yellow solid (53%, 1.162 g). Its isomer (9%, 0.205 g) was
also isolated; m.p. 91–92 °C. 1H NMR (400 MHz, 21 °C, CDCl3,
TMS): δ = 7.99 (d, J = 8.0 Hz, 1 H, HNp), 7.93 (d, J = 8.0 Hz, 1
H, HNp), 7.46–7.58 (m, 4 H, HNp), 7.21 (d, J = 8.0 Hz, 1 H,
HNp), 6.85 (d, J = 0.5 Hz, 1 H, 4-H), 4.43 (q, J = 7.2 Hz, 2 H,
CH3CH2O), 2.10 (d, J = 0.5 Hz, 3 H, 5-CH3), 1.40 (t, J = 7.2 Hz,
3 H, CH3CH2O) ppm. 13C NMR (100 MHz, 21 °C, CDCl3, TMS):
δ = 162.8, 144.2, 142.6, 135.4, 134.1, 130.4, 130.1, 128.2, 127.7,
126.8, 125.5, 125.0, 122.6, 108.2, 61.0, 14.5, 11.5 ppm. ESI-MS: m/z
H]+. IR (KBr): ν = 2979, 1719, 1598, 1510, 1478, 1447, 1388, 1235,
˜
1150, 1099, 1026, 869, 833, 773, 749 cm–1. C17H16N2O2 (280.33):
calcd. C 72.84, H 5.75, N 9.99; found C 72.61, H 5.68, N 9.86.
A sample of this ester (0.510 g, 1.82 mmol) was dissolved in xylene
(10 mL) containing one drop of nitrobenzene, and treated with di-
methyl sulfate (0.17 mL, 1.82 mmol). After heating at reflux tem-
perature for 2 h and cooling to room temp., the solvent was distilled
off in vacuo. The residue was dissolved in ethanol (10 mL) and then
treated with KOH (0.306 g, 5.46 mmol). The solution was heated at
reflux temperature over a period of 2 h, then neutralized with HCl,
evaporated to dryness, and then extracted with EtOH (6 ϫ 10 mL).
The solvent was distilled off and the residue was purified by
chromatography (MeOH) to give 14 as a beige solid (88%, 0.425 g);
m.p. 137 °C (dec.). 1H NMR (400 MHz, 21 °C, [D6]DMSO): δ =
8.45 (s, 1 H, HNp), 8.27 (d, J = 8.8 Hz, 1 H, HNp), 8.14 (d, J =
8.0 Hz, 1 H, HNp), 8.08 (d, J = 8.0 Hz, 1 H, HNp), 7.70–7.81 (m,
3 H, HNp), 6.91 (s, 1 H, 4-H), 4.05 (s, 3 H, 2-CH3), 2.22 (s, 3 H,
5-CH3) ppm. 13C NMR (100 MHz, 21 °C, [D6]DMSO): δ = 157.4,
147.5, 145.8, 133.8, 132.5, 130.4, 129.3, 128.7, 128.7, 128.3, 128.0,
(%) = 281.1 (50) [M + H]+. IR (KBr): ν = 1707, 1480, 1446, 1426,
˜
1398, 1382, 1233, 1191, 1162, 1106, 1022, 976, 806, 776 cm–1.
C17H16N2O2·0.5H2O (280.33): calcd. C 70.57, H 5.92, N 9.68;
found C 70.79, H 5.32, N 9.66.
2,5-Dimethyl-1-(naphthalen-1-yl)pyrazolium-3-carboxylate (12): A
sample of compound 11 (1.068 g, 3.81 mmol) was dissolved in xyl-
ene (10 mL) containing one drop of nitrobenzene, and treated with
dimethyl sulfate (0.36 mL, 3.81 mmol). After heating at reflux tem-
perature for 2 h, and cooling to room temp., the solvent was dis-
tilled off in vacuo. The residue was dissolved in ethanol (10 mL)
and then treated with KOH (0.641 g, 11.43 mmol). The solution
was heated at reflux temperature over a period of 2 h, then neutral-
ized with HCl, evaporated to dryness, and then extracted with
EtOH (6 ϫ 10 mL). The solvent was then distilled off and the resi-
due was purified by chromatography (MeOH) to give a yellow solid
(98%, 1.042 g); m.p. 122 °C (dec.). 1H NMR (400 MHz, 21 °C,
[D6]DMSO): δ = 8.40 (d, J = 8.4 Hz, 1 H, HNp), 8.22 (dd, J = 7.4,
1.4 Hz, 1 H, HNp), 8.09 (dd, J = 7.4, 1.0 Hz, 1 H, HNp), 7.84 (dd,
J = 8.4, 7.4 Hz, 1 H, HNp), 7.68–7.77 (m, 2 H, HNp), 7.12 (dd, J
= 8.4, 1.0 Hz, 1 H, HNp), 7.03 (s, 1 H, 4-H), 3.90 (s, 3 H, 2-CH3),
2.09 (s, 3 H, 5-CH3) ppm. 13C NMR (100 MHz, 21 °C, [D6]-
DMSO): δ = 157.3, 148.1, 146.7, 133.8, 133.0, 129.6, 129.3, 129.2,
129.0, 127.8, 126.7, 126.0, 120.4, 108.9, 34.9, 11.4 ppm. IR (KBr):
127.7, 124.8, 108.6, 35.5, 11.9 ppm. IR (KBr): ν = 3406, 1645, 1435,
˜
1335, 831, 788, 757 cm–1. HRMS (ESI): calcd. for C16H15N2O2 [M
+ H]+ 267.1134; found 267.1131.
N,2-Dimethylbenzo[f]quinolin-4-amine (15): A sample of betaine 14
(266 mg, 1.0 mmol) was suspended in toluene (4 mL) and heated
at reflux temperature for 1 h. The solvent was then distilled off in
vacuo and the residue was purified by chromatography (MeOH/
EtOAc, 1:1). Compound 15 was obtained as a yellow solid (77%,
0.172 g); m.p. 150–151 °C. 1H NMR (600 MHz, 21 °C, CDCl3,
TMS): δ = 8.79 (dd, J = 8.4, 1.2 Hz, 1 H, HBq), 7.89 (dd, J = 8.0,
1.5 Hz, 1 H, HBq), 7.82 (s, 2 H, HBq), 7.56 (ddd, J = 8.4, 7.0,
1.5 Hz, 1 H, HBq), 7.51 (ddd, J = 8.0, 7.0, 1.2 Hz, 1 H, HBq), 6.55
(s, 1 H, 3-H), 5.55 (q, J = 5.4 Hz, 1 H, HN), 2.99 (d, J = 5.4 Hz, 3
H, H3CN), 2.66 (s, 3 H, 2-CH3) ppm. 13C NMR (150 MHz, 21 °C,
CDCl3, TMS): δ = 158.0, 153.6, 149.1, 131.8, 130.2, 129.6, 129.2,
128.5, 126.5, 125.3, 123.9, 112.8, 102.3, 30.9, 25.0 ppm. ESI-MS:
ν = 3419, 1647, 1489, 1418, 1335, 1239, 843, 818, 779, 746 cm–1.
˜
HRMS (ESI): calcd. for C16H15N2O2 [M + H]+ 267.1134; found
267.1136.
N,2-Dimethylbenzo[h]quinolin-4-amine (13): A sample of betaine 12
(266 mg, 1.0 mmol) was suspended in toluene (4 mL) and heated
at reflux temperature for 1 h. The solvent was then distilled off in
vacuo and the residue was purified by chromatography (MeOH/
EtOAc, 1:1). Compound 13 was obtained as a brown solid (93%,
0.207 g); m.p. 109–110 °C. 1H NMR (400 MHz, 21 °C, CDCl3,
TMS): δ = 9.30 (dd, J = 8.3, 1.3 Hz, 1 H, HBq), 7.83 (dd, J = 8.3,
1.3 Hz, 1 H, HBq), 7.66 (ddd, J = 8.3, 7.0, 1.3 Hz, 1 H, HBq), 7.64
(d, J = 9.0 Hz, 1 H, HBq), 7.61 (ddd, J = 8.3, 7.0, 1.3 Hz, 1 H,
HBq), 7.54 (d, J = 9.0 Hz, 1 H, HBq), 6.45 (s, 1 H, 3-H), 5.04 (q,
m/z (%) = 223.1 (100) [M + H]+. IR (KBr): ν = 3341, 1625, 1584,
˜
1557, 1531, 1506, 1447, 1389, 1350, 1207, 997, 836, 759 cm–1.
C15H14N2·H2O (222.29): calcd. C 74.97, H 6.71, N 11.66; found C
74.93, H 6.36, N 12.22.
Ethyl 1-(4-Chlorophenyl)-5-methylpyrazole-4-carboxylate (18): A
J = 5.2 Hz, 1 H, HN), 2.99 (d, J = 5.2 Hz, 3 H, H3CN), 2.72 (s, 3 sample of ethyl 2-(dimethylamino)methylen-3-oxobutanoate
H, 2-CH3) ppm. 13C NMR (100 MHz, 21 °C, CDCl3, TMS): δ = (870 mg, 4.702 mmol) was dissolved in ethanol (16 mL) with (4-
158.3, 151.0, 145.8, 133.5, 131.6, 127.5, 127.5, 126.6, 125.0, 124.6,
chlorophenyl)hydrazine (670 mg, 4.702 mmol) and stirred for 2.5 h
4301
Eur. J. Org. Chem. 2010, 4296–4305
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org

A. Schmidt et al.
FULL PAPER
at 78 °C. After cooling, the solvent was distilled off and the re-
sulting residue was purified by chromatography (silica gel; petro-
leum ether/ethyl acetate, 8:1) to give 18 as an orange solid (80%,
1.033 g); m.p. 56 °C. 1H NMR (400 MHz, 21 °C, CDCl3): δ = 8.02
(s, 1 H, 3-H), 7.48 (d, J = 8.4 Hz, 2 H, HAr), 7.38 (d, J = 8.4 Hz,
(silica gel; dichloromethane/EtOH, 15:1) to give a colorless solid
(58%, 122 mg); m.p. 122 °C. H NMR (400 MHz, 21 °C, CDCl3):
δ = 8.72 (d, J = 3.0 Hz, 1 H, 3-H), 7.85 (d, J = 8.7 Hz, 2 H, HAr),
7.76 (d, J = 8.7 Hz, 2 H, HAr), 6.81 (d, J = 3.0 Hz, 1 H, 4-H), 4.35
(t, J = 7.6 Hz, 2-CH2), 2.34 (s, 3 H, 5-CH3), 1.79–1.72 (m, 2 H,
1
2 H, HAr), 4.33 (q, J = 7.1 Hz, 2 H, CH3CH2O), 2.57 (s, 3 H, 5- HAlk), 1.26–1.19 (m, 10 H, HAlk), 0.86 (t, J = 6.8 Hz, 3 H, Alk-
CH3), 1.38 (t, J = 7.1 Hz, CH3CH2O) ppm. 13C NMR (100 MHz, CH3) ppm. 13C NMR (100 MHz, 21 °C, CDCl3): δ = 148.4, 138.3,
21 °C, CDCl3): δ = 163.7, 143.6, 142.2, 137.4, 134.5, 129.5, 126.7, 134.5, 130.9, 129.5, 128.0, 108.7, 52.0, 31.7, 29.1, 29.0, 28.8, 26.1,
113.3, 60.1, 14.4, 12.0 ppm. IR (KBr): ν = 3072, 3001, 2981, 2939,
22.7, 14.2, 13.2 ppm. IR (KBr): ν = 3084, 3018, 2954, 2925, 2855,
1695, 1636, 1518, 1487, 1467, 1397, 1226, 1069, 1007, 842, 785
˜
˜
2906, 1713, 1558, 1504, 1414, 1228, 1099, 1021, 832, 772 cm–1.
HRMS (ESI): calcd. for C13H14ClN2O2 [M + H]+ 265.0744; found cm–1. HRMS (ESI): calcd. for C18H26BrN2 [M]+ 349.1279; found
265.0745.
349.1269.
1-(4-Chlorophenyl)-5-methylpyrazole (20) – A. Ester Cleavage: A
sample of ethyl 1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylate
(3.089 g, 11.680 mmol) was dissolved in ethanol (40 mL) with KOH
(1.962 g, 35.040 mmol) and stirred for 3.5 h at 78 °C. The solvent
was distilled off in vacuo and the residue was dissolved in H2O
(50 mL) and acidified to pH 1 with HCl. The resulting 1-(4-chlo-
rophenyl)-5-methylpyrazole-4-carboxylic acid was filtered and
washed with water (80 mL), and finally dried to give a white solid
(91%, 2.516 g); m.p. 195 °C. 1H NMR (400 MHz, 21 °C, [D6]-
DMSO): δ = 12.76 (s, 1 H, OH), 7.98 (s, 1 H, 3-H), 7.63–7.57
(AAЈBBЈ, J = 8.9 Hz, 4 H, HAr), 2.51 (s, 3 H, 5-CH3) ppm. 13C
NMR (100 MHz, 21 °C, CDCl3): δ = 164.4, 143.4, 141.8, 137.4,
1-(4-Chlorophenyl)-2-decyl-5-methylpyrazolium Iodide (21c):
A
sample of 1-(4-chlorophenyl)-5-methylpyrazole (20; 400 mg,
2.078 mmol) was dissolved in 1-iododecane (2.786 g, 10.390 mmol)
and stirred for 48 h at 132 °C. After cooling, the mixture was puri-
fied by chromatography (silica gel; dichloromethane/ethanol, 15:1)
1
to give a light-brown solid (14%, 0.133 g); m.p. 56.8 °C. H NMR
(400 MHz, 21 °C, CDCl3): δ = 8.64 (d, J = 2.7 Hz, 1 H, 3-H), 7.78–
7.59 (AAЈBBЈ, J = 8.7 Hz, 4 H, HAr), 6.72 (d, J = 2.7 Hz, 1 H, 4-
H), 4.22 (t, J = 7.6 Hz, 2 H, 2-CH2-Alk), 2.27 (s, 3 H, 5-CH3), 1.64
(quint, J = 7.6 Hz, 2 H, HAlk), 1.16–1.06 (m, 14 H, HAlk), 0.75
(t, J = 7.0 Hz, 3 H, Alk-CH3) ppm. 13C NMR (100 MHz, 21 °C,
CDCl3): δ = 148.5, 139.3, 138.0, 131.3, 130.7, 128.6, 108.5, 51.6,
133.0, 129.3, 127.0, 113.2, 11.4 ppm. IR (KBr): ν = 2972, 2693,
˜
31.7, 29.3, 29.1, 29.0, 28.6, 25.9, 22.5, 14.0, 13.3 ppm. IR (KBr): ν
˜
2606, 2361, 2343, 1698, 1663, 1562, 1501, 1290, 1255, 1095, 936,
830, 781 cm–1. HRMS (ESI): calcd. for C11H10ClN2O2 [M + H]+
237.0431; found 237.0427.
= 3457, 3078, 3021, 2925, 2854, 1516, 1491, 1464, 1391, 1091, 1009,
845 cm–1. HRMS (ESI): calcd. for C20H30ClN2 [M]+ 333.2098;
found 333.2094.
B. Decarboxylation: A sample of 1-(4-chlorophenyl)-5-methylpyr-
azole-4-carboxylic acid (2.492 g, 10.537 mmol) was mixed with
quinoline (2.845 mL, 24.235 mmol) and stirred for 6.5 h at 238 °C.
The reaction mixture was then purified by chromatography (silica
gel; petroleum ether/ethyl acetate, 8:1) to give a light-brown liquid
(80%, 1.600 g). 1H NMR (400 MHz, 21 °C, CDCl3): δ = 7.60 (d, J
= 1.2 Hz, 1 H, 3-H), 7.48–7.42 (AAЈBBЈ, J = 8.5 Hz, 4 H, HAr),
6.23 (d, J = 1.2 Hz, 1 H, 4-H), 2.37 (s, 3 H, 5-CH3) ppm. 13C NMR
(100 MHz, 21 °C, CDCl3): δ = 140.2, 138.7, 138.5, 133.3, 129.2,
1-(4-Chlorophenyl)-2-hexadecyl-5-methylpyrazolium Iodide (21d):
A
sample of 1-(4-chlorophenyl)-5-methylpyrazole (250 mg,
1.299 mmol) was dissolved in 1-iodohexadecane (2.289 g,
6.494 mmol) and then subjected to microwave irradiation under
vigorous stirring. Conditions were as follows: 30 min at 130 °C,
30 min at 150 °C, 70 min at 170 °C, 35 min at 180 °C, 240 min at
190 °C, then 420 min at 200 °C. The mixture was then purified by
chromatography (silica gel; dichloromethane/ethanol, 15:1) to give
a brown solid (8%, 0.057 g); m.p. 79 °C. 1H NMR (400 MHz,
21 °C, CDCl3): δ = 8.70 (d, J = 2.5 Hz, 1 H, 3-H), 7.84–7.68
(AAЈBBЈ, J = 8.7 Hz, 4 H, HAr), 6.81 (d, J = 2.5 Hz, 1 H, 4-H),
4.34 (t, J = 7.5 Hz, 2 H, 2-CH2-Alk), 2.34 (s, 3 H, 5-CH3), 1.76
(qu, J = 7.2 Hz, 2 H, HAlk), 1.34–1.19 (m, 26 H, HAlk), 0.88 (t,
J = 6.5 Hz, 3 H, Alk-CH3) ppm. 13C NMR (100 MHz, 21 °C,
CDCl3): δ = 148.4, 139.7, 138.2, 131.4, 130.7, 128.8, 108.6, 51.9,
31.9, 29.7, 29.6, 29.5, 29.4, 29.3, 29.1, 28.8, 26.1, 22.7, 14.1,
126.0, 107.3, 12.5 ppm. IR (NaCl): ν = 1545, 1500, 1468, 1444,
˜
1410, 1389, 1206, 1095, 1011, 921, 833, 780, 537 cm–1. HRMS
(ESI): calcd. for C10H10ClN2 [M + H]+ 193.0533; found 193.0531.
2-Benzyl-1-(4-bromophenyl)-5-methylpyrazolium Bromide (21a): A
sample of 1-(4-bromophenyl)-5-methylpyrazole (19; 153 mg) was
dissolved in benzyl bromide (1.7 mL) and then subjected to micro-
wave irradiation under vigorous stirring. Conditions were as fol-
lows: 10 min at 120 °C, 10 min at 130 °C, 20 min at 140 °C, then
70 min at 150 °C (max. power: 400 W). The reaction mixture was
then purified by chromatography (silica gel; dichloromethane/
EtOH, 9:1) to give a colorless solid (60%, 0.157 g); m.p. 170 °C.
1H NMR (400 MHz, 21 °C, CDCl3): δ = 9.22 (d, J = 2.9 Hz, 1 H,
3-H), 7.67 (d, J = 8.7 Hz, 2 H, HAr), 7.44 (d, J = 8.7 Hz, 2 H,
HAr), 7.28–7.24 (m, 3 H, HAr), 7.00 (d, J = 6.9 Hz, 2 H, HAr),
6.77 (s, J = 2.9 Hz, 1 H, 4-H), 5.80 (s, 2 H, CH2), 2.27 (s, 3 H,
CH3) ppm. 13C NMR (100 MHz, 21 °C, CDCl3): δ = 148.7, 139.7,
134.0, 131.7, 130.8, 129.7, 129.4, 129.3, 128.6, 127.6, 108.3, 55.5,
13.1 ppm. IR (KBr): ν = 3425, 2920, 2851, 1512, 1493, 1467, 1441,
˜
1383, 1234, 1090, 837, 822 cm–1. HRMS (ESI): calcd. for
C26H42ClN2 [M]+ 417.3037; found 417.3036.
N-Benzyl-6-bromo-2-methylquinolin-4-amine (22a): A sample of 2-
benzyl-1-(4-bromophenyl)-5-methylpyrazolium bromide (21a;
60 mg, 0.147 mmol) was mixed with potassium tert-butoxide
(19 mg, 0.176 mmol) and added rapidly into hot anhydrous toluene
(2 mL). Heating at reflux temperature was continued for 1 h. After
cooling, the solvent was distilled off and the resulting residue was
purified by chromatography (silica gel; MeOH/EtOAc, 1:10) to give
22a (29%, 0.014 g); m.p. 195 °C. 1H NMR (400 MHz, 21 °C,
CDCl3): δ = 7.84 (d, J = 2.1 Hz, 1 H, 5-H), 7.81 (d, J = 8.9 Hz, 1
H, 8-H), 7.67 (dd, J = 8.9, 2.1 Hz, 1 H, 7-H), 7.42–7.36 (m, 5 H,
HAr), 6.39 (s, 1 H, 3-H), 5.15 (s, 1 H, NH), 4.51 (d, J = 5.1 Hz, 2
H, CH2), 2.58 (s, 3 H, CH3) ppm. 13C NMR (100 MHz, 21 °C,
CDCl3): δ = 160.0, 148.9, 146.7, 137.3, 132.6, 130.7, 129.1, 128.1,
12.8 ppm. IR (KBr): ν = 3109, 3051, 2988, 2929, 1635, 1532, 1516,
˜
1484, 1456, 1402, 1387, 1363, 1222, 1186, 1070, 1004, 834, 705,
696, 551 cm–1. HRMS (ESI): calcd. for C17H16BrN2 [M]+ 327.0497;
found 327.0491.
1-(4-Bromophenyl)-5-methyl-2-octylpyrazolium Iodide (21b): A sam-
ple of 1-(4-bromophenyl)-5-methylpyrazole (19; 105 mg) was dis-
solved in 1-iodoctane (532 mg, 2.214 mmol) and stirred for 11 h at
140 °C. After cooling, the mixture was purified by chromatography
127.8, 122.3, 118.8, 117.8, 100.3, 47.7, 25.7 ppm. IR (KBr): ν =
˜
2924, 1631, 1590, 1562, 1488, 1445, 1410, 1350, 1249, 1128, 826,
4302
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 4296–4305

Rearrangements of N-Heterocyclic Carbenes
572 cm–1. HRMS (ESI): calcd. for C17H16BrN2 [M + H]+ 327.0497; functional theory,[40,41] and their nature (minimum or first-order
found 327.0494.
saddle point) was confirmed by harmonic vibrational analysis at
the same level (having 0 and 1 imaginary frequency, respectively).
Thermodynamic corrections were estimated from unscaled fre-
quencies, using standard formulae in the ideal gas – rigid rotor –
harmonic oscillator approximation as implemented in Gaussian,
and refer to a standard state of 298.15 K and 1 mol/dm3 concentra-
tion. Relative electronic energies were determined using single-
point M05–2X/6-311++G** calculations.[42,43] Free energies of sol-
vation were estimated from the IEF-PCM model[44] with M05-2X/
6-31G* wave function, using the in vacuo optimized geometries,
UA0 radii, and toluene as solvent. Reported energy values refer to
relative Gibbs free energies of solvated species, but the same quali-
tative trends could be obtained using solely the electronic energies
(see comparison in the Supporting Information). Transition states
were further analyzed by intrinsic reaction coordinate (IRC) calcu-
lations.[45] These usually failed before reaching the respective min-
ima, but they revealed a significant portion of the path. Aromatic-
ity was studied using NICS values[33] calculated 1 Å above the geo-
metrical centers of the forming rings, on the opposite side to the
hydrogen atom of the attacked phenyl carbon or to the N2-methyl
group. These points were chosen in order to assess the effect
of π-electrons, and to minimize the disturbance of the σ-frame-
6-Bromo-N-octyl-2-methylquinolin-4-amine (22b): A sample of pyr-
azolium salt 21b (60 mg, 0.26 mmol) was mixed with potassium
tert-butoxide (36 mg, 0.32 mmol) and added rapidly to a hot solu-
tion of anhydrous toluene (2 mL). Heating at reflux temperature
was continued for 1 h, and then the solvent was distilled off in
vacuo and the residue was purified by chromatography (silica gel;
MeOH/ethyl acetate, 1:8) to give 22b (31%, 0.027 g); m.p. 95 °C.
1H NMR (400 MHz, 21 °C, CDCl3): δ = 7.85 (d, J = 1.7 Hz, 1 H,
5-H), 7.78 (d, J = 8.9 Hz, 1 H, 8-H), 7.64 (dd, J = 8.9, 1.7 Hz, 1
H, 7-H), 6.31 (s, 1 H, 3-H), 5.01 (s, 1 H, NH), 3.28 (q, J = 7.0 Hz,
N-CH2), 2.60 (s, 3 H, 2-CH3), 1.80–1.72 (m, 2 H, CH2), 1.49–1.25
(m, 10 H, HAlk), 0.90 (t, J = 6.9 Hz, 3 H, Alk-CH3) ppm. 13C
NMR (100 MHz, 21 °C, CDCl3): δ = 159.8, 149.3, 146.4, 132.6,
130.4, 122.2, 118.7, 117.6, 99.7, 43.5, 31.9, 29.5, 29.3, 29.0, 27.3,
25.5, 22.8, 14.2 ppm. IR (KBr): ν = 2924, 2853, 2361, 1634, 1587,
˜
1560, 1466, 1412, 1355, 1314, 1249, 1197, 1081, 994, 827, 668, 558
cm–1. HRMS (ESI): calcd. for C18H25BrN2 [M]+ 348.1201; found
348.1199.
6-Chloro-N-decyl-2-methylquinolin-4-amine (22c): A sample of 2-
decyl-5-methyl-1-(4-chlorophenyl)pyrazolium iodide (21c; 51 mg,
0.111 mmol) was mixed with potassium tert-butoxide (12.4 mg
(0.111 mmol) and added rapidly to a hot solution of anhydrous
toluene (2 mL). Heating at reflux temperature was continued for
1 h and then the solvent was distilled off in vacuo and the residue
was purified by chromatography (silica gel; ethyl acetate) to give
22c (41%, 0.015 g) as a brown solid; m.p. 77 °C. 1H NMR
(400 MHz, 21 °C, CDCl3): δ = 7.84 (d, J = 8.9 Hz, 1 H, 5-H), 7.66
(d, J = 2.2 Hz, 1 H, 8-H), 7.51 (dd, J = 8.9, 2.2 Hz, 1 H, 7-H), 6.32
(s, 1 H, 3-H), 4.87 (s, 1 H, NH), 3.28 (t, J = 7.3 Hz, 2 H, N-CH2-
Alk), 2.60 (s, 3 H, 5-CH3), 1.75 (quint, J = 7.3 Hz, 2 H, HAlk),
1.46 (quint, J = 7.3 Hz, 2 H, HAlk), 1.39–1.24 (m, 12 H, HAlk),
0.88 (t, J = 6.8 Hz, 3 H, Alk-CH3) ppm. 13C NMR (100 MHz,
21 °C, CDCl3): δ = 149.1, 146.4, 130.5, 129.8, 129.5, 118.7, 118.1,
99.6, 43.3, 31.9, 29.6, 29.4, 29.3, 28.9, 27.2, 25.6, 22.7, 14.1 ppm.
work.[34,35]
Single-point
GIAO-B3LYP/6-31+G*
calcula-
tions[41,43,46,47] were used for this purpose. All DFT calculations
were carried out with the “ultrafine” integration grid consisting of
99 radial shells and 590 angular points per shell.
Supporting Information (see also the footnote on the first page of
this article): Comparison of electronic and free energies, Cartesian
coordinates and total energies of all calculated stationary points.
Acknowledgments
The Deutsche Forschungsgemeinschaft (DFG) is gratefully ac-
knowledged for financial support. Dr. Gerald Dräger (University
of Hannover, Germany) is gratefully acknowledged for measuring
the HRMS (ESI) spectra. This work was also supported by the
Hungarian Research Foundation (grant NK-77784).
IR (KBr): ν = 3431, 3241, 3061, 2927, 2851, 1589, 1562, 1464,
˜
1411, 1358, 1259, 1091, 840, 829 cm–1. HRMS (ESI): calcd. for
C20H30ClN2 [M + H]+ 333.2098; found 333.2096.
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[4] A. J. Arduengo, R. L. Harlow, M. Kline, J. Am. Chem. Soc.
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6-Chloro-N-hexadecyl-2-methylquinolin-4-amine (22d): A sample of
2-hexadecyl-5-methyl-1-(4-chlorophenyl)pyrazolium iodide (21d;
33 mg, 0.061 mmol) was mixed with potassium tert-butoxide
(8.0 mg, 0.072 mmol) and added rapidly to a hot solution of anhy-
drous toluene (2 mL). Heating at reflux temperature was continued
for 1 h, and then the solvent was distilled off in vacuo. The residue
was then purified by chromatography (silica gel; ethyl acetate) to
give 22d (28%, 0.007 g) as a brown solid; m.p. 79 °C. 1H NMR
(400 MHz, 21 °C, CDCl3): δ = 7.85 (d, J = 8.9 Hz, 1 H, 5-H), 7.66
(d, J = 2.1 Hz, 1 H, 8-H), 7.52 (dd, J = 7.5, 2.2 Hz, 1 H, 7-H), 6.32
(s, 1 H, 3-H), 4.88 (s, 1 H, NH), 3.28 (t, J = 7.3 Hz, 2 H, N-CH2-
Alk), 2.61 (s, 3 H, 5-CH3), 1.76 (quint, J = 7.3 Hz, 2 H, HAlk),
1.47 (quint, J = 7.3 Hz, 2 H, HAlk), 1.39–1.26 (m, 24 H, HAlk),
0.88 (t, J = 6.8 Hz, 3 H, Alk-CH3) ppm. 13C NMR (100 MHz,
21 °C, CDCl3): δ = 159.7, 149.1, 130.4, 129.8, 129.6, 118.7, 118.0,
99.6, 43.4, 32.0, 29.7, 29.6, 29.4, 28.9, 27.2, 25.5, 22.7, 14.2 ppm.
IR (KBr): ν = 3431, 2926, 2849, 1591, 1561, 1523, 1475, 1460, 1408,
˜
1374, 1253, 1192, 1131, 1087, 990, 881, 840, 823, 811, 731 cm–1.
HRMS (ESI): calcd. for C26H42ClN2 [M + H]+ 417.3034; found
417.3037.
Computational Details: The Gaussian 03 software package[39] was
used throughout this study. Stationary points of the potential en-
ergy surface were located at the M05–2X/6-31G* level of density
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Received: April 13, 2010
Published Online: June 22, 2010
Eur. J. Org. Chem. 2010, 4296–4305
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4305