Functionalized 4-aminoquinolines by rearrangement of pyrazole N-heterocyclic carbenes

Article abstract of DOI:10.1002/anie.200905436

(Figure Presented) Thermal decarboxylation of 1-phenyl pyrazolium-3- carboxylates from the mesomeric betaine class of substances leads to pyrazole-N-heterocyclic carbenes, which immediately rearrange to multiply substituted 4-aminoquinolines (see scheme). These species are of interest for the synthesis of heterocycles and pharmacologically active compounds.

Full text of DOI:10.1002/anie.200905436

Communications
DOI: 10.1002/anie.200905436
N-Heterocyclic Carbenes
Functionalized 4-Aminoquinolines by Rearrangement of Pyrazole
N-Heterocyclic Carbenes**
Andreas Schmidt,* Niels Mꢀnster, and Andrij Dreger
The quinoline[1] and pyrazole[2] class of substances feature
diverse biological activities and other interesting properties.
From the viewpoint of the chemistry of pharmacologically
active compounds, considerable attention is being paid to 4-
aminoquinolines, especially because after decades of use
Plasmodium falciparum genotypes resistant to the active anti-
malarial compound chloroquine[3] have spread to almost all
tropical regions of the world.[4] As the use of alternative active
compounds is similarly restricted because of adverse effects
or resistance,[5] variation of the substitution of 4-aminoquino-
lines still remains highly promising despite of the decoding of
the genome of the pathogen in the meantime.[6] Herein we
present a useful thermal rearrangement to new substituted 4-
aminoquinolines starting from pyrazolium-3-carboxylates
that proceeds by an N-heterocyclic carbene (NHC) of
pyrazole. Carbenes of pyrazole and its relative, indazole,[7]
have so far stood in the shadow of other NHCs.[8] In 1997,
Herrmann’s group described the rhodium complex 2 of
pyrazol-3-ylidene 1;[9] there have also been reports on the
catalytic activities of iridium,[10] ruthenium,[11] and palladium
complexes[12] of 1.
The isomeric pyrazol-4-ylidene 3 can be construed as an
rNHC (“remote N-heterocyclic carbene”[13]). The corre-
sponding palladium complex 4 has been investigated regard-
ing its activity in the Suzuki–Miyaura and Mizoroki–Heck
reactions.[14] Whether the cyclic allene 5[15] is more appropri-
ately formulated as the mesomeric resonance structure 5’ and
regarded as aromatic zwitterion[16] has recently been under
discussion.[17]
Pseudo-cross-conjugated
mesomeric
betaines
(PCCMB),[18] which contain the structural element I, readily
cleave heterocumulenes on warming with formation of N-
heterocyclic carbenes II. For example, NHCs of quinoline,[19]
pyridine,[20] or imidazole[21] can be formed in situ by decar-
boxylation of the corresponding hetarenium-2-carboxylates;
metal complexes may also be obtained in this way.[22]
Conversely, trapping reactions of these carbenes with hetero-
cumulenes to form 1:1-adducts has meanwhile become a
classic reaction.[23]
Pyrazolium-3-carboxylates 7a–o are also interesting pre-
cursors of pyrazol-3-ylidenes.[24] The alkylation of the 1-aryl-
pyrazole-3-carboxylic esters 6a–o to pyrazolium salts takes
place in high yields with dimethylsulfate or diethylsulfate as
an advantageous one-pot reaction in combination with
subsequent hydrolysis to betaines 7a–o (Scheme 1).[25] All of
the betaines 7 are stable solids that lose water of crystalliza-
tion at 1008C (TGA and DSC measurements) and decarbox-
ylate exothermally upon further heating (7a: at 115–1208C)
and then decompose. In toluene, however, even mild heating
of 7a at 348C leads to decarboxylation within a few hours and
within 30 minutes under reflux with subsequent rearrange-
ment to 4-aminoquinoline 8a, which immediately precipitates
in analytically pure form (Table 1, No. 1). Identical results
were obtained in the aprotic solvents benzene and chloro-
benzene, which also remove the stabilizing water of crystal-
lization of the betaines as an azeotrope. The betaines are
correspondingly stable in boiling 1-propanol or water.
[*] Prof. Dr. A. Schmidt, N. Mꢀnster, Dipl.-Chem. A. Dreger
Technische Universitꢁt Clausthal, Institut fꢀr Organische Chemie
Leibnizstrasse 6, 38678 Clausthal-Zellerfeld (Germany)
Fax: (+49)5323-72-2858
E-mail: schmidt@ioc.tu-clausthal.de
Homepage: http://www.ioc.tu-clausthal.de
As shown in Table 1, di- (8a,b), tri- (8c–i), tetra- (8k,l),
and pentasubstituted quinolines (8m–o) can be obtained from
the betaines 7a–o by this rearrangement; of these compounds,
only 8a is known.[26] The substitution patterns realizable in
[**] This work was supported by the Deutsche Forschungsgemeinschaft
(DFG).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/ange.200905436.
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Scheme 1. Synthesis of the pyrazolium-3-carboxylates 7 as starting
compounds for the rearrangement to quinolines 8.
Scheme 2. Suggested mechanism for the rearrangement.
8 f,g,i,l are very rare, and the C2,N4,C5,Cl6,O8- (8m) and
C2,N4,O5,O6,O7 substitution patterns (8n,o) have not been
reported before. Substitution of only one m-position of the
phenyl ring of pyrazolium-3-carboxylate leads to a mixture of
products, as expected: 8h is thus obtained as an isomeric
mixture in a 3:1 ratio. In agreement with the observed solvent
effects, the acid function in the betaine 7j prevents decar-
boxylation.
the presence of sulfur produced the thione 10 in 72% yield in
a carbene trapping reaction (Scheme 3).
Attempts to trap the carbene formed from 7a with 3,5-
dichlorophenylisocyanate gave no pyrazolium-3-amidate, but
The reaction clearly proceeds by ring opening of the
pyrazole-3-ylidene A formed by decarboxylation to the
zwitterionic intermediate B, the non-polar mesomeric reso-
nance structure of which is the keteneimine C (Schema 2).
The subsequent ring closure to D can be seen as electrophilic
aromatic substitution (of B) or 6p electrocyclization (of C).
Tautomerization of D leads to the 4-aminoquinoline.
Along with signals for the pyrazolium ions 9, [A + Na]+
peaks for N-heterocyclic carbenes, such as A, were also
detected by ESI mass spectrometry. Decarboxylation of 7a in
Scheme 3. Trapping reactions of the carbene to give 9 and 10.
Table 1: Substitution pattern and yields in the sequence 6!7!8 (Scheme 1).
No.
R1
R2
R3
R4
R5
R6
R7
7
Yield [%]
8
Yield [%]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
OMe
H
H
H
Cl
H
OMe
OMe
H
H
H
H
Me
Cl
Br
H
H
H
Cl
H
Cl
OMe
OMe
H
H
H
H
H
H
H
H
H
H
H
Cl
Me
OMe
OMe
Me
Me
Et
Me
2-thienyl
Ph
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
2-thienyl
H
H
Et
Et
H
H
H
H
H
H
H
H
H
H
H
7a
7b
7c
7d
7e
7 f
7g
7h
7i
7j
7k
7l
7m
7n
7o
89
66
55
81
42
93
54
94
94
92
96
49
51
97
39
8a
79
89
99
95
65
59
94
54
30
0
81
54
37
87
58
8b
8c
8d
8e
8 f
8g
8h[a]
8i
8j
8k
8l
8m
8n
8o
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
F
COOH
Me
H
OMe
H
H
[a] As mixture with its isomers.
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Communications
J = 8.3 Hz), 7.33 (dd, 1H, 6-H, J = 8.3 Hz, 6.9 Hz), 7.16 (q, 1H, HN,
J = 4.8 Hz), 6.27 (s, 1H, 3-H), 2.87 (d, 3H, H3CN, J = 4.8 Hz),
2.47 ppm (s, 3H, 2-CH3); 13C NMR ([D6]DMSO, 100 MHz): d =
159.2, 151.3, 148.3, 129.0, 128.8, 123.5, 121.7, 118.0, 98.2, 29.7,
25.7 ppm; ESI-MS: 173.1 (M+H+, 100%); IR (KBr): n˜ = 3225,
1594, 1561, 1443 cmꢀ1. HR-ESI-MS: calcd for C11H13N2: 173.1079;
found: 173.1076.
quinoline 8a instead (Scheme 4). As the amidate contained
the structure element I mentioned above, thermal cleavage of
heterocumulenes occurs with regeneration of the carbene,
Received: September 28, 2009
Published online: March 12, 2010
Keywords: carbenes · heterocycles · rearrangements ·
.
synthetic methods · zwitterions
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8a: Betaine 7a (108 mg, 0.5 mmol) was suspended in toluene (4 mL)
and heated to reflux for 30 minutes. The precipitate that formed was
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1
2348C. H NMR ([D6]DMSO, 400 MHz): d = 8.07 (d, 1H, 5-H, J =
8.3 Hz), 7.69 (d, 1H, 8-H, J = 8.3 Hz), 7.54 (dd, 1H, 7-H, J = 6.9 Hz,
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