Pyrido[1,2-c][1,2,4]triazol-3-ylidene: Reactivity and its application in organocatalysis and organometallic catalysis

Article abstract of DOI:10.1039/b910073c

The reactivity and catalytic performance of 2-ethylpyrido[1,2-c][1,2,4]- triazol-3-ylidene 6 have been comprehensively investigated. The carbene 6 has shown unusual properties owing to the effect of the pyrido-annulation. While formohydrazide 8 and hydrazine 9 are obtained via the destruction of the triazole skeleton of the carbene, 3-((1Z,3E)-4-(1H-pyrrol-1-yl)buta-1,3-dienyl)- 1-ethyl-1H-1,2,4-triazole 10 is achieved through the cleavage of the C-N bond of the pyridine ring. The carbene 6 has turned out to be a powerful catalyst in a variety of organocatalyzed and Pd(II)-catalyzed transformations.

Full text of DOI:10.1039/b910073c

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Pyrido[1,2-c][1,2,4]triazol-3-ylidene: reactivity and its application
in organocatalysis and organometallic catalysis†
Siping Wei, Bo Liu, Dongbing Zhao, Zhen Wang, Jie Wu, Jingbo Lan and Jingsong You*
Received 21st May 2009, Accepted 3rd July 2009
First published as an Advance Article on the web 7th August 2009
DOI: 10.1039/b910073c
The reactivity and catalytic performance of 2-ethylpyrido[1,2-c][1,2,4]-triazol-3-ylidene 6 have been
comprehensively investigated. The carbene 6 has shown unusual properties owing to the effect of the
pyrido-annulation. While formohydrazide 8 and hydrazine 9 are obtained via the destruction of the
triazole skeleton of the carbene, 3-((1Z,3E)-4-(1H-pyrrol-1-yl)buta-1,3-dienyl)-1-ethyl-1H-1,2,4-
triazole 10 is achieved through the cleavage of the C–N bond of the pyridine ring. The carbene 6 has
turned out to be a powerful catalyst in a variety of organocatalyzed and Pd(II)-catalyzed
transformations.
carbenes.5d,9a,9b Despite detailed investigations into their structures,
Introduction
properties, stability and transition metal coordination chemistry,
to our knowledge, their reactivity and catalysis have rarely been
documented as yet. Quite recently, we have reported for the
first time a highly efficient method for the preparation of the
pyrido-annulated triazolium salts and described the spectroscopic
properties, dimerization behavior and coordination chemistry of
the corresponding triazol-3-ylidenes.11 Among these triazolium
salts, 2-ethylpyrido[1,2-c][1,2,4]triazol-2-ium tetrafluoroborate 7
has demonstrated the highest catalytic efficiency in benzoin
condensation and transesterification. It is conceivable that this
excellent catalytic performance could be due to the much greater
stability of 2-ethylpyrido[1,2-c][1,2,4]-triazol-3-ylidene 6, result-
ing in less likelihood of dimerization or decomposition of the
triazole skeleton.11 In this context, we further wish to present a
relatively comprehensive investigation into the reactivity as well as
organocatalysis and organometallic catalysis of 6.
N-Heterocyclic carbenes (NHCs), as a class of nucleophilic singlet
carbenes, have grown tremendously from being regarded as chem-
ical curiosities1 to versatile ligands in organic2 and organometal-
lic catalysis,3 and reagents in organic reactions.4 In the past
decades, thiazol-2-ylidenes, imidazol-2-ylidenes, imidazolidin-2-
ylidenes and 1,2,4-triazol-5-ylidenes have represented the typical
architectures of stable nucleophilic N-heterocyclic carbenes, and
the chemistry of these compounds has been studied intensively.1–4
Currently, much work has been devoted to the design and
development of carbene species with novel structures to tune their
steric and electronic properties by slight modification of the ring
framework.5 Some new families of diaminocarbenes annulated by
carbo-or heterocycles 1–5 havebeendevelopedrecently.5d,6–10 More
importantly, the morpholino-annulated triazol-5-ylidenes 5 have
exhibited highly catalytic performances in various enantioselective
reactions, and their chemical properties are starting to attract
interest.9e,10
Recent investigations indicate that pyrido-annulation, as is
illustrated in 3 and 4, significantly influences the stability
and the s-donor/p-acceptor ligand properties of carbenes and
may be a useful tool for tuning the electronic properties of
Results and discussion
Reactivity of 2-ethylpyrido[1,2-c][1,2,4]-triazol-3-ylidene 6
With the isolated carbene 6 now to hand, prepared by deprotona-
tion of the triazolium salt 7 in the presence of NaH,11 a variety of
typical carbene reactions towards organic and inorganic substrates
were performed, offering a detailed impression of its chemical
nature.
In terms of reactivity, the NHCs behave as nucleophiles due
to their lone electron pair. Initial studies of the nucleophilicity
of 6 led to a surprising result (Scheme 1). Unlike other well-
defined triazolylidenes available in the literature,12 6 did not
Key Laboratory of Green Chemistry and Technology of Ministry of
Education, College of Chemistry, and State Key Laboratory of Biotherapy,
West China Hospital, West China Medical School, Sichuan University, 29
Wangjiang Road, Chengdu 610064, People’s Republic of China. E-mail:
jsyou@scu.edu.cn; Fax: (+86)-28-8541-2203
† Electronic supplementary information (ESI) available: Crystallographic
data in CIF format, copies of 1H NMR and 13C NMR spectra. CCDC
reference numbers 725112–725114. For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/b910073c
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Scheme 1 Reactivity of the triazolylidene 6.
react with alcohols (i.e., methanol, ethanol and iso-propanol),
phenol or amines (i.e., aniline, phenylmethanamine, pyrrolidine
and morpholine) via insertion into the O–H or N–H bond
respectively, even at up to 120 ◦C under nitrogen. In sharp
contrast, the reactions of the classic 1,3,4-triphenyl-1,2,4-triazol-
5-ylidene with alcohols, phenols and amines could proceed at
ambient temperature within ten minutes, affording the analytically
pure alkoxytriazolines, phenoxytriazolines and aminotriazolines
in good yields, respectively.12 Our previous studies demonstrated
that the pyrido[1,2-c][1,2,4]-triazol-3-ylidenes were quite stable in
solution and in the solid state for a long period under nitrogen
at room temperature. In this study, we found that the carbene
6 was converted to N-ethyl-N¢-(pyridin-2-yl)formohydrazide 8 in
a 78% yield after column chromatography on silica gel in the
presence of air. Surprisingly, with the aid of basic pyrrolidine, the
triazolylidene framework of 6 was destroyed with the formation
of 1-ethylidene-2-(pyridin-2-yl)hydrazine 9 in an 80% yield in air
at 80 ◦C. More interestingly, the replacement of amines with
1H-pyrrole resulted in the cleavage of the C–N bond of the pyri-
dine ring to form 3-((1Z,3E)-4-(1H-pyrrol-1-yl)buta-1,3-dienyl)-
1-ethyl-1H-1,2,4-triazole 10 in a 70% yield under N2. Compounds
8, 9 and 10 (CCDC 725112–725114) were characterized by X-ray
structure analysis.† Notably, there are two independent molecules
of 8 and of 10 in the relevant asymmetric units (Fig. 1).13
Fig. 1 ORTEP drawings of the molecular structures of 8 (a), (E)-9 (b),
and 10 (c). Thermal ellipsoids are set at the 50% probability level.
Overall, the pyrido-annulated carbene 6 exhibited unusual
reactivity owing to the effect of the pyrido-annulation. It is
therefore reasonable to assume that it would be a unique molecular
architecture for the development of new organometallic processes,
catalysts in organocatalytic reactions, and reagents in multicom-
ponent coupling reactions.
Similarly to other well-established carbenes, 6 readily underwent
addition reactions with chalcogens such as sulfur and selenium
to give the corresponding triazolinthione 11a and triazolinse-
lenone 11b in 95% and 98% yields, respectively. The carbene 6
could also be alkylated using triethyloxonium tetrafluoroborate,
affording the 3-ethyltriazolium salt 12 in a 95% yield. These two
kinds of reactivity, which were described earlier for nucleophilic
carbenes, clearly exemplify the nucleophilic character of the
carbene 6.
Catalytic direct amidation of cinnamaldehyde with nitrosobenzene
N-Heterocyclic carbenes have been widely used as a type of
efficient catalyst for metal-free carbon–carbon bond formations,
which are assumed to proceed through the electrophilic “Breslow
intermediate”14 or the homoenolate equivalent15 in umpolung
aldehyde chemistry.
As simple neutral polyfunctional molecules, N-arylhydroxamic
acids can not only provide novel N-OH mediators for
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Table 1 Addition of cinnamaldehyde to nitrosobenzene catalyzed by the various triazolium saltsa,b
7 (95%)
14 (93%)
17 (72%)
15 (95%)c
16 (87%)
a Reactions were performed with (E)-cinnamaldehyde (132 mg, 1mmol), nitrosobenzene (117 mg, 1.1 mmol), triazolium salts (0.1 mmol) and DBU
(0.1 mmol) in 5.0 mL of CH2Cl2 under N2 at rt for 10 min. b Yield of isolated product. c See ref. 17.
oxidoreductase catalysis, but also play important roles as phar-
macophores in a variety of biologically active agents.16 Quite
recently, Seayad and Zhang et al. described the direct amidation of
aldehydes with nitroso compounds catalyzed by achiral triazolium
salts 15 to give N-arylhydroxamic acids in excellent yields, which
possibly involves the “Breslow intermediates”.17 In our case, the
pyrido-annulated triazolium salt 7 proved to be a powerful catalyst
for this type of amidation reaction, affording a 95% yield of
product (Table 1).
triazolium salt 18 afforded the g-hydroxyl amino ester in a 75%
yield with a 4:1 diastereoselectivity. In this study, the pyrido-
annulated carbene 6 generated in situ from 7 proved to be a
powerful catalyst for this type of addition reaction (Table 2). To
our surprise, the triazolium salt 7 exhibited not only high catalytic
activity giving up to 94% total yield of 19, but also an excellent
level of diastereoselectivity. Indeed, the 1H NMR analysis of
unpurified reaction mixtures indicated that the reaction afforded
the g-hydroxyl amino ester 19 as a nearly single diastereomer,
which was superior to that of 20 (a 20:1 dr and 93% ee).19
Catalytic cinnamaldehyde addition to nitrone
Direct C-arylation of heteroaromatics with aryl bromide catalyzed
by the Pd complex of 6
Addition of homoenolate nucleophiles to nitrones would be a
significant transformation since the related products may be
converted to g-amino acids as well as g-lactam structures.18 Very
recently, Scheidt et al. described the first formal [3+3] addition
of a,b-unsaturated cinnamaldehyde to nitrones catalyzed by
N-heterocyclic carbenes to give g-amino ester derivatives upon
addition of alcohol.19 While thiazolium and imidazolium salts
failed to provide the target product, the use of 10 mol% of achiral
More recently, direct C-arylation of heteroaromatics has received
prominent attention as an effective approach for creating aryl–
heteroaryl linkages extensively throughout the natural products,
pharmaceutical and materials industries.20 Among these catalytic
systems, a variety of transition-metal–tertiary phosphane com-
plexes have been extensively employed as catalysts, whereas few
Table 2 Cinnamaldehyde addition to nitrone catalyzed by various achiral triazolium saltsabc
7 (>50:1 dr, 94%)
17 (28%)
14 (>3:1 dr, 80%)
18 (4:1 dr, 75%)d
16 (12%)
20 (20:1 dr, 93% ee, 70%)d
a Reactions were performed with (E)-cinnamaldehyde (0.4 mmol), (Z)-N-benzylideneaniline oxide (0.8 mmol), triazolium salts (0.04 mmol) and DBU
◦
1
(0.04 mmol) in 4.0 mL of CH2Cl2 under N2 at 0 C for 2 days. b Yield of isolated product. c Diastereomeric ratio determined by H NMR analysis of
unpurified reaction mixtures. d See ref. 19.
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Table 3 Direct C-arylation of pyridine-N-oxide catalyzed by various
Table 4 Direct C-arylation of caffeine catalyzed by various
triazolylidene–palladium complexesa,b
triazolylidene–palladium complexesa,b
7 (94%)
14 (46%)
17 (75%)
7 (78%)
14 (trace)
17 (47%)
16 (70%)
22 (60%)
16 (trace)
22 (<10%)
a Reactions were performed with K2CO3 (1 mmol), triazolium salts
(0.05 mmol), Pd(OAc)2 (0.05 mmol), caffeine (0.5 mmol) and 4-
bromotoluene (1 mmol) in DMF (1 mL) under N2 at 115 ◦C for 22 h.
b Yield of isolated product.
a Reactions were performed with K2CO3 (1 mmol), triazolium salts
(0.05 mmol), Pd(OAc)2 (0.05 mmol), pyridine N-oxide (1.5 mmol) and
4-bromotoluene (0.5 mmol) in toluene (2 mL) under N2 at 110 ◦C for 20 h.
b Yield of isolated product.
framework of this “bottle stable” carbene can be destroyed to
form formohydrazide 8 and hydrazine 9 in the presence of air. The
C–N bond of the pyridine ring can also be broken by reacting with
1H-pyrrole, with the formation of the 1,2,4-triazole derivative 10.
Moreover, the carbene 6 has turned out to be a powerful catalyst
in a variety of organocatalyzed and palladium-mediated direct
C-arylations of heteroaromatics, and was comparable with or even
superior to other well-established triazolylidenes. Further inves-
tigations into other types of organocatalysis and organometallic
catalysis are currently underway and will be reported in due course.
examples based on metal complexes of NHCs have been known
hitherto.21
Triazolylidenes have not been as widely explored as imidazole-
based carbenes in organometallic catalysis in spite of extensive
application in organocatalysis.20–22 To our knowledge, the suc-
cessful use of transition-metal–triazolylidene complexes for direct
arylation reactions of arene and heterocycle C–H bonds has not
yet been described. Inspired by these factors, we herein wish
to evaluate the catalytic performance of the pyrido-annulated
triazol-3-ylidenes in the palladium-mediated C-arylation of het-
eroaromatics. Our initial exploration started with the coupling of
pyridine N-oxide with p-bromotoluene.23 A screen of triazolium
salts revealed that the C-arylation process smoothly occurred in
a 78% yield with complete selectivity for the 2-position in the
presence of 7 (10 mol%) and Pd(OAc)2 (10 mol%). Moreover,
the catalytic performance of the triazolium salt 7 turned out to
be better than those of the other well-established triazolium salts
investigated (Table 3).
We subsequently turned our attention to xanthine derivatives.24
8-Aryl-substituted xanthines are highly potent and selective
antagonists at human A2B adenosine receptors. We were pleased
to find that the C-arylation of caffeine with p-bromotoluene could
proceed in the presence of 10 mol% of 7 and 10 mol% of Pd(OAc)2,
affording the 8-aryl-substituted caffeine 23 in a 94% yield (Table 4).
Further investigation indicated that the catalytic efficiency of 7 was
superior to the other classic types of triazolium salts examined.
Experimental section
General
1H NMR spectra were obtained with a Bruker AV-300, Bruker
AV II-400, Bruker AV II-600, Varian Inova-400 or a Varian
Inova-600 spectrometer, while 13C NMR spectra were recorded
with a Bruker AV-300, Bruker AV II-400, Varian Inova-400
1
or a Varian Inova-600. The H chemical shifts were measured
relative to tetramethylsilane as the internal reference, while the 13
C
NMR chemical shifts were recorded with CDCl3 as the internal
standard. Elemental analyses were performed with a CARLO
ERBA1106 instrument. The mass spectra (ESI) were obtained
by a Finnigan-LCQDECA spectrometer. Unless otherwise noted,
all liquid reagents were freshly distilled under reduced pressure
prior to use. Solvents were dried by refluxing for at least 24 h over
CaH2 (CH2Cl2), or sodium/benzophenone (THF or diethyl ether),
and freshly distilled prior to use. Unless otherwise indicated, all
syntheses and manipulations were carried out under a dry N2
atmosphere.
Conclusions
In summary, the pyrido[1,2-c][1,2,4]triazol-3-ylidene 6 has shown
unusual properties owing to the effect of the pyrido-annulation.
As compared with other well-defined triazolylidenes described
in the literature, 6 is not capable of reacting with alcohols,
phenol, or amines to form the corresponding alkoxytriazolines,
phenoxytriazolines and aminotriazolines. However, the triazole
X-Ray crystallography
X-Ray single-crystal diffraction data for 8 and 9 were collected
on an Enraf-Nonius CAD-4 diffractometer at room temperature
˚
with Mo Ka radiation (l = 0.71073 A) with w/2q scan mode, and
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for 10 was collected on a Bruker SMART 1000 CCD areadetector
diffractometer at 100 K with graphite monochromated Cu Ka
70% yield. Mp: 56–57 ◦C; 1H NMR (400 MHz, CDCl3): d = 1.53
(t, J = 7.2 Hz, 3H), 4.20 (q, J = 7.2 Hz, 2H), 6.25–6.30 (m, 3H),
6.39 (t, J = 11.2 Hz, 1H), 7.00–7.03 (m, 3H), 7.87–7.99 (m, 1H),
8.03 (s, 1 H); 13C NMR (100 MHz, CDCl3): d = 15.2, 44.7, 110.7,
112.5, 116.5, 119.4, 130.8, 132.7, 142.3, 162.0; MS (ESI+) m/z =
215 [M + H]+; Anal. calcd for C12H14N4: C, 67.27; H, 6.59; N,
26.15. Found: C, 67.15; H, 6.64; N, 26.08.
˚
radiation (l = 1.54184 A) with w scan mode. All the structures
were solved by direct methods using the SHELXS program and
refined by full-matrix least-squares methods with SHELXL.25 All
non-hydrogen atoms were located in successive difference Fourier
syntheses and refined with anisotropic thermal parameters on F2.
Hydrogen atoms were included in calculated positions and refined
with constrained thermal parameters riding on their parent atoms.
Drawings were produced with PLATON.26
Procedure for the preparation of 2-ethylpyrido[1,2-c][1,2,4]-
triazol-3-thione (11a). A mixture of the triazolium salt 7
(117.5 mg, 0.5 mmol) and NaH (13.2 mg, 0.55 mmol) in THF
(5.0 mL) was stirred under a N2 atmosphere at room temperature
for 30 min. After the solid was filtered, the filtrate was evaporated
under vacuum, and the resulting carbene 6 further reacted with
elemental sulfur (19.2 mg, 0.6 mmol) in toluene (5 mL) at reflux
for 6 h. The mixture was cooled to room temperature and
concentrated in vacuo. The resulting residue was recrystallized
from hexane to aff◦ord the thiourea 11a as colorless crystals in 95%
Procedure for the preparation of N-ethyl-N¢-(pyridin-2-
yl)formohydrazide (8). A mixture of the triazolium salt 7 (235 mg,
1.0 mmol) and NaH (26.4 mg, 1.1 mmol) in THF (5.0 mL) was
stirred under a N2 atmosphere at room temperature for 30 min.
After the solid was filtered, the filtrate was evaporated under
vacuum and purified by column chromatography on silica gel
eluting with ethyl acetate/petroleum ether (1/2) to provide 8 in
78% yield under air. Single crystals suitable for X-ray◦analysis were
obtained in diethyl ether under -40 ◦C. Mp: 49–51 C; 1H NMR
(400 MHz, CDCl3): d = 1.18 (t, J = 7.2 Hz, 3H), 3.64 (q, J =
7.2 Hz, 2H), 6.60 (d, J = 8.4 Hz, 1H), 6.73–6.76 (m, 1H), 7.17 (br,
1H), 7.53–7.56 (m, 1H), 8.20 (d, J = 5.2 Hz, 1H), 8.33 (s, 1H);
13C NMR (150 MHz, CDCl3): d = 12.4, 39.8, 107.1, 116.4, 138.6,
149.1, 160.1, 165.8 (Note: The conformation of 8 is disordered in
crystal and in CDCl3.); MS (ESI+) m/z = 166 [M + H]+; Anal.
calcd for C8H11N3O: C, 58.17; H, 6.71; N, 25.44; Found: C, 58.01;
H, 6.80; N, 25.31.
1
yield. Mp: 59–60 C; H NMR (300 MHz, CDCl3): d = 1.43 (t,
J = 7.2 Hz, 3H), 4.40 (q, J = 7.2 Hz, 2H), 6.74 (t, J = 6.5 Hz, 1H),
7.20–7.35 (m, 2H), 8.28 (d, J = 7.1 Hz, 1H); 13C NMR (75 MHz,
CDCl3): d = 13.3, 44.9, 113.0, 115.1, 126.2, 130.7, 145.3, 158.5;
MS (ESI+) m/z = 181 [M + H]+; Anal. calcd for C8H9N3S: C,
53.61; H, 5.06; N, 23.44; S, 17.89. Found: C, 53.46; H, 5.23; N,
22.23; S, 17.70.
Procedure for the preparation of 2-ethylpyrido[1,2-c][1,2,4]-
triazol-3-selenone (11b). A mixture of the triazolium salt 7
(117.5 mg, 0.5 mmol) and NaH (13.2 mg, 0.55 mmol) in THF
(5.0 mL) was stirred under a N2 atmosphere at room temperature
for 30 min. After the solid was filtered, the filtrate was evaporated
under vacuum, and the resulting carbene 6 further reacted with
selenium (59 mg, 0.75 mmol) in toluene (5 mL) at reflux for 6 h. The
mixture was then cooled to room temperature and concentrated
in vacuo. The resulting residue was recrystallized from hexane to
afford th◦e selenone 11b as a pale yellow solid in 98% yield. Mp:
103–104 C; 1H NMR (400 MHz, CDCl3): d = 1.54 (t, J = 7.2 Hz,
3H), 4.58 (q, J = 7.2 Hz, 2H), 6.88 (t, J = 7.6 Hz, 1H), 7.37–7.48
(m, 2H), 8.51 (d, J = 7.1 Hz, 1H); 13C NMR (100 MHz, CDCl3):
d = 13.5, 46.5, 113.9, 114.9, 127.3, 131.3, 146.8, 152.0; MS (ESI+)
m/z = 227 [M + H]+; Anal. calcd for C8H9N3Se: C, 42.49; H, 4.01;
N, 18.58. Found: C, 42.30; H, 4.12; N, 18.16.
Procedure for the preparation of 1-ethylidene-2-(pyridin-2-
yl)hydrazine (9). A mixture of the triazolium salt 7 (235 mg,
1.0 mmol) and NaH (26.4 mg, 1.1 mmol) in THF (5.0 mL)
was stirred under a N2 atmosphere at room temperature for
30 min. After the solid was filtered, the filtrate was evaporated
under vacuum to afford the carbene 6. Pyrrolidine (0.71 g,
10 mmol) was then added at ambient temperature. The solution
was stirred at 80 ◦C for 10 h, and the excess pyrrolidine was then
removed in vacuo. The resulting residue was purified by column
chromatography on silica gel eluting with ethyl acetate/petroleum
ether (1/5) to provide 9 in 80% yield. Single crystals suitable for
X-ray analysis were obtained by slow evaporation of diethyl ether
solution. Mp: 57–60 ◦C; 1H NMR (400 MHz, CDCl3): d = 1.98 (d,
J = 5.6 Hz, 3H), 6.68–6.71 (m, 1H), 7.14–7.18 (m, 2H), 7.52–7.56
(m, 1H), 8.06–8.08 (m, 1H), 8.12 (br, 1H); 13C NMR (100 MHz,
CDCl3): d = 18.1, 106.9, 114.6, 137.8, 138.5, 146.9, 157.5 (Note:
Compound 9 is a mixture of (E)- and (Z)- isomers in CDCl3.); MS
(ESI+) m/z = 136 [M + H]+; Anal. calcd for C7H9N3: C, 62.20; H,
6.71; N, 31.09. Found: C, 62.11; H, 6.80; N, 30.97.
Procedure for the preparation of 2-ethyl-3-ethyl-pyrido[1,2-
c][1,2,4]-triazol-2-ium tetrafluoroborate (12). A mixture of the
triazolium salt 7 (235 mg, 1.0 mmol) and NaH (26.4 mg,
1.1 mmol) in THF (5.0 mL) was stirred under a N2 atmosphere
at room temperature for 30 min. After the solid was filtered,
the filtrate was evaporated under vacuum to afford the carbene
6. Triethyloxonium tetrafluoroborate (228 mg, 1.2 mmol) was
then added to a solution of 6 in 5 mL of CH2C12 at ambient
temperature. The solution was stirred for 3 h, and ethanol (1 mL)
was then added and the solvent was evaporated. To the residue
was added diethyl ether, and the generated crystals were collected
by filtration, washed with ether and dried in vacuo. The resulting
residue was recrystallized from hexane to afford 12 as colorless
crystals in 95% yield. Mp: 162–163 ◦C; 1H NMR (400 MHz,
DMSO-d6): d = 1.28 (t, J = 7.6 Hz, 3H), 1.50 (t, J = 7.2 Hz,
3H), 3.51 (q, J = 7.6 Hz, 2H), 4.61 (q, J = 7.2 Hz, 2H), 7.42 (t,
J = 6.8 Hz, 1H), 7.80 (q, J = 6.8 Hz, 1H), 8.03 (d, J = 9.6 Hz,
Procedure for the preparation of 3-((1Z,3E)-4-(1H-pyrrol-1-
yl)buta-1,3-dienyl)-1-ethyl-1H-1,2,4-triazole (10). A mixture of
the triazolium salt 7 (235 mg, 1.0 mmol) and NaH (26.4 mg,
1.1 mmol) in THF (5.0 mL) was stirred under a N2 atmosphere
at room temperature for 30 min. After the solid was filtered, the
filtrate was evaporated under vacuum to afford the carbene 6.
Pyrrole (335 mg, 5 mmol) was then added to 6 at room temperature.
The solution was stirred at 120 ◦C for 12 h, and the excess
pyrrole was then removed in vacuo. The resulting residue was
purified by column chromatography on silica gel eluting with ethyl
acetate/petroleum ether (1/2) to provide 10 as colorless crystal in
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1H), 8.83 (d, J = 7.2 Hz, 1H); 13C NMR (100 MHz, DMSO): d =
15.6, 19.4, 21.1, 51.5, 120.5, 122.7, 130.3, 138.4, 151.5, 152.0; MS
(ESI+) m/z = 176 [M - BF4]+; Anal. calcd for C10H14BF4N3: C,
45.66; H, 5.36; N, 15.97. Found: C, 45.36; H, 5.44; N, 15.81.
1H), 7.70 (d, J = 8.0 Hz, 2H), 8.30 (d, J = 6.4 Hz, 1H); 13C NMR
(100 MHz, CDCl3): d = 21.4, 124.2, 125.5, 127.2, 129.0, 129.1,
130.0, 139.7, 140.5, 149.4; MS (ESI+) m/z = 186 [M + H]+; HR-
MS (ESI) calcd for C12H11NO [M]+ 185.0841, found: 185.0813.
General procedure for synthesis of
1,3,7-trimethyl-8-(p-tolyl)-xanthine (23)
General procedure for synthesis of
N-hydroxy-N-phenylcinnamamide (13)17
A flame-dried Schlenk test tube with a magnetic stirring bar was
charged with Pd(OAc)2 (11.2 mg, 0.05 mmol), triazolium salt
(0.05 mmol), caffeine (97 mg, 0.5 mmol), 4-bromotoluene (172 mg,
1 mmol), K2CO3 (138 mg, 1 mmol) and anhydrous DMF (1 mL)
under N2. A rubber septum was replaced with a glass stopper,
and the system was then evacuated three times and backfilled
A flame-dried Schlenk tube with a magnetic stirring bar was
charged with nitrosobenzene (117 mg, 1.1 mmol), triazolium salt
(0.1 mmol) and dichloromethane (5 mL), followed by addition
of (E)-cinnamaldehyde (132 mg, 1mmol) and DBU (15 mL,
0.1 mmol). The reaction mixture was stirred at room temperature
for 10 min. The solvent was removed in vacuo, and the pure prod-
uct was obtained through flash silica gel column chromatography
of the residue using hexane and ethyl acetate as eluents. Mp: 162–
164 ◦C; 1H NMR (400 MHz, DMSO-d6): d = 7.18 (t, J = 7.2 Hz,
1H), 7.38–7.47 (m, 6H), 7.69–7.73 (m, 5H), 10.88 (s, 1H); 13C NMR
(50 MHz, DMSO-d6): d = 118.8, 121.2, 125.2, 128.2, 128.6, 129.1,
130.1, 135.1, 142.0, 142.4, 164.9; MS (ESI+) m/z = 223 [M - O]+;
Anal. calcd for C15H13NO2: C, 75.29, H, 5.48; N, 5.85. Found: C,
75.36; H, 5.43; N, 5.82.
◦
with N2. After being heated at 115 C for 22 hours, the reaction
mixture was allowed to cool to room temperature. The resulting
suspension was filtered through a plug of silica gel, and washed
with dichloromethane (20 mL). The filtrate was concentrated
under vacuum to a volume of about 2 mL. The mixture was
absorbed on silica gel and subjected to flash chromatography
eluting using ethyl acetate/petroleum ether (3/2) to provide the
desired product 23. Mp: 193–194 ◦C; 1H NMR (400 MHz, CDCl3):
d = 2.43 (s, 3H), 3.43 (s, 3H), 3.62 (s, 3H), 4.04 (s, 3H), 7.32 (d,
J = 8.0 Hz, 2H), 7.56 (d, J = 8.0 Hz, 2H); 13C NMR (100 MHz,
CDCl3): d = 21.5, 28.0, 29.8, 33.9, 108.5, 125.5, 129.1, 129.6, 140.7,
148.3, 151.8, 152.4, 155.6; MS (AP) m/z: 285 [M + H]+; HR-MS
(ESI) calcd for C15H17N4O2 [M+H]+ 285.1352, found: 285.1346.
General procedure for the catalytic cinnamaldehyde addition to
nitrone (19)19
To a Schlenk tube equipped with a magnetic stirrer were added
triazolium salt (0.04 mmol), (Z)-N-benzylideneaniline oxide
(158 mg, 0.8 mmol) and CH2Cl2 (4 mL) under a N2 atmosphere
at room temperature. The mixture was then cooled to 0 ◦C,
followed by addition of cinnamaldehyde (50 mL, 0.4 mmol) and
dry freshly distilled DBU (6 mL, 0.04 mmol). After the mixture
was stirred for 2 days, NaOMe (0.4 mL, 1.0 M in MeOH) was
added via syringe. The mixture was then diluted with diethyl
ether and filtered. The filtrate was concentrated in vacuo, and
the resulting residue was purified by column chromatography on
silica gel eluting with diethyl ether/hexane (1/9) to afford methyl
4-(hydroxy(phenyl)amino)-3,4-diphenylbutanoate 19 as a yellow
solid. Mp: 89–95 ◦C (decomposed); 1H NMR (600 MHz, CDCl3):
d = 2.53 (s, 2H), 3.46 (s, 3H), 4.22 (s, 1H), 4.74 (s, 1H), 4.88 (s, 1H),
6.85 (s, 3H), 7.11–7.44 (m, 12H); 13C NMR (100 MHz, CDCl3):
d = 38.5, 43.9, 51.2, 74.7, 117.0, 121.4, 124.1, 126.3, 127.0, 127.6,
128.0, 129.1, 129.5, 135.3, 141.8, 151.0, 171.9; MS (ESI+) m/z =
362 [M + H]+; IR (film) 3531, 3061, 3024, 2955, 2941, 1737, 1488,
1267 cm-1.
Acknowledgements
This work was supported by grants from the National NSF of
China (Nos. 20772086 and 20602027). We also thank the Centre
of Testing and Analysis, Sichuan University for NMR, MS,
Elemental Analysis and X-ray crystal measurements.
Notes and references
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A flame-dried Schlenk test tube with a magnetic stirring bar
was charged with K2CO3 (138 mg,1 mmol), triazolium salt
(0.05 mmol), Pd(OAc)2 (11.2 mg, 0.05 mmol), pyridine N-oxide
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1
product 21. Mp: 129–131 C; H NMR (400 MHz, CDCl3): d =
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4246 | Org. Biomol. Chem., 2009, 7, 4241–4247
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The Royal Society of Chemistry 2009
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g = 90 , U = 723.0(5) A , Z = 4, Dc = 1.242 g cm , F000 = 288, Mo-Ka
radiation, l = 0.71073 A, T = 294(2) K, 1408 reflections collected, 1288
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0.56 ¥ 0.48 ¥ 0.42 mm3, monoclinic, space group P21/c, a = 13.5774(4),
◦
˚
b = 7.9769(2), c = 22.4305(6) A, a =90, b = 106.670(3), g =90 , U =
3
-3
˚
2327.25 A , Z = 8, Dc = 1.223 g cm , F000 = 912, Cu-Ka radiation,
˚
l = 1.54184 A, T = 100(2) K, 6159 reflections collected, 3133 unique
(Rint = 0.0170). R indices (all data) R1 = 0. 0.0405, wR2 = 0.1229,
Final GooF = 1.033, R1 = 0.0349, wR2 = 0.1187, R indices based on
2750 reflections with I >2s(I) (refinement on F2), 289 parameters, 0
restraints. Lp and absorption corrections applied, m = 0.612 mm-1.
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¨
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25 G. M. Scheldrick, SHELX-97 and SHELXL-97, Program for Solution
and Refinement of Crystal StructuresUniversity of Go¨ttingen: Germany,
1997.
13 Crystal data for 8: C8H11N3O, M = 165.20, orange block, 0.42 ¥ 0.40 ¥
3
¯
0.26 mm , triclinic, space group P1, a = 9.825(4), b = 10.199(4), c =
◦
3
˚
˚
10.461(4) A, a = 62.00(3), b = 73.41(4), g = 83.80(4) , U = 886.5(6) A ,
Z = 4, Dc = 1.238 g cm-3, F000 = 352, Mo-Ka radiation, l = 0.71073 A,
˚
T = 294(2) K, 3669 reflections collected, 3258 unique (Rint = 0.0065). R
indices (all data) R1 = 0.1664, wR2 = 0.1155, Final GooF = 0.962, R1 =
0.0472, wR2 = 0.0948, R indices based on 1362 reflections with I >2s(I)
(refinement on F2), 246 parameters, 12 restraints. Lp and absorption
corrections applied, m = 0.086 mm-1. Crystal data for 9: C7H9N3, M =
135.17, orange block, 0.42 ¥ 0.40 ¥ 0.20 mm3, monoclinic, space group
26 A. L. Spek, PLATON. A Multipurpose Crystallographic Tool, Utrecht
˚
P21/c, a = 5.329(3), b = 9.235(2), c = 14.718(4) A, a = 90, b = 93.53(3),
University, Utrecht, The Netherlands, 2001.
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The Royal Society of Chemistry 2009
Org. Biomol. Chem., 2009, 7, 4241–4247 | 4247
©