Trimethoxyarene as a highly ionizable tag for reaction analysis by atmospheric pressure photoionization mass spectrometry (APPI/MS): Exploration of heterocyclic synthesis

Article abstract of DOI:10.1002/ejoc.201100919

A mass spectrometry (MS) method was developed to rapidly analyze crude reaction mixtures. This method relies on highly effective ionization by atmospheric pressure photoionization (APPI) of molecules with a prosthetic trimethoxyarene (TMOA) residue. In a

Full text of DOI:10.1002/ejoc.201100919

FULL PAPER
DOI: 10.1002/ejoc.201100919
Trimethoxyarene as a Highly Ionizable Tag for Reaction Analysis by
Atmospheric Pressure Photoionization Mass Spectrometry (APPI/MS):
Exploration of Heterocyclic Synthesis
Mathieu Bui The Thuong,[a,b] Cédric Catala,[b] Cyril Colas,[c] Christine Schaeffer,[c]
Alain Van Dorsselaer,[c] André Mann,[a] and Alain Wagner*[d]
Keywords: Heterocycles / Mass spectrometry / Reaction mechanisms / Trimethoxyarenes
A mass spectrometry (MS) method was developed to rapidly
analyze crude reaction mixtures. This method relies on
highly effective ionization by atmospheric pressure photo-
ionization (APPI) of molecules with a prosthetic trimethoxy-
arene (TMOA) residue. In a crude reaction mixture, products
resulting from the reaction of the TMOA-labeled substrate
will be selectively ionized to afford an easily readable mass
spectrum. Interestingly, we noticed that TMOA-labeled mo-
lecules were not fragmented and gave the preferred [M +
H]+ ion peak. This APPI-MS reaction mixture analysis
method was used for the optimization of heterocycle synthe-
sis. By comparing results obtained by APPI/MS, GC, and
HPLC analysis, it appeared that a semi-quantification could
be achieved by integrating the MS peak intensities.
rapidly evaluating the composition of crude reaction mix-
ture, a vital information for reaction optimization.
One valuable technique that has been developed is atmo-
spheric pressure photoionization (APPI) coupled to MS,
which enables the analysis of mixtures of nonpolar and low-
molecular-mass compounds; a feature frequently found in
organic synthesis.[8] Previously, the groups of Chen[8d,8g]
and Wilson[8h,8i] demonstrated that labeling a catalyst or
biomolecule with an ionizable prosthetic cation or with an
ionophore was a valuable tool for detecting the catalyst or
biomolecule by using a combination of electrospray ioniza-
tion and MS (ESI-MS). Herein, we report on the use and
validation of APPI-MS as a tool to rapidly monitor organic
reactions by using tagged substrates. We have used tri-
methoxybenzene as a tag that significantly enhanced the
MS sensitivity and enabled us to obtain an overview of the
various adducts formed at the expense of the labeled sub-
strates.
Introduction
High-throughput analytical methods[1] based on IR ther-
mography,[2] fluorescence,[3] colorimetric assays,[4] immuno-
assay,[5] mass spectrometry (MS) analysis,[6] have been de-
veloped to monitor chemical reactions and catalysts. These
methods are very powerful and are well suited for the
screening of large numbers of similar reactions; however,
they are less proficient for evaluating multistep organic re-
actions. For instance, they often cannot distinguish between
products, byproducts, and molecules resulting from decom-
position of the starting chemicals. Consequently, these
methods appear to be tailored to optimize high-value in-
dustrial reactions, but are less flexible to deal with a wide
variety of chemical reactions.
To address this particular problem, more suitable and
versatile methods have been developed by using equipment
available in chemical laboratories. For example, serial and
fast analytical methods (such as TLC, GC, and HPLC) can
identify products and/or quantify yields.[7] These methods
aim to facilitate the routine work of organic chemists by
Results and Discussion
APPI is used as a soft ionization technique that, under
given conditions, preferentially generates [M + H]+ ions by
proton transfer and minimizes fragmentation.[8] Unfortu-
nately, when using this method to quantitatively analyze
crude reaction mixtures, the chemical properties of the ana-
lytes and the presence of reagents or catalysts can affect the
analysis of the different products.
To overcome these limitations, we decided to label one
of the reaction partners with a molecular tag compatible
with the APPI ionization source. After testing a large vari-
ety of molecules, including polyaromatics, natural products,
[a] Laboratoire d’Innovation Thérapeutique, UMR 7200,
CNRS – Université de Strasbourg,
74 route du Rhin, 67401 Illkirch, France
[b] Novalix,
Bld. Sébastien Brant, 67405 Illkirch, France
[c] Laboratoire de Spectrométrie de Masse Bio-Organique IPHC-
DSA, Université de Strasbourg, CNRS, UMR 7178,
Strasbourg, France
[d] Laboratoire des Systèmes Chimiques Fonctionnels, Université
de Strasbourg, CNRS, UMR 7199,
74 route du Rhin, 67401 Illkirch, France
E-mail: wagner@bioorga.u-strasbg.fr
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100919.
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A. Wagner et al.
FULL PAPER
heterocycles, and synthetic intermediates, we found that the
1,3,5-trimethoxyarene (TMOA) fragment was highly sensi-
tive to APPI ionization and provided intense ions due to its
high proton affinity, relative to the other compounds
tested.[9] To facilitate the introduction of the TMOA label,
alkyl spacers were attached to the substrates under study.
TMOA handles (TAG-Br, TAG-CH2Br) were obtained by
BuLi deprotonation of 1,3,5-trimethoxybenzene followed
by reaction with an excess of 1,5-dibromopentane or 1,6-
dibromohexane (Scheme 1). This approach is rapid and
easy to implement because the crude mixture is injected
into the MS device without any prior treatment.
Scheme 1. Reagents and conditions: (a) nBuLi, 0 °C, THF, 1 h; (b)
1,6-dibromohexane; (c) 1,5-dibromopentane; (d) NaH, DMF,
–10 °C, then 4-bromobutynol, –10 °C, 1 h; (e) NaH, DMF, 0 °C,
then 4-iodophenol, 80 °C, 16 h; (f) abietic acid, Cs2CO3, DMF.
To validate this approach, native abietic acid and TAG-
abietic were submitted to APPI-MS analyses (Figure 1).
Abietic acid was selected as a nonpolar and low-molecu-
lar-weight compound (MW = 538 Da) to represent routine
adducts encountered in organic synthesis. Thus, both native
abietic acid and TAG-abietic ester were analyzed by APPI-
MS under our optimized conditions. Interestingly, the
TMOA-labeled molecule was detected as a single intense
[M + H]+ ion at m/z 539, whereas the native compound
yielded a complex picture of peaks from which the molecu-
lar ion was absent.[9] Interestingly, Wilson and Wu reported
comparable observations with vitamin D3 labeled with a
crown ether when using ESI-MS detection in diluted condi-
tions.[8i]
Next, TMOA tags were evaluated in a commonly used
chemical transformation: the Sonogashira coupling. The
performance of the APPI-MS method was compared with
other analytical methods (HLPC or GC). The tagged al-
kyne substrate 1 (MW = 320 Da) was prepared by treating
TAG-CH2Br with 4-bromobutynol. The Sonogashira reac-
tion was then performed with iodobenzene in presence of
several additives in THF at 50 °C (Table 1).
Figure 1. APPI-MS analysis of (a) abietic acid and (b) TAG-abietic.
Spectra were recorded by flow injection analysis (1 μL sample at
5ϫ10–4 m sample injection) of samples in a mixture of MeOH/
toluene (8:2). Both mass spectra are on the same absolute intensity
scale.
Table 1. Comparison of the yields of the Sonogashira reaction by
APPI-MS, HPLC and GC.
Entry[a] Additive
Yield [%][b]
HPLC
GC
APPI-MS[c]
1
2
3
4
5
CuBr
CuCl
CuI
Cu2O
Ag2CO3
44
43
40
60
8
43
43
44
55
11
42
43
45
61
12
[a] Conditions: 1 (1 equiv.), iodobenzene (1.2 equiv.), [Pd(PPh3)2-
Cl2] (0.04 equiv.), additive (0.1 equiv.), THF/aqueous NH3, 50 °C,
12 h. [b] The yields were determined by the ratio of the area of
the selected peak to the total area of all peaks. [c] Representative
procedure for APPI/MS analyses: a sample of the crude mixture
(9 μL) was added to a mixture of MeOH/toluene (991 μL 8:2) to
give a final concentration of 5ϫ10–4 m (based on starting material),
To determine the conversion of the reaction with the
APPI-MS method, aliquots of the crude reaction mixture
were infused directly in the MS without prior purification.
It was anticipated that only the tagged compounds (1, 3,
and side products, if any were present) would respond then an aliquot (5 μL) was injected into the mass spectrometer.
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Trimethoxyarene as a Tag for Reaction Analysis
strongly to the APPI analysis. In these experiments the addition of 5 to the acylpalladium intermediate derived
yields were not optimized and the reactions were stopped from 2. The structure of 8 was unambiguously confirmed
before completion. Indeed the mass spectrum displayed by synthesis followed by NMR spectroscopic analysis.[9,11]
only two peaks at m/z 321 and 397, which corresponded to Interestingly, the ability to detect unexpected side products
starting protonated alkyne 1 and to the protonated Sonoga- by APPI-MS/TMAO analysis may provide a hint to under-
shira adduct 3 (MW = 396 Da), respectively. Interestingly, stand the failure of the one-pot, four-component reaction
a peak at m/z 640 could be detected in all crude reaction (Figure 3).
mixtures and corresponded to a small amount of the diyne
formed by the homocoupling of 1. The peak ratio 1/3 is
directly correlated to the chemical conversion of 1 and to
the yield of 3. These results agreed with HPLC and GC
analyses of the respective reaction aliquots (Table 1). As ex-
pected, CuI was an excellent additive with respect to AgI
(44–60% yield with CuI, 8% with AgI). Thus, excellent cor-
Figure 3. Structure of 8, a side product obtained in the four-com-
ponent sequence with 5 as the nucleophile.
relations were found among the three methods, even for the
low conversion with AgI. To evaluate the application of the
APPI/MS-TMOA analytic method for the optimization of
Therefore, we decided to use a sequential two-step pro-
elaborated chemical reactions, we decided to focus on the cedure for dinucleophiles 5–7. First, ynone 9a was prepared
syntheses of N-heterocycles. To extend the scope of Mori’s by a carbonylative Sonogashira reaction (2, alkyne, CO)
one-pot, four-component pyrazole synthesis[10] to other and submitted reaction with dinucleophiles 4–7 for the het-
class of heterocycles, we substituted the hydrazine with erocyclization step under various reaction conditions (Fig-
other nitrogen dinucleophiles, such as phenylamidine (5), ure 4). The reaction mixtures were first analyzed by APPI-
aminopyrazole (6), aminobenzimidazole (7) (Figure 2).
MS using our optimized protocol and the tagged heterocy-
clic adducts 10a–13a were identified by their corresponding
[M + H]+ ions. The yields were evaluated by the ratio of
the intensity of the expected isotopic mass of the compound
with the sum of the intensity of all detected peaks. The re-
sults are depicted in Figure 4 by using a color code to indi-
cate the percentage yield of each reaction. As expected, re-
actions with nucleophile 4 proceeded successfully in all con-
ditions. Reactions with 5 and 6 gave satisfactory yields with
K2CO3 in neat conditions or in a mixture of THF/H2O.
The condensation of 9a with 7 showed a strong solvent de-
pendency: the cyclodehydration went to completion in
THF/H2O, but did not proceed in CH2Cl2.
Figure 2. Mori’s multicomponent reaction with a series of dinucleo-
philes.[10]
To confirm the accuracy of the APPI-MS/TMOA
In this one-pot reaction, the formation of ynone 9a by method, the crude reaction mixtures were also analyzed by
alkynylcarbonylation, assisted by Pd0, was expected to pro- 1H NMR spectroscopy (Figure 4, right box). A comparison
ceed in situ and to directly react with the dinucleophilic of the estimated yields obtained by APPI-MS and 1H NMR
reagent through Michael addition. Further dehydration spectroscopy revealed good overall consistency. Nucleo-
should deliver the expected heterocycles of type I. Thus, phile 6 was the exception (Figure 4): the yield of the forma-
compounds 2, 3, and 4 were treated with [PdCl2(PPh3)2] tion of pyrazolo-pyrimidine 12a was slightly overestimated
and CuI in a mixture of THF/H2O (1:1) under a blanket of by APPI-MS (APPI-MS indicated 38% yield of 12a,
CO. By using a modification of Mori’s procedure,[9] pyr- whereas a yield of 15% was determined by H NMR spec-
1
azole 10a (Figure 2) was identified by APPI-MS in the troscopy). Indeed, the presence of a basic site seems to en-
crude reaction mixture in 95% yield. Purification by col- hance the proton affinity of the substrate, and therefore,
umn chromatography afforded the product in 79% yield yields a higher peak in APPI-MS. Nevertheless, the results
and NMR spectroscopic analysis confirmed the structure obtained demonstrate that the APPI-MS/TMOA method is
of pyrazole 10a contaminated with a regioisomer (less than a reliable and rapid tool for determining optimal productive
5%).
reaction conditions.
Next, the one-pot, four-component reaction was at-
Finally, for each dinucleophile of 4–7, the most efficient
tempted with dinucleophiles 5, 6, and 7. However, unknown reaction conditions were selected and applied to the unlab-
products were observed, for instance, MS analysis of the eled ynone 9b (R = Me instead of R = TAG). Adducts 10b,
crude mixture for the reaction with 5 did not lead to the 11b, 12b, and 13b were isolated by column chromatography
1
expected pyrimidine adduct 11a (Figure 4), but produced a and analyzed by H NMR spectroscopy. As expected, high
[M + H]+ ion at m/z 477, corresponding to a molecular yields were obtained in all cases. It is noteworthy that 10b
mass at 476 Da. The latter was attributed to acylbenzamid- and 12b were contaminated by regioisomers 10bЈ (10b/10bЈ:
ine 8, which was obtained as a consequence of the direct 95:5) and 12bЈ (12b/12bЈ: 90:10) and they could be sepa-
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87

A. Wagner et al.
FULL PAPER
Figure 4. Screening of cyclodehydration reaction conditions. Synthesis of heterocycles 10b, 11b, 12b, and 13b. Conditions: the reagents
are indicated above the arrows; the duration of the carbonylation is 24 h at room temp. and 48 h at 50 °C for the heterocyclization. For
easy readability, yields are indicated by using a color code: red for yields Ͻ 25%, orange for yields between 25 and 50%, blue for yields
between 51% and 75%, and green for yields above 76%.
NMR spectra were recorded on Bruker spectrometers (400 and
100, 300 and 75, and 200 and 50 MHz, respectively). Conditions
are specified for each spectrum (temperature 25 °C unless speci-
fied). Splitting patterns are designated as s, singlet; d, doublet; t,
triplet; q, quartet; quint, quintet; m, multiplet. Chemical shifts (δ)
are given in ppm relative to the resonance of their respective resid-
ual solvent peak, CHCl3 (δ = 7.27 ppm, 1H; 77.16 ppm, the middle
peak, 13C). IR spectra were recorded with a Nicolet 380 FTIR spec-
trometer. High-resolution mass spectroscopy analyses were con-
ducted by the Institut Fédératif de Recherche 85 at the University
of Strasbourg, and low-resolution APPI mass spectrometry analy-
ses were conducted by Novalix. APPI-MS experiments were carried
out by using a MSD mass spectrometer equipped with an APPI
source (Agilent Technologies) and a quadrupole mass analyzer.
High-resolution mass spectra were obtained with a Bruker Micro-
TOF-Q (ESI q-TOF, positive ion) spectrometer. Melting points
were determined on a Büchi Melting Point B-540 apparatus in open
capillary tubes.
rated by chromatography. In contrast, the reaction of 9b
with 7 afforded 13b as a single regioisomer. Ynones have
been largely used with methylhydrazine and benzamidine
for the construction of combinatorial libraries of pyr-
azoles[12] and pyrimidines,[13] whereas the reactions between
ynone and 2-aminobenzimidazole or 3-aminopyrazole have
scarcely been described.[14] The APPI-MS/TMOA method
has enabled us to successfully and rapidly optimize the reac-
tion conditions of these reactions.
Conclusions
The TMOA fragment was identified as a label with a
high ionization potential. Therefore, when a substrate was
tagged with TMOA, chemical transformations could be fol-
lowed conveniently by MS/APPI and applications towards
the syntheses of heterocycles were developed. Other benefits
of the procedure are (i) the direct overview of the composi-
tion and conversion (semiquantitative yield) of crude reac-
tion mixtures and (ii) the detection of side products. Fur-
ther studies are currently ongoing towards the development
of a second-generation tag with an improved selectivity of
ionization for the APPI-MS mode.
2-(6-Bromohexyl)-1,3,5-trimethoxybenzene (TAG-CH2Br): 1.6 m
nBuLi (8.9 mL, 14.2 mmol, 1.2 equiv.) was added to a solution of
1,3,5-trimethoxybenzene (2.00 g, 11.9 mmol, 1 equiv.) in THF
(60 mL) at 0 °C under an argon atmosphere. The reaction mixture
was stirred for 30 min at 0 °C then for 1 h at room temperature.
1,6-Dibromohexane (5.4 mL, 35.7 mmol, 3 equiv.) was added at
0 °C and the reaction mixture was stirred at 0 °C for 30 min and
for 1 h at room temperature. Water (15 mL) and ethyl acetate
(15 mL) were added and the aqueous layer was extracted with ethyl
acetate (3ϫ15 mL). The combined organic layers were dried with
Na2SO4, filtered, and evaporated under reduced pressure. Excess
1,6-dibromohexane was removed by distillation. The residue was
purified by column chromatography on silica gel (pentane/ethyl
acetate, 97:3) to give TAG-CH2Br as a colorless solid (3.4 g, 86%);
m.p. 58–59 °C. 1H NMR (CDCl3, 300 MHz): δ = 6.20 (s, 2 H), 3.83
(s, 3 H), 3.80 (s, 6 H), 3.48 (t, J = 6.7 Hz, 2 H), 2.57 (t, J = 6.9 Hz,
Experimental Section
General: All reagents were used as purchased from commercial sup-
pliers without further purification. Solvents were dried and purified
by conventional methods prior to use. THF was freshly distilled
from sodium/benzophenone and dichloromethane was distilled
from CaH2. Flash column chromatography was performed with
Merck silica gel 60, 0.040–0.063 mm (230–400 mesh). Merck alumi-
num-backed plates precoated with silica gel 60 (UV254) were used
2 H), 1.89–1.46 (m, 6 H) ppm. IR (neat): ν = 2955, 2928, 2854,
˜
2836, 1590 cm–1. HRMS (ESI): calcd. for C15H23BrO3 [M + H]+
331.0908; found 331.0912.
for TLC and were visualized by staining with KMnO4. 1H and 13
C
88
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Trimethoxyarene as a Tag for Reaction Analysis
2-(5-Bromopentyl)-1,3,5-trimethoxybenzene (TAG-Br): 1.6 m nBuLi
(8.9 mL, 14.2 mmol, 1.2 equiv.) was added to a solution of 1,3,5-
trimethoxybenzene (2.00 g, 11.9 mmol, 1 equiv.) in THF (60 mL)
at 0 °C under an argon atmosphere. The reaction mixture was
stirred for 30 min at 0 °C then for 1 h at room temperature. 1,5-
Dibromopentane (4.8 mL, 35.7 mmol, 3 equiv.) was added at 0 °C
and the reaction mixture was stirred at 0 °C for 30 min and for 1 h
at room temperature. Water (15 mL) and ethyl acetate (15 mL) were
added and the aqueous layer was extracted with ethyl acetate
2-[5-(4-Iodophenoxy)pentyl]-1,3,5-trimethoxybenzene (2): NaH
(60%) (607 mg, 15.1 mmol, 1.2 equiv.) was added to a solution of
4-iodophenol (3.34 g, 15.1 mmol, 1.2 equiv.) in DMF (45 mL) at
0 °C under an argon atmosphere. The reaction mixture was stirred
for 10 min at room temperature and then TAG-Br (4.0 g,
12.6 mmol, 1 equiv.) was added. The reaction mixture was stirred
at 80 °C overnight. Water (25 mL) and ethyl acetate (25 mL) were
added and the aqueous layer was extracted with ethyl acetate
(3ϫ20 mL). The combined organic layers were dried with Na2SO4,
(3ϫ15 mL). The combined organic layers were dried with Na2SO4, filtered, and evaporated under reduced pressure. The residue was
filtered, and evaporated under reduced pressure. Excess 1,5-di-
bromopentane was removed by distillation. The residue was puri-
fied by column chromatography on silica gel (pentane/ethyl acetate,
97:3) to give TAG-Br as a colorless solid (2.79 g, 74%); m.p. 49–
50 °C. 1H NMR (CDCl3, 300 MHz): δ = 6.14 (s, 2 H), 3.81 (s, 3
H), 3.80 (s, 6 H), 3.42 (t, J = 6.8 Hz, 2 H), 2.57 (t, J = 6.8 Hz, 2
H), 1.91 (quint, 3J = 6.8 Hz, 2 H), 1.48–1.46 (m, 4 H) ppm. 13C
NMR (CDCl3, 75 MHz): δ = 159.2, 158.8, 111.5, 90.6, 55.7, 55.4,
purified by column chromatography on silica gel (pentane/ethyl
acetate, 8:2) to give 2 as white crystals (4.61 g, 80%); m.p. 86–87 °C.
3
1H NMR (CDCl3, 300 MHz): δ = 7.54 (d, J = 8.7 Hz, 2 H), 6.67
3
(d, 3J = 8.7 Hz, 2 H), 6.13 (s, 2 H), 3.91 (t, J = 6.8 Hz, 2 H), 3.81
3
3
(s, 3 H), 3.79 (s, 6 H), 2.58 (t, J = 7.0 Hz, 2 H), 1.80 (quint, J =
6.8 Hz, 2 H), 1.50–1.46 (m, 4 H) ppm. 13C NMR (CDCl3,
75 MHz): δ = 159.2, 158.9, 138.2, 117.0, 111.6, 90.6, 82.4, 68.3,
3
3
55.7, 55.4, 29.2, 29.1, 25.9, 22.4 ppm. IR (neat): ν = 2935, 2836,
˜
34.2, 32.8, 28.6, 28.2, 22.2 ppm. IR (neat): ν = 2955, 2928, 2854,
1588 cm–1. HRMS (ESI): calcd. for C20H26IO4 [M + H]+ 457.0870;
found 457.0879.
˜
2836, 1590 cm–1. HRMS (ESI): calcd. for C14H21BrO3 [M + H]+
317.0747, 319.0728; found 319.0734.
1,3,5-Trimethoxy-2-{6-[(4-phenylbut-3-ynyl)oxy]hexyl}benzene (3):
5-(2,4,6-Trimethoxyphenyl)pentyl Abieta-7,13-dien-18-oate (TAG-
abietic): Cs2CO3 (487 mg, 1.5 mmol, 1.5 equiv.) was added to a
solution of abietic acid (453 mg, 1.5 mmol, 1.5 equiv.) in DMF
(5 mL) at 0 °C under argon atmosphere. The mixture was stirred
for 5 min at room temperature and then TAG-Br (316 mg, 1 mmol,
1 equiv.) was added at 0 °C. The mixture was stirred during 6 h at
0 °C and 1.5 h at 80 °C. The reaction was quenched by the addition
of water and the mixture was extracted with ethyl acetate. The com-
bined organic layers were washed with brine, dried with Na2SO4,
filtered, and evaporated under reduced pressure. The residue was
purified by column chromatography on silica gel (cyclohexane/ethyl
acetate, 95:5) to give TAG-abietic as a waxy oil (219 mg, 40%). 1H
NMR (CDCl3, 400 MHz): δ = 6.13 (s, 2 H), 5.77 (s, 1 H), 5.37 (m,
1 H), 4.02 (m, 2 H), 3.81 (s, 3 H), 3.79 (s, 6 H), 2.55 (t, 3J = 7.6 Hz,
2 H), 2.30–1.10 (m, other aliphatic protons), 1.27 (s, 3 H), 1.02 (d,
Compound 3 was obtained as an orange oil by following the condi-
tions described in Table 1. H NMR (CDCl3, 300 MHz): δ = 7.40
1
(m, 2 H), 7.28 (m, 3 H), 6.13 (s, 2 H), 3.81 (s, 3 H), 3,79 (s, 6 H),
3
3
3
3.63 (t, J = 7.2 Hz, 2 H), 3.49 (t, J = 6.7 Hz, 2 H), 2.69 (t, J =
3
7.2 Hz, 2 H), 2.55 (t, J = 7.3 Hz, 2 H), 1.63–1.53 (m, 2 H), 1.36–
1.44 (m, 6 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 159.1, 158.9,
131.7, 128.3, 127.8, 123.8, 112.1, 90.6, 87.0, 81.5, 71.4, 69.1, 55.7,
55.4, 29.8, 29.6, 26.1, 22.5, 20.9 ppm. HRMS (ESI): calcd. for
C25H33O4 [M + H]+ 397.2373; found 397.2374.
N-[Imino(phenyl)methyl]-4-{[5-(2,4,6-trimethoxyphenyl)pentyl]-
oxy}benzamide (8): [PdCl2(PPh3)2] (7.5 mg, 0.01 mmol, 0.05 equiv.),
H2O (1.5 mL), K2CO3 (91 mg, 0.6 mmol, 3 equiv.), and 5 (68 mg,
0.4 mmol, 2 equiv.) were added successively to a solution of 2
(100 mg, 0.2 mmol, 1 equiv.) in THF (1.5 mL). Carbon monoxide
was bubbled through the solution and the reaction was stirred for
36 h under an atmosphere of carbon monoxide (balloon filled with
carbon monoxide) at room temperature. Water was added and then
the mixture was extracted with ethyl acetate, the combined organic
layers were dried with Na2SO4, filtered, and evaporated under re-
duced pressure. The residue was purified by column chromatog-
raphy on silica gel (cyclohexane/ethyl acetate, 7:3) to give 8 as white
solid (59 mg, 56 %); m.p. 117–119 °C. 1H NMR (CDCl3,
3
3J = 6.8 Hz, 3 H), 1.00 (d, J = 6.8 Hz, 3 H), 0.83 (s, 3 H) ppm.
13C NMR (CDCl3, 100 MHz): δ = 178.6, 159.2, 158.9, 145.2, 135.5,
122.6, 120.9, 111.7, 90.6, 64.8, 55.7, 55.4, 51.0, 46.6, 45.2, 38.4,
37.2, 35.0, 34.6, 29.1, 28.5, 27.5, 25.8, 25.7, 22.6, 22.3, 21.5, 20.9,
18.3, 17.1, 14.1 ppm. IR (neat): ν = 2931, 2835, 1717, 1593 cm–1.
˜
HRMS (ESI): calcd. for C34H50O5 for [M + H]+ 539.3731; found
539.3726.
2-[6-(But-3-ynyloxy)hexyl]-1,3,5-trimethoxybenzene
(1):
NaH
3
3
400 MHz): δ = 8.34 (d, J = 8.8 Hz, 2 H), 8.03 (d, J = 8.8 Hz, 2
(60wt.-%, 1.45 g, 36.2 mmol, 1.2 equiv.) was added to a solution of
3-butyn-1-ol (2.51 mL, 33.2 mmol, 1.1 equiv.) in DMF (200 mL) at
–10 °C under argon atmosphere. The reaction mixture was stirred
for 1 h at –10 °C and then TAG-CH2-Br (10.0 g, 30.1 mmol,
1 equiv.) was added. The reaction mixture was stirred at –10 °C for
1 h. Water (200 mL) and ethyl acetate (200 mL) were added and
the aqueous layer was extracted with ethyl acetate (3ϫ200 mL).
The combined organic layers were dried with MgSO4, filtered, and
evaporated under reduced pressure. The residue was purified by
column chromatography on silica gel (cyclohexane/ethyl acetate,
98:2) to give 1 as a white solid (4.2 g, 44%); m.p. 51–52 °C. 1H
3
3
H), 7.58 (d, J = 8.8 Hz, 2 H), 7.50 (d, J = 7.6 Hz, 2 H), 6.94 (d,
3J = 8.8 Hz, 2 H), 6.14 (s, 2 H), 4.04 (t, J = 6.5 Hz, 2 H), 3.81 (s,
3
3 H), 3.79 (s, 6 H), 2.61 (t, 3J = 6.8 Hz, 2 H), 1.85 (quint, 3J =
6.5 Hz, 2 H), 1.53–1.51 (m, 4 H) ppm. 13C NMR (CDCl3,
75 MHz): δ = 180.1, 166.2, 162.7, 159.1, 158.8, 135.4, 132.3, 131.8,
130.2, 128.9, 127.5, 113.9, 111.7, 90.6, 68.3, 55.7, 55.4, 29.2, 29.1,
26.0, 22.4 ppm. IR (neat): ν = 3338, 2930, 2849, 2358, 1592, 1543
˜
cm–1. HRMS (ESI): calcd. for C28H32N2O5 [M + H]+ 477.2384;
found 477.2386.
1-(4-{[5-(2,4,6-Trimethoxyphenyl)pentyl]oxy}phenyl)oct-2-yn-1-one
NMR (CDCl3, 400 MHz): δ = 6.13 (s, 2 H), 3.81 (s, 3 H), 3, 79 (s, (9a): [PdCl2(PPh3)2] (138 mg, 0.19 mmol, 0.03 equiv.), H2O
3
3
6 H), 3.55 (t, J = 7.0 Hz, 2 H), 3.45 (t, J = 6.6 Hz, 2 H), 2.54 (t, (20 mL), Et3N (2.7 mL, 19.5 mmol, 3 equiv.), and 1-heptyne
3J = 7.6 Hz, 2 H), 2.47 (dt, J = 7.2, J = 2.6 Hz, 2 H), 1.98 (t, J
(1.7 mL, 13.1 mmol, 2 equiv.) were added successively to a solution
3
4
4
= 2.6 Hz, 1 H), 1.62–1.55 (m, 2 H), 1.47–1.39 (m, 2 H), 1.36–1.34 of 2 (3.0 g, 6.5 mmol, 1 equiv.) in CH2Cl2 (20 mL). Carbon mon-
(m, 4 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 159.1, 158.9, oxide was bubbled through the solution and the reaction was
112.1, 90.7, 81.6, 71.4, 69.3, 68.8, 55.8, 55.4, 29.7, 29.6, 26.0, 22.5, stirred for 24 h under an atmosphere of carbon monoxide (balloon
20.0 ppm. HRMS (ESI): calcd. for C19H29O4 [M + H]+ 321.2060;
found 321.2072.
filled with carbon monoxide) at room temperature. Water was
added and then the mixture was extracted with ethyl acetate, the
Eur. J. Org. Chem. 2012, 85–92
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
89

A. Wagner et al.
FULL PAPER
combined organic layers were dried with Na2SO4, filtered, and
evaporated under reduced pressure. The residue was purified by
column chromatography on silica gel (cyclohexane/ethyl acetate,
9:1) to give 9a as a red oil (2.8 g, 94 %). 1H NMR (CDCl3,
2856, 1610, 1596, 1495, 1455, 1432, 1249, 1149, 1138 cm–1. HRMS
(ESI): calcd. for C29H41N2O4 [M + H]+ 481.3061; found 481.3076.
3-(4-Methoxyphenyl)-1-methyl-5-pentyl-1H-pyrazole (10b): Com-
pound 4 (68 μL, 1.3 mmol, 3 equiv.) was added to a solution of 9b
(100 mg, 0.4 mmol, 1 equiv.) in CH2Cl2 (2 mL). The reaction mix-
ture was stirred under reflux until the end of the reaction (2 d).
Water was added and the aqueous layer was extracted with CH2Cl2.
The combined organic layers were dried with Na2SO4, filtered, and
evaporated under reduced pressure. Purification by column
chromatography on silica gel (pentane/diethyl ether, 1:1) afforded
the product as a mixture of regioisomers [10b/10bЈ (≈ 95:5) deter-
mined by 1H NMR spectroscopic analysis of the crude reaction
mixture] as an orange solid (105 mg, 93% ); m.p. 40–42 °C. 1H
3
3
300 MHz): δ = 8.10 (d, J = 8.7 Hz, 2 H), 6.93 (d, J = 8.7 Hz, 2
3
H), 6.13 (s, 2 H), 4.03 (t, J = 6.5 Hz, 2 H), 3.80 (s, 3 H), 3.79 (s,
6 H), 2.60 (t, 3J = 6.8 Hz, 2 H), 2.48 (t, 3J = 7.1 Hz, 2 H), 1.85
3
3
(quint, J = 6.5 Hz, 2 H), 1.68 (quint, J = 7.1 Hz, 2 H), 1.52–1.27
(m, 8 H), 0.94 (t, 3J = 7.0 Hz, 3 H) ppm. 13C NMR (CDCl3,
75 MHz): δ = 176.8, 163.9, 159.0, 158.6, 131.7, 129.9, 114.0, 111.2,
95.7, 90.3, 79.6, 68.3, 55.4, 55.1, 31.0, 29.0, 28.8, 27.5, 25.7, 22.2,
22.0, 19.0, 13.8 ppm. IR (neat): ν = 2932, 2858, 2235, 2198, 1635,
˜
1593 cm–1. HRMS (ESI): calcd. for C28H37IO5 [M + H]+ 453.2636;
found 453.2649.
3
NMR (CDCl3, 200 MHz): δ = 7.71 (d, J = 8.8 Hz, 2 H), 6.92 (d,
3J = 8.8 Hz, 2 H), 6.26 (s, 1 H), 3.83 (br. s, 6 H), 2.60 (t, 3J =
7.6 Hz, 2 H), 1.64 (m, 2 H), 1.39–1.38 (m, 4 H), 0.93 (t, 3J = 6.3 Hz,
3 H) ppm. 13C NMR (CDCl3, 50 MHz): δ = 159.0, 149.6, 144.4,
129.8, 126.5, 113.8, 100.8, 55.1, 35.9, 31.3, 28.1, 25.5, 22.4, 13.9
1-(4-Methoxyphenyl)oct-2-yn-1-one (9b): [PdCl2(PPh3)2] (300 mg,
0.4 mmol, 0.05 equiv.), H2O (15 mL), Et3N (3.5 mL, 25.5 mmol,
3 equiv.), and 1-heptyne (2.2 mL, 17.0 mmol, 2 equiv.) were added
successively to a solution of 4-iodoanisole (2.0 g, 8.5 mmol,
1 equiv.) in CH2Cl2 (15 mL). Carbon monoxide was bubbled
through the solution and the reaction was stirred for 24 h under an
atmosphere of carbon monoxide (balloon filled with carbon mon-
oxide) at room temperature. Water was added and then the mixture
was extracted with ethyl acetate, the combined organic layers were
dried with Na2SO4, filtered, and evaporated under reduced pres-
sure. The residue was purified by column chromatography on silica
gel (cyclohexane/ethyl acetate, 9:1) to give 9b as a red oil (1.9 g,
96%). 1H NMR (CDCl3, 300 MHz): δ = 8.07 (d, 3J = 8.7 Hz, 2
ppm. IR (neat): ν = 2926, 2857, 1612, 1520, 1456, 1433, 1248 cm–1.
˜
HRMS (ESI): calcd. for C16H23N2O [M + H]+ 259,1805; found
259,1807.
5-(4-Methoxyphenyl)-1-methyl-3-pentyl-1H-pyrazole (10bЈ): Diag-
nostic signals: 1H NMR (CDCl3, 200 MHz): δ = 7.33 (d, 3J =
3
8.8 Hz, 2 H), 6.94 (d, J = 8.8 Hz, 2 H), 6.06 (s, 1 H) ppm.
4-Pentyl-2-phenyl-6-(4-{[5-(2,4,6-trimethoxyphenyl)pentyl]oxy}-
phenyl)pyrimidine (11a): White solid; m.p. 72–74 °C. 1H NMR
3
(CDCl3, 200 MHz): δ = 8.60 (m, 2 H), 8.20 (d, J = 8.5 Hz, 2 H),
3
3
H), 6.90 (d, J = 8.7 Hz, 2 H), 3.82 (s, 3 H), 2.43 (t, J = 7.2 Hz,
3
7.51 (m, 3 H), 7.39 (s, 1 H), 7.03 (d, J = 8.5 Hz, 2 H), 6.15 (s, 2
3
2 H), 1.63 (quint, 3J = 7.2 Hz, 2 H), 1.46–1.27 (m, 4 H), 0.94 (t, J
3
H), 4.05 (t, J = 6.6 Hz, 2 H), 3.82 (s, 3 H), 3.81 (s, 6 H), 2.86 (t,
= 7.2 Hz, 3 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 176.8, 164.2,
131.8, 130.3, 113.6, 95.9, 79.6, 55.5, 31.0, 27.5, 22.1, 19.1, 13.8 ppm.
Data are consistent with those reported in the literature.[15]
3
3J = 7.6 Hz, 2 H), 2.62 (t, J = 6.8 Hz, 2 H), 1.94–1.81 (m, 4 H),
1.55–1.27 (m, 8 H), 0.94 (t, 3J = 6.8 Hz, 3 H) ppm. 13C NMR
(CDCl3, 50 MHz): δ = 171.3, 164.1, 163.3, 161.2, 159.2, 158.9,
138.5, 130.3, 129.6, 128.7, 128.4, 114.8, 112.5, 111.7, 90.6, 68.4,
55.7, 55.4, 38.3, 31.7, 29.2, 29.2, 28.7, 26.0, 22.6, 22.4, 14.1 ppm.
General Procedure for Cyclodehydration Conditions: Reactions were
performed in a MiniBlock® XT Mettler Toledo reactor (24 posi-
tions).
IR (neat): ν = 2929, 2856, 1606, 1589, 1569, 1527, 1512, 1370, 1251,
˜
1147, 1130 cm–1. HRMS (ESI): calcd. for C35H43N2O4 [M + H]+
555.3217; found 555.3232.
Dinucleophile 4–7 (0.33 mmol, 3 equiv.) was added to a solution of
9a (50 mg, 0.11 mmol, 1 equiv.) diluted in solvent (2 mL) before
base (0.33 mmol, 3 equiv.) was added. The reaction mixtures were
stirred at 50 °C and analyzed by APPI mass spectrometry.
4-(4-Methoxyphenyl)-6-pentyl-2-phenylpyrimidine (11b): Com-
pound 5 (406 mg, 2.3 mmol, 3 equiv.) was added to a solution of
9b (200 mg, 0.8 mmol, 1 equiv.) in THF/H2O (1:1) (2 mL) followed
by K2CO3 (356 mg, 2.5 mmol, 3 equiv.). The reaction mixture was
stirred at 50 °C until the end of the reaction (2 d). Water was added
and the aqueous layer was extracted with ethyl acetate. The com-
bined organic layers were dried with Na2SO4, filtered, and evapo-
rated under reduced pressure. Purification by column chromatog-
raphy on silica gel (pentane/ethyl acetate, 8:2) afforded 11b as a
white solid (263 mg, 92 %); m.p. 53–55 °C. 1H NMR (CDCl3,
Representative Procedure for APPI Mass Spectrometry Analyses: A
sample of the crude mixture (9 μL) was added to a solution of
MeOH/toluene (991 μL; 8:2) to give a final concentration of
5ϫ10–4 m (based on starting material) and was then transferred to
the mass spectrometer. The yields were evaluated by the ratio of
the integral of the isotopic mass of the expected compound to the
sum of the integrals of all detected compounds.
3
Mass spectrometer settings: Fragmentor voltage: 110 V. Capillary
voltage: 1400 V. Drying gas flow: 5 Lmin–1. Drying gas tempera-
ture: 250 °C. Nebulizer pressure: 250 psi. Mobile phase flow (meth-
anol): 0.5 mLmin–1. Injection flow: 250 μLmin–1; time per run:
2 min; volume transferred into the mass spectrometer: 5 μL.
200 MHz): δ = 8.60 (m, 2 H), 8.21 (d, J = 8.6 Hz, 2 H), 7.50 (m,
3
3 H), 7.39 (s, 1 H), 7.04 (d, J = 8.6 Hz, 2 H), 3.90 (s, 3 H), 2.86
3
(t, J = 7.7 Hz, 2 H), 1.89–1.84 (m, 2 H), 1.45–1.40 (m, 4 H), 0.93
(t, 3J = 6.5 Hz, 3 H) ppm. 13C NMR (CDCl3, 50 MHz): δ = 171.8,
164.0, 163.17, 161.7, 138.5, 130.3, 129.8, 128.7, 128.4, 114.1, 112.5,
55.4, 38.2, 31.6, 28.6, 22.6, 14.1 ppm. IR (neat): ν = 2918, 2850,
˜
1-Methyl-5-pentyl-3-(4-{[5-(2,4,6-trimethoxyphenyl)pentyl]-
1607, 1589, 1570, 1530, 1512, 1371, 1258, 1170 cm–1. HRMS (ESI):
calcd. for C22H25N2O [M + H]+ 333.1961; found 333.1954.
oxy}phenyl)-1H-pyrazole (10a): Light yellow solid; m.p. 67–69 °C.
3
1H NMR (CDCl3, 300 MHz): δ = 7.69 (d, J = 8.8 Hz, 2 H), 6.92
(d, 3J = 8.8 Hz, 2 H), 6.26 (s, 1 H), 6.14 (s, 1 H), 3.98 (t, 3J = 5-Pentyl-7-(4-{[5-(2,4,6-trimethoxyphenyl)pentyl]oxy}phenyl)-
6.6 Hz, 2 H), 3.81 (s, 6 H), 3.79 (s, 6 H), 2.59 (t, 3J = 7.4 Hz, 2 H),
1.84 (quint, 3J = 6.6 Hz, 2 H), 1.68 (quint, 3J = 7.4 Hz, 2 H), 1.54–
pyrazolo[1,5-a]pyrimidine (12a): Waxy solid. 1H NMR (CDCl3,
3
3
300 MHz): δ = 8.10 (d, J = 2.4 Hz, 1 H), 8.02 (d, J = 9.0 Hz, 2
3
3
3
1.50 (m, 4 H), 1.40–1.37 (m, 4 H), 0.94 (t, J = 6.7 Hz, 3 H) ppm.
H), 7.06 (d, J = 7.04 Hz, 2 H), 6.75 (s, 1 H), 6.64 (d, J = 2.4 Hz,
13C NMR (CDCl3, 75 MHz): δ = 159.1, 158.8, 149.9, 144.5, 129.9, 1 H), 6.14 (s, 2 H), 4.05 (t, J = 6.5 Hz, 2 H), 3.81 (s, 3 H), 3.81
3
3
126.5, 126.4, 114.5, 111.6, 100.9, 90.5, 68.15, 55.6, 55.3, 36.1, 31.5,
29.2, 28.2, 25.9, 25.7, 22.5, 22.3, 14.0 ppm. IR (neat): ν = 2928,
(s, 6 H), 2.60 (t, J = 7.8 Hz, 2 H), 2.48 (t, 3J = 7.1 Hz, 2 H), 1.90–
3
1.75 (m, 4 H), 1.53–1.50 (m, 4 H), 1.44–1.34 (m, 4 H), 0.92 (t, J
˜
90
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 85–92

Trimethoxyarene as a Tag for Reaction Analysis
3
3
= 6.7 Hz, 3 H) ppm. 13C NMR (CDCl3, 50 MHz): δ = 162.7, 161.5,
159.2, 158.9, 149.6, 146.4, 144.6, 131.0, 123.1, 114.7, 111.75, 106.9,
95.8, 90.6, 68.5, 55.8, 55.4, 38.5, 31.7, 29.8, 29.2, 29.0, 26.0, 22.6,
300 MHz): δ = 8.10 (d, J = 8.6 Hz, 2 H), 7.91 (d, J = 7.9 Hz, 1
3
3
H), 7.71 (d, J = 8.2 Hz, 1 H), 7.44 (t, J = 7.6 Hz, 1 H), 7.20 (t,
3J = 7.6 Hz, 1 H), 6.87 (s, 1 H), 6.87 (d, J = 8.6 Hz, 2 H), 3.77 (s,
3
22.4, 14.1 ppm. IR (neat): ν = 2929, 2856, 1603, 1503, 1130 cm–1.
3 H), 3.11 (t, 3J = 7.6 Hz, 2 H), 1.82 (quint, 3J = 7.4 Hz, 2 H),
1.56–1.36 (m, 4 H), 0.95 (t, 3J = 6.9 Hz, 3 H) ppm. 13C NMR
(CDCl3, 75 MHz): δ = 162.1, 160.2, 152.3, 151.7, 145.3, 129.2,
129.0, 127.5, 125.4, 121.2, 119.8, 114.6, 114.0, 102.1, 55.3, 33.1,
˜
HRMS (ESI): calcd. for C31H40N3O4 [M + H]+ 518.3013; found
518.3026.
7-(4-Methoxyphenyl)-5-pentylpyrazolo[1,5-a]pyrimidine (12b): A
solution of 6 (108 mg, 1.3 mmol, 3 equiv.) in CH2Cl2 (1 mL) was
added to a Schlenk tube containing 9b (100 mg, 0.4 mmol, 1 equiv.)
followed by K2CO3 (180 mg, 1.3 mmol, 3 equiv.). CH2Cl2 was evap-
orated by heating the reaction mixture at 65 °C. The reaction mix-
ture was stirred at 65 °C until the end of the reaction (2 d). A satu-
rated aqueous solution of NH4Cl was added and the aqueous layer
was extracted with ethyl acetate. The combined organic layers were
dried with Na2SO4, filtered, and evaporated under reduced pres-
sure. Purification by column chromatography on silica gel (pentane/
diethyl ether, 7:3) afforded the products 12b (107 mg, 83%) and
12bЈ (13 mg, 10%); m.p. 52–54 °C. 1H NMR (CDCl3, 300 MHz): δ
31.4, 25.8, 22.4, 14.0 ppm. IR (neat): ν = 2954, 2934, 2867, 1597,
˜
1574, 1529, 1176 cm–1. HRMS (ESI): calcd. for C22H24N3O [M +
H]+ 346.1914; found 346.1912.
Supporting Information (see footnote on the first page of this arti-
cle): Copies of 1H and 13C NMR spectra of all compounds are
provided.
Acknowledgments
This work was supported by a grant (to M. B. T. T) from NOVA-
LIX (Illkirch, France), who also provided free access to the MS-
APPI spectrometer.
3
3
= 8.10 (d, J = 1.89 Hz, 1 H), 8.04 (d, J = 8.6 Hz, 2 H), 7.07 (d,
3
3J = 8.6 Hz, 2 H), 6.75 (s, 1 H), 6.64 (d, J = 2.2 Hz, 1 H), 3.90 (s,
3 H), 2.85 (t, 3J = 7.7 Hz, 2 H), 1.82 (quint, 3J = 7.5 Hz, 2 H),
1.41–1.38 (m, 4 H), 0.92 (t, 3J = 6.7 Hz, 3 H) ppm. 13C NMR
(CDCl3, 50 MHz): δ = 162.4, 161.4, 149.6, 145.8, 144.3, 130.7,
123.3, 113.8, 106.8, 95.6, 55.3, 38.4, 31.5, 28.7, 22.4, 13.9 ppm. IR
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[8] a) I. Marchi, S. Rudaz, J. L. Veuthey, Talanta 2009, 78, 1–18;
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(neat): ν = 2934, 2872, 2839, 1614, 1540, 1504, 1454, 1270, 1252,
˜
1180, 1162 cm–1. HRMS (ESI): calcd. for C18H22N3O [M + H]+
296.1757; found 296.1756.
5-(4-Methoxyphenyl)-7-pentylpyrazolo[1,5-a]pyrimidine (12bЈ):
Waxy solid. 1H NMR (CDCl3, 400 MHz): δ = 8.11 (d, 3J = 2.4 Hz,
3
1 H), 8.06 (d, J = 8.8 Hz, 2 H), 7.08 (s, 1 H), 7.03 (d, 3J = 8.8 Hz,
3
3
2 H), 6.68 (d, J = 2.4 Hz, 1 H), 6.64 (d, J = 2.2 Hz, 1 H), 3.89 (s
3 H), 3.21 (t, 3J = 7.8 Hz, 2 H), 1.93 (quint, 3J = 7.6 Hz, 2 H),
1.53–1.40 (m, 4 H), 0.94 (t, 3J = 7.2 Hz, 3 H) ppm. 13C NMR
(CDCl3, 100 MHz): δ = 161.5, 155.6, 149.7, 149.1, 144.7, 130.3,
128.9, 114.4, 103.3, 96.6, 55.5, 31.7, 30.8, 25.9, 22.5, 14.1 ppm. IR
(neat): ν = 2953, 2926, 2854, 2872, 1601, 1577, 1551, 1513, 1419,
˜
1377, 1257, 1234, 1172 cm– 1 . HRMS (ESI): calcd. for
C18H22N3O [M + H]+ 296.1757; found 296.1756.
4-Pentyl-2-(4-{[5-(2,4,6-trimethoxyphenyl)pentyl]oxy}phenyl)-
pyrimido[1,2-a]benzimidazole (13a): Orange solid; m.p. 130–132 °C.
3
1H NMR (CDCl3, 300 MHz): δ = 8.18 (d, J = 8.7 Hz, 2 H), 7.96
(d, 3J = 8.1 Hz, 1 H), 7.82 (d, 3J = 8.4 Hz, 1 H), 7.50 (t, 3J =
3
3
7.6 Hz, 1 H), 7.30 (t, J = 7.1 Hz, 1 H), 7.01 (s, 1 H), 6.95 (d, J =
3
9.0 Hz, 2 H), 6.14 (s, 2 H), 3.99 (t, J = 6.5 Hz, 2 H), 3.80 (s, 9 H),
3
3
3.24 (t, J = 7.6 Hz, 2 H), 2.61 (t, J = 7.0 Hz, 2 H), 1.93–1.83 (m,
4 H), 1.60–1.42 (m, 8 H), 0.98 (t, 3J = 7.1 Hz, 3 H) ppm. 13C NMR
(CDCl3, 75 MHz): δ = 162.0, 160.5, 159.2, 158.9, 151.7, 145.5,
129.4, 128.9, 127.6, 125.6, 121.3, 120.1, 114.7, 114.6, 111.6, 102.5,
90.6, 68.4, 55.7, 55.4, 33.3, 31.5, 29.2, 29.1, 26.0, 22.5, 22.4, 14.1
ppm. IR (neat): ν = 2927, 2855, 2837, 1595, 1577, 1134 cm–1.
˜
HRMS (ESI): calcd. for C35H42N3O4 [M + H]+ 568.3170; found
568.3175.
2-(4-Methoxyphenyl)-4-pentylpyrimido[1,2-a]benzimidazole (13b):
Compound 7 (173 mg, 1.3 mmol, 3 equiv.) was added to a solution
of 9b (100 mg, 0.4 mmol, 1 equiv.) in THF/H2O (1:1) (2 mL). The
reaction mixture was stirred at 50 °C until the end of the reaction
(2 d). A saturated aqueous solution of NH4Cl was added and the
aqueous layer was extracted with ethyl acetate. The combined or-
ganic layers were dried with Na2SO4, filtered, and evaporated un-
der reduced pressure. Purification by column chromatography on
silica gel (diethyl ether/dichloromethane, 6:4) afforded 13b as a yel-
low solid (88 mg, 78%); m.p. 136–138 °C. 1H NMR (CDCl3,
Eur. J. Org. Chem. 2012, 85–92
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Received: June 23, 2011
Published Online: November 22, 2011
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Eur. J. Org. Chem. 2012, 85–92