Alkanoylation of quinazoline by nucleophilic aromatic substitution: Combined experimental and computational study

Article abstract of DOI:10.1016/j.tet.2017.11.071

A combined experimental and computational study on the key intermediates of NHC-catalyzed acylation reaction, Breslow intermediates (BIs), has been conducted in order to achieve a direct nucleophilic alkanoylation of N-heterocycles. Various BI precursors

Full text of DOI:10.1016/j.tet.2017.11.071

Tetrahedron xxx (2017) 1e9
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Alkanoylation of quinazoline by nucleophilic aromatic substitution:
Combined experimental and computational study
Yumiko Suzuki a *, Naoto Iwata a, Kohei Dobashi a, Ryo Takashima a,
,
,
, c, **
Sundaram Arulmozhiraja b c, Erika Ishitsubo b, Naoya Matsuo b, Hiroaki Tokiwa b
a Department of Materials and Life Sciences, Faculty of Science and Technology, Sophia University, 7-1 Kioicho, Chiyoda-ku, Tokyo 102-8554, Japan
b Department of Chemistry, Rikkyo University, 3-34-1 Nishi-Ikebukuro, Toshima-ku, Tokyo 171-8501, Japan
c Research Center for Smart Molecules, Rikkyo University, 3-34-1 Nishi-Ikebukuro, Toshima-ku, Tokyo 171-8501, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A combined experimental and computational study on the key intermediates of NHC-catalyzed acylation
reaction, Breslow intermediates (BIs), has been conducted in order to achieve a direct nucleophilic
alkanoylation of N-heterocycles. Various BI precursors are alternatively prepared and used in the reaction
with 4-chloroquinazoline. The present study reveals that the intermediates having benzimidazole moiety
serve as acylating agents for the introduction of straight-chain alkanoyl groups. Natural bond orbital
analysis indicates that the reactivity of intermediates partly correlates to the occupancy of the pC-C bonds
of the hydroxyl enamine moieties. The putative rate-determining step of the acylation reaction has been
theoretically investigated. Several new 4-alkanoylquinazolines are synthesized using the BI precursors.
© 2017 Elsevier Ltd. All rights reserved.
Received 15 November 2017
Received in revised form
24 November 2017
Accepted 27 November 2017
Available online xxx
Keywords:
Nitrogen heterocycles
Breslow intermediate
Alkanoylation
Natural bond orbital
CeC bond formation
1. Introduction
intermediate (BI)”, which is produced from NHC and aldehyde. This
reaction allows to access synthetically versatile ketones through
Heterocycles are important class of frameworks in medicinal
and agricultural chemistry.1,2 Compounds containing heterocycles
often exhibit bioactivities, as they can interact with biomolecules
through ionic and hydrogen bonds, ion-dipole, dipole-dipole, hy-
drophobic, and Van der Waals interactions. Thus, heterocycles,
especially nitrogen-containing ones, are frequently seen as cores
for pharmacophores in medicines.
We have been investigating methodologies to construct het-
erocyclic compounds,3 and to introduce functionalities to hetero-
arenes.4 Earlier, we focused on N-heterocyclic carbene (NHC)-
catalyzed nucleophilic substitution reaction,4 through which aroyl
CeC bond formation. In fact, the product ketones have been suc-
cessfully used as intermediates to synthesize natural products5 and
anticancer agents.6
It should be noted, however, that this catalytic reaction suffers
from the use of aldehydes. When aliphatic aldehydes and 4-
nitrobenzaldehyde were used, the corresponding acylated prod-
ucts were not obtained. Furthermore, although the keto product
could be obtained depending on the substrates, in the case of 4-
(N,N-dimethylamino)benzaldehyde, the yield is very low.4d To
elucidate the cause of this limitation so as to expand substrate
scope, the present study is conducted in the following steps: (1)
firstly, various BI precursors7 were synthesized (Scheme 1), (2)
secondly, BIs were generated from these precursors by treatment
with a base, and (3) finally, the intermediates were used as acyl-
ating agents in the nucleophilic aromatic substitution reaction of 4-
chloroquinazoline. Computational studies were performed to sup-
port the experimental results. It should be mentioned that Taylor
et al.8 synthesized 4-alkanoylquinazolines in the early 1970s, and a
few studies were made in the recent years to synthesize these
quinazolines.9 However, the product examples are very much
limited and all of them should go through multistep routes either
groups originating from aromatic aldehydes are introduced to p-
deficient heteroarenes in one step. In this reaction, the nucleophile
is the acylanion equivalent, also known as the “Breslow
* Corresponding author. Department of Materials and Life Sciences, Faculty of
Science and Technology, Sophia University, 7-1 Kioicho, Chiyoda-ku, Tokyo 102-
8554, Japan.
** Corresponding author. Department of Chemistry, Rikkyo University, 3-34-1
Nishi-Ikebukuro, Toshima-ku, Tokyo 171-8501, Japan.
E-mail address: yumiko_suzuki@sophia.ac.jp (Y. Suzuki).
https://doi.org/10.1016/j.tet.2017.11.071
0040-4020/© 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Suzuki Y, et al., Alkanoylation of quinazoline by nucleophilic aromatic substitution: Combined experimental
and computational study, Tetrahedron (2017), https://doi.org/10.1016/j.tet.2017.11.071

2
Y. Suzuki et al. / Tetrahedron xxx (2017) 1e9
(entries 4e6). There is a tendency in which BIs with a longer
straight-chain alkyl group afford the corresponding 4-
alkanoylquinazolines in higher yields (Table 2, entries 4,8;
Table 3, entries 1e3). In the cases of benzimidazole-based BIs with
branched-alkyl chains, the desired acylated quinazolines were not
obtained (Table 3, entries 4e7). The nucleophilic attack at the ipso-
position of 5 may be less favorable than the dissociation to NHC and
aldehydes due to the steric bulkiness around the carbon atom
originating from the carbonyl group of the aldehydes.
The proposed reaction mechanism is shown in Scheme 2. Our
previous study revealed that imidazolium-derived NHCs are the
most effective catalysts for the reaction.4 It has been previously
shown that the BIs are the key intermediates for the catalytic
aroylation reaction by generating them in situ from precursor 3 and
4 bearing aromatic substituents.7 The precursors used in that
earlier study7 were prepared from aromatic aldehydes, which
successfully served as acylating agents in the catalytic reaction.
However, the reactions using the precursors originating from 2- or
4-nitrobenzaldehyde, and 4-dimethylaminobenzaldehyde have not
been conducted. In general, NHC-catalyzed aroylation of hal-
oheteroarenes with aromatic aldehydes having either strong
electron-withdrawing or strong electron-donating groups does not
provide the desired aroylated product, except that aroylation of 5
with 4-dimethylaminobenzaldehyde using 25 mol% of 1,3-
dimethylimidazolium iodide produced 6m in 31% yield.4d Thus,
the reactions of 4k and 4m using DBN as a base in NMP were
performed to obtain aroylated product 6k and 6m in 40% and 68%
yield, respectively (Table 4, entries 1, 2). The product yield of the
reaction of 4m using NaH as a base in THF is dropped significantly
to 14% (entry 3). In comparison, the reaction yield using 4n derived
from benzalehyde as a catalyst together with extra benzaldehyde in
the same condition was 80% (entry 4).7
Scheme 1. Generation of Breslow Intermediate and Acylation of 4-Chloroquinazoline.
from 4-chloroquinazolines or from quinazolines without sub-
stituents at C4 position. Considering the synthetic versatilities of
alkanoyl groups and the importance of quinazolines in medicinal
chemistry,10 finding a way to synthesize these biologically impor-
tant compounds by directly introducing alkanoyl groups to quina-
zoline's p-deficient positions would be highly useful and it would
allow us facile access to
derivatives.
a variety of potentially bioactive
2. Results and discussion
2.1. Synthesis of BI precursors
2.3. Computational study
Synthesis of the BI precursors was commenced with the lith-
iation of azoles using nBuLi in THF (Table 1). The resulting lith-
ioazoles derived from thiazole, benzimidazole, and triazole, were
then reacted with aliphatic aldehydes to afford adducts, which
were then treated with iodomethane to obtain the quaternized
azoles 1e3, the BI precursors for alkanoylation. The use of
imidazolium-derived NHCs as catalysts in alkanoylation reaction is
not favorable; since imidazoliums are less acidic than thiazoliums,
benzimidazoliums, and triazoliums, and strong bases are needed to
deprotonate to generate NHCs, causing undesired products such as
aldols.
The reactions of 4-(N,N-dimethyamino)benzaldehyde and 2-
nitrobenzaldehyde with lithioimidazole afforded the correspond-
ing adducts quantitatively, whereas the reaction of 4-
nitrobenzaldehyde with the same lithioazole produced the
adduct only in low yield. Quaternization of the imidazole-based
adducts with MeI yielded imidazolium 4.
2.3.1. Natural bond orbital analysis
The reactivity of BIs was studied using density functional theory
(DFT). The B3LYP functional11 with two different basis sets [6-
311þG(d) and 6-311þþG(2d,p)] was utilized for this purpose. All
the calculations were performed by considering bulk solvent effect
with DMF as the solvent using polarizable continuum model
(PCM).12 Gaussian09 package was used for all the theoretical cal-
culations.13 Orbital occupancies were calculated by using natural
bond orbital (NBO) analysis.14 The results of NBO analysis (Table 5)
indicate that the reactivity of the intermediates 1aBI, 2aBI, 3bBI,
and 4nBI correlates with the occupancy of the pC-C bond [pC1-C2
(BD)] but not with that of the two lone pairs of the oxygen atom [O3
(LP1), O3 (LP2)] in the hydroxyenamine moieties (The related or-
bitals were given in Fig. S1 of the Supporting Information). The
results roughly indicate that when the occupancy of the pC-C bond
is smaller than those of the oxygen lone pairs, the acylation pro-
ceeds (3bBI and 4nBI).
Fig. 1 shows the schematic structures of various BIs, and occu-
pancy values and the energies of pC1eC2 (BD) bond orbitals. Among
the BIs derived from aromatic aldehydes, there is no significant
difference in the electronic state between experimentally the
“more reactive” intermediate 4nBI and the “less reactive” ones
4kBI, 4lBI, and 4mBI. The pC1eC2 bond occupancy values of BIs
derived from aliphatic aldehydes (3bBI and 3hBI) are higher than
those derived from aromatic aldehydes (4nBI, 4kBI, 4lBI, and
4mBI). As expected, 4lBI and 4kBI have the least pC1eC2 bond oc-
cupancies. The results of NBO analysis on the nucleophiles, how-
ever, did not fully explain the differences in the reactivity of the BIs
with various substituents. The occupancy and the orbital energy
values of 3bBI and 3hBI are comparable, whereas only 3bBI served
2.2. Acylation reactions of 4-chloroquinazolines using BI precursors
Next, the acylation reactions were investigated using BI pre-
cursor 1e3 bearing various azoles (Table 2). When triazole 1a and
thiazole 2a with straight-chain alkyl groups originating from
octanal were used in the reaction with 4-chloroquinazoline 5, the
desired acylated compounds 6a were not obtained (entries 1e3). In
contrast, the reaction of benzimidazole 3a, and 3b bearing straight-
chain alkyl groups with 5 in THF, DMF, or NMP produces 6a, and 6b,
respectively (entries 4e8). Either DBU or DBN was used as a base to
produce BIs in situ from the precursors. N-methyl-2-pyrrolidone
(NMP) suits better as a reaction medium than THF and DMF
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and computational study, Tetrahedron (2017), https://doi.org/10.1016/j.tet.2017.11.071

Y. Suzuki et al. / Tetrahedron xxx (2017) 1e9
3
Table 1
Synthesis of the Breslow intermediate precursors.
as an acylating agent to afford 6b. It indicates that NBO results alone
cannot explain the reactivity of these compounds.
The calculated activation energy (Ea), free energy of activation
zGo), and free energy of reactions (
G) were also given in Fig. 2.
The results show that the Ea and
zGo values are ranging from 11 to
17 and 29e34 kcal/mol, respectively, and all the reactions are
exothermic ( G of around 22e26 kcal/mol). The study also shows
that though there is no difference in calculated Ea and
zGo values
of the reactions involving 3bBI and 3hBI, acylation of the former
(D
D
D
2.3.2. Rate-determining step
D
Next, the transition state of the putative rate-determining step
was investigated. Fig. 2 shows the related transition state structures
of the reaction between BIs 4nBI, 3bBI, and 3hBI and quinazoline 4.
D
Table 2
Reaction using BI precursor 1e3 bearing a straight-chain alkyl group.
Entry
Azolium salt
R
Solvent
Base
Temp. (ꢀC)
Time (h)
Product
Yield (%)
1
2
3
4
5
6
7
8
1a
2a
2a
3a
3b
3b
3b
3b
-C7H15-n
-C7H15-n
-C7H15-n
-C7H15-n
-C9H19-n
-C9H19-n
-C9H19-n
-C9H19-n
NMP
THF
DMF
NMP
THF
DMF
NMP
NMP
DBU
TEA
80
40
80
80
reflux
80
80
1.5
12
6a
6a
6a
6a
6b
6b
6b
6b
e
e
DBU
DBN
DBU
DBU
DBU
DBN
6.5
1.5
2.5
1.5
1.5
1.5
e
63
18
46
68
70
80
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and computational study, Tetrahedron (2017), https://doi.org/10.1016/j.tet.2017.11.071

4
Y. Suzuki et al. / Tetrahedron xxx (2017) 1e9
Table 3
the reactions using alternatively synthesized BI precursors and
through performing DFT calculations. The BIs bearing a benzimid-
azole and a straight-chain alkyl group react with 5 to afford 4-
alkanoylquinazolines 6, which had not been synthesized before.
This is the first evidence to obtain alkanoylquinazolines from easily
accessible starting material 5 in one step. NBO analysis shows that
the occupancy values of the pC-C bonds of the BIs and the reactivity
toward the acylation are partly correlated. However, the bulkiness
of the nucleophiles impedes the reaction when the intermediates
with branched alkyl groups are used. In the case of benzaldehydes
bearing either strong electron-withdrawing groups or strong
electron-donating groups, the reaction using the precursors affor-
ded the products. Thus, the generation of the intermediates in
catalytic condition should be considered as unfavorable. Further
investigation is going on to find a suitable catalyst and an appro-
priate reaction condition to successfully perform the catalytic
version of the alkanoylation reaction.
Reaction using BI precursor 3 bearing a straight-chain or a branched-chain alkyl
group.
Entry
3
R
Time (h)
Product
Yield (%)
1
2
3a
4
5
6
7
8
3c
3d
3e
3f
3g
3h
3i
-C5H11-n
-C3H7-n
-C2H4Ph
-CH(Et)C4H9
-CMe3
cyclopropyl
cyclohexyl
-CH¼CMe2
1.5
2
3
2
2
2
2
2
6c
6d
6e
6f
6g
6h
6i
43
34
11
e
e
e
e
3j
6j
13
a
4. Experimental section
DBU was used as a base.
4.1. General information
Chemicals were purchased and used without further purifica-
tion unless otherwise specified. All non-aqueous reactions were
conducted under an atmosphere of argon. Analytical thin layer
chromatography (TLC) was performed on silica gel 60 F245 plates
(Merck). Column chromatograpy was performed using spherical
silica gel (63e219
mm) (Kanto Chemicals). Melting points were
uncorrected. NMR measurements were recorded with 300, 400 or
500 MHz spectrometers for 1H NMR and with 76, 100, or 126 MHz
spectrometer for 13C NMR. Chemical shifts ( ) of 1H NMR are
d
expressed in parts per million. Multiplicities are indicated as s
(singlet), br s (broad singlet), d (doublet), t (triplet), q (quartet), m
(multiplet), and coupling constants (J) are reported in hertz units.
Mass spectra were recorded using a TOF (ESI) analyzer or a mag-
netic sector (EI and FAB) analyzer.
4.2. 1-(4-Methyl-4H-1,2,4-triazol-3-yl)octan-1-ol
To a solution of 4-methyl-1,2,4-triazole (681 mg, 7.78 mmol),
TMEDA (0.40 ml) in dry THF (10 ml) and at ꢁ60 ꢀC, 2.69 M n-BuLi
solution (2.9 ml, 7.80 mmol) was added drop wise. After stirring
at ꢁ60 ꢀC for 30 min, 10 ml of dry THF solution of octanol (1.30 mL,
8.33 mmol) was added and the mixture was stirred for additional
4 h at ꢁ60 ꢀC to ꢁ30 ꢀC. Then H2O was added and the mixture was
extracted three times with ethyl acetate. The organic layer was
washed with saturated brine and dried over Na2SO4 and concen-
trated under reduced pressure. The residue was purified by silica
gel column chromatography (1e5% methanol/chloroform) as a
colorless solid (1.13 g, 69%): Mp. 63e65 ꢀC; 1H NMR (500 MHz,
Scheme 2. Proposed reaction mechanism. (a) In situ generation of BI from 4. (b) For
catalytic version.
alone proceeds (Table 2, entry 8; Table 3, entry 6). In fact, the Ea and
CDCl3)
d
0.87 (3H, t, J ¼ 6.6 Hz), 1.30e1.26 (9H, m), 1.46 (1H, q,
D
zGo values obtained for the reaction involving 4nBI, which pro-
J ¼ 5.2 Hz), 1.93e1.84 (2H, m), 3.50 (1H, br s), 3.93 (3H, s), 4.82 (1H,
ceeds experimentally,7 is around 5 kcal/mol larger than those ob-
tained for the reaction involving 3bBI. The calculated reaction free
energies also are not decisive. A close look reveals that all these
calculated values differ within 4e5 kcal/mol among these re-
actions. By considering the fact that this putative step is one among
a few reaction steps in the whole acylation process, the calculated
values indicate the importance of studying the remaining reactions
of the acylation process to have a clear picture.
q, J ¼ 6.3 Hz), 7.76 (1H, s); 1H NMR (300 MHz, DMSO)
d 0.88 (3H, t,
J ¼ 6.9 Hz), 1.26e1.49 (14H, m), 1.87e1.93 (2H, m), 2.70 (1H, d,
J ¼ 7.5 Hz) 3.92 (3H, s), 4.84 (1H, q, J ¼ 6.9 Hz), 7.79 (1H, s); 13C NMR
(126 MHz)
d 14.1, 22.7, 25.2, 29.5, 31.9, 33.7, 35.4, 39.8, 64,2, 143.6,
155.0; HRMS (ESI) m/z calcd for C11H21N3NaO (M þ Na)þ 234.1582,
found. 234.1573.
4.3. 1-(4-Methylthiazol-2-yl)octan-1-ol
3. Conclusions
To a solution of 4-methylthiazole (1.40 mL, 15.3 mmol), TMEDA
(0.70 ml) in dry THF (10 ml) at ꢁ78 ꢀC, 1.66 M n-BuLi solution
(10 mL, 10 mmol) was added drop wise. After stirring at ꢁ78 ꢀC for
30 min, 10 ml of dry THF solution of octanol (2.40 mL, 15.3 mmol)
In summary, we have demonstrated the difference in reactivity
of various BIs in acylation of 5 through experimentally examining
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Y. Suzuki et al. / Tetrahedron xxx (2017) 1e9
5
Table 4
Reaction using BI precursor 4 bearing an aromatic group.
Entry
4
R
Solvent
Base
Temp. (ꢀC)
Time (h)
Product
Yield (%)
1
2
4k
-C6H4NO2-o
-C6H4NMe2-p
-C6H4NMe2-p
-Ph
NMP
NMP
THF
DBN
DBN
NaH
NaH
80
80
reflux
reflux
1.5
1.5
0.5
1
6k
40
68
14
80
4m
4m
4n7
6m
6m
6n
3
4a
THF
a
10 mol% of 4n was used as a catalyst with benzaldehyde.7
was added and the mixture was stirred for additional 4 h at ꢁ60 ꢀC
to ꢁ30 ꢀC. The rest of the procedure is the same as described above.
10% methanol/chloroform was used as an eluent in silica gel
chromatography: Yellow oil (3.25 g, 93%): 1H NMR (300 MHz,
4.95e4.91 (1H, m), 6.81 (1H, d, J ¼ 1.1 Hz); 13C NMR (126 MHz,
CDCl3) d 14.1, 17.0, 22.6, 25.2, 29.1, 29.3, 31.8, 38.4, 72.0, 113.2, 152.3,
174.3; HRMS (EIþ) m/z calcd for C12H21NOS Mþ 227.1334, found.
227.1326.
CDCl3)
d
0.87 (3H, t, J ¼ 6.9 Hz), 1.51e1.24 (10H, m), 1.86e1.79 (1H,
m), 1.90e1.96 (1H, m), 2.42 (3H, s), 2.86 (1H, d, J ¼ 4.6 Hz),
Table 5
Occupancies [at B3LYP/6-311þþG(2d,p)] of Breslow intermediates.
Nu
acylation
Occupancy
pC1-C2 (BD)a
O3 (LP1)b
O3 (LP2)b
1aBI
2aBI
3bBI
4nBI
Not detected
Not detected
Proceeded
1.95
1.96
1.94
1.82
1.98
1.98
1.98
1.98
1.94
1.91
1.94
1.95
Proceeded
a
p
bond of the enamine-carbons (C1¼C2 in A).
b
lone pair of the oxygen atom (O3 in A).
Fig. 2. Transition state structures of the reaction between BIs 4nBI, 3bBI, 3hBI, and
quinazoline 4. Activation energy (Ea), free energy of activation (D
zGo), and the free
energy of reaction (DG) in kcal/mol at 353 K, R and n (of the newly forming bond) in Å
and in cmꢁ1, respectively: (A) Ea ¼ 16.83;
D
zGo ¼ 33.71;
D
G ¼ 26.03; R ¼ 2.339;
n
¼ 209.3i; (B) Ea ¼ 11.16;
D
zGo ¼ 28.62;
DG ¼ 21.90; R ¼ 2.260;
n
¼ 239.9i; (C)
Fig. 1. Occupancies of the pC1-C2 bonds and orbital energies (in hartree) of Breslow
Intermediates. All the values obtained at B3LYP/6-311þþG(2d,p) level.
Ea ¼ 11.47;
D
zGo ¼ 29.48;
DG ¼ 25.44; R ¼ 2.282;
n
¼ 241.7i. All the values were
obained at B3LYP/6-311þG(d) level.
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4.4. General procedure for the preparation of benzimidazole-
aldehyde adducts
2.73e2.81 (1H, m), 2.81 (3H, s), 4.80e4.84 (1H, m), 5.68 (1H, d,
J ¼ 3.9 Hz), 7.13e7.28 (7H, m), 7.49 (1H, d, J ¼ 8 Hz), 7.57 (1H, d,
J ¼ 8 Hz); 13C NMR (126 MHz, CDCl3)
d 29.9, 31.6, 37.6, 66.4, 109.2,
To a dry THF solution (10 ml) of N-methylbenzimidazole (1.33 g,
10 mmol) and TMEDA (0.3 eq), 1.6 M n-butyllithium solution
(6.4 mL, 10 mmol) was added dropwise at ꢁ78 ꢀC and the reaction
mixture was stirred for 30 min. Then, to the mixture, a dry THF
solution (10 mL) of aldehydes (10 mmol) was added dropwise
at ꢁ78 ꢀC and was stirred allowing the reaction mixture to warm
to ꢁ20 ꢀC for 4 h unless otherwise noted. After reaction, water was
added to the reaction mixture and it was stirred for 10 min at room
temperature. The mixture was extracted three times with ethyl
acetate and washed with saturated brine. After concentrating un-
der reduced pressure, the residue was purified by silica gel column
chromatography (10% ethyl acetate/n-hexane) to give a desired
product.
119.3, 122.2, 122.7, 126.0, 128.4, 128.5, 136.1, 141.2, 155.7; HRMS
(FABþ) m/z calcd for C17H19N2O (M þ H)þ 267.1497. Found. 267.1495.
4.4.6. 2-Ethyl-1-(1-methyl-1H-benzo[d]imidazol-2-yl)hexan-1-ol
After the lithiation, 2-ethylhexanal was added, and the mixture
was stirred at ꢁ78 ꢀC to ꢁ20 ꢀC for 5 h: From N-methyl-
benzimidazole (664 mg, 5.0 mmol), the title compound was ob-
tained as a colorless solid (936 mg, 72%): Mp. 95e96 ꢀC; 1H NMR
(500 MHz, DMSO-d6)
d
0.71 (3H, t, J ¼ 7 Hz), 0.85 (3H, t, J ¼ 6.5 Hz),
1.44e1.53 (1H, m), 1.68e1.67 (1H, m), 1.95e1.98 (1H, bs), 3.82 (3H,
s), 4.66e4.69 (1H, m), 5.53 (1H, d, J ¼ 5.5 Hz), 7.14 (1H, t, J ¼ 7.5 Hz),
7.19 (1H, t, J ¼ 7.5 Hz), 7.48 (1H, d, J ¼ 7.5 Hz), 7.55 (1H, d, J ¼ 7.5 Hz);
13C NMR (100 MHz, DMSO-d6)
d 10.1, 11.5, 14.3, 14.4, 21.3, 21.8, 22.7,
23.1, 27.7, 27.9, 28.2, 28.7, 33.1, 43.0, 43.5, 67.3, 67.4, 113.7, 127.1,
127.7, 128.1, 130.0, 132.1, 153.5; HRMS (EIþ) m/z calcd for C16H24N2O
Mþ 260.1889. Found. 260.1873.
4.4.1. 1-(1-Methyl-1H-benzo[d]imidazol-2-yl)decan-1-ol
Colorless solid (2.13 g, 74%): Mp. 81e82 ꢀC; 1H NMR (300 MHz,
CDCl3)
m), 3.77 (3H, s), 4.87 (1H, dd, J ¼ 3.0 Hz, 13.8 Hz), 7.21e7.26 (3H, m),
7.69e7.72 (1H, m); 13C NMR (126 MHz)
14.1, 22.6, 25.6, 29.3, 29.4,
d
0.87 (3H, t, J ¼ 6.6 Hz), 1.14e1.38 (14H, m), 1.89e1.99 (2H,
4.4.7. 2,2-Dimethyl-1-(1-methyl-1H-benzo[d]imidazol-2-yl)
propan-1-ol
d
29.5, 30.0, 31.9, 36.0, 67.7, 109.1, 119.1, 122.0, 122.6, 135.8, 141.3,
156.2; HRMS (EIþ) m/z calcd for C18H29N2O (M þ H)þ 289.2280,
found. 289.2272.
After the lithiation, pivaladehyde was added, and the mixture
was stirred at ꢁ78 ꢀC to ꢁ20 ꢀC for 4.5, and then at room tem-
perature for 1.5 h: From N-methylbenzimidazole (663 mg,
5.0 mmol), the title compound was obtained as a colorless solid
(565 mg, 52%): Mp. 229e230 ꢀC; 1H NMR (300 MHz, DMSO-d6)
4.4.2. 1-(1-Methyl-1H-benzo[d]imidazol-2-yl)octan-1-ol
From N-methylbenzimidazole (1.38 g, 10.4 mmol), the title
compound was obtained as a colorless solid (1.62 g, 62%): Mp.
d
1.01 (9H, s), 3.36 (3H, s), 3.87 (1H, s), 4.62 (1H, s), 7.19 (1H, sextet d,
J ¼ 1.2, 7.2 Hz), 7.19 (1H, dd, J ¼ 1.2, 6.9 Hz), 7.58 (1H, dd, J ¼ 1.2,
6.9 Hz); 13C NMR (126 MHz, DMSO-d6)
26.2, 30.8, 36.2, 73.8, 109.9,
75e77 ꢀC; 1H NMR (500 MHz, CDCl3)
d
0.86 (3H, t, J ¼ 6.9 Hz),
d
1.25e1.56 (10H, m), 1.90e2.02 (2H, m), 3.30 (1H, br s), 3.80 (3H, t,
J ¼ 6.0 Hz), 4.94 (1H, dd, J ¼ 7.7, 5.4 Hz), 7.21e7.31 (4H, m),
118.7, 121.3, 121.6, 135.7, 141.7, 154.8; HRMS (FABþ) m/z calcd for
C
13H19N2O (M þ H)þ 219.1492. Found. 219.1501.
7.70e7.74 (1H, m); 13C NMR (126 MHz)
d 14.1, 22.6, 25.6, 29.2, 29.4,
29.6, 30.1, 31.8, 36.1, 67.6, 109.1, 119.2, 122.0, 122.6, 136.0, 141.3,
156.1; HRMS (FABþ) m/z calcd for C16H25N2O (M þ H)þ 261.1961.
Found. 261.1975.
4.4.8. Cyclopropyl(1-methyl-1H-benzo[d]imidazol-2-yl)methanol15
After the lithiation, cyclopropane carboaldehyde was added, and
the mixture was stirred at ꢁ78 ꢀC to ꢁ20 ꢀC for 6 h; Colorless solid
(365 mg, 18%): Mp. 179e180 ꢀC; 1H NMR (300 MHz, CD3OD)
4.4.3. 1-(1-Methyl-1H-benzo[d]imidazol-2-yl)hexan-1-ol
d 0.37e0.39 (1H, m), 0.56e0.62 (2H, m), 0.71e0.76 (1H, m), 1.56
After the lithiation, hexanal was added, and the mixture was
(1H, dd, J ¼ 3.0, 5.2 Hz), 3.96 (3H, s), 4.42 (1H, d, J ¼ 8.7 Hz),
stirred at ꢁ78 ꢀC to ꢁ20 ꢀC for 3 h: Colorless solid (2.41 g, 65%): Mp.
7.21e7.33 (2H, m), 7.49 (1H, dd, J ¼ 1.2, 7.5 Hz), 7.62 (1H, dd, J ¼ 1.2,
90e92 ꢀC; 1H NMR (300 MHz, CDCl3)
d
0.90e0.83 (3H, m),
7.5 Hz); 1H NMR (500 MHz, CDCl3)
d 0.66e0.39 (4H, m), 1.49e1.42
1.42e1.25 (5H, m), 1.56e1.47 (1H, m), 1.99e1.91 (2H, m), 3.80e3.60
(3H, m), 4.16 (1H, s), 4.91 (1H, t, J ¼ 6.9 Hz), 7.25e7.20 (3H, m),
(1H, m), 3.77 (3H, s), 4.33 (1H, dd, J ¼ 8.0, 1.7 Hz), 4.98 (1H, s),
7.26e7.18 (3H, m), 7.68e7.66 (1H, m); 13C NMR (126 MHz, DMSO-
7.67e7.71 (1H, m); 13C NMR (126 MHz)
d
14.0, 22.5, 25.3, 30.1, 31.6,
d6) d 3.1, 4.8, 16.6, 30.88, 73.5, 110.83, 119.6, 123.4, 124.1, 137.4, 142.4,
36.0, 67.6, 109.1, 119.2, 122.0, 122.6, 136.0, 141.4, 156.1; HRMS (FABþ)
156.3; HRMS (FABþ) m/z calcd for C12H15N2O (M þ H)þ 203.1184.
m/z calcd for C14H21N2O (M þ H)þ 233.1654, found. 233.1670.
Found. 203.1206.
4.4.4. 1-(1-Methyl-1H-benzo[d]imidazol-2-yl)butan-1-ol
4.4.9. Cyclohexyl(1-methyl-1H-benzo[d]imidazol-2-yl)methanol
After the lithiation, cyclopropane carboaldehyde was added, and
the mixture was stirred at ꢁ78 ꢀC to ꢁ20 ꢀC for 4.5 h: From N-
methylbenzimidazole (672 mg, 5.05 mmol), the title compound
was obtained as a colorless solid (800 mg, 65%): Mp.135e136 ꢀC; 1H
After the lithiation, butanal was added, and the mixture was
stirred at ꢁ78 ꢀC to ꢁ20 ꢀC for 17 h: Colorless solid (1.40 g, 67%):
Mp. 104-104 ꢀC; 1H NMR (300 MHz, CDCl3)
d
0.93 (3H, t, J ¼ 20 Hz),
1.35e1.60 (2H, m), 1.89e1.98 (2H, m), 3.74 (3H, s), 4.93 (1H, dd,
J ¼ 8, 10.4 Hz), 7.17e7.26 (3H, m), 7.65e7.69 (1H, m); 13C NMR
NMR (300 MHz, CDCl3)
1.64 (2H, t, J ¼ 2.4 Hz), 1.73e1.94 (1H, m), 2.01e2.05 (1H, d,
J ¼ 10.5 Hz), 3.75 (3H, s), 4.54 (1H, bs), 4.61e4.65 (1H, m), 7.18e7.25
d
0.99e1.15 (5H, m), 1.35 (1H, d, J ¼ 12.3 Hz),
(126 MHz, CDCl3)
d
13.8, 18.9, 30.0, 38.0, 67.4, 109.1, 119.1, 122.0,
122.5, 135.9, 141.3, 156.1; HRMS (EIþ) m/z calcd for C12H16N2O Mþ
204.1263. Found. 204.1261.
(3H, m), 7.62e7.69 (1H, m); 13C NMR (126 MHz, CDCl3)
d 25.8, 25.9,
28.8, 29.3, 30.3, 43.4, 72.3, 109.1, 119.2, 122.0, 122.5, 135.9, 141.5,
155.8; HRMS (FABþ) m/z calcd for C15H21N2O (M þ H)þ 245.1648.
Found. 245.1655.
4.4.5. 1-(1-Methyl-1H-benzo[d]imidazol-2-yl)-3-phenylpropan-1-
ol
From N-methylbenzimidazole (1,32 g, 9.9 mmol), the title
compound was obtained as a colorless solid (1.66 g, 63%): Mp.
4.4.10. 3-Methyl-1-(1-methyl-1H-benzo[d]imidazol-2-yl)but-2-en-
1-ol
126e128 ꢀC; 1H NMR (300 MHz, CDCl3)
d 2.20e2.35 (2H, m),
2.73e2.90 (2H, m), 1.89e1.98 (2H, m), 3.63 (3H, s), 4.89 (1H, dd,
After the lithiation, cyclopropane carboaldehyde was added, and
the mixture was stirred at ꢁ78 ꢀC to ꢁ20 ꢀC for 7 h: From N-
methylbenzimidazole (403 mg, 3.03 mmol), the title compound
J ¼ 7.6, 10 Hz), 7.14e7.33 (9H, m), 7.66e7.71 (1H, m); 1H NMR
(500 MHz, DMSO-d6)
d 2.15e2.29 (2H, m), 2.61e2.69 (1H, m),
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7
was obtained as a yellow solid (464 mg, 71%): Mp. 145e146 ꢀC; 1H
NMR (300 MHz, CDCl3)
1.77 (3H, d, J ¼ 2 Hz), 1.84 (3H, d, J ¼ 2 Hz),
3.71 (3H, s), 5.54e5.58 (1H, m), 5.67 (1H, d, J ¼ 11.6 Hz), 7.17e7.27
(4H, m), 7.65e7.70 (1H, m); 13C NMR (126 MHz, CDCl3)
18.4, 25.9,
4.7. General procedure for the synthesis of azolium salts 1e4
d
To an acetonitrile solution (8e15 ml) of 2-hydroxymethylazoles
(1e10 mmol), iodomethane (1.5e5 equiv.) was added and the
mixture was stirred at reflux for 1e13 h at 90 ꢀC. After concen-
trating under reduced pressure, the residue was purified by silica
gel column chromatography (chloroform) or recrystallization from
acetonitrile/ethyl acetate.
d
30.0, 64.7, 109.1, 119.4, 122.0, 122.6, 123.4, 136.3, 138.1, 141.5, 155.7;
HRMS (EIþ) m/z calcd for C13H16N2O Mþ 216.1263. Found. 216.1257.
4.4.11. Synthesis of (1-methyl-1H-imidazol-2-yl)(2-nitrophenyl)
methanol
The procedure is the same as the general procedure of
4.7.1. 5-(1-Hydroxyoctyl)-1,4-dimethyl-4H-1,2,4-triazol-1-ium
iodide (1a)
benzimidazole-aldehyde adducts as
a yellow solid. From 1-
methylimidazole (410 mg, 5.0 mmol), the title compound was ob-
From the corresponding triazole (1.01 g, 4.8 mmol), the title
compound was obtained as a slightly yellow solid (1.36 g, 77%): Mp.
tained in quantitive yield (1.17 g) Mp. 187e188 ꢀC; 1H NMR
62e64 ꢀC; 1H NMR (500 MHz, CDCl3)
d
0.88 (3H, t, J ¼ 6.9 Hz),
(300 MHz, DMSO-d6)
d 3.75 (3H, s), 6.42 (2H, bs), 6.59 (1H, s), 7.07
(1H, s), 7.56 (1H, t, J ¼ 7.5 Hz), 7.80 (1H, t, J ¼ 7.5 Hz), 7.99 (2H, d,
1.37e1.24 (9H, m), 1.60e1.55 (1H, m), 1.69e1.76 (1H, m), 1.95e2.02
(1H,m), 4.10 (3H, s), 4.18 (3H, s), 5.22 (1H, d, J ¼ 4.0 Hz), 5.37e5.33
J ¼ 8.1 Hz); 1H NMR (300 MHz, CD3OD)
d 3.84 (6H, s), 6.57 (1H. s),
6.70 (1H, d, J ¼ 1.5 Hz), 7.04 (1H, d, J ¼ 1.5 Hz), 7.54 (1H, td, J ¼ 7.5,
(1H, m), 8.76 (1H, s); 13C NMR (126 MHz, CDCl3)
d 14.0, 22.5, 25.2,
1.5 Hz), 7.78 (1H, td, J ¼ 7.5, 1.5 Hz), 8.03e8.08 (2H, m); 13C NMR
28.9,29.0, 31.6, 33.7, 35.3, 39.7, 64.6, 143.6, 154.9; HRMS (ESI) m/z
calcd for C12H24N3O Mþ 226.1919, found. 226.1928.
(126 MHz)
d 33.2, 65.0, 123.1, 125.7, 127.0, 129.6, 129.7, 134.7, 138.5,
148.8, 149.3; HRMS (FABþ) m/z calcd for C11H12N3O3 (M þ H)þ
234.0877. Found. 234.0891.
4.7.2. 3,4-Dimethyl-2-(1-hydroxyoctyl)thiazolium iodide (2a)
From the corresponding thiazole (2.22 g, 9.79 mmol), the title
compound was obtained as a slightly yellow solid (3.39 g, 94%): Mp.
4.5. Synthesis of (1-methyl-1H-imidazol-2-yl)(4-nitrophenyl)
methanol
104e106 ꢀC; 1H NMR (300 MHz, CDCl3)
d 0.85e0.93 (5H, m),
1.23e1.40 (10H, m), 2.59 (3H, s), 4.06 (3H, s), 5.50 (2H, s), 7.65 (1H,
d 14.5,14.7, 24.0, 26.4, 30.6,
30.7, 33.2, 37.4, 38.6, 70.3, 119.5, 149.6, 183.2; Anal. Calcd for
d, J ¼ 1.2 Hz); 13C NMR (76 MHz, CD3OD)
To a solution of 1-methylimidazole (0.79 ml, 10 mmol) in dry
THF (10 ml), TMEDA (1.35 ml, 30 mmol) was added under argon
atmosphere. Then, at 0 ꢀC, 1.65 M n-BuLi solution (7 ml, 10 mmol)
was added drop wise. After stirring at r.t. for 30 min, a solution of 4-
nitrobenzaldehyde (1.50 g, 10 mmol) in dry THF (15 ml) was added
at ꢁ40 ꢀC and the mixture was stirred for additional 2.5 h at r.t.
Then H2O was added and the organic layer was extracted three
times with ethyl acetate and washed with saturated brine. After
drying over sodium sulfate, the organic layer was concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography (20% hexane/ethylacetate) and (10%
methanol/chloroform) to give the product (0.21 g, 9%) as a yellow
C13H24INOS: C, 42.28; H, 6.55; N, 3.79, found: C, 42.26; H, 6.73; N,
3.68.
4.7.3. 2-(1-Hydroxyoctyl)-1,3-dimethyl-1H-benzo[d]imidazol-3-
ium iodide (3a)
From the corresponding benzimidazole (786 mg, 3.02 mmol),
the title compound was obtained as a colorless solid (1.20 g, 99%):
Mp. 123e124 ꢀC; 1H NMR (300 MHz, DMSO-d6)
d 0.87 (3H, t,
J ¼ 6.5 Hz),1.26e1.64 (9H, m),1.74e2.02 (1H, m), 2.04e2.12 (2H, m),
4.13 (6H, s), 5.35e5.45 (1H, m), 6.44 (1H, br s), 7.65e7.72 (2H, m),
solid: Mp. 175e176 ꢀC; 1H NMR (300 MHz, CD3OD)
d 3.47 (3H, s),
7.90e8.06 (2H, m); 13C NMR (126 MHz, CDCl3)
d 14.0, 22.5, 25.4,
6.01 (1H, s), 6.85(1H, s), 6.99(1H, s), 7.55 (2H, d, J ¼ 9.6 Hz) 8.21 (2H,
29.0, 31.6, 33.6, 34.3, 65.1, 112.5, 127.0, 131.7, 154.10; HRMS (FABþ)
d, J ¼ 9.6 Hz); 13C NMR (126 MHz, DMSO-d6)
d 32.66, 67.29, 122.52,
123.10, 126.22, 127.49, 146.51, 147.62, 149.99; HRMS (FABþ) m/z
m/z calcd for C17H27N2O Mþ 275.2123, found. 275.2148.
calcd for C11H11N3O3 (M þ H)þ 234.0879. Found. 234.0866.
4.7.4. 2-(1-Hydroxydecyl)-1,3-dimethyl-1H-benzo[d]imidazol-3-
ium iodide (3b)
4.6. Synthesis of (4-N,N-dimethylamino)phenyl)(1-methyl-1H-
imidazol-2-yl)methanol
From the corresponding benzimidazole (2.13 g, 7.39 mmol), the
title compound was obtained as a colorless solid (2.47 g, 78%): Mp.
131e132 ꢀC; 1H NMR (300 MHz, CDCl3)
d
0.82 (3H, t, J ¼ 6.5 Hz),
To a solution of 1-methylimidazole (0.80 ml, 10 mmol) in dry
THF (10 ml), TMEDA (0.45 ml, 3.0 mmol) was added under argon
atmosphere. Then, at 0 ꢀC, 1.65 M n-BuLi solution (7 ml, 10 mmol)
was added drop wise. After stirring at r.t. for 30 min, a solution of p-
dimethylaminobenzaldehyde (1.45 g, 10 mmol) in dry THF (15 ml)
was added at ꢁ20 ꢀC and the mixture was stirred for additional
4.5 h at r.t. Then H2O was added at 0 ꢀC and the organic layer was
extracted three times with ethyl acetate and washed with saturated
brine. After drying over sodium sulfate, the organic layer was
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (30% ethyl acetate/hexane) to
give 13b (1.44 g, 62%) as a yellow solid: Mp. 157e159 ꢀC; (lit.2
1.14e1.39 (13H. m), 1.50e1.82 (2H, m), 1.96e2.10 (1H, m), 4.15 (6H,
s), 5.41e5.62 (2H, m), 7.55e7.69 (4H, m); 13C NMR (126 MHz,
CDCl3)
d 14.0, 22.5, 25.3, 29.1, 29.3, 31.7, 33.3, 33.3, 34.2, 65.0,
112.5, 127.0, 131.6, 153.9; Anal. Calcd for C19H31IN2O: C, 53.03; H,
7.26; N, 6.51, found: C, 53.24; H, 7.20; N, 6.49. IR (ATR, cmꢁ1
3291.9 (OH).
)
4.7.5. 2-(1-Hydroxyhexyl)-1,3-dimethyl-1H-benzo[d]imidazol-3-
ium iodide (3c)
From the corresponding benzimidazole (1.98 g, 8.5 mmol), the
title compound was obtained as a colorless solid (2.79 g, 88%): Mp.
141e142 ꢀC). 1H NMR (300 MHz, CD3OD)
d
2.89 (6H, s), 3.49 (3H, s),
167e169 ꢀC; 1H NMR (300 MHz, DMSO-d6)
d
0.85 (3H, t, J ¼ 7.2 Hz),
5.88 (1H, s), 6.73 (2H, d, J ¼ 6.9 Hz), 6.85 (1H, d, J ¼ 1.4 Hz), 6.95 (1H,
1.23e1.60 (6H, m), 1.80e2.00 (2H, m), 4.11 (3H, s), 5.36e5.42 (1H,
d, J ¼ 1.4 Hz), 7.14e7.12 (2H, d, J ¼ 6.9 Hz); 13C NMR (76 MHz,
m), 6.43e6.44 (1H, m), 7.64e7.70 (2H, m), 7.95e8.02 (2H, m); 13C
CD3OD)
d
32.3, 39.7, 68.9, 112.6, 122.2, 125.3, 126.6, 128.8, 149.2,
NMR (126 MHz, DMSO-d6) d 14.5, 22.5, 25.0, 31.4, 33.0, 34.3, 65.0,
150.4; HRMS (FABþ) m/z calcd for C13H18N3O (M þ H)þ 232.1450,
113.7, 127.0, 132.1, 153.5; HRMS (FABþ) m/z calcd for C15H23N2O Mþ
found. 232.1447.
247.1805, found. 247.1824.
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8
Y. Suzuki et al. / Tetrahedron xxx (2017) 1e9
4.7.6. 2-(1-Hydroxybutyl)-1,3-dimethyl-1H-benzo[d]imidazol-3-
ium iodide (3d)
25.1, 25.6, 27.7, 28.4, 32.6, 41.8, 68.7, 113.2, 126.5, 131.5, 152.5; HRMS
(FABþ) m/z calcd for C16H23N2O Mþ 259.1810, found. 259.1822.
From the corresponding benzimidazole (1.17 g, 5.73 mmol), the
title compound was obtained as a colorless solid (1.87 g, 92%); Mp.
4.7.12. 2-(1-Hydroxy-3-methylbut-2-enyl)-1,3-dimethyl-1H-benzo
[d]imidazol-3-ium iodide (3j)
185e186 ꢀC; 1H NMR (300 MHz, DMSO-d6)
d
0.94 (3H, t, J ¼ 7.2 Hz),
1.35e1.63 (2H, m), 1.79e2.00 (2H, m), 4.09 (6H, s), 5.40e5.47 (1H,
From the corresponding benzimidazole (350 mg, 1.62 mmol),
the title compound was obtained as a yellow solid (510 mg, 88%):
m) 6.60 (1H, br s), 7.71e7.72 (2H, m), 8.00e8.06 (2H, m); 13C NMR
(126 MHz, DMSO-d6)
d
2.1, 4.0, 14.7, 32.5, 66.9, 113.2, 126.6, 131.5,
Mp. 200e202 ꢀC; 1H NMR (500 MHz, CDCl3)
d 1.83 (3H, s), 1.95 (3H,
152.6; HRMS (FABþ) m/z calcd for C13H19N2O Mþ 219.1492, found.
s), 4.22 (6H, s), 5.44e5.48 (1H, m), 5.72 (1H, d, J ¼ 4 Hz), 6.40 (1H,
219.1511.
dd, J ¼ 9 Hz, 4 Hz), 7.60e7.68 (4H, m); 13C NMR (126 MHz, CD3CD)
d
18.7, 26.0, 33.1, 64.0, 113.8, 120.2, 128.1, 133.4, 143.6, 153.6; HRMS
4.7.7. 2-(1-Hydroxy-3-phenylpropyl)-1,3-dimethyl-1H-benzo[d]
imidazol-3-ium iodide (3e)
(FABþ) m/z calcd for C14H19N2O Mþ 231.1497, found. 231.1507.
From the corresponding benzimidazole (815 mg, 3.1 mmol), the
title compound was obtained as a colorless solid (1.20 g, 96%) Mp.
4.7.13. 2-(Hydroxy(2-nitrophenyl)methyl)-1,3-dimethyl-1H-
imidazol-3-ium iodide (4k)
185e187 ꢀC; 1H NMR (300 MHz, DMSO-d6)
d
2.20e2.30 (2H, m),
From the corresponding imidazole (731 mg, 3.15 mmol), the title
compound was obtained as a yellow solid (1.13 g, 96%): Mp.
2.68e2.78 (1H, m), 2.86e2.97 (1H. m), 2.90e2.93 (1H, m), 4.09 (6H,
s), 5.43 (1H, s), 6.61 (1H, s), 7.08e7.16 (1H, m), 7.19e7.27 (4H, m),
7.64e7.70 (2H, m), 7.95e8.02 (2H, m); 13C NMR (126 MHz, CD3OD)
175e177 ꢀC; 1H NMR (300 MHz, DMSO-d6)
d 3.67 (6H, s), 6.85 (1H.
s), 7.54 (1H, bs), 7.70 (2H, bs), 7.74 (1H, dt, J ¼ 1.2, 7.5 Hz), 7.94 (1H,
d
32.0, 32.9, 36.9, 65.5, 113.8, 127.4, 128.0, 129.4, 129.6, 133.4, 141.3,
dt, J ¼ 1.2, 7.5 Hz), 8.08 (2H, d, J ¼ 7.8 Hz), 8.21 (1H, d, J ¼ 7.8 Hz); 13
C
154.0; HRMS (FABþ) m/z calcd for C18H21N2O Mþ 281.1654, found.
NMR (126 MHz, DMSO-d6) d 35.7, 61.3, 123.2, 125.6, 129.1, 130.3,
281.1636.
132.2, 134.6, 144.2, 146.6; HRMS (FABþ) m/z calcd for C12H14N3O3
Mþ 248.1030, found. 248.1051.
4.7.8. 2-(2-Ethyl-1-hydroxyhexyl)-1,3-dimethyl-1H-benzo[d]
imidazol-3-ium iodide (3f)
4.7.14. 2-((4-(Dimethylamino)phenyl)(hydroxy)methyl)-1,3-
dimethyl-1H-imidazol-3-ium iodide (4m)
From the corresponding benzimidazole (1.45 g, 5.58 mmol), the
title compound was obtained as a colorless solid (2.13 g, 92%): Mp.
From the corresponding imidazole (685 mg, 2.95 mmol), the
title compound was obtained quanititively as a yellow solid (1.1 g):
166e168 ꢀC; 1H NMR (300 MHz, CDCl3)
d 1.10e1.33 (7H, m),
1.55e2.22 (7H, m), 2.21e2.30 (1H, m), 1.99 (1H, bs), 4.15 (6H, s),
5.21e5.26 (1H, m), 6.49 (1H, d, J ¼ 4.5 Hz), 7.71 (2H, quint,
Mp.184e186 ꢀC; 1H NMR (300 MHz, CD3OD)
d
2.93 (6H, s), 3.87 (6H.
s), 6.32 (1H, s), 6.77 (2H, d, J ¼ 9.0 Hz), 7.15 (2H, d, J ¼ 9.0 Hz), 7.51
J ¼ 3.0 Hz), 8.02e8.07 (2H, m); 13C NMR (126 MHz, CDCl3)
d
9.5,
(1H, s); 13C NMR (100 MHz, CDCl3)
d 37.1, 40.3, 65.3, 112.5, 122.5,
13.8, 21.3, 22.7, 28.0, 28.9, 33.5, 43.4, 67.2, 112.1, 127.1, 131.7, 154.6;
HRMS (FABþ) m/z calcd for C17H27N2O Mþ 275.2123, found.
275.2099.
122.6, 126.7, 148.3, 150.8; HRMS (FABþ) m/z calcd for C14H20N3O Mþ
246.1606, found. 246.1613.
4.8. Synthesis of 2-(hydroxy(4-nitrophenyl)methyl)-1,3-dimethyl-
4.7.9. 2-(1-Hydroxy-2,2-dimethylpropyl)-1,3-dimethyl-1H-benzo
[d]imidazol-3-ium iodide (3g)
1H-imidazol-3-ium iodide (4l)
From the corresponding benzimidazole (837 mg, 3.84 mmol),
the title compound was obtained as a colorless solid (1.12 g, 81%):
To a solution of 13a (18 mg, 0.078 mmol) in toluene (2 ml) in a
sealed tube, iodomethane was added. The mixture was stirred at
115 ꢀC for 9 h, and then cooled. The mixture was filtrated to obtain
15a (6 mg, 19%) as a yellow solid: Mp. 172e174 ꢀC; 1H NMR
Mp. 184e186 ꢀC; 1H NMR (300 MHz, DMSO-d6)
d 1.07 (9H, s),
1.19e1.44 (13H, m), 4.11 (3H, s), 4.27 (3H, s), 5.24 (1H, d, J ¼ 5.1 Hz),
6.58e6.61 (1H, m), 7.69e7.74 (2H, m), 7.97e8.01 (1H, m); 13C NMR
(300 MHz, CD3OD)
d 3.89 (6H,s), 6.62 (1H, s), 7.60 (2H, s), 7.65 (2H,
(100 MHz, DMSO-d6)
d
26.5, 33.9, 34.9, 72.8,113.6,113.9,127.0,127.1,
d, J ¼ 11.4 Hz), 8.31 (2H, d, J ¼ 11.4 Hz). 13C NMR (126 MHz, DMSO-
132.0, 132.9, 152.6; HRMS (FABþ) m/z calcd for C14H21N2O Mþ
d6) d
35.7, 63.2, 123.8, 123.9, 127.1, 144.3, 144.6, 147.4; HRMS (FABþ)
233.1654, found. 233.1661.
m/z calcd for C12H14N2O Mþ 248.1030, found.1021.
4.7.10. 2-(Cyclopropyl(hydroxy)methyl)-1,3-dimethyl-1H-benzo[d]
imidazol-3-ium iodide (3h)
4.9. General procedure for the synthesis of 4-acylquinazoline 6
From the corresponding benzimidazole (379 g, 1.87 mmol), the
title compound was obtained as a colorless solid (617 mg, 92%): Mp.
Under argon atmosphere, to a dry THF, DMF, or NMP solution
(10 ml) of 4-chloroquinazoline (164 mg, 1 mmol) and azolium salts
(1 mmol), a base (2 mmol) was added and stirred. The organic layer
was extracted three times with ethyl acetate and then washed with
saturated brine for one time. Then, the organic layer was concen-
trated under reduced pressure. The residue was purified by silica
gel column chromatography (30% ethyl acetate/n-hexane).
189e191 ꢀC; 1H NMR (300 MHz, DMSO-d6)
d
0.86 (3H, t, J ¼ 7.2 Hz),
1.19e1.44 (13H. m), 1.58e2.18 (3H, m), 4.20 (6H, s), 5.57 (1H, d,
J ¼ 4.2 Hz), 5.64 (1H, dt, J ¼ 4.2 Hz, 9.9 Hz), 7.64 (4H, m); 13C NMR
(100 MHz, DMSO-d6):
d 2.6, 4.5, 15.2, 33.1, 67.5, 113.8, 127.1, 132.0,
153.1; HRMS (FABþ) m/z calcd for C13H17N2O Mþ 217.1341, found.
217.1350.
4.9.1. 1-(Quinazolin-4-yl)octan-1-one (6a)
4.7.11. 2-(Cyclohexyl(hydroxy)methyl)-1,3-dimethyl-1H-benzo[d]
imidazol-3-ium iodide (3i)
Yellow oil (179 mg, 70%; entry 8, Table 2): 1H NMR (300 MHz,
CDCl3)
d
0.88 (3H, t, J ¼ 6.7 Hz),1.30e1.39 (8H, m), 1.73e1.82 (2H, td,
From the corresponding benzimidazole (245 mg, 1.0 mmol), the
title compound was obtained as a colorless solid (197 mg, 51%): Mp.
J ¼ 7.4 14.7 Hz), 3.28 (2H, t, J ¼ 7.4 Hz), 7.69e7.74 (1H, m), 7.92e7.98
(1H, m), 8.11 (1H, d, J ¼ 8.6 Hz), 8.66 (1H, ddd, J ¼ 8.6, 0.7, 0.3 Hz),
189e190 ꢀC; 1H NMR (300 MHz, DMSO-d6)
d
1.10e1.30 (6H, m),
9.41 (1H, s); 13C NMR (126 MHz, CDCl3)
d 14.1, 22.6, 23.8, 29.1, 29.2,
1.57e1.64 (2H, m), 1.72e1.78 (1H, m), 1.90e2.07 (2H, m), 4.12 (6H,
s), 5.1 (1H, dd, J ¼ 8.3 Hz, 4.5 Hz), 6.44 (1H, d, J ¼ 4.5 Hz), 7.64e7.70
31.7, 40.2, 120.9, 126.3, 128.8, 129.3, 134.2, 152.0, 154.0, 159.9, 204.1;
HRMS (FABþ) m/z calcd for C16H21N2O (M þ H)þ 257.1648, found:
257.1666.
(2H, m), 7.96e8.03 (2H, m); 13C NMR (126 MHz, DMSO-d6)
d 25.1,
Please cite this article in press as: Suzuki Y, et al., Alkanoylation of quinazoline by nucleophilic aromatic substitution: Combined experimental
and computational study, Tetrahedron (2017), https://doi.org/10.1016/j.tet.2017.11.071

Y. Suzuki et al. / Tetrahedron xxx (2017) 1e9
9
4.9.2. 1-(Quinazoline-4-yl)decan-1-one (6b)
J ¼ 0.9, 1.5 Hz), 8.12 (1H, d, J ¼ 8.4 Hz), 9.39 (1H, s); 13C NMR
(126 MHz, CDCl3) 40.0, 110.8, 122.3, 122.9, 126.3, 128.3, 128.8,
Yellow oil (157 mg, 63%; entry 7, Table 2): 1H NMR (300 MHz,
d
CDCl3)
d
0.82 (3H, t, J ¼ 6.0 Hz), 1.13e1.42 (m, 13H), 7.64 (1H, t,
132.9, 150.9, 154.0, 154.3, 166.0, 190.5.
J ¼ 15 Hz), 7.88 (1H, t, J ¼ 15 Hz), 8.04 (1H, d, J ¼ 9.0 Hz), 8.61 (1H, d,
J ¼ 9.0 Hz), 9.35 (1H, s); 13C NMR (125 MHz, CDCl3)
d 14.1, 22.6, 23.7,
Acknowledgments
27.1, 29.2, 29.4, 29.7, 31.8, 40.1, 120.1, 126.3, 128.8, 129.2, 134.1, 152.0,
154.0, 159.8, 204.1; HRMS (EIþ) m/z calcd for C18H24N2O Mþ
284.1889, found: 284.1880.
We are very appreciative of the funding received via a Grant-in-
Aid for Scientific Research on Innovative Areas “Advanced Molec-
ular Transformations by Organocatalysts” from the Japan Society
for the Promotion of Science and MEXT, Japan (24105529). H.T.
acknowledges Rikkyo SFR project, 2014e2016, and MEXT Sup-
ported Program for the Strategic Research Foundation at Private
Universities, 2013e2018. The computations in this work were
performed using the Center for Computational Sciences, University
of Tsukuba, Research Center for Computational Science, and the
facilities of the Supercomputer Center, the Institute for Solid State
Physics, the University of Tokyo.
4.9.3. 1-(Quinazolin-4-yl)hexan-1-one (6c)
Yellow oil (98 mg, 43%; entry 9, Table 2): 1H NMR (300 MHz,
CDCl3) 0.88 (3H, t, J ¼ 6.7 Hz), 1.30e1.39 (4H, m), 1.73e1.82 (2H, td,
J ¼ 7.4 14.7 Hz), 3.28 (2H, t, J ¼ 7.4 Hz), 7.69e7.74 (1H, m), 7.92e7.98
(1H, m), 8.11 (1H, d, J ¼ 8.6 Hz), 8.66 (1H, ddd, J ¼ 8.6, 0.7, 0.3 Hz),
9.41 (1H, s); 13C NMR (126 MHz, CDCl3)
d 13.9, 22.5, 23.4, 31.4, 40.1,
120.9, 126.3, 128.8, 129.3, 134.2, 151.9, 154.0, 159.9, 204.1; HRMS
(FABþ) m/z calcd for C14H17N2O (M þ H)þ 229.1341, found:
229.1334.
Appendix A. Supplementary data
4.9.4. 1-(Quinazolin-4-yl)butan-1-one (6d)16
Yellow oil (68 mg, 34%; entry 10, Table 2): 1H NMR (500 MHz,
Supplementary data related to this article can be found at
https://doi.org/10.1016/j.tet.2017.11.071.
CDCl3)
d
1.05 (3H, t, J ¼ 7.5 Hz), 1.82 (2H, q, J ¼ 7.5 Hz), 3.28 (2H, t,
J ¼ 7.5 Hz), 7.72 (1H, t, J ¼ 7.5 Hz), 7.96 (1H, t, J ¼ 7.5 Hz), 8.11 (1H, d,
J ¼ 8.6 Hz), 8.67 (1H, d, J ¼ 8.6 Hz), 9.42 (1H, s); 13C NMR (126 MHz,
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d 13.7, 17.2, 42.0120.6, 126.3,
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J ¼ 4.3 Hz), 8.66 (1H, dt, J ¼ 0.6, 4.3 Hz), 9.39 (1H, s); 13C NMR
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d 29.8, 41.6, 121.0, 126.3, 126.5, 128.55, 128.6,
128.9,129.5,134.3,140.8,152.2,154.1, 159.2, 203.1; HRMS (FABþ) m/
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4.9.6. 3-Methyl-1-(quinazolin-4-yl)but-2-en-1-one (6j)
Yellow oil (26 mg, 12%; entry 16, Table 2); 1H NMR (300 MHz,
CDCl3)
d
2.10 (3H, s), 2.39 (3H, s), 7.08 (1H, s), 7.69 (1H, t, J ¼ 7.5 Hz),
7.94 (1H, t, J ¼ 7.5 Hz), 8.10 (1H, d, J ¼ 8.7 Hz), 8.63 (1H, d, J ¼ 8.7 Hz),
9.39 (1H, s); 13C NMR (126 MHz, CDCl3)
d 21.7, 28.6, 121.8, 126.6,
128.8,128.9,134.2,151.8,153.9,162.2,162.4,191.3; HRMS (FABþ) m/z
calcd for C13H13N2O (M þ H)þ 213.1028, found. 213.1034.
4.9.7. (2-Nitrophenyl)(quinazolin-4-yl)methanone (6k)
Colorless solid (112 mg, 40%; entry 17, Table 2): Mp. 230e231 ꢀC;
1H NMR (300 MHz, CDCl3)
d
7.73e7.87 (4H, m), 7.69 (1H, dt, J ¼ 1.5,
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J ¼ 0.6, 8.7 Hz), 9.20 (1H, s); 13C NMR (126 MHz, CDCl3)
d 121.6,
123.9, 126.5, 128.8, 129.9, 130.3, 131.4, 134.5, 135.9, 147.1, 152.1,
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4.9.8. (4-(Dimethylamino)phenyl)(quinazolin-4-yl)methanone
(6m)6,17
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pound was obtained as a yellow solid (184 mg, 68%): Mp.
157e159 ꢀC; 1H NMR (300 MHz, CDCl3)
d 3.08 (6H, s), 6.65 (2H, d,
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Please cite this article in press as: Suzuki Y, et al., Alkanoylation of quinazoline by nucleophilic aromatic substitution: Combined experimental
and computational study, Tetrahedron (2017), https://doi.org/10.1016/j.tet.2017.11.071