Efficient Conversion of Tertiary Propargylamides into Imidazoles via Hydroamination-Cyclization

Article abstract of DOI:10.1055/s-0036-1591599

A method to convert tertiary N -propargylamides into 1,2,4-trisubstituted imidazoles using ammonium chloride and zinc triflate as the catalyst is reported. The method is convenient, practical and employs conventional heating. It is also applicable to N -propargyl lactams and tends to populate the so-called 'lead-like' chemistry space.

Full text of DOI:10.1055/s-0036-1591599

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–K
paper
A
en
A. Safrygin et al.
Paper
Synthesis
Efficient Conversion of Tertiary Propargylamides into Imidazoles
via Hydroamination–Cyclization
Alexander Safrygin
O
Elena Krivosheyeva
NH4Cl
Zn(OTf)2
O
Me
HO
R1
N
R2
H
R2
Dmitry Dar’in
Mikhail Krasavin*1
R1
N
R1
N
R1
N
Me
– H2O
N
R2
PhOMe
Me
N
R2
NH
Saint Petersburg State University, Saint Petersburg, 199034,
Russian Federation
20 examples
36–74%
m.krasavin@spbu.ru
Received: 15.04.2018
Accepted: 30.05.2018
Published online: 25.06.2018
DOI: 10.1055/s-0036-1591599; Art ID: ss-2018-z0257-op
a hydrogen bond as well as participating in π-stacking in-
teractions.3 This is why imidazole is likely to be explored as
a peripheral group in virtually any drug discovery program.
As a core scaffold, imidazole is similarly versatile: in addi-
tion to forming said non-covalent interactions with the bio-
target, it can project, in a spatially defined fashion, up to
four peripheral groups, all of which can be independently
varied depending on the chemistry employed to assemble
the imidazole compound.4 The diversity of clinical applica-
tions of drugs containing an imidazole moiety in their
structure is quite striking. Illustrative of this range are ther-
apeutic agents such as the anticancer agents nilotinib (1)5
and tipifarnib (2),6 the antifungals ketoconazole (3)7 and
luliconazole (4),8 the classical antibacterial nitroimidazoles
metronidazole (5) and tinidazole (6)9 and the antihyperten-
sive blockbuster drugs losartan (7) and eprosartan (8)10
(Figure 1). Considering the versatility of imidazole in drug
design, the invention of novel, flexible synthetic methods to
assemble imidazole compounds and control their peripher-
Abstract A method to convert tertiary N-propargylamides into 1,2,4-
trisubstituted imidazoles using ammonium chloride and zinc triflate as
the catalyst is reported. The method is convenient, practical and em-
ploys conventional heating. It is also applicable to N-propargyl lactams
and tends to populate the so-called ‘lead-like’ chemistry space.
Keywords N-propargylamides, hydroamination, cyclodehydration,
Lewis acid catalysis, privileged structures, imidazoles, lead-oriented
synthesis
The importance of the imidazole moiety in the design of
biologically active compounds—and ultimately, drugs—can-
not be overstated. Thus, imidazole should be regarded as a
privileged structure.2 This compact, polar, planar aromatic
motif with two nitrogen atoms can act as a partner in vari-
ous contacts with a protein target by donating or accepting
Me
Me
N
H
N
O
N
Me
N
N
O
O
N
NC
N
N
N
F3C
N
O
S
S
NH2
Cl
Cl
N
O
Cl
N
O
H
N
N
Cl
N
N
Cl
1
2
Cl
3
4
Me
Me
Me
O
O
N
S
Me
OH
Me
N
N
N
Me
HO
N
N
NH
NO2
NO2
N
N
HO2C
CO2H
N
N
N
Cl
Me
7
5
S
8
6
Figure 1 Examples of clinically used imidazole-containing drugs
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

B
A. Safrygin et al.
Paper
Synthesis
al substitution patterns remains a worthy goal in synthetic
organic chemistry.11
lar to the published results,12 using a greater amount of the
catalyst [10% Zn(OTf)2] lowered the reaction yield nearly
twofold. Using other ammonium salts led to product forma-
tion, albeit in lower (t-BuCO2NH4) or negligible (NH4OAc)
yields. Interestingly, apart from PhOMe (giving the best re-
sult), the reaction appears to be relatively insensitive to the
solvent as well as the Lewis acid catalyst [except for
AuNTf2·PPh3 (entry 7), which gave no product at all]. In-
deed, most of the GC yields listed in Table 1 are in the low to
moderate range. Notably, the Zn(OTf)2-catalyzed reaction in
toluene (entry 2) gave an extremely low product yield due
to the poor solubility of NH4Cl in this solvent. Contrasting
with this result is the high-yielding conversion of 9 into 10
conducted in toluene under microwave irradiation.12 Nota-
bly, however, the reaction appears to be distinctly sensitive
to temperature. Indeed, raising (entry 10 vs entry 3) or low-
ering (entry 9 vs entry 3) the reaction temperature gave
significantly worse results. Thus, the conditions (entry 19)
which had been established to give the best yield of 12a
were employed for the preparation of other imidazoles
12b–t (Table 2).
In 2011, Beller reported a serendipitous discovery of a
powerful method to construct polysubstituted imidazoles.12
In an attempt to hydroaminate secondary N-propargyl-
amides 9 with a primary amine using zinc triflate as the
catalyst (initially aiming at the respective imine intermedi-
ates13), 1,2,5-trisubstituted imidazoles 10 were isolated in
good yields, presumably as a result of a hydroamination–
cyclization reaction (Scheme 1). The method was expanded
to a wide scope of substrates and was recently employed for
the preparation of a large library of imidazoles (patented by
the Salk Institute for Biological Studies) as PPAR agonists
useful for the treatment of muscular, vascular, demyelinat-
ing and metabolic diseases.14
R2
O
R1
R2NH2
N
R1
NH
Me
N
Beller (2011):
Zn(OTf)2
9
10
As follows from the results presented in Table 2, the
newly developed transformation works well for a variety of
tertiary N-propargylamides 11a–r. A notable part of the re-
action scope is the ability to transform N-propargyl lactams
11s,t into the corresponding bicyclic imidazoles 12s,t. This
type of cycloalkane–imidazole fusion is of special impor-
tance in the biologically active chemical space and is pres-
ent, for example, in recently reported cyclin-dependent ki-
nase inhibitors,15 antiallergy compounds,16 and the ap-
proved drug alcaftadine (a histamine receptor antagonist)
marketed under the trade name Lastacaft for the treatment
of conjunctivitis.17 All of the starting N-propargylamide
substrates were prepared using conventional methods (see
the experimental section for details).
From a mechanistic perspective, the observed conver-
sion of N-propargylamides 11 into imidazoles 12 is likely to
involve hydroamination of the alkyne moiety followed by
dehydrative cyclization of the initial imine intermediate 13,
presumably driven by the formation of the aromatic imid-
azole nucleus (Scheme 2).
Besides having emphasized the scope, we would regard
the method described above as a transformation particular-
ly suitable for lead-oriented synthesis,18 i.e., a method that
tends to populate the chemical space corresponding to low-
er molecular weight (MW <300) and lower lipophilicity
characteristics (cLogP <3) compared to Lipinski’s rule-of-
five criteria of druglikeness (MW <500, cLogP <5).19 This al-
lows ample room for medicinal chemistry optimization,
which normally results in an increase of these crucial mo-
lecular parameters. Indeed, all the compounds synthesized
in this work have molecular weights lower than 300 and
only a few compounds (12l, 12n–q) exceed the lead-like-
ness threshold of cLogP (Figure 2).
R2
O
R1
"NH3"
R2
N
This work:
R1
N
N
catalyst
Me
12
11
Scheme 1 The hydroamination–cyclization of N-propargylamides re-
ported by Beller12 and studied in this work
One of the examples reported by Beller included the use
of gaseous ammonia (in lieu of a primary amine) in an auto-
clave, which enabled the preparation of an N-unsubstituted
imidazole.12 Inspired by this example, we became interest-
ed in identifying a practical and convenient source of am-
monia (such as ammonium salts) and then applying this
method to tertiary N-propargylamides 11 (including N-
propargyl lactams, i.e., where R1 and R2 form a cycle), which
would provide a novel route to 1,2,4-trisubstituted imidaz-
oles 12, in contrast to the 1,2,5-trisubstituted imidazoles 10
synthesized from secondary N-propargylamides and pri-
mary amines (Scheme 1). Herein, we report on the success-
ful realization of these goals.
Initial screening of the reaction conditions suitable for
carrying out the hydroamination–cyclization of tertiary N-
propargylamides was carried out for substrate 11a, which
allowed quantitative determination of the yield of the cor-
responding imidazole 12a by gas chromatography (Table 1).
The best result (entry 19) was achieved in methoxyben-
zene as the solvent with ammonium chloride as the ammo-
nia source. Prolonged conventional heating (150 °C, 40 h)
appears to be a prerequisite for a successful reaction: in
contrast to the method reported by Beller,12 conducting the
same reaction in a microwave reactor led to incomplete
conversion and, consequently, a lower yield. However, simi-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

C
A. Safrygin et al.
Paper
Synthesis
Table 1 Screening of the Hydroamination–Cyclization Reaction Conditions for the Conversion of 11a into 12aa
catalyst
solvent
N
N
Me
ammonia
source
+
N
Me
Me
12a
Me
O
Me
11a
Entry
Ammonia source
Solvent
Catalyst
T (°C)
Time (h)
Yield (%)b
1
2
NH4OAc
NH4Cl
toluene
toluene
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
PhCl
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Sc(OTf)3
Yb(OTf)3
InCl3
150
150
150
150
150
150
100
150
100
180
150
150
150
150
150
150
150
150
150
150
150
150
150
150
150
150
150
150
40
40
40
40
40
40
40
60
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
52
3
3
NH4Cl
37
21
39
33
–
4
NH4Cl
5
NH4Cl
6
NH4Cl
7
NH4Cl
AuNTf2·PPh3
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Sc(OTf)3
Sc(OTf)3
8
NH4Cl
32
–
9
NH4Cl
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
NH4Cl
complex mixture
NH4OAc
t-BuCO2NH4
Ph2C=NH
t-BuNH2
NH4Cl
4
13
–
–
48
56
38
54
72c
52
26
43
36
19
46
38
17
51
t-BuCO2NH4
NH4Cl
PhCl
1,2-C6H3Cl2
1,2-C6H3Cl2
PhOMe
t-BuCO2NH4
NH4Cl
t-BuCO2NH4
NH4Cl
PhOMe
PhCF3
t-BuCO2NH4
NH4Cl
PhCF3
pyridine
pyridine
DMAA
t-BuCO2NH4
NH4Cl
t-BuCO2NH4
NH4Cl
DMAA
(CH2OH)2
(CH2OH)2
t-BuCO2NH4
a All reactions were carried out with ammonia source (2 equiv), catalyst (5 mol%) and solvent (4 mL).
b GC yield.
c Yield of isolated product (GC yield: 85%).
O
NH4Cl
Zn(OTf)2
O
Me
HO
R1
N
R2
H
R2
R1
N
R1
N
R1
N
Me
– H2O
N
R2
PhOMe
Me
N
R2
NH
13
11
12
Scheme 2 Zn(OTf)2-catalyzed conversion of N-propargylamides 11 into imidazoles 12
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

D
A. Safrygin et al.
Paper
Synthesis
Table 2 Imidazoles 12a–t Prepared in this Work
R2
O
R1
R2
NH4Cl (2 equiv)
N
R1
N
N
Zn(OTf)2 (5 mol%)
PhOMe
150 °C, 40 h
Me
12a–t
11a–t
Entry
1
Substrate
R1
R2
Product
Yield (%)a
72
N
Me
12a
11a
Me
4-MeC6H4CH2
N
Me
Me
Me
N
Me
12b
2
3
11b
11c
Me
Me
CH3CH2CH2CH2
(CH3)2CHCH2
67
64
N
Me
Me
Me
N
Me
12c
N
Me
Me
N
Me
12d
4
5
11d
11e
Me
Me
CH3CH2CH2
(CH3)2CH
74
51
N
Me
Me
Me
N
Me
N
Me
12e
N
Me
12f
6
7
11f
Me
Me
p-Cl-C6H4CH2
p-F-C6H4CH2
62
60
N
Cl
Me
N
Me
11g
N
F
Me
12g
Me
Me
N
8
9
11h
11i
Et
(CH3)2CHCH2
71
65
Me
12h
Me
Me
N
N
Me
Me
(CH3)2CH
CH3CH2CH2CH2
N
12i
Me
Me
Me
Me
N
10
11j
(CH3)2CH
(CH3)2CHCH2
60
Me
12j
N
Me
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

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Synthesis
Table 2 (continued)
Entry
Substrate
R1
R2
Product
Yield (%)a
Me
Me
N
11
11k
11l
(CH3)2CHCH2
(CH3)2CHCH2
72
Me
Me
12k
N
Me
Me
Me
N
12
(CH3)3C
(CH3)2CHCH2
45
Me
12l
Me
Me
N
Me
Me
Me
N
13
14
11m
11n
c-C3H7
(CH3)2CHCH2
37
54
Me
12m
N
Me
N
Me
12n
Ph
CH3CH2CH2CH2
N
Me
Me
N
15
16
11o
11p
Ph
(CH3)2CHCH2
48
52
Me
N
12o
Me
Me
N
p-F-C6H4
(CH3)2CHCH2
Me
12p
N
F
Me
Me
N
17
18
11q
11r
p-MeO-C6H4
(CH3)2CHCH2
46
36
Me
12q
N
MeO
N
Me
Ph
Me
12r
N
Me
N
Me
12s
19
20
11s
11t
(CH2)5
65
68
N
N
Me
12t
(CH2)6
N
a Yield of isolated product.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

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A. Safrygin et al.
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Synthesis
N-(4-Methylbenzyl)-N-(prop-2-yn-1-yl)acetamide (11a)
Yield: 1.449 g (72%); yellow oil; Rf = 0.3.
1H NMR (400 MHz, DMSO-d6, 110 °C): δ = 7.16 (s, 4 H), 4.58 (s, 2 H),
4.09 (d, J = 2.4 Hz, 2 H), 2.93 (br s, 1 H), 2.31 (s, 3 H), 2.11 (s, 3 H).
13C NMR (101 MHz, DMSO-d6, 110 °C): δ = 170.2, 136.9, 134.7, 129.5,
127.8, 80.1, 74.4, 49.6, 36.0, 21.6, 20.9.
HRMS (ESI+): m/z [M + Na]+ calcd for C13H15NNaO: 224.1046; found:
224.1054.
N-Butyl-N-(prop-2-yn-1-yl)acetamide (11b)
Yield: 1.042 g (68%); dark yellow oil; Rf = 0.25.
1H NMR (400 MHz, DMSO-d6, 110 °C): δ = 4.12 (d, J = 2.4 Hz, 2 H), 3.37
(t, J = 7.4 Hz, 2 H), 2.94 (br s, 1 H), 2.05 (s, 3 H), 1.57 (quin, J = 7.4 Hz, 2
H), 1.33 (sext, J = 7.3 Hz, 2 H), 0.93 (t, J = 7.3 Hz, 3 H).
Figure 2 Molecular weights and cLogP parameters of compounds
12a–t. cLogP values were calculated using publicly available software
(www.molinspiration.com)
13C NMR (101 MHz, DMSO-d6, 110 °C): δ = 169.7, 80.7, 73.8, 47.0,
35.7, 30.3, 21.4, 19.9, 13.8.
In conclusion, we have developed an efficient, conve-
nient and practical method to convert tertiary N-propargyl-
amides into 1,2,4-trisubstituted imidazoles using ammoni-
um chloride and zinc triflate. The substrate scope of this
method includes N-propargyl lactams, which allows the
preparation of medicinally important cycloalkane-fused
imidazoles. The method offers a practical and convenient
alternative to the earlier reported protocol involving the
use of gaseous ammonia and an autoclave. The imidazoles
obtained in this work predominantly conform to the crite-
ria of lead-likeness, which make them suitable starting
points for medicinal chemistry optimization.
HRMS (ESI+): m/z [M + H]+ calcd for C9H16NO: 154.1226; found:
154.1225.
N-Isobutyl-N-(prop-2-yn-1-yl)acetamide (11c)
Yield: 1.088 g (71%); orange oil; Rf = 0.25.
1H NMR (400 MHz, DMSO-d6, 110 °C): δ = 4.12 (d, J = 2.5 Hz, 2 H), 3.21
(d, J = 7.4 Hz, 2 H), 2.95 (br s, 1 H), 2.06 (s, 3 H), 1.99 (nonet, J = 6.8 Hz,
1 H), 0.90 (d, J = 6.7 Hz, 6 H).
13C NMR (101 MHz, DMSO-d6, 110 °C): δ = 170.1, 80.6, 73.9, 54.7,
36.6, 27.2, 21.6, 20.2.
HRMS (ESI+): m/z [M + H]+ calcd for C9H16NO: 154.1226; found:
154.1230.
N-(Prop-2-yn-1-yl)-N-propylacetamide (11d)
Yield: 0.487 g (35%); orange oil; Rf = 0.2.
1H NMR (400 MHz, DMSO-d6, 110 °C): δ = 4.12 (d, J = 2.5 Hz, 2 H), 3.34
(t, J = 7.4 Hz, 2 H), 2.94 (br s, 1 H), 2.05 (s, 3 H), 1.60 (sext, J = 7.4 Hz, 2
H), 0.89 (t, J = 7.4 Hz, 3 H).
13C NMR (101 MHz, DMSO-d6, 110 °C): δ = 169.7, 80.7, 73.8, 48.9,
36.0, 21.4, 21.3, 11.3.
Column chromatography was performed on Merck silica gel 60 (230–
400 mesh). TLC analysis was performed using Sorbfil UV254 silica gel
coated plates. Melting points were measured with a SMP 50 instru-
ment and are uncorrected. NMR spectroscopic data were recorded
with a Bruker Avance III 400 MHz (400.13 MHz for 1H and 100.61
MHz for 13C) spectrometer in CDCl3 or DMSO-d6 and were referenced
to residual solvent signals (δH = 7.26 and δC = 77.2 for CDCl3; δH = 2.51
and δC = 40.6 for DMSO-d6). Coupling constants (J) are reported in Hz.
Mass spectra were recorded with a Bruker QTOF maXis II HRMS-ESI-
qTOF spectrometer (electrospray ionization mode).
HRMS (ESI+): m/z [M + H]+ calcd for C8H14NO: 140.1070; found:
140.1073.
N-Isopropyl-N-(prop-2-yn-1-yl)acetamide (11e)
Yield: 0.445 g (32%); orange oil; Rf = 0.2.
1H NMR (400 MHz, DMSO-d6, 110 °C): δ = 4.38 (br s, 1 H), 4.01 (d, J =
2.4 Hz, 2 H), 2.88 (br s, 1 H), 2.07 (s, 3 H), 1.19 (d, J = 6.7 Hz, 6 H).
13C NMR (101 MHz, DMSO-d6, 110 °C): δ = 169.5, 82.4, 72.9, 47.0,
31.2, 22.0, 20.6.
N-Propargyl Amides 11a–q; General Procedure
A mixture of the corresponding aldehyde (or acetone for 11d) (10
mmol), propargyl amine (10 mmol, 551 mg) and anhydrous MgSO4
(500 mg) in CH2Cl2 (5 mL) was stirred at r.t. overnight. The solids were
filtered off and washed twice with CH2Cl2. After removal of the sol-
vent in vacuo, the residue was dissolved in MeOH (8 mL). NaBH4 (15
mmol, 567 mg) was added in portions and the resulting mixture was
stirred at r.t. for 2 h. H2O (20 mL) was added and the mixture was ex-
tracted with CH2Cl2 (2 × 20 mL). The combined organic extracts were
washed with brine (20 mL) and sat. aq NaHCO3 (20 mL), dried over
anhydrous MgSO4 and concentrated to a volume of 25 mL. The solu-
tion was cooled in an ice bath, Et3N (20 mmol, 2.024 g) was added fol-
lowed by slow addition of the corresponding acyl chloride (10 mmol)
with stirring. The mixture was stirred for an additional 2 h at r.t.,
washed with H2O (20 mL), brine (20 mL) and sat. aq NaHCO3 (2 × 20
mL) and concentrated in vacuo. The residue was purified by column
chromatography using n-hexane/EtOAc (1:1) as eluent.
HRMS (ESI+): m/z [M + H]+ calcd for C8H14NO: 140.1070; found:
140.1065.
N-(4-Chlorobenzyl)-N-(prop-2-yn-1-yl)acetamide (11f)
Yield: 1.840 g (83%); dark yellow oil; Rf = 0.25.
1H NMR (400 MHz, DMSO-d6, 110 °C): δ = 7.40–7.36 (m, 2 H), 7.32–
7.28 (m, 2 H), 4.61 (s, 2 H), 4.13 (d, J = 2.4 Hz, 2 H), 2.98 (br s, 1 H),
2.12 (s, 3 H).
13C NMR (101 MHz, DMSO-d6, 110 °C): δ = 170.3, 136.9, 132.5, 129.7,
128.8, 80.0, 74.7, 49.5, 36.8, 21.6.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

G
A. Safrygin et al.
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Synthesis
HRMS (ESI+): m/z [M + Na]+ calcd for C12H12ClNNaO: 244.0500; found:
244.0509.
N-Isobutyl-N-(prop-2-yn-1-yl)pivalamide (11l)
Yield: 1.191 g (61%); yellow oil; Rf = 0.6.
1H NMR (400 MHz, CDCl3): δ = 4.23 (d, J = 2.4 Hz, 2 H), 3.34 (d, J = 7.6
Hz, 2 H), 2.23 (t, J = 2.4 Hz, 1 H), 2.07 (nonet, J = 7.0 Hz, 1 H), 1.33 (s, 9
H), 0.93 (d, J = 6.7 Hz, 6 H).
N-(4-Fluorobenzyl)-N-(prop-2-yn-1-yl)acetamide (11g)
Yield: 1.170 g (57%); dark yellow oil; Rf = 0.25.
1H NMR (400 MHz, DMSO-d6, 110 °C): δ = 7.35–7.29 (m, 2 H), 7.16–
13C NMR (101 MHz, CDCl3): δ = 177.5, 79.4, 71.8, 54.0, 39.0, 37.4, 28.6,
7.09 (m, 2 H), 4.60 (s, 2 H), 4.12 (d, J = 2.4 Hz, 2 H), 2.97 (br s, 1 H),
26.4, 20.0.
2.12 (s, 3 H).
HRMS (ESI+): m/z [M + Na]+ calcd for C12H21NNaO: 218.1515; found:
218.1522.
13C NMR (101 MHz, DMSO-d6, 110 °C): δ = 170.3, 162.1 (d, JC–F
=
1
243.5 Hz), 134.0, 129.9, 115.5 (d, 2JC–F = 21.2 Hz), 80.0, 74.5, 49.4, 36.6,
21.6.
N-Isobutyl-N-(prop-2-yn-1-yl)cyclopropanecarboxamide (11m)
Yield: 1.524 g (85%); light yellow oil; Rf = 0.25.
1H NMR (400 MHz, DMSO-d6, 110 °C): δ = 4.22 (br s, 2 H), 3.34 (d, J =
7.2 Hz, 2 H), 2.94 (br s, 1 H), 2.04 (nonet, J = 6.8 Hz, 1 H), 1.96–1.88 (m,
1 H), 0.92 (d, J = 6.7 Hz, 6 H), 0.83–0.72 (m, 4 H).
13C NMR (101 MHz, DMSO-d6, 110 °C): δ = 173.0, 80.8, 73.8, 54.3,
36.7, 27.4, 20.2, 11.6, 7.6.
HRMS (ESI+): m/z [M + Na]+ calcd for C12H12FNNaO: 228.0795; found:
228.0806.
N-Isobutyl-N-(prop-2-yn-1-yl)propionamide (11h)
Yield: 1.371 g (82%); yellow oil; Rf = 0.4.
1H NMR (400 MHz, DMSO-d6, 110 °C): δ = 4.13 (d, J = 2.5 Hz, 2 H), 3.22
(d, J = 7.4 Hz, 2 H), 2.94 (br s, 1 H), 2.38 (q, J = 7.4 Hz, 2 H), 1.99 (nonet,
J = 6.9 Hz, 1 H), 1.06 (t, J = 7.4 Hz, 3 H), 0.90 (d, J = 6.7 Hz, 6 H).
HRMS (ESI+): m/z [M + H]+ calcd for C11H18NO: 180.1383; found:
180.1389.
13C NMR (101 MHz, DMSO-d6, 110 °C): δ = 173.4, 80.7, 73.8, 54.0,
36.4, 27.1, 26.1, 20.2, 9.6.
HRMS (ESI+): m/z [M + Na]+ calcd for C10H17NNaO: 190.1202; found
190.1207.
N-Butyl-N-(prop-2-yn-1-yl)benzamide (11n)
Yield: 1.615 g (75%); yellow viscous oil; Rf = 0.5.
1H NMR (400 MHz, DMSO-d6, 110 °C): δ = 7.49–7.43 (m, 3 H), 7.42–
7.37 (m, 2 H), 4.17 (d, J = 1.9 Hz, 2 H), 3.43 (t, J = 7.3, 2 H), 3.03 (t, J =
2.3 Hz, 1 H), 1.62 (quin, J = 7.4 Hz, 2 H), 1.28 (sext, J = 7.3 Hz, 2 H), 0.86
(t, J = 7.4 Hz, 3 H).
N-Butyl-N-(prop-2-yn-1-yl)isobutyramide (11i)
Yield: 1.106 g (61%); light orange oil; Rf = 0.5.
1H NMR (400 MHz, DMSO-d6, 110 °C): δ = 4.14 (br s, 2 H), 3.37 (t, J =
7.4 Hz, 2 H), 3.09 (s, 1 H), 2.86 (br s, 1 H), 1.54 (br s, 2 H), 1.30 (sext, J =
7.1 Hz, 2 H), 1.04 (d, J = 6.7 Hz, 6 H), 0.92 (t, J = 7.3 Hz, 3 H).
13C NMR (101 MHz, DMSO-d6, 110 °C): δ = 170.8, 137.0, 129.8, 128.8,
126.9, 80.3, 74.5, 47.0, 36.8, 29.9, 19.8, 13.7.
HRMS (ESI+): m/z [M + H]+ calcd for C14H18NO: 216.1383; found:
216.1379.
13C NMR (101 MHz, DMSO-d6, 110 °C): δ = 176.4, 80.9, 73.7, 46.5,
35.9, 30.5, 29.9, 19.9, 13.8.
HRMS (ESI+): m/z [M + H]+ calcd for C11H20NO: 182.1539; found:
182.1531.
N-Isobutyl-N-(prop-2-yn-1-yl)benzamide (11o)
Yield: 1.744 g (81%); dark yellow viscous oil; Rf = 0.5.
1H NMR (400 MHz, DMSO-d6, 110 °C): δ = 7.48–7.43 (m, 3 H), 7.43–
7.37 (m, 2 H), 4.16 (d, J = 2.3 Hz, 2 H), 3.31 (d, J = 7.4 Hz, 2 H), 3.03 (t,
J = 2.4 Hz, 1 H), 2.07 (nonet, J = 6.9 Hz, 1 H), 0.88 (d, J = 6.7 Hz, 6 H).
N-Isobutyl-N-(prop-2-yn-1-yl)isobutyramide (11j)
Yield: 1.178 g (65%); yellow oil; Rf = 0.5.
1H NMR (400 MHz, DMSO-d6, 110 °C): δ = 4.14 (d, J = 2.5 Hz, 2 H), 3.23
(d, J = 7.4 Hz, 2 H), 2.95 (s, 1 H), 2.91 (sept, J = 6.7 Hz, 1 H), 1.99 (nonet,
J = 6.9 Hz, 1 H), 1.06 (d, J = 6.7 Hz, 6 H), 0.89 (d, J = 6.7 Hz, 6 H).
13C NMR (101 MHz, DMSO-d6, 110 °C): δ = 171.2, 137.1, 130.0, 128.8,
127.0, 80.1, 74.6, 54.3, 37.6, 26.8, 20.3.
HRMS (ESI+): m/z [M + H]+ calcd for C14H18NO: 216.1383; found:
216.1389.
13C NMR (101 MHz, DMSO-d6, 110 °C): δ = 176.8, 80.8, 73.9, 53.9,
36.5, 30.0, 27.2, 20.2, 19.9.
HRMS (ESI+): m/z [M + H]+ calcd for C11H20NO: 182.1539; found:
182.1536.
4-Fluoro-N-isobutyl-N-(prop-2-yn-1-yl)benzamide (11p)
Yield: 1.143 g (49%); yellow viscous oil; Rf = 0.6.
1H NMR (400 MHz, DMSO-d6, 110 °C): δ = 7.50–7.43 (m, 2 H), 7.28–
7.21 (m, 2 H), 4.15 (d, J = 2.1 Hz, 2 H), 3.30 (d, J = 7.4 Hz, 2 H), 3.04 (t,
J = 2.4 Hz, 1 H), 2.06 (nonet, J = 6.8 Hz, 1 H), 0.88 (d, J = 6.6 Hz, 6 H).
1
N-Isobutyl-3-methyl-N-(prop-2-yn-1-yl)butanamide (11k)
Yield: 1.602 g (82%); yellow oil; Rf = 0.5.
1H NMR (400 MHz, DMSO-d6, 110 °C): δ = 4.13 (d, J = 2.4 Hz, 2 H), 3.22
(d, J = 7.4 Hz, 2 H), 2.94 (br s, 1 H), 2.26 (d, J = 6.8 Hz, 2 H), 2.10 (nonet,
J = 6.7 Hz, 1 H), 1.99 (nonet, J = 6.9 Hz, 1 H), 0.95 (d, J = 6.6 Hz, 6 H),
0.90 (d, J = 6.7 Hz, 6 H).
13C NMR (101 MHz, DMSO-d6, 110 °C): δ = 170.3, 163.1 (d, JC–F
=
4
3
247.1 Hz), 133.4 (d, JC–F = 3.1 Hz), 129.6 (d, JC–F = 8.5 Hz), 115.7 (d,
2JC–F = 21.8 Hz), 80.0, 74.7, 54.5, 37.8, 26.8, 20.3.
HRMS (ESI+): m/z [M + H]+ calcd for C14H17FNO: 234.1289; found:
234.1300.
13C NMR (101 MHz, DMSO-d6, 110 °C): δ = 172.0, 80.7, 73.8, 54.0,
41.9, 36.6, 27.2, 25.6, 22.8, 20.2.
HRMS (ESI+): m/z [M + Na]+ calcd for C12H21NNaO: 218.1515; found:
218.1523.
N-Isobutyl-4-methoxy-N-(prop-2-yn-1-yl)benzamide (11q)
Yield: 0.957 g (39%); light yellow viscous oil; Rf = 0.4.
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1H NMR (400 MHz, DMSO-d6, 110 °C): δ = 7.40–7.35 (m, 2 H), 7.02–
6.97 (m, 2 H), 4.16 (d, J = 2.4 Hz, 2 H), 3.83 (s, 3 H), 3.32 (d, J = 7.4 Hz,
2 H), 3.03 (t, J = 2.4 Hz, 1 H), 2.07 (nonet, J = 6.8 Hz, 1 H), 0.88 (d, J =
6.7 Hz, 6 H).
13C NMR (101 MHz, DMSO-d6, 110 °C): δ = 171.1, 160.9, 129.2, 129.0,
114.4, 80.3, 74.6, 55.9, 54.5, 37.8, 26.8, 20.3.
HRMS (ESI+): m/z [M + Na]+ calcd for C10H15NNaO: 188.1046; found:
188.1054.
Imidazoles 12a–t; General Procedure
A mixture of the corresponding N-propargyl amide 11 (1 mmol),
NH4Cl (2 mmol, 107 mg) and Zn(OTf)2 triflate (0.05 mmol, 18 mg) in
anhydrous anisole (4 mL) was heated in an oil bath at 150 °C with
stirring for 40 h. The solvent was evaporated under reduced pressure.
The residue was partitioned between EtOAc (15 mL) and sat. aq NaH-
CO3 (15 mL) and the aq phase was additionally extracted with EtOAc
(2 × 10 mL). The combined organic phases were concentrated in vac-
uo and the residue was purified by column chromatography on silica
gel using the indicated eluent.
HRMS (ESI+): m/z [M + H]+ calcd for C15H20NO2: 246.1489; found:
246.1492.
N-Phenyl-N-(prop-2-yn-1-yl)acetamide (11r)
To a mixture of N-phenylacetamide (10 mmol, 1.35 g) and anhydrous
DMF (15 mL) was slowly added NaH (60% suspension in mineral oil,
10 mmol, 0.40 g) while stirring. Stirring was continued at r.t. for 2 h.
Propargyl bromide (14 mmol, 1.67 g) was then added dropwise. The
resulting mixture was stirred at r.t. for 3 h. The solvent was evaporat-
ed, H2O (50 mL) and Et2O (50 mL) were added, and the mixture was
shaken thoroughly. The organic layer was separated, the solvent re-
moved, and the residue purified by column chromatography with n-
hexane/EtOAc (1:1) as eluent.
2,4-Dimethyl-1-(4-methylbenzyl)-1H-imidazole (12a)
Eluted with EtOAc/EtOH (10:1).
Yield: 144 mg (72%); brown viscous oil; Rf = 0.1.
1H NMR (400 MHz, CDCl3): δ = 7.16 (br d, J = 7.9 Hz, 2 H), 6.98 (br d, J =
7.9 Hz, 2 H), 6.54 (br s, 1 H), 4.95 (s, 2 H), 2.35 (s, 3 H), 2.34 (s, 3 H),
2.20 (br s, 3 H).
Yield: 1.213 g (70%); light yellow crystals; mp 74–75 °C; Rf = 0.35.
1H NMR (400 MHz, CDCl3): δ = 7.49–7.38 (m, 3 H), 7.33–7.28 (m, 2 H),
4.50 (d, J = 2.2 Hz, 2 H), 2.22 (t, J = 2.2 Hz, 1 H), 1.89 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 144.0, 137.8, 135.5, 133.3, 129.6,
126.8, 116.2, 49.4, 21.1, 13.1, 12.7.
13C NMR (101 MHz, CDCl3): δ = 170.1, 142.3, 129.7, 128.4, 128.1, 79.2,
HRMS (ESI+): m/z [M + H]+ calcd for C13H17N2: 201.1386; found:
72.0, 38.2, 22.4.
201.1385.
HRMS (ESI+): m/z [M + Na]+ calcd for C11H11NNaO: 196.0733; found:
196.0742.
1-Butyl-2,4-dimethyl-1H-imidazole (12b)
Eluted with EtOAc/EtOH (10:1).
N-Propargyl Lactams 11s,t; General Procedure
Yield: 102 mg (67%); brown viscous oil; Rf = 0.1.
To a stirred solution of the corresponding lactam (10 mmol) in anhy-
drous THF (50 mL) was added NaH (60% suspension in mineral oil, 12
mmol, 0.48 g) in portions. The stirring was continued at r.t. for 45 min
and then propargyl bromide (20 mmol, 2.379 g) was added dropwise.
The resulting mixture was heated at reflux for 4 h, cooled to r.t. and
stirred overnight. The solvent was evaporated and the residue was
treated with Et2O (50 mL), filtered through a small bed of Celite
(which was then washed twice with Et2O). The filtrate and washings
were combined, the solvent removed under reduced pressure and the
residue purified by column chromatography on silica gel using n-hex-
ane/EtOAc (1:1) as eluent.
1H NMR (400 MHz, CDCl3): δ = 6.51 (br s, 1 H), 3.75 (t, J = 7.2 Hz, 2 H),
2.34 (s, 3 H), 2.17 (br s, 3 H), 1.68 (quin, J = 7.4 Hz, 2 H), 1.34 (sext, J =
7.4 Hz, 2 H), 0.95 (t, J = 7.4 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 143.4, 135.5, 115.3, 45.6, 32.8, 19.8,
13.6, 13.3, 12.8.
HRMS (ESI+): m/z [M + H]+ calcd for C9H17N2: 153.1386; found:
153.1379.
1-Isobutyl-2,4-dimethyl-1H-imidazole (12c)
Eluted with EtOAc/EtOH (10:1).
Yield: 97 mg (64%); brown viscous oil; Rf = 0.1.
1-(Prop-2-yn-1-yl)azepan-2-one (11s)
1H NMR (400 MHz, CDCl3): δ = 6.49 (br s, 1 H), 3.55 (d, J = 7.4 Hz, 2 H),
2.33 (s, 3 H), 2.18 (br s, 3 H), 1.98 (nonet, J = 6.8 Hz, 1 H), 0.92 (d, J =
6.7 Hz, 6 H).
13C NMR (101 MHz, CDCl3): δ = 143.7, 135.5, 115.8, 53.3, 29.9, 19.9,
13.4, 13.0.
Yield: 1.285 g (85%); yellow viscous oil; Rf = 0.25.
1H NMR (400 MHz, CDCl3): δ = 4.24 (d, J = 2.5 Hz, 2 H), 3.50–3.44 (m, 2
H), 2.57–2.51 (m, 2 H), 2.19 (t, J = 2.5 Hz, 1 H), 1.78–1.65 (m, 6 H).
13C NMR (101 MHz, CDCl3): δ = 175.4, 79.3, 71.3, 48.7, 36.9, 36.3, 29.9,
28.2, 23.2.
HRMS (ESI+): m/z [M + H]+ calcd for C9H17N2: 153.1386; found:
153.1389.
HRMS (ESI+): m/z [M + Na]+ calcd for C9H13NNaO: 174.0889; found:
174.0897.
1-Propyl-2,4-dimethyl-1H-imidazole (12d)
Eluted with EtOAc/EtOH (10:1).
1-(Prop-2-yn-1-yl)azocan-2-one (11t)
Yield: 0.744 g (45%); light yellow crystals; mp 75–76 °C; Rf = 0.25.
Yield: 102 mg (74%); brown viscous oil; Rf = 0.1.
1H NMR (400 MHz, CDCl3): δ = 4.22 (d, J = 2.4 Hz, 2 H), 3.67–3.60 (m, 2
H), 2.56–2.48 (m, 2 H), 2.21 (t, J = 2.5 Hz, 1 H), 1.85–1.69 (m, 4 H),
1.60–1.45 (m, 4 H).
13C NMR (101 MHz, CDCl3): δ = 174.6, 79.3, 71.6, 46.4, 34.1, 33.8, 28.9,
28.8, 26.2, 24.3.
1H NMR (400 MHz, CDCl3): δ = 6.51 (br s, 1 H), 3.72 (t, J = 7.2 Hz, 2 H),
2.33 (s, 3 H), 2.17 (br s, 3 H), 1.73 (sext, J = 7.3 Hz, 2 H), 0.93 (t, J = 7.4
Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 143.5, 135.6, 115.3, 47.4, 24.0, 13.3,
12.8, 11.1.
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HRMS (ESI+): m/z [M + H]+ calcd for C8H15N2: 139.1230; found:
HRMS (ESI+): m/z [M + H]+ calcd for C11H21N2: 181.1699; found:
139.1234.
181.1695.
1-Isopropyl-2,4-dimethyl-1H-imidazole (12e)
Eluted with EtOAc/EtOH (10:1).
1-Isobutyl-2-isopropyl-4-methyl-1H-imidazole (12j)
Eluted with EtOAc.
Yield: 70 mg (51%), brown viscous oil; Rf = 0.1.
Yield: 108 mg (60%); dark brown viscous oil; Rf = 0.25.
1H NMR (400 MHz, CDCl3): δ = 6.59 (br s, 1 H), 4.23 (sept, J = 6.8 Hz, 1
H), 2.35 (s, 3 H), 2.18 (br s, 3 H), 1.38 (d, J = 6.7 Hz, 6 H).
13C NMR (101 MHz, CDCl3): δ = 142.7, 135.8, 110.9, 47.1, 23.3, 13.4,
1H NMR (400 MHz, CDCl3): δ = 6.45 (br s, 1 H), 3.57 (d, J = 7.5 Hz, 2 H),
2.93 (sept, J = 6.9 Hz, 1 H), 2.19 (br s, 3 H), 1.97 (nonet, J = 6.9 Hz, 1 H),
1.30 (d, J = 6.9 Hz, 6 H), 0.91 (d, J = 6.7 Hz, 6 H).
12.9.
13C NMR (101 MHz, CDCl3): δ = 152.4, 135.6, 115.3, 52.7, 30.1, 25.7,
22.0, 20.0, 13.6.
HRMS (ESI+): m/z [M + H]+ calcd for C8H15N2: 139.1230; found:
139.1232.
HRMS (ESI+): m/z [M + H]+ calcd for C11H21N2: 181.1699; found:
181.1705.
1-(4-Chlorobenzyl)-2,4-dimethyl-1H-imidazole (12f)
Eluted with EtOAc/EtOH (10:1).
1,2-Diisobutyl-4-methyl-1H-imidazole (12k)
Eluted with EtOAc.
Yield: 137 mg (62%); light brown crystals; mp 93–94 °C; Rf = 0.1.
Yield: 140 mg (72%); dark brown viscous oil; Rf = 0.2.
1H NMR (400 MHz, CDCl3): δ = 7.35–7.30 (m, 2 H), 7.03–6.98 (m, 2 H),
6.53 (br s, 1 H), 4.96 (s, 2 H), 2.31 (s, 3 H), 2.20 (br s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 144.0, 136.4, 135.1, 133.8, 129.1,
128.0, 116.0, 48.9, 13.5, 13.0.
HRMS (ESI+): m/z [M + H]+ calcd for C12H14ClN2: 221.0840; found:
1H NMR (400 MHz, CDCl3): δ = 6.47 (br s, 1 H), 3.55 (d, J = 7.5 Hz, 2 H),
2.47 (d, J = 7.3 Hz, 2 H), 2.20 (br s, 3 H), 2.14 (nonet, J = 6.8 Hz, 1 H),
1.98 (nonet, J = 6.9 Hz, 1 H), 0.96 (d, J = 6.6 Hz, 6 H), 0.91 (d, J = 6.7 Hz,
6 H).
13C NMR (101 MHz, CDCl3): δ = 147.0, 135.8, 115.3, 53.1, 35.8, 30.0,
28.4, 22.6, 20.0, 13.6.
221.0835.
HRMS (ESI+): m/z [M + H]+ calcd for C12H23N2: 195.1856; found:
195.1855.
1-(4-Fluorobenzyl)-2,4-dimethyl-1H-imidazole (12g)
Eluted with EtOAc/EtOH (10:1).
Yield: 123 mg (60%); dark brown viscous oil; Rf = 0.1.
1H NMR (400 MHz, CDCl3): δ = 7.08–7.01 (m, 4 H), 6.53 (br s, 1 H),
4.95 (s, 2 H), 2.31 (s, 3 H), 2.19 (br s, 3 H).
2-(tert-Butyl)-1-isobutyl-4-methyl-1H-imidazole (12l)
Eluted with EtOAc.
Yield: 87 mg (45%); dark brown viscous oil; Rf = 0.3.
1
13C NMR (101 MHz, CDCl3): δ = 162.3 (d, JC–F = 246.6 Hz), 144.0,
1H NMR (400 MHz, CDCl3): δ = 6.55 (br s, 1 H), 3.76 (d, J = 7.6 Hz, 2 H),
2.19 (br s, 3 H), 2.10 (nonet, J = 6.8 Hz, 1 H), 1.43 (s, 9 H), 0.97 (d, J =
6.7 Hz, 6 H).
13C NMR (101 MHz, CDCl3): δ = 153.5, 134.6, 116.9, 54.3, 33.3, 30.3,
29.9, 20.2, 13.6.
136.2, 132.3 (d, 4JC–F = 3.2 Hz), 128.4 (d, 3JC–F = 8.2 Hz), 116.0, 115.9 (d,
2JC–F = 21.7 Hz), 48.9, 13.3, 12.9.
HRMS (ESI+): m/z [M + H]+ calcd for C12H14FN2: 205.1136; found:
205.1140.
HRMS (ESI+): m/z [M + H]+ calcd for C12H23N2: 195.1856; found:
195.1860.
2-Ethyl-1-isobutyl-4-methyl-1H-imidazole (12h)
Eluted with EtOAc.
Yield: 118 mg (71%); orange viscous oil; Rf = 0.15.
2-Cyclopropyl-1-isobutyl-4-methyl-1H-imidazole (12m)
Eluted with EtOAc/n-hexane (1:1).
1H NMR (400 MHz, CDCl3): δ = 6.49 (br s, 1 H), 3.56 (d, J = 7.5 Hz, 2 H),
2.64 (q, J = 7.6 Hz, 2 H), 2.20 (br s, 3 H), 1.99 (nonet, J = 6.9 Hz, 1 H),
1.32 (t, J = 7.6 Hz, 3 H), 0.92 (d, J = 6.7 Hz, 6 H).
13C NMR (101 MHz, CDCl3): δ = 148.6, 135.6, 115.7, 53.0, 30.0, 20.1,
20.0, 13.5, 12.5.
Yield: 66 mg (37%); orange viscous oil; Rf = 0.1.
1H NMR (400 MHz, CDCl3): δ = 6.49 (br s, 1H), 3.70 (d, J = 7.4 Hz, 2 H),
2.16 (br s, 3 H), 2.07 (nonet, J = 6.6 Hz, 1 H), 1.73 (tt, J = 8.3, 5.0 Hz, 1
H), 1.03–0.98 (m, 2 H), 0.95 (d, J = 6.7 Hz, 6 H), 0.94–0.88 (m, 2 H).
13C NMR (101 MHz, CDCl3): δ = 148.5, 135.3, 116.0, 52.9, 30.0, 20.1,
13.6, 7.2, 6.9.
HRMS (ESI+): m/z [M + H]+ calcd for C10H19N2: 167.1543; found:
167.1546.
HRMS (ESI+): m/z [M + H]+ calcd for C11H19N2: 179.1543; found:
179.1549.
1-Butyl-2-isopropyl-4-methyl-1H-imidazole (12i)
Eluted with EtOAc.
Yield: 117 mg (65%); dark brown viscous oil; Rf = 0.25.
1-Butyl-4-methyl-2-phenyl-1H-imidazole (12n)
Eluted with EtOAc/n-hexane (1:1).
1H NMR (400 MHz, CDCl3): δ = 6.49 (br s, 1 H), 3.78 (t, J = 7.4 Hz, 2 H),
2.96 (sept, J = 6.9 Hz, 1 H), 2.21 (br s, 3 H), 1.70 (quin, J = 7.5 Hz, 2 H),
1.36 (sext, J = 7.7 Hz, 2 H), 1.33 (d, J = 6.9 Hz, 6 H), 0.96 (t, J = 7.4 Hz, 3
H).
13C NMR (101 MHz, CDCl3): δ = 152.0, 135.6, 114.8, 45.0, 33.3, 25.7,
21.9, 19.9, 13.7, 13.5.
Yield: 116 mg (54%); light brown viscous oil; Rf = 0.2.
1H NMR (400 MHz, CDCl3): δ = 7.59–7.54 (m, 2 H), 7.47–7.36 (m, 3 H),
6.74 (br s, 1 H), 3.93 (t, J = 7.5 Hz, 2 H), 2.30 (br s, 3 H), 1.72 (quin, J =
7.5 Hz, 2 H), 1.29 (sext, J = 7.4 Hz, 2 H), 0.88 (t, J = 7.4 Hz, 3 H).
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13C NMR (101 MHz, CDCl3): δ = 147.0, 137.4, 131.2, 128.8, 128.4,
13C NMR (101 MHz, CDCl3): δ = 149.7, 134.4, 117.2, 48.1, 30.8, 29.2,
116.8, 46.3, 33.2, 19.8, 13.7, 13.5.
29.0, 25.8, 13.1.
HRMS (ESI+): m/z [M + H]+ calcd for C14H19N2: 215.1543; found:
HRMS (ESI+): m/z [M + H]+ calcd for C9H15N2: 151.1230; found:
215.1553.
151.1230.
1-Isobutyl-4-methyl-2-phenyl-1H-imidazole (12o)
Eluted with EtOAc/n-hexane (1:1).
2-Methyl-5,6,7,8,9,10-hexahydroimidazo[1,2-a]azocine (12t)
Eluted with EtOAc/EtOH (10:1).
Yield: 103 mg (48%); dark brown viscous oil; Rf = 0.2.
Yield: 112 mg (68%); light yellow viscous oil; Rf = 0.1.
1H NMR (400 MHz, CDCl3): δ = 7.59–7.54 (m, 2 H), 7.47–7.37 (m, 3 H),
6.72 (br s, 1 H), 3.75 (d, J = 7.5 Hz, 2 H), 2.29 (br s, 3 H), 1.98 (nonet, J =
6.9 Hz, 1 H), 0.83 (d, J = 6.7 Hz, 6 H).
1H NMR (400 MHz, CDCl3): δ = 6.46 (br s, 1 H), 3.94–3.90 (m, 2 H),
2.80–2.75 (m, 2 H), 2.19 (br s, 3 H), 1.81–1.70 (m, 4 H), 1.49–1.41 (m,
2 H), 1.32–1.24 (m, 2 H).
13C NMR (101 MHz, CDCl3): δ = 147.3, 137.2, 131.4, 129.0, 128.4,
13C NMR (101 MHz, CDCl3): δ = 148.8, 136.2, 115.0, 43.9, 31.7, 31.3,
117.2, 54.0, 30.1, 19.9, 13.7.
26.2, 25.6, 23.8, 13.5.
HRMS (ESI+): m/z [M + H]+ calcd for C14H19N2: 215.1543; found:
HRMS (ESI+): m/z [M + H]+ calcd for C10H17N2: 165.1386; found:
215.1546.
165.1381.
2-(4-Fluorophenyl)-1-isobutyl-4-methyl-1H-imidazole (12p)
Eluted with EtOAc/n-hexane (1:1).
Funding Information
Yield: 121 mg (52%); light brown crystals; mp 52–53 °C; Rf = 0.2.
This research was supported by the Russian Scientific Foundation
(project grant 14-50-00069). A.S. is grateful to Saint Petersburg State
1H NMR (400 MHz, CDCl3): δ = 7.55–7.49 (m, 2 H), 7.16–7.09 (m, 2 H),
6.70 (br s, 1 H), 3.71 (d, J = 7.5 Hz, 2 H), 2.28 (br s, 3 H), 1.95 (nonet, J =
6.9 Hz, 1 H), 0.82 (d, J = 6.7 Hz, 6 H).
University for a postdoctoral fellowship.
)(
13C NMR (101 MHz, CDCl3): δ = 162.8 (d, JC–F = 248.3 Hz), 146.4,
1
Acknowledgment
137.3, 130.9 (d, 3JC–F = 8.1 Hz), 127.6 (d, 4JC–F = 3.2 Hz), 117.3, 115.5 (d,
2JC–F = 21.7 Hz), 54.0, 30.1, 19.9, 13.6.
We thank the Research Center for Magnetic Resonance and the Center
for Chemical Analysis and Materials Research of Saint Petersburg
State University Research Park for the analytical data.
HRMS (ESI+): m/z [M + H]+ calcd for C14H18FN2: 233.1449; found:
233.1457.
1-Isobutyl-2-(4-methoxyphenyl)-4-methyl-1H-imidazole (12q)
Eluted with EtOAc/n-hexane (1:1).
Supporting Information
Yield: 112 mg (46%); light brown viscous oil; Rf = 0.3.
Supporting information for this article is available online at
1H NMR (400 MHz, CDCl3): δ = 7.50–7.45 (m, 2 H), 6.98–6.93 (m, 2 H),
6.68 (br s, 1 H), 3.85 (s, 3 H), 3.71 (d, J = 7.5 Hz, 2 H), 2.27 (br s, 3 H),
1.96 (nonet, J = 6.9 Hz, 1 H), 0.82 (d, J = 6.7 Hz, 6 H).
https://doi.org/10.1055/s-0036-1591599.
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References
13C NMR (101 MHz, CDCl3): δ = 159.7, 147.2, 136.9, 130.4, 123.8,
116.9, 113.8, 55.3, 54.0, 30.0, 19.9, 13.6.
HRMS (ESI+): m/z [M + H]+ calcd for C15H21N2O: 245.1648; found:
245.1657.
(1) Address correspondence to Mikhail Krasavin at the Laboratory
of Chemical Pharmacology, Institute of Chemistry, Saint Peters-
burg State University, 26 Universitetskyi prospekt, Peterhof
198504, Russian Federation.
(2) Privileged Structures in Drug Discovery: Medicinal Chemistry and
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2,4-Dimethyl-1-phenyl-1H-imidazole (12r)
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Yield: 62 mg (36%); light yellow viscous oil; Rf = 0.1.
1H NMR (400 MHz, CDCl3): δ = 7.50–7.44 (m, 2 H), 7.43–7.37 (m, 1 H),
7.29–7.25 (m, 2 H), 6.73 (br s, 1 H), 2.34 (s, 3 H, Me), 2.25 (br s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 143.8, 138.0, 136.2, 129.4, 128.0,
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K