Microwave-promoted reaction of N-(alk-1-enyl)chloroacetamides with sodium azide unexpectedly yields 1H-imidazol-5(4H)-ones

Article abstract of DOI:10.1016/j.mencom.2017.01.031

A novel method to prepare biologically relevant 1H-imidazol-5(4H)-ones from aliphatic amines, isobutyraldehyde, chloroacetyl chloride and sodium azide under microwave irradiation has been developed.

Full text of DOI:10.1016/j.mencom.2017.01.031

Mendeleev
Communications
Mendeleev Commun., 2017, 27, 95–96
Microwave-promoted reaction of N-(alk-1-enyl)chloroacetamides
with sodium azide unexpectedly yields 1H-imidazol-5(4H)-ones
Grigory P. Kantin and Mikhail Yu. Krasavin*
St. Petersburg State University, 199034 St. Petersburg, Russian Federation. Fax: +7 812 428 6939;
e-mail: m.krasavin@spbu.ru
DOI: 10.1016/j.mencom.2017.01.031
Cl
Me
Me
Cl
R
O
A novel method to prepare biologically relevant 1H-imid-
azol-5(4H)-ones from aliphatic amines, isobutyraldehyde,
chloroacetyl chloride and sodium azide under microwave
irradiation has been developed.
RNH2
N
Me
Cl
O
O
NaN3
Me
Me
N
Me
N
Al2O3, MW
110 °C, 1 h
O
N
Me
R
Me
examples
0–69% over 3 steps
R
7
4
Multicomponent chemistry facilitates the design of compound
arrays as it directly links the molecular periphery to a specific
choice of mutually reactive reagents. The resulting products can
producible results, acylation of 1 should be performed in the
absence of any HCl scavenger as described in the literature,16
with removal of gaseous HCl from crude 2 by co-evaporation with
CH Cl .
1
already contain a requisite scaffold determined by a particular
2
2
2
multicomponent reaction (MCR) employed (e.g., the Ugi diamides,
1H-Imidazol-5(4H)-ones 4 are of high medicinal and bio-
3
4
the Biginelli dihydropyrimidines, the Hantzsch pyridines, the
Castagnoli–Cushman lactams, etc.) or they further modified,
logical relevance as they are principal structural component of
5
17,18
fluorescent protein fluorophores,
which are gaining pro-
1
9,20
as diversely substituted building blocks, via the final scaffold-
minence as fluorescent biosensor probes.
Their synthesis
6
defining post-MCR transformation. The power of using pre-
usually entails multistep sequences involving, as a key step, aza-
2
1
meditated post-MCR chemical events in generating broad skeletal
diversity has been amply unveiled for the Ugi isocyanide-based
Wittig reaction of azidoacetic acid imides, cyclocondensation
7
CH2Cl
multicomponent reaction. In our scaffold-oriented research
i
Me
R
ii
Me
Me
CHO
program, we have been interested in applying a similar strategy
N
N
R
O
8
toward other MCRs and recently, turned our attention to the
Me
Me
Me
R
reaction of acylating agents (acyl chlorides or carboxylic acid
1
2
anhydrides) with imines containing a proton in the a-position
iii
(
a-C–H imines) that is known9–13 to furnish enamides. In parti-
O
N
N
a R = n-Bu
b R = PhCH2
cular, we have shown that the latter can be employed directly as
building blocks for 1,3-diploar cycloaddition of nitrile oxides
to afford, with a high degree of atom economy, 4,5-dihydro-
isoxazoles containing four elements of diversity.14 In the present
study, we sought to investigate an intramolecular 1,3-dipolar cyclo-
addition between enamide and an appropriately positioned alkyl
N
N
Me
c R = 4-MeC6H4CH2
d R = 4-MeOC6H4CH2
e R = 4-FC6H4CH2
Me
Me
N
N
O
R
Me
4a–g
40–69% (3 steps)
f
R = 4-ClC H CH
2
6
4
3
g R = 4-ClC6H4(CH2)2
15
azide moiety. This has led to an unexpected, yet practically sound
and mechanistically intriguing outcome which we report herein.
Isobutyraldehyde was reacted with a series of alkylamines in
Scheme 1 Reagents and conditions: i, RNH , MgSO , CH Cl , room tem-
2
4
2
2
perature, 18 h; ii, ClCH COCl, CH Cl , room temperature, 18 h; iii, NaN /
2
2
2
3
Al O , THF, 110°C, MW, 1 h.
2
3
the presence of MgSO as dehydrating agent to give imines 1.
4
The latter, without further purification, were acylated with chloro-
acetylchloride to give enamides 2, which, in turn, were reacted
with sodium azide under microwave irradiation in the presence
of alumina as an HCl scavenger. The microwave-assisted step
was expected to furnish, after chloride-to-azide displacement,
1H-Imidazol-5(4H)-ones 4 (general procedure). Isobutyric aldehyde
(20 mmol) and an aliphatic amine (10 mmol) were combined in CH Cl
2
2
(
10 ml). Anhydrous MgSO (1.5 g) was added and the mixture was stirred
4
at room temperature for 18 h. The solids were filtered off and the filtrate
was concentrated in vacuo. The resulting Schiff base 1 (2.5 mmol) was
dissolved in CH Cl2 (5 ml) and treated, dropwise, with a solution of
2
3
a,4-dihydro-3H-imidazo[1,2-c][1,2,3]triazol-5(6H)-one products
chloroacetyl chloride (2.5 mmol) in CH Cl2 (2 ml). The mixture was
2
of Huisgen-type 1,3-dipolar cycloaddition reaction 3. Instead,
stirred at room temperature for 18 h and concentrated in vacuo. The
gaseous HCl formed in the course of acylation of 1 was additionally
co-evaporated with CH Cl (3×5 ml). The resulting slightly coloured oil
2
4
-isopropyl-1-alkyl-1H-imidazol-5(4H)-ones 4 were formed in
0–69% yield over three steps (Scheme 1). Notably, for re-
†
2
2
1
(
0.5 mmol) containing 70–85% of 2 according to H NMR analysis, was
†
NMR spectra were recorded in CDCl using a Bruker Avance III spec-
dissolved in THF (5 ml) and the solution was added to a 5 ml microwave
3
1
13
trometer (400 MHz for H and 100 MHz for C, relative to TMS). Mass
spectra were recorded on a Bruker microTOF spectrometer (electrospray
ionization, positive ions detection). Column chromatography was carried
out on silica gel 60 (0.040–0.063 mm). MW experiments were implemented
by a Biotage Initiator+ microwave reactor. Monitoring of processes was
realized using TLC.
reactor vial containing NaN (1.5 mmol) absorbed on column chromato-
3
graphy grade Al O (1:5 w/w). The vigorously stirred mixture was irra-
2
3
diated at 110°C (50 W, 2 bar) in a microwave reactor for 1 h. The solids
were filtered off, washed with copious amount of THF, concentrated
in vacuo and the desired product was isolated by column chromatography
i
on silica gel using 0®10% Pr OH in CH Cl as the eluent.
2
2
©
2017 Mendeleev Communications. Published by ELSEVIER B.V.
–
95 –
on behalf of the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.

Mendeleev Commun., 2017, 27, 95–96
R
of amino acid amides and carboxylic acid components (as ortho
2
22
23
H
O
esters or imino esters ), intramolecular cyclization of amidine-
N
iii
a
Me
Me
24
substituted acetic acid derivatives or biomimetic cyclodehydra-
O
– N2
tion of dipeptide fragments.25 To the best of our knowledge,
R
N
N
N
N
compound 4 has never been reported as prepared in an atom
economical and practically convenient fashion as described herein.
3
Me
4
N3
O
O
N
The formation of 4 in the reaction of 2 with NaN under
R
R
3
Me
microwave irradiation can be rationalized by two alternative
plausible mechnisms. The reaction obviously proceeded via
displacement of the chloride with azide anion to give a-azido-
acetamide 5. The latter could really undergo the Huisgen-type
N
N
N
H
5
b
Me
Me
–
N2
Me
Me
6
1
,3-dipolar cycloaddition (intended for it initially) to form 3
which, due to somewhat strained nature, could lose a nitrogen
Scheme 2
2
6
molecule via a concerted process and afford 4. However, said
cycloaddition may not be a feasible evolution path for 5 and it
may lose a nitrogen molecule first, to give nitrene 6, in which the
reactive nitrogen center can be intercepted intramolecularly and
provide observed products 4 (Scheme 2). In order to select
between these two mechanistic interpretations, additional studies
will be required.
course of the reaction between N-chloroacetyl enamines and
sodium azide under microwave irradiation.
This work was supported by the Russian Science Foundation
(grant no. 14-50-00069). NMR spectroscopy and mass spectro-
metry studies were performed at the Research Centre for Magnetic
Resonance, the Centre for Chemical Analysis and Materials
Research of Research park of St. Petersburg State University.
In summary, we have reported a practical procedure to access
biologically important 1H-imidazol-5(4H)-ones via an unexpected
1
-Butyl-2-isopropyl-1H-imidazol-5(4H)-one 2a.Yield 40%, yellow oil.
Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi: 10.1016/j.mencom.2017.01.031.
1
H NMR (CDCl ) d: 0.95 (t, 3H, Me, J 7.4 Hz), 1.28 (d, 6H, Me, J 6.7 Hz),
.30–1.40 (m, 2H, CH ), 1.53–1.61 (m, 2H, CH ), 2.71 (br. sept, 1H, CH,
J 6.9 Hz), 3.47 (t, 2H, CH N, J 7.6 Hz), 4.05 [d, 2H, CH (CO), J 1.2 Hz].
C NMR (CDCl ) d: 13.6, 20.1 (3C), 27.7, 31.4, 40.2, 58.2, 170.7, 182.0.
3
1
2
2
4
2
2
13
3
References
+
HRMS, m/z: 183.1485 [M + H] (calc. for C H N O, m/z: 183.1492).
10
19
2
1
-Benzyl-2-isopropyl-1H-imidazol-5(4H)-one 2b. Yield 69%, yellow
1 A. Dömling and I. I. Ugi, Angew. Chem. Int. Ed., 2000, 39, 3168.
2 I. Ugi, R. Meyr, U. Fetzer and C. Steinbrückner, Angew. Chem., 1959,
71, 386.
1
oil. H NMR (CDCl ) d: 1.17 (d, 6H, Me, J 6.8 Hz), 2.62 (br.sept, 1H, CH,
J 6.8 Hz), 4.20 [d, 2H, CH (CO), J 0.9 Hz], 4.75 [s, 2H, CH (Ar)], 7.20
d, 2H, 2,2'-CH(Ar), J 7.0 Hz], 7.28–7.37 [m, 3H, CH(Ar)]. C NMR
CDCl ) d: 19.9, 28.0, 43.6, 58.2, 126.8, 127.9, 129.0, 136.2, 170.8, 181.8.
HRMS, m/z: 217.1334 [M + H] (calc. for C H N O, m/z: 217.1335).
1
yellow oil. H NMR (CDCl ) d: 1.16 (d, 6H, Me, J 6.8 Hz), 2.33 [s, 3H,
Me(Ar)], 2.62 (br.sept, 1H, CH, J 6.8 Hz), 4.16 [d, 2H, CH (CO),
J 1.2 Hz], 4.69 [s, 2H, CH (Ar)], 7.08 [d, 2H, 2,2'-CH(Ar), J 8.1 Hz],
.14 [d, 2H, 3,3'-CH(Ar), J 7.9 Hz]. C NMR (CDCl ) d: 19.9, 21.1,
8.0, 43.3, 58.2, 126.8, 129.6, 133.2, 137.6, 170.8, 181.8. HRMS, m/z:
31.1490 [M + H] (calc. for C H N O, m/z: 231.1492).
3
4
2
2
13
3 P. Biginelli, Ber. Dtsch. Chem. Ges., 1891, 24, 1317.
[
(
4
A. Hantzsch, Ber. Dtsch. Chem. Ges., 1881, 14, 1637.
3
+
5 M. Krasavin and D. Dar’in, Tetrahedron Lett., 2016, 57, 1635.
13
17
2
6
7
U. K. Sharma, N. Sharma, D. D. Vachhani and E. V. Van der Eycken,
Chem. Soc. Rev., 2015, 44, 1836.
A. V. Ivachtchenko, Ya. A. Ivanenkov, V. M. Kysil, M. Yu. Krasavin and
A. P. Ilyin, Russ. Chem. Rev., 2010, 79, 787 (Usp. Khim., 2010, 79, 861).
P. Sarnpitak and M. Krasavin, Tetrahedron Lett., 2014, 55, 2299.
G. R. Cook, N. S. Barta and J. R. Stille, J. Org. Chem., 1992, 57, 461.
-(4-Methylbenzyl)-2-isopropyl-1H-imidazol-5(4H)-one 2c. Yield 46%,
1
3
2
4
2
8
9
13
7
2
2
3
1
1
0 A. Padwa, T. M. Heidelbaugh, J. T. Kuethe, M. S. McClure and Q. Wang,
J. Org. Chem., 2002, 67, 5928.
1 S. Lesniak and B. Pasternak, Synth. Commun., 2002, 32, 875.
12 S. Dekeukeleire, M. D’hooghe, C. Müller, D. Vogt and N. De Kimpe,
New J. Chem., 2010, 34, 1079.
13 E. Shinkevich, J. Deblander, S. Matthijg, J. Jacobs, N. De Kimpe and
K. A. Tehrani, Org. Biomol. Chem., 2011, 9, 538.
14 A. Kulyashova and M. Krasavin, Tetrahedron Lett., 2016, 57, 4395.
15 R. Huisgen, G. Szeimies and L. Mobius, Chem. Ber., 1967, 100, 2494.
16 K. Moonen and C. V. Stevens, Synthesis, 2005, 3603.
17 C. R. S. Mooney, D.A. Horke,A. S. Chatterley,A. Simperler, H. H. Fielding
and J. R. R. Verlet, Chem. Sci., 2013, 4, 921.
+
14
19
2
1
-(4-Methoxybenzyl)-2-isopropyl-1H-imidazol-5(4H)-one 2d. Yield
1
5
0%, yellow oil. H NMR (CDCl ) d: 1.16 (d, 6H, Me, J 6.7 Hz), 2.63
br.sept, 1H, CH, J 6.9 Hz), 3.78 [s, 3H, MeO(Ar)], 4.15 [d, 2H, CH (CO),
J 1.0 Hz], 4.66 [s, 2H, CH (Ar)], 6.85 [d, 2H, 2,2'-CH(Ar), J 8.7 Hz],
.12 [d, 2H, 3,3'-CH(Ar), J 8.7 Hz]. C NMR (CDCl ) d: 19.9, 28.0,
3.1, 55.3, 58.1, 114.3, 128.2, 128.3, 159.2, 170.8, 181.8. HRMS, m/z:
47.1430 [M + H] (calc. for C H N O , m/z: 247.1441).
1
3
(
2
4
2
13
7
4
2
3
+
14
19
2
2
-(4-Fluorobenzyl)-2-isopropyl-1H-imidazol-5(4H)-one 2e. Yield 56%,
1
yellow oil. H NMR (CDCl ) d: 1.16 (d, 6H, Me, J 6.7 Hz), 2.60 (br.sept,
H, CH, J 6.7 Hz), 4.16 [d, 2H, CH (CO), J 1.2 Hz], 4.69 [s, 2H,
3
4
1
2
CH (Ar)], 6.98–7.06 (m, 2H, 3,3'-CH), 7.14–7.21 (m, 2H, 2,2'-CH).
18 M. S. Baranov, K. M. Solntsev, N. S. Baleeva, A. S. Mishin, S. A. Lukyanov,
K. A. Lukyanov and I. V. Yampolsky, Chem. Eur. J., 2014, 20, 13234.
19 H. Huang, N. B. Suslov, N.-S. Li, S.A. Shelke, M. E. Evans,Y. Koldobskaya,
2
13
2
C NMR (CDCl ) d: 19.9, 28.0, 42.9, 58.1, 115.9 (d, J 22.0 Hz),
3
CF
3
4
1
1
1
28.6 (d, J 8.0 Hz), 132.1 (d, J 3.0 Hz), 162.3 (d, J 246.5 Hz),
CF CF CF
+
P. A. Rice and J. A. Piccirilli, Nat. Chem. Biol., 2014, 10, 686.
0 T. A. Rogers, G. E. Andrews, L. Jaeger and W. W. Grabow, ACS Synth.
Biol., 2015, 4, 162.
70.4, 181.8. HRMS, m/z: 235.1251 [M + H] (calc. for C H FN O,
13 16 2
2
m/z: 235.1241).
1
-(4-Chlorobenzyl)-2-isopropyl-1H-imidazol-5(4H)-one 2f. Yield 40%,
1
21 (a) H. Takeuchi, S. Hagiwara and S. Eguchi, Tetrahedron, 1989, 45, 6375;
(b) Y. A. O. Barbosa, D. J. Hart and N. A. Magomedov, Tetrahedron,
yellow oil. H NMR (CDCl ) d: 1.16 (d, 6H, Me, J 6.8 Hz), 2.58 (br.sept,
H, CH, J 6.8 Hz), 4.17 [d, 2H, CH (CO), J 1.3 Hz], 4.69 [s, 2H,
3
4
1
2
2
006, 62, 8748.
2 L. H. Jones, T. Dupont, C. E. Mowbray and S. D. Newman, Org. Lett.,
006, 8, 1725.
CH (Ar)], 7.13 [d, 2H, 2,2'-CH(Ar), J 8.5 Hz], 7.31 [d, 2H, 3,3'-CH(Ar),
2
2
13
J 8.6 Hz]. C NMR (CDCl ) d: 19.9, 28.0, 43.0, 58.1, 128.2, 129.1,
33.8, 134.8, 170.3, 181.7. HRMS, m/z: 251.0953 [M + H] (calc. for
3
2
+
1
2
2
3 A. Rottmann and J. Liebscher, J. Heterocycl. Chem., 1996, 33, 811.
4 F. Campagna, A. Carotti and G. Casini, J. Heterocycl. Chem., 1990,
C H ClN O, m/z: 251.0946).
13
16
2
1
-(4-Chlorophenethyl)-2-isopropyl-1H-imidazol-5(4H)-one 2g. Yield
2
7, 1973.
1
4
5%, yellow oil. H NMR (CDCl ) d: 1.16 (d, 6H, Me, J 6.9 Hz), 2.34
3
2
5 C.-Y. Lee, Y.-C. Chen, H.-C. Lin, Y. Jhong, C.-W. Chang, C.-H. Tsai,
(
br.sept, 1H, CH, J 6.9 Hz), 2.88 (t, 2H, CH N, J 7.4 Hz), 3.68 (t, 2H,
2
C.-L. Kao and T.-C. Chien, Tetrahedron, 2012, 68, 5898.
26 H. S. López, J. E. Enciso, A. Ochoa-Terán, J. I. Velazquez and J. I.
4
CH , J 7.3 Hz), 4.05 [d, 2H, CH (CO), J 0.6 Hz], 7.09 [d, 2H, 2,2'-CH(Ar),
J 7.8 Hz], 7.28 [d, 2H, 3,3'-CH(Ar), J 8.3 Hz]. C NMR (CDCl ) d:
2
2
13
3
Sarmiento, Mendeleev Commun., 2016, 26, 69.
1
9.7, 27.6, 34.3, 41.9, 58.1, 128.9, 130.2, 132.8, 136.2, 170.3, 181.9.
+
HRMS, m/z: 265.1112 [M + H] (calc. for C H ClN O, m/z: 265.1102).
Received: 8th August 2016; Com. 16/5021
14
18
2
–
96 –