A photochemical one-pot three-component synthesis of tetrasubstituted imidazoles

Article abstract of DOI:10.1021/ol502667h

Tetrasubstituted imidazoles can be formed in a photochemical one-pot synthesis from aldehydes, α-aminonitriles, and isoxazoles. Condensation of the first two components produces α-(alkylideneamino)nitriles which react under basic conditions with the acylazirines formed in situ by photochemical ring transformation of the isoxazole component. This process includes an unusual cleavage of the C²-C³ bond of the acylazirine. The reaction mechanism was studied by DFT calculations. (Chemical Equation Presented)

Full text of DOI:10.1021/ol502667h

Letter
pubs.acs.org/OrgLett
A Photochemical One-Pot Three-Component Synthesis of
Tetrasubstituted Imidazoles
Stefan Pusch and Till Opatz*
Institute of Organic Chemistry, Johannes Gutenberg University, Duesbergweg 10-14, 55128 Mainz, Germany
*
S Supporting Information
ABSTRACT: Tetrasubstituted imidazoles can be formed in a
photochemical one-pot synthesis from aldehydes, α-amino-
nitriles, and isoxazoles. Condensation of the first two
components produces α-(alkylideneamino)nitriles which react
under basic conditions with the acylazirines formed in situ by
photochemical ring transformation of the isoxazole component.
2
3
This process includes an unusual cleavage of the C −C bond
of the acylazirine. The reaction mechanism was studied by DFT
calculations.
midazole rings are common structural motifs in biologically
active molecules, including both natural products and
Scheme 2. Azirine-Based Imidazole Synthesis
I
synthetic pharmaceuticals. In particular, imidazoles containing
an arylethanone side chain linked to N-1 have recently been
shown to be potent inhibitors of the neuronal nitric oxide
1
synthase (nNOS). An attractive concept for the synthesis of
imidazoles is the utilization of the ring strain of azirines. To this
end, imidazoles have been prepared from azirinyl acrylates and
2
3
amidines as well as from azirines and parabanic acid or from
4
azirines and imines. The azirines themselves are frequently
synthesized by the Neber rearrangement. However, we chose
5
the photochemical isomerization of isoxazoles 1 to acylazirines
6
of type 2 (Scheme 1) to generate the three-membered ring. It
Scheme 1. Photochemical Isomerization of an Isoxazole to
an Azirine and an Oxazole
is known that the efficiency of this reaction can be enhanced by
triplet sensitizers. Nevertheless, the isolated yields of azirine 2
Figure 1. Molecular structure of compound 5a in the solid state at
173 K (ORTEP-ellipsoids drawn at 30% probability).
7
were limited to around 50% in our hands under all tested
conditions due to the competing irreversible formation of the
oxazole 3 (see Supporting Information for NMR-based reaction
kinetics).
are incorporated into the imidazole ring. The structure of
imidazole 5a led to the hypothesis that the α-(alkylidene-
amino)nitrile 6a may be formed as an intermediate in the
reaction from two molecules 4a under elimination of HCN.
This assumption was supported by the fact that, after the
Our investigation on the synthesis of imidazoles from
acylazirines was initiated by the finding that azirine 2 reacted
8
9
with α-aminonitrile 4a to give the imidazole 5a upon heating
heating of compound 4a in pyridine-d for 1 h, the formation of
5
in pyridine (Scheme 2). The structure of the product was
13
13
imine 6a (approximately 14%) could be detected. Furthermore,
preformed imine 6a and azirine 2a produced the imidazole 5a
in a comparable yield under the same reaction conditions.
elucidated based on NMR data, especially a 2D C− C
4
5
INADEQUATE contact between atoms C and C of the
imidazole ring and could finally be supported by a crystal
structure (Figure 1).
2
3
This reaction includes an unusual ring opening of the C −C
Received: September 9, 2014
Published: October 6, 2014
bond of the azirine, and only two of the three azirine ring atoms
©
2014 American Chemical Society
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dx.doi.org/10.1021/ol502667h | Org. Lett. 2014, 16, 5430−5433

Organic Letters
Letter
A reaction screening with HPLC-ESI-MS monitoring and
preformed α-(alkylideneamino)nitriles showed that an elec-
tron-withdrawing substituent is required in the alkylidene
portion. Using the preformed α-(alkylideneamino)nitrile 6b,
imidazole 5b was obtained by refluxing the reactants in pyridine
intermediates has already been employed in photoreactions of
pyridinium salts, the area of organic one-pot photoreactions is
still largely underdeveloped.
Stirring of aldehydes 7 with α-aminonitriles 4 in dry
acetonitrile in the presence of molecular sieves and an acid
catalyst proved to be inefficient and slow as judged by NMR
10
(
Scheme 3). An extensive screening proved that the same
reaction monitoring (CD CN as the solvent). However, simple
3
Scheme 3. Improvement of the Reaction Conditions
evaporation of an aldehyde/α-aminonitrile mixture in acetoni-
trile containing catalytic amounts of acetic acid at 40 °C on a
rotary evaporator resulted in almost quantitative conversion to
the desired α-(alkylideneamino)nitriles 6. These compounds
turned out to be sufficiently pure for all further transformations.
The isoxazole is added from the beginning and does not react
until its light-induced activation. In the final three-component
procedure, potassium tert-butoxide turned out to be the optimal
base for the imidazole formation.
transformation can also be effected at room temperature by
cesium hydroxide monohydrate, potassium tert-butoxide, or
DBU as bases in THF. Gratifyingly, imidazole 5b could also be
obtained when azirine 2 was replaced by isoxazole 1a and the
reaction mixture was irradiated with UV light (300 nm). In this
case, the yield-limiting formation of the undesired oxazole
byproduct (see Scheme 1) and the tedious chromatographic
separation of the isoxazole/azirine/oxazole mixture could be
circumvented by an in situ formation of the azirine. The α-
We never observed the formation of regioisomeric mixtures
as judged by HPLC-ESI-MS of the crude reaction mixtures.
The substitution pattern of the imidazoles was carefully
deduced from 2D NMR experiments, in particular from
NOESY correlations. For all reactions except one case (Table
1, entry 12), the same regioselectivity was observed.
The cause for the inverted regioselectivity in the reaction of
1a with 4e and 7a remains unclear but might be attributed to
4
the mixed +M/−I nature of the fluorine substituent in R ,
(
alkylideneamino)nitrile component did not interfere with the
whereas all other substituents in the table are either of the −I or
the −M/−I type. The unusual substitution pattern of 5l could
finally be supported by X-ray crystallography (Figure 2).
If the phenacyl-type N-substituent is not desired in the final
product, a dephenacylation can be easily performed under
photochemical generation of 2. For this photochemical two-
step process, the solvent was switched from THF to MeCN as
the latter gives better yields and cannot form peroxides during
the irradiation. Triplet sensitizers such as benzophenone did
not improve the yield.
Based on this finding, we attempted to develop a one-pot
three-component procedure which also includes the formation
of the α-(alkylideneamino)nitriles without prior isolation
11
reducing conditions. This can also be combined with a
preceding alkylation of N-3 allowing the regioselective
12
introduction of alkyl substituents. By this method, com-
pounds 8 and 9 were obtained from the parent imidazoles
(Scheme 4).
(
Table 1). Although the photochemical generation of strained
Table 1. One-Pot Three-Component Imidazole Synthesis from Isoxazoles, α-Aminonitriles, and Aldehydes
entry
isoxazole
R1
R2
α-aminonitrile
R3
aldehyde
R4
imidazole
yield ,
ab
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1c
1c
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
4a
4a
4a
4a
p-F-C H4
7a
7b
7c
7d
7c
7b
7c
7d
7b
7c
7e
7a
7c
7b
7c
7c
7b
p-F-C H4
5a
5c
5d
5e
5f
40%
83%
70%
38%
32%
82%
88%
55%
85%
66%
56%
56%
56%
24%
68%
50%
50%
6
6
p-F-C H4
p-O N-C H
6
2
6
4
p-F-C H4
p-NC-C H4
6
6
p-F-C H4
p-F C-C H
4
6
3
6
c
4b
Me
Cy
Cy
Cy
Ph
Ph
Ph
Bn
Bn
p-NC-C H4
6
4c
4c
4c
4d
4d
4d
4e
4e
4a
4c
4c
4d
p-O N-C H
5b
5g
5h
5i
2
6
4
p-NC-C H4
6
p-F C-C H
4
3
6
p-O N-C H
2
6
4
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
p-NC-C H4
5j
6
4-pyridyl
5k
5l
d
p-F-C H4
6
p-NC-C H4
5m
5n
5o
5p
5q
6
p-F-C H4
p-O N-C H
6
2
6
4
Me
Cy
Cy
Ph
p-NC-C H4
6
i
p-F-C H
p- Pr-C H
p-NC-C H4
6
4
6
4
6
i
p-F-C H
p- Pr-C H
p-O N-C H
6
4
6
4
2
6
4
a
b
Isolated yields after chromatography. Reaction conditions: 1.0 equiv of isoxazole, 2.0 equiv of α-aminonitrile, 1.5 equiv of aldehyde, 5.0 equiv of
c
d
3
4
base. As hydrochloride. Inverted regiochemistry in the imidazole (R /R interchanged); see main text.
5
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Organic Letters
Letter
Figure 2. Molecular structure of compound 5l in the solid state at
173 K (ORTEP-ellipsoids drawn at 30% probability).
Scheme 4. Dephenacylations
Figure 3. Energy profile for the reaction shown in Scheme 5 (numbers
in square brackets: Gibbs free enthalpy in kcal/mol at 1 atm and
2
98 K).
15
syntheses of nitrogen heterocycles, and anionic 5-endo-trig
cyclizations have recently been interpreted as aborted [2,3]-
16
sigmatropic shifts. A competing direct cycloaddition of 12 to
4 could be ruled out based on a scan of the potential energy
1
surface (Figure 4). However, the activation energy for the
The reaction mechanism of the imidazole formation was
studied using DFT calculations (Scheme 5, Orca program
package, PW6B95/ma-def2-SVP level of theory including
solvation and dispersion correction; see Supporting Informa-
1
3
tion for details).
Scheme 5. Proposed Reaction Mechanism for the
Condensation of an Azirine and a Deprotonated α-
(
Alkylideneamino)nitrile
Figure 4. Contour plot showing the potential energy surface near
compounds 11/12/14 (blue and red represent regions of low and high
electronic energy, respectively).
cyclization is very low and the 12 → 14 transformation seems
to be almost at the border between a stepwise addition/ring
closure and a concerted cycloaddition mechanism. Accordingly,
the isosurface of the HOMO of the 11 → 12 transition state
not only resembles the formation of the C−C bond but also
shows C/N secondary orbital interactions (Figure 5).
From 14 on, the reaction proceeds in an all-exergonic
manner via elimination of cyanide (to 15), deprotonation (to
1
6), and ring opening to give enolate 17. This anion is then
After formation of a loose van der Waals complex (11)
protonated to the final product 5f.
between azirine 2 and the deprotonated α-(alkylideneamino)-
nitrile 10, the addition product 12 is formed. The electrocyclic
ring opening of 12 to 13 was found to proceed via a higher-
lying transition state than its ring closure to the bicyclic anion
In summary, a simple photochemical one-pot three-
component synthesis of tetrasubstituted imidazoles from
disubstituted isoxazoles, α-aminonitriles, and aldehydes has
been developed. The isoxazoles are readily available from
enones by cyclocondensation with hydroxylamine and
1
4 (Figure 3). The latter transformation is a 5-endo-trig
17
7,18
cyclization and formally disfavored according to Baldwin’s
oxidation, from 1,3-diketones and hydroxylamine,
by 1,3-
1
4
19
rules. However, similar observations have been made in other
dipolar cycloaddition of nitrile oxides to terminal alkynes or
5
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Organic Letters
Letter
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ASSOCIATED CONTENT
Supporting Information
■
*
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(
16) Gilmore, K.; Manoharan, M.; Wu, J. I. C.; Schleyer, P. v. R.;
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Experimental procedures, analytical data, 1D/2D NMR spectra,
crystal structures, computational chemistry. This material is
available free of charge via the Internet at http://pubs.acs.org.
(
̃
̃
4
3
AUTHOR INFORMATION
Corresponding Author
982.
■
*
(18) Sechi, M.; Sannia, L.; Orecchioni, M.; Carta, F.; Paglietti, G.;
Neamati, N. J. Heterocycl. Chem. 2003, 40, 1097.
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b) Willy, B.; Frank, W.; Rominger, F.; Mu
Chem. 2009, 694, 942.
E-mail: opatz@uni-mainz.de.
Notes
(
7
(
̈
ller, T. J. J. Synthesis 2008, 293.
ller, T. J. J. J. Organomet.
The authors declare no competing financial interest.
(
̈
ACKNOWLEDGMENTS
■
We thank Dr. J. C. Liermann (Mainz) for NMR spectroscopy,
Dr. N. Hanold (Mainz) for mass spectrometry, Dr. D.
Schollmeyer (Mainz) for X-ray crystallography, Dorota Ferenc
(
̈
Mainz) for expert technical assistance, and the Zentrum fur
Datenverarbeitung (Mainz) for access to the MOGON
supercomputer. S. P. is grateful for a scholarship of the
Fonds der Chemischen Industrie.
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