Efficient 4,5-dihydro-1H-imidazol-5-one formation from amidines and ketones under transition-metal free conditions?

Article abstract of DOI:10.1039/c4gc01515k

An efficient procedure for 4,5-dihydro-1H-imidazol-5-one preparation from aryl amidines and ketones under transition-metal free conditions is described. When cyclic ketones were employed, various spiro-fused 4,5-dihydro-1H-imidazol-5-ones were formed in h

Full text of DOI:10.1039/c4gc01515k

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Efficient 4,5-dihydro-1H-imidazol-5-one
formation from amidines and ketones under
Cite this: DOI: 10.1039/c4gc01515k
transition-metal free conditions†
Received 6th August 2014,
Accepted 26th September 2014
Yanjun Xie,a Xiufang Cheng,a Saiwen Liu,a Hui Chen,a Wang Zhou,b Luo Yanga and
DOI: 10.1039/c4gc01515k
Guo-Jun Deng*a,c
www.rsc.org/greenchem
An efficient procedure for 4,5-dihydro-1H-imidazol-5-one prepa-
ration from aryl amidines and ketones under transition-metal free
conditions is described. When cyclic ketones were employed,
various spiro-fused 4,5-dihydro-1H-imidazol-5-ones were formed
in high yields via rearrangement reaction.
Scheme 1 Selected important drugs containing the spiro structure.
Nitrogen-containing heterocycles are frequently found in
natural alkaloids, functional materials, agrochemicals and
pharmaceutical drugs.1 Therefore, development of efficient
methods for the synthesis of heterocycles with multi-nitrogen
atoms is of great importance for drug development.2 Tradition-
ally, imidazole and pyrimidine derivatives were prepared by
the condensation of 1,3-dicarbonyl compounds and 1,3-dia-
mines such as ureas, thioureas, amidines and guanidines under
acidic or basic conditions.3 In recent years, transition-metal
catalyzed cross-coupling reactions were successfully employed
for the construction of nitrogen-containing heterocycles.4
Spirans which contain at least two rings and share one
spirocarbon atom widely exist in natural products and pharma-
ceutical drugs.5 For example, natural and synthetic com-
pounds such as acorenone B,6 β-vetivone,7 isocomene,8
triangulanes9 and coronane10 all contain spirocarbon atoms.
Due to their unique structural features, the synthesis of spiro-
cycles has attracted much attention from organic chemists and
great progress has been made in the past few decades.11 Com-
pared to the extensively investigated preparation of spirocarbo-
cycles, methods for the synthesis of nitrogen-containing spiro-
heterocycles were much less developed. A number of substi-
tuted 4,5-dihydro-1H-imidazol-5-ones which contain a highly
strained spiro structure belong to selective and non-toxic her-
bicides.12 For example, Avapro and Avalide (both contain a
spiro structure produced by Bristol-Myers Squibb) are angio-
tensin II receptor blockers used to treat hypertension
(Scheme 1).13 The limited methods for spiro-fused 4,5-dihydro-
1H-imidazol-5-ones are mainly based on the cyclization reac-
tion of the five-membered rings, such as the acylation of
amide or nitrile of 1-aminocyclopentancarboxylic acid with
pentanoic acid chloride followed by ring closure reaction,14
the condensation of ethyl 1-aminocyclopentancarboxylate with
ethyl pentanimidate,15 and the reaction of 1-aminocyclopenta-
necarboxamide with trimethyl orthopentanoate.16 Dehydro-
genation of the corresponding saturated spiro-heterocycles can
afford an alternative route for the preparation of 4,5-dihydro-
1H-imidazol-5-ones.17 Oxidative rearrangement of tetrahydro-
benzimidazoles with dimethyldioxirane can provide spiro-
fused 5-imidazolones with good selectivity.18 However, these
methods require highly functionalized five-membered hetero-
cycles usually prepared by several steps which severely limit
the reaction scope and their further application. Due to the
importance of 4,5-dihydro-1H-imidazol-5-ones in pharmaceuti-
cals, it is highly desirable to develop efficient methods to
prepare them using readily available raw materials. Herein, we
describe a strategy for the preparation of 4,5-dihydro-1H-imid-
azol-5-ones from commercially available amidines and ketones
via a rearrangement reaction strategy under transition-metal
free conditions (Scheme 2).
aKey Laboratory of Environmentally Friendly Chemistry and Application of Ministry
of Education, College of Chemistry, Xiangtan University, Xiangtan 411105, China.
E-mail: gjdeng@xtu.edu.cn; Fax: (+86)0731-5829-2251; Tel: (+86)0731-5829-8601
bCollege of Chemical Engineering, Xiangtan University, Xiangtan 411105, China
cKey Laboratory of Molecular Recognition and Function, Institute of Chemistry,
To obtain the optimized reaction conditions, the reaction of
benzamidine hydrochloride hydrate (1a) with cyclohexanone
(2a) was chosen as the model reaction in the absence of the
metal catalyst under an oxygen atmosphere (for details, see
Table S1 in ESI†). The desired product 3a was observed in 5%
Chinese Academy of Sciences, Beijing 100080, China
†Electronic supplementary information (ESI) available. CCDC 1017138.
For ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c4gc01515k
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desired product 3b was obtained in 88% yield when 4-methyl-
benzimidamide (1b) was treated with cyclohexanone (2a)
under the optimized conditions. Halogen functional groups
such as chloro, bromo and trifluoromethyl were well tolerated
to give the corresponding spiro-fused heterocycles (3c–3e) in
high yields. A nitro substituent was also compatible, and the
corresponding product 3f was obtained in 74% yield. The posi-
tion of the methyl substituent did not show much impact on
the reactivity (3b and 3g, 3c and 3h). To our delight, nitrogen-
containing hetero amidines such as 1i and 1j smoothly reacted
with 2a to give the desired products 3i and 3j in good yields.
Unfortunately, aliphatic amidines were not active under the
current optimized reaction conditions.
The scope of the reaction with symmetrical cyclic ketones is
outlined in Table 2. Cyclohexanones bearing alkyl substituents
at the para position were able to smoothly react with 1a to give
the corresponding spiro-fused heterocycles in high yields
(entries 1–5). Other cyclic ketones such as cycloheptanone (2h)
and cyclooctanone (2i) also could be used for this kind of reac-
tion, and the corresponding products 3q and 3r were obtained
in 81% and 89% yields, respectively (entries 7 and 8). In all
cases, spiro-fused heterocycles were selectively formed in good
to high yields when cyclic ketones were used.
Scheme 2 New strategy for the synthesis of 4,5-dihydro-1H-imidazol-
5-ones.
yield when the reaction was carried out in pyridine (entry 2).
Basic conditions are favorable to this kind of reaction, and the
reaction yield could be improved to 33% when NaOH was used
as the base (entry 4). The amount of base is very important to
the reaction yield, and the desired product was obtained in
93% GC yield when 4.5 equiv. of NaOH was used (entry 8).
Besides pyridine, another nitrogen-containing solvent quino-
line was also proved to be a good reaction medium for this
kind of reaction (entry 11). A slightly lower yield was obtained
when the reaction was carried out in other organic solvents
such as NMP and toluene (entries 10 and 12). Other solvents
such as DMSO, DMF, DMA, 1,4-dioxane and 1,2-dichloroben-
zene were less effective for this reaction. High yield still could
be obtained when the reaction temperature was decreased to
60 °C (entry 14). Oxygen was necessary and a much lower
yield was obtained when the reaction was carried out in air
(entry 16).
Besides cyclic ketones, linear ketones were also investigated
to form non-spiro-fused heterocycles and the results are sum-
marized in Table 3. The reaction showed good selectivity when
various methyl–alkyl ketones were reacted with 1a, and only
the longer alkyl group selectively shifted while the methyl
With the optimized reaction conditions established, the
substrate scope with respect to amidines was examined, and
the results were summarized in Table 1. The isolated yield of
3a was 86%. When the same reaction was carried out on a
5 mmol scale, 3a was obtained in 81% isolated yield. The
Table 2 Reaction of 1a with various cyclic ketones (2)a
Table 1 Reaction of 2a with various aryl amidines (1)a
Entry
Substrate
Product
Yieldb (%)
1
2
3
4
5
6
R = Me
R = Et
R = iso-C3H7
R = n-C5H11
R = tert-C5H11
R = Ph
2b
2c
2d
2e
2f
3k
3l
3m
3n
3o
3p
80
84
83
85
71
76
2g
7
2h
81
8
2i
89
a Conditions: 1 (0.2 mmol), 2a (0.3 mmol), NaOH (4.5 equiv.), pyridine
(0.8 mL), 80 °C, 24 h. Yields refer to isolated products based on 1.
b 5 mmol scale reaction yield in parenthesis.
a Conditions: 1a (0.2 mmol), 2 (0.3 mmol), NaOH (4.5 equiv.), pyridine
(0.8 mL), 80 °C, 24 h. b Isolated yield based on 1a.
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Table 3 Reaction of 1a with non-cyclic ketones (2)a
Yieldb
(%)
Entry
Substrate
Product
1
2
3
4
5
6
7
R2 = C2H5
2j
2k
2l
2m
2n
2o
2p
3s
3t
3u
3v
3w
3x
3y
68
71
61
80
77
75
73
R2 = n-C3H7
R2 = iso-C3H7
R2 = n-C4H9
R2 = n-C5H11
R2 = n-C6H13
R2 = n-C7H15
Scheme 3 Control experiments.
8
9
10
11
12
R1 = C2H5, R2 = CH3
R1 = n-C3H7, R2 = n-C2H5
R1 = n-C4H9, R2 = n-C3H7
R1 = Ph, R2 = CH3
2q
2r
2s
2t
3z (3s)
3aa
3ab
3ac
3ad
74
70
81
85
86
carbon atom in 2t appeared at two different sites in the
product 3ac (eqn (1)). The result of 18O labeling reaction
showed that part of the carbonyl oxygen atom in the product
came from the molecular oxygen (eqn (2)). Benzamidine hydro-
chloride hydrate (1a) could smoothly react with benzil to
afford the desired product 3ad in 85% yield (eqn (3)). However,
2u could not be converted into benzil in the absence of 1a
(eqn (4)). This means the CH2 group ortho to the carbonyl
group in ketone might be oxidized to the carbonyl group and
serves as a key intermediate under the standard reaction con-
ditions with the aid of the amidine substrate.
R1 = Ph, R2 = Ph
2u
a Conditions: 1a (0.2 mmol), 2 (0.3 mmol), NaOH (4.5 equiv.), pyridine
(0.8 mL), 80 °C, 24 h. b Isolated yield based on 1a.
Based on our observations and the literature, a plausible
mechanism with two pathways is outlined in Scheme 4. The
Fig. 1 X-ray structure of 3y.
group remained (entries 1–7). When 2-decanone (2p) was
used, the desired product 3y was obtained in 73% yield. The
structure of 3y was confirmed by X-ray crystallography (Fig. 1).
Besides methyl–alkyl ketones, several other symmetrical alkyl–
alkyl ketones were also employed for this reaction to give the
corresponding products in good yields (entries 8–10). To our
delight, non-symmetrical aromatic ketones such as propiophe-
none (2t) and 1,2-diphenylethanone (2u) also could be used
for this reaction and the desired products 3ac and 3ad were
obtained in 85% and 86% yields (entries 11 and 12).
To gain insight into the reaction mechanism, several
control experiments were conducted (Scheme 3). The reaction
result of 1a with 13C labeled 2t showed that the 13C-labeled
Scheme 4 Proposed reaction mechanism.
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reaction of 2a with 1a generates intermediate 1, which converts
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anion of 4-A attacks the carbon atom of the carbonyl group to
form 6-A,20 and 6-A traps a hydrogen ion to yield 7-A which
can be further resonated to give the final product 3a-A (path
A). In another pathway, 4-A is converted into 4-B by isomeriza-
tion and hydrolysis reaction. The nitrogen anion of 4-B attacks
the carbon atom of the carbonyl group to form 6-B,20 and 6-B
traps a hydrogen ion to yield 7-B which can be further reso-
nated to give the final product 3a-B (path B).
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Conclusions
In summary, we have developed a base-promoted approach for
the synthesis of 4,5-dihydro-1H-imidazol-5-ones using ami-
dines and ketones under transition-metal free conditions.
Various amidines and ketones are suitable substrates for this
reaction to give the corresponding products in good yields.
When cyclic ketones were employed, various spiro-fused 4,5-
dihydro-1H-imidazol-5-ones were selectively formed in good to
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Acknowledgements
This work was supported by the National Natural Science
Foundation of China (21172185, 21372187), the New Century
Excellent Talents in University from Ministry of Education of
China (NCET-11-0974) and the Hunan Provincial Innovative
Foundation for Postgraduate (CX2013B269).
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