A new synthetic approach to the imidazo[1,5-: A] imidazole-2-one scaffold and effective functionalization through Suzuki-Miyaura cross coupling reactions

Article abstract of DOI:10.1039/c5ra25520a

We report herein a synthetic pathway to new 7-bromo-1-(4-methoxybenzyl)-5-methyl-imidazo[1,5-a]imidazole-2-one. The synthetic potential of this scaffold was demonstrated by displacing bromine by Suzuki-Miyaura cross-coupling reactions. A large panel of bo

Full text of DOI:10.1039/c5ra25520a

View Article Online
View Journal
RSC Advances
This article can be cited before page numbers have been issued, to do this please use: M. Loubidi, C.
Pillard, A. El Hakmaoui, P. Bernard, M. Akssira and G. Guillaumet, RSC Adv., 2016, DOI:
10.1039/C5RA25520A.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. This Accepted Manuscript will be replaced by the edited,
formatted and paginated article as soon as this is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the Ethical guidelines still
apply. In no event shall the Royal Society of Chemistry be held
responsible for any errors or omissions in this Accepted Manuscript
or any consequences arising from the use of any information it
contains.
www.rsc.org/advances

Please do not adjust margins
Page 1 of 10
RSC Advances
View Article Online
DOI: 10.1039/C5RA25520A
Journal Name
ARTICLE
A new synthetic approach to the imidazo[1,5-a]imidazol-2-one
scaffold and effective functionalization through Suzuki-Miyaura
cross coupling reactions
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
M. Loubidi,a,b C. Pillard,c A. El Hakmaoui,b P. Bernard,c M. Akssira,*b and G. Guillaumet.*a
We report herein a synthetic pathway to new 7-bromo-1-(4-methoxybenzyl)-5-methyl-imidazo[1,5-a]imidazol-2-one. The
synthetic potential of this scaffold was demonstrated by displacing bromine by Suzuki–Miyaura cross-coupling reactions. A
large panel of boronic acids (aryl, heteroaryl or vinyl) were easily introduced, giving access to a broad and diversified
library of 1-(4-methoxybenzyl)-5-methyl-7-(substituted)-imidazo[1,5-a]imidazol-2-ones.
Introduction
Results and discussion
In recent years, nitrogen-bridgehead heterocycles have received
considerable attention from many different research teams in
organic synthesis due to their interesting biological activities.1 In
addition, this family of compounds possesses a high reactivity for
functionalization with new coupling methods.
The required starting compound for the Suzuki-Miyaura reaction
was synthesized in four steps from the commercially available 2-
methylimidazole 1. After dibromation of 1,7 compound 2 was
engaged in
acetamide
a
4
N-alkylation with 2-bromo-N-(4-methoxybenzyl)
(obtained from reaction between 4-
a
methoxybenzylamine 3 and bromoacetyl bromide).8
The condensation reaction between 2 and 4 was performed in the
presence of sodium hydride in dry tetrahydrofuran and afforded
amide 5 in 90% yield. 9
Among nitrogen cycles, 5-5 bicycles have received particular
attention due to their biologically interesting properties exploited in
drug manufacture.2 The imidazo[1,5-a]imidazole is a nitrogenous
heterocycle with significant interest in drug synthesis and
functionalization. It was reported that its oxoanalog imidazo[1,5-
a]imidazolinone has also proved to be a structurally pertinent
skeleton for the development of biologically active and
pharmaceutically relevant compounds.3
Current strategies for preparing imidazo[1,5-a]imidazolinone
derivatives generally consist in building the 5-5 fused ring with
the desired substituents in appropriate position.4 A careful
literature survey revealed that no method for the
functionalization of the heterocyclic moiety has yet been
described. In this context, the overall goal of our research was
to develop an efficient synthesis of imidazo[1,5-a]imidazol-2-
one synthon that permits its subsequent functionalization,
thereby enabling molecular diversity.
Scheme 1. Preparation of 2-(4,5-dibromo-2-methyl-1H-imidazol-1-yl)-N-(4-
methoxybenzyl)acetamide 5. (a) Br2, KHCO3, DMF, 0–100 °C, 2 h, 62 %; (b)
bromoacetyl bromide, DIPEA, DCM, 0 °C to RT., 24 h, 95 %; (c) NaH, THF, 0
°C to RT., 24 h, 90 %.
Based on the interest of our group in the synthesis of nitrogen-
based heterocycles,5 we disclose herein the access to a library of
original 5-methyl-7-(hetero)arylated-imidazo[1,5-a]imidazol-2-one
derivatives. Our synthetic strategy is based on an efficient four-step
synthesis of the bicycle followed by palladium catalyzed Suzuki-
Miyaura cross-coupling.6 To the best of our knowledge, no example
of palladium cross-coupling reaction on the imidazo[1,5-
a]imidazolinone core has yet been reported.
Product
5 was engaged in an intramolecular cyclization. First, a
Buchwald-type cyclization using palladium acetate, xantphos
as ligand and cesium carbonate as base was tested10 (Table 1,
entries 1-4) but low conversion was observed. Replacing the
catalyst by copper iodide11 resulted in better conversion (Table
1, entry 5). The use of K3PO4 as base considerably improved
the conversion rate to 89% in toluene and to 80% in N,N-
dimethylformamide (Table 1, entries 6 and 7). The addition of
a ligand such as N,N’-dimethylethylenediamine12 did not
improved the yield (Table 1, entries 8 and 9). We also carried
out the reaction in different solvents (Table 1, entries 10-12).
Finally, a total conversion was obtained in toluene at 160 °C
during 4 hours (Table 1, entry 13). We also found that the
heating system has a significant influence, since heating
a.Institut de Chimie Organique et Analytique, Université d’Orléans, UMR CNRS
7311, 45067 Orléans Cedex, France.
b.Equipe de Chimie Bioorganique & Analytique, URAC 22 Université Hassan II
Mohammedia-Casablanca, BP 146, 28800 Mohammedia, Morocco.
c. Greenpharma S.A.S. 3, allée du Titane, 45100, Orleans, France.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
RSC Advances
Page 2 of 10
View Article Online
DOI: 10.1039/C5RA25520A
Journal Name
ARTICLE
in a sealed tube for 20 hours also led to a conversion rate of efficiency (Table 1, entry 16). On the other hand, the catalyst
100%, and a yield after column chromatography of 81% loading could be reduced to 10 mol% of CuI without impacting
(table1- entry 15). To complete the optimization, we evaluated the yield of the reaction (Table 1, entry 17). However 5 mol%
the impact of the amount of base and CuI. Decreasing the involved a partial conversion rate and a low yield (table 1,
quantity of K3PO4 to 2 equivalents did not maintain a coupling entry 18).
Table1. Optimisation of intramolecular cyclisation.
Entry
Catalyst
Ligand
Base
Solvent
Time
(h)
4
T (°C)
Heating
system
Conv. (a)
Yield(b)
(c)
1
2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
CuI
Xantphos
Cs2CO3 (2eq)
Cs2CO3 (2eq)
Cs2CO3 (2eq)
Cs2CO3 (4eq)
Cs2CO3 (4eq)
K3PO4 (4eq)
K3PO4 (4eq)
K3PO4 (4eq)
Cs2CO3 (4eq)
K3PO4 (4eq)
K3PO4 (4eq)
K3PO4 (4eq)
K3PO4 (4eq)
K3PO4 (4eq)
K3PO4 (4eq)
K3PO4 (2eq)
K3PO4 (4eq)
K3PO4 (4eq)
K3PO4 (4eq)
1,4-Dioxane
tBuOH
150°C
150°C
150°C
150°C
150°C
150°C
150°C
150°C
150°C
150°C
150°C
150°C
160 °C
MW
MW
MW
MW
MW
MW
MW
MW
MW
MW
MW
MW
MW
0
0
-
(c)
Xantphos
4
-
3
Xantphos
Toluene
4
38
46
72
89
80
55
28
0
29
37
55
74
58
42
19
4
Xantphos
Toluene
4
5
-
Toluene
4
6
CuI
-
Toluene
4
7
CuI
-
DMF
4
8
CuI
DMEDA
DMF
2
9
CuI
DMEDA
DMF
2
(c)
10
11
12
13
14
15
16
17
18
19
CuI
-
-
-
-
-
-
-
-
-
-
1,4-Dioxane
Toluene/DMF (4/1)
Toluene/Ethanol (4/1)
Toluene
4
-
CuI
4
57
25
100
87
100
57
100
78
0
44
17
80
68
81
46
80
64
CuI
4
CuI
4
CuI
Toluene
16
20
20
20
20
4
150°C Sealed tube
150°C Sealed tube
150°C Sealed tube
150°C Sealed tube
150°C Sealed tube
CuI
Toluene
CuI
Toluene
CuI(d)
CuI(e)
-
Toluene
Toluene
(f)
Toluene
160 °C
MW
-
(a) 1H NMR ratio based on the integration of CH3.
(b) Yield of isolated product after column chromatography.
(c) Degradation of the reaction mixture.
(f) 100% of starting material 5 is recovered.
(d) With 10 mol % of copper iodide (CuI).
(e) With 5 mol % of copper iodide (CuI).
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 2
Please do not adjust margins

Page 3 of 10
RSC Advances
Please do not adjust margins
Journal Name
ARTICLE
View Article Online
DOI: 10.1039/C5RA25520A
These functionalizable intermediate 6 open the way to design a acetate, [1,1 bis(diphenylphosphino) ferrocene] dichloropalladium)
chemical library of imidazo[1,5-a]imidazolinone derivatives from complexed with dichloromethane Pd(dppf)Cl2.CH2Cl2, or
the bromide in position 7.
bis(dibenzylideneacetone)palladium(0)) as the catalyst, potassium
carbonate as the base and a mixture of 1,4-dioxane/ethanol 2/1 as
solvent. The coupling product 7 was obtained in the three tests with
acceptable yields but with only a partial conversion rate (Table 2,
entries 1-3).
Initial optimization trials of the Suzuki-Miyaura cross coupling
reaction were performed on the imidazole skeleton 6 synthesized
previously using p-tolylboronic acid. As a model, we began with the
investigation using different palladium sources, (palladium (II)
Table 2: Screening Suzuki reaction conditions with 4-tolylboronic acid.
Entry Catalyst
Ligand
Solvent
Time
[min]
Heating
system
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
MW, 130 °C
Conv [%](a) Yield [%](b)
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd(dppf)Cl2.CH2Cl2
Pd2(dba)3
Pd(dppf)Cl2.CH2Cl2
Pd(OAc)2
Pd(dppf)Cl2.CH2Cl2
Pd2(dba)3
Xantphos
-
-
-
1,4-Dioxane/EtOH(2/1) 180
1,4-Dioxane/EtOH(2/1) 90
1,4-Dioxane/EtOH(2/1) 90
82
61
72
44
21
67
88
51
73
91
71
1,4-Dioxane
90
180
90
90
20
52
90
Xantphos
Toluene/EtOH (2/1)
Toluene/EtOH (2/1)
Toluene/EtOH (2/1)
Toluene/EtOH (2/1)
-
-
-
100
79
Pd(dppf)Cl2.CH2Cl2
100
(a) 1H NMR ratio based on the integration of CH3 or OCH3.
(b) Yield of isolated product after column chromatography.
Without ethanol, even after 90 minutes of heating, only 52% of optimized conditions proved to be efficient with boronic acids
conversion was achieved (Table 2, entry 4), showing that a protic containing a large variety of functional groups. More precisely,
solvent is essential in this coupling process.
para-substituted phenylboronic acids bearing electron-rich (CH3,
OCH3) or electron-poor (COOEt, NO2, CF3, CN) groups led to 7-aryl-
1H-imidazo[1,5-a]imidazol-2-ones in good yields (Table 3, entries 1-
7). Notably, meta-substitution did not disfavor the cross-coupling
reaction. In fact, derivatives 15-18 were obtained in satisfactory
yields (Table 3, entries 9-12). However, using ortho-sustituted
phenylboronic acids provided only the dehalogenation product 19
(Table 3, entries 13-15). Steric hindrance could explain this result.
Replacing 1,4-dioxane by toluene led to a significant increase in
conversion rate (Table, entries 5-7). The best conditions were found
with a mixture of toluene/ethanol 2/1 as solvent. We next focused
our attention on the influence of the catalyst. The use of palladium
(0) instead a palladium (II) (i.e. Pd2dba3 in replacement of Pd(OAc)2
or Pd(dppf)Cl2.CH2Cl2), the yield significantly decreased (Table 2,
entries 5-7). Finally, replacing conventional thermal heating by
microwave irradiation produced no real improvement in terms of Finally, hererocycles such as 3-furane and 3-thiophene were
yield and time (Table 2, entry 8).
introduced with moderate yields of 46% and 65% respectively
(Table 3, entries 17 and 18). The strategy was also compatible with
vinylboronic acid, since styryl derivative 20 was obtained in 67%
yield (entry 16).
Optimum conditions were found to be boronic acid (1.5 equiv),
Pd(dppf)Cl2.CH2Cl2 (0.10 equiv), K2CO3 (1.5 equiv) in a mixture of
toluene/ ethanol 2/1, refluxing for a short time of 1.5 hour.
To explore the scope of the methodology, we applied these
selected conditions using different boronic acids. Gratifyingly, the
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
RSC Advances
Page 4 of 10
ARTICLE
Table 3. Scope of Suzuki–Miyaura cross coupling of 6.
Journal Name
View Article Online
DOI: 10.1039/C5RA25520A
Entry
1
RB(OH)2
Reaction time [h]
1.5
Product
Yield [%][a]
7
88
2
3
4
1,5
8
79
79
83
2
9
2
10
5
6
1.5
1.5
11
12
82
80
7
1.5
13
61
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 5 of 10
RSC Advances
Please do not adjust margins
Journal Name
ARTICLE
View Article Online
DOI: 10.1039/C5RA25520A
8
1.5
14
75
9
1.5
1.5
1.5
15
16
17
18
79
74
74
10
11
12
13
1.5
1.5
56
52
14
15
16
1.5
1.5
2
19
49
50
67
20
21
22
17
18
2
2
46
65
(a) Yield of isolated product after column chromatography.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
Please do not adjust margins

Please do not adjust margins
RSC Advances
Page 6 of 10
ARTICLE
Journal Name
Conclusion
View Article Online
In conclusion, we have reported here a new method to access the effective. Good yields were obtained fDoOr I: 10.1039/C5RA25520A
a wide range of
imidazo[1,5-a]imidazol-2-one core. We then developed the first C-7 (hetero)aryl boronic acids with both electron-poor and electron-rich
pallado-catalyzed functionalization of this bicycle by Suzuki-Miyaura substituents, giving access to a library of new 7-substituted-1-(4-
cross-coupling reactions. The methodology described is original and methoxybenzyl)-5-methyl-1H-imidazo[1,5-a]imidazol-2-ones.
Experimental
General: All reagents were purchased from commercial (neat, cm-1): 818, 1030, 1179, 1212, 1243, 1512, 1645, 3280; 1H
suppliers and were used without further purification. The NMR (400 MHz, CDCl3): δ 3.81 (s, 3 H), 3.92 (s, 2 H), 4.41 (d, J = 5.7
reactions were monitored by thin-layer chromatography (TLC) Hz, 2 H), 6.89 (d, J = 8.5 Hz, 2H), 6.70 (br. s, 1H), 7.22 (d, J =8.5
Hz,2H); 13C NMR (101 MHz, DMSO-d6): δ 29.5, 42.0, 55.1, 113.8
(2C), 128.7 (2C), 130.1, 158.3, 165.9; HRMS (ESI): calcd. for
C10H13BrNO2 258.01242 [M+H]+ 279.99436 [M+Na]+ found
258.01227 [M+H]+ 279.9944 [M+Na]+.
analysis by using silica gel (60 F254) plates. Compounds were
visualized by UV irradiation at 256 or 365 nm. Flash column
chromatography was performed on silica gel 60 (230–400
mesh, 0.040–0.063 mm). Melting points (m.p. [°C]) were taken
on samples in open capillary tubes. Infrared spectra of
compounds were recorded with a Thermo Scientific Nicolet
iS10 instrument. 1H and 13C NMR spectra were recorded with a
Bruker spectrometer at 250 MHz (13C, 61.5 MHz) or 400 MHz
(13C, 101 MHz). Chemical shifts are given in parts per million
(ppm) from tetramethylsilane (TMS) as internal standard in
CDCl3, and the residual peak of DMSO in [D6]DMSO. The
following abbreviations are used for the 1H NMR spectra
multiplicities: br. s: broad singlet, s: singlet, d: doublet, t:
triplet, q: quartet, qt: quintuplet, m: multiplet. Coupling
constants (J) are reported in Hertz [Hz]. CIV is the abbreviation
for quaternary carbon atoms. High-resolution mass spectra
(HRMS) were performed with a Maxis Bruker 4G instrument.
2-(4,5-Dibromo-2-methyl-1H-imidazol-1-yl)-N-(4-methoxybenzyl)
acetamide (5).
Sodium hydride (1.26 g, 31.5 mmol, 1.2 equiv.) was slowly added to
a solution of the imidazole 2 (6.25 g, 26.3 mmol) in 130 mL of dry
tetrahydrofuran under argon at 0 °C. After 15 minutes stirring, the
acetamide 4 (6.80 g, 26.3 mmol, 1.0 equiv.) was added portion
wise. The reaction mixture was allowed to warm up to room
temperature and stirred for 24 hours before being quenched with
water (100 mL). The tetrahydrofuran was then removed under
reduced pressure and the resulting solid was filtered off, washed
with water and pentane then dried to afford product 5 (9.90 g,
90%).
White solid (9.90 g, 90%); mp: 132-134 °C; IR (neat, cm-1): 700,
846, 1017, 1245, 1462, 1504, 1600; 1H NMR (250 MHz, DMSO-
d6): δ 2.28 (s, 3H), 3.73 (s, 3H), 4.25 (d, J = 5.7 Hz, 2H), 4.69 (s,
2H), 6.90 (d, J = 8.7 Hz, 2H), 7.20 (d, J = 8.7 Hz, 2H), 8.73 (s,
1H); 13C NMR (101 MHz, DMSO-d6) δ 13.8, 42.1, 48.1, 55.3,
103.3 (2C), 114.0 (2C), 128.8 (2C), 130.8, 147.3, 158.5, 165.6;
HRMS (ESI): calcd. for C14H16Br2N3O2 415.9606 [M+H]+ found
415.9604 [M+1]+.
4,5-Dibromo-2-methyl-1H-imidazole (2)
Bromine (6.2 mL, 122 mmol) was added slowly to a solution of the
2-methyl-1H-imidazole
1
(5g, 61mmol) and potassium
hydrogenocarbonate (12.19 g, 122 mmol) in dry DMF at 0 °C under
argon, the reaction mixture was allowed to warm to room
temperature for half an hour and heated at 100 °C for 3 hours. After
cooling, the reaction mixture was poured into an aqueous saturated
solution of Na2S2O3 and extracted with ethyl acetate. The combined
organic layers were washed with brine, dried over MgSO4, filtered
off and concentrated under reduced pressure. The desired product
2 was obtained by precipitation in pentane (9.06 g, 62%).
7-Bromo-1-(4-methoxybenzyl)-5-methyl-1H-imidazo[1,5-
a]imidazol-2(3H)-one (6).
A sealed tube containing a stirring bar was charged with the 2-
(4,5-dibromo-2-methyl-1H-imidazol-1-yl)-N-(4-methoxybenzyl)
White solid (9.06 g, 62%); M.p. 235–237 °C (ref.13 239-240 °C), IR
(neat, cm-1): 1397, 1556, 3122, 3216, 3490; 1H NMR (400 MHz,
DMSO-d6): δ, 2.23 (s, 3H, CH3); 13C NMR (101 MHz, DMSO-d6): δ
14.3, 105.95 (2C), 146.0 (CIV); HRMS (ESI): calcd for C4H5Br2N2
238.88140 [M+H]+, 260.86334 [M+Na]+ found 238.88134 [M+H]+
260.86327 [M+Na]+.
acetamide
5 (500 mg, 1.2 mmol), and potassium phosphate
tribasic (1.02 g, 4.82 mmol) in dry toluene (10 ml), copper
iodide (46 mg, 0.24 mmol) was added and the mixture was
heated at 150 °C for 20 hours. After cooling down to room
temperature, the solvent was removed under reduced
pressure and the residue was purified by flash
chromatography (petroleum ether`/ethyl acetate 70:30) to
provide the desired product 6.
2-Bromo-N-(4-methoxybenzyl)acetamide (4)
Bromoacetylbromide (3.2 mL, 36.4 mmol, 1.0 equiv.) was added
slowly to a solution of 4-methoxybenzylamine 3 (5 g, 36.4 mmol, 1
equiv.) and diisoopropylethylamine (6.3 mL, 36.4 mmol, 1 equiv.) in
150 mL of DCM at 0 °C. The reaction mixture was allowed to warm
up to room temperature and stirred for 24 hours before being
quenched with an aqueous solution of HCl (1 M) and extracted with
dichloromethane (3x75 mL). The combined organic layers were
washed with brine (3x50 mL), dried over MgSO4, filtered off and
concentrated under reduced pressure and the resulting solid was
filtered off, washed with water and pentane then dried to afford
product 4 (8.9 g, 95 %).
White solid (328 mg, 81%); mp: 132-134 °C; IR (neat, cm-1):
1
810, 1239, 1577, 1730, 2940; H NMR (400 MHz, CDCl3) δ 2.28
(s, 3H). 3.77 (s, 3H), 4.35 (s, 2H), 4.86 (s, 2H), 6.84 (d, J = 8.3 Hz,
2H), 7.39 (d, J = 8.3 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 13.4,
43.7, 47.7, 55.4, 86.9, 114.2 (2C), 127.7, 129.9 (2C), 132.6,
138.3, 159.6, 169.8; HRMS (ESI): calcd. for C14H15BrN3O2
336.03394 [M+H]+ found 336.03421 [M+H]+.
General procedure: Suzuki Coupling on imidazo[1,5-a]imidazoles
6. A flask containing a stirring bar was charged with the
imidazole[1,2-a]imidazole
6 (100 mg), boronic acid (1.5 equiv.)
White solid (8.9 g, 95 %); mp. 119–121 °C (ref.14 120–121 °C); IR
6 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 7 of 10
RSC Advances
Please do not adjust margins
Journal Name
ARTICLE
and potassium carbonate (1.5 equiv.) in a mixture of toluene/ purified by flash chromatography on silicaViegweAlrtic(le7O5n:l2in5e
ethanol (2/1 v/v). Pd(dppf)Cl2.CH2Cl2 (0.1 equiv.) was added dichloromethane / ethyl acetate).
DOI: 10.1039/C5RA25520A
and the mixture was refluxed for the indicated time. After Brown solid (100 mg; 83%); mp:173-175 °C; IR (neat, cm-1):
1
cooling down, solvents were removed under reduced pressure 990, 1175, 1248, 1510, 1607, 1722, 2835; H NMR (400 MHz,
and the residue was purified by flash chromatography to CDCl3) δ 1.43 (t, J = 7.1 Hz, 3H), 2.40 (s, 3H), 3.75 (s, 3H), 4.43
provide the desired products
7
-
22
.
(q, J = 7.1 Hz, 2H), 4.49 (s, 2H), 4.90 (s, 2H), 6.72 (d, J = 8.5 Hz,
2H), 6.89 (d, J = 8.5 Hz, 2H), 7.48 (d, J = 8.1 Hz, 2H), 8.03 (d, J =
8.1 Hz, 2H).13C NMR (101 MHz, CDCl3) δ 13.4, 14.5, 44.4, 47.2,
55.4, 61.1, 114.2 (2C), 117.4, 127.2, 128.1 (2C), 128.9, 129.8
(2C), 130.0(2C), 132.7, 138.2, 138.5, 159.4, 166.7, 171.1; HRMS
(ESI): calcd. for C23H24N3O4 406.17607 [M+H]+ found 406.17613
[M+H]+.
1-(4-Methoxybenzyl)-5-methyl-7-(p-tolyl)-1H-imidazo[1,5-
a]imidazol-2(3H)-one (7).
Following the general procedure A with p-tolylboronic acid (61
mg, 0.45 mmol) the mixture was refluxed for 1.5 hours. The
crude product was purified by flash chromatography on silica
gel (75:25 dichloromethane / ethyl acetate).
1-(4-Methoxybenzyl)-5-methyl-7-(4-nitrophenyl)-1H-imidazo
[1,5-a]imidazol-2(3H)-one (11).
Brown solid (88 mg; 85%); mp: 152-153 °C; IR (neat, cm-1):
1
825, 1247, 1514, 1608, 1720, 2919; H NMR (400 MHz, CDCl3)
δ 2.34 (s, 3H), 2.37 (s, 3H), 3.72 (s, 3H), 4.41 (s, 2H), 4.82 (s, Following the general procedure with 4-nitrophenylboronic
2H), 6.67 (d, J = 8.6 Hz, 2H), 6.84 (d, J = 8.6 Hz, 2H), 7.13 (d, J = acid (74 mg, 0.45 mmol), the mixture was refluxed for 1.5
7.9 Hz, 2H), 7.27 (d, J = 7.9 Hz, 2H); 13C NMR (101 MHz, CDCl3) hours. The crude product was purified by flash
δ 13.0, 21.0, 44.1, 46.9, 55.3, 114.0 (2C), 118.0, 127.7, 128.6 chromatography on silica gel (95:5 dichloromethane / ethyl
(2C), 128.6 (2C), 129.9 (2C), 130.7, 131.4, 136.8, 137.7, 159.3, acetate).
170.9; HRMS (ESI): calcd. For C21H22N3O2 348.17084 [M+H]+ Brown solid (92 mg, 82%); mp: 169-171 °C; IR (neat, cm-1): 814,
1
found 348.17065 [M+H]+.
1048, 1097, 1249, 1318, 1509, 1723, 2923; H NMR (400 MHz,
CDCl3): δ 2.39 (s, 3H), 3.74 (s, 3H), 4.52 (s, 2H), 4.91 (s, 2H),
6.74 (d, J = 8.0 Hz, 2H), 6.91 (d, J = 7.9 Hz, 2H), 7.51 (d, J = 8.0
Hz, 2H), δ 8.15 (d, J = 7.9 Hz, 2H); 13C NMR (101 MHz, CDCl3): δ
13.3, 44.6, 47.2, 55.4, 114.4 (2C), 116.4, 123.9 (2C), 126.7,
128.3 (2C), 128.4 (2C), 133.6, 139.1, 140.4, 146.3, 159.5, 171.1;
HRMS (ESI): calcd. for C20H19N4O4 379.14009 [M+H]+ found
379.14008 [M+H]+.
1-(4-Methoxybenzyl)-7-(4-methoxyphenyl)-5-methyl-1H-
imidazo[1,5-a]imidazol-2(3H)-one. (8)
Following
the
general
procedure
with
4-
methoxyphenylboronic acid (68 mg, 0.45 mmol),the mixture
was refluxed for 1.5 hours. The crude product was purified by
flash chromatography on silica gel (75:25 dichloromethane /
ethyl acetate).
1-(4-Methoxybenzyl)-5-methyl-7-(4-(trifluoromethyl)phenyl)-
Brown solid (85 mg; 79%); mp: 175-177 °C; IR (neat, cm-1): 811,
1H-imidazo[1,5-a]imidazol-2(3H)-one (12).
1029, 1184, 1230, 1525, 1572, 1730; 1H NMR (400 MHz, CDCl3)
δ 2.33 (s, 3H), 3.71 (s, 3H), 3.82 (s, 3H), 4.41 (s, 2H), 4.79 (s, Following
the
general
procedure
with
4-
2H), 6.67 (d, J = 8.6 Hz, 2H), 6.82 (d, J = 8.6 Hz, 2H), 6.88 (d, J = (trifluoromethyl)phenylboronic acid (85 mg, 0.45mmol), the
8.6 Hz, 2H), 7.28 (d, J = 8.6 Hz, 2H); 13C NMR (101 MHz, CDCl3) mixture was refluxed for 1.5 hours. The crude product was
δ 13.3, 44.0, 47.2, 55.3, 113.9 (2C), 114,0 (2C), 117.5, 126.2, purified by flash chromatography on silica gel (75:25
127.7, 129.2 (2C), 130.0 (2C), 131.1, 137.6, 158.9, 159.2, 170.8; dichloromethane / ethyl acetate).
HRMS (ESI): calcd. for C21H22N3O3 364.16557 [M+H]+ found White solid (96 mg; 80%); mp: 195-197 °C; IR (neat, cm-1): 858,
1
364.16579 [M+H]+.
1062, 1102, 1245, 1317, 1600, 1721, 2930; H NMR (400 MHz,
CDCl3): δ 2.37 (s, 3H), 3.73 (s, 3H), 4.48 (s, 2H), 4.86 (s, 2H),
6.69 (d, J = 8.3 Hz, 2H), 6.84 (d, J = 8.3 Hz, 2H), 7.46 (d, J = 8.0
Hz, 2H), 7.56 (d, J = 8.0 Hz, 2H); 13C NMR (101 MHz, CDCl3): δ
7-(3,5-Dimethoxyphenyl)-1-(4-methoxybenzyl)-5-methyl-1H-
imidazo[1,5-a]imidazol-2(3H)-one (9).
1
13.3, 44.4, 47.2, 55.4, 114.2(2C), 116.9, 124.4 (q, JC-F = 273 Hz,
CF3), 125.36 (2C) (q, JCHAr-F = 3.8 Hz, CHAr), 127.0, 128.5 (2C),
128.6 (2C), 128.9 (q, JCIV-F = 32.4 Hz, CIV), 132.6, 137.3, 138.5,
159.4, 171.0; HRMS (ESI): calcd. for C21H19F3N3O2 402.14217
Following
the
general
procedure
with
3,5-
3
dimethoxyphenylboronic acid (81 mg, 0.45 mmol), the mixture
was refluxed for 2 hours. The crude product was purified by
flash chromatography on silica gel (75:25 dichloromethane /
ethyl acetate).
2
[M+H]+ found 402.14239 [M+H]+.
White solid (93 mg; 79%); mp: 110-112 °C; IR (neat, cm-1): 842,
1061, 1177, 1247, 1513, 1597, 1722; 1H NMR (400 MHz,
CDCl3): δ 2.34 (s, 3H), 3.71 (s, 9H), 4.41 (s, 2H), 4.87 (s, 2H),
6.40 (s, 1H), 6.55 (s, 2H), 6.68 (d, J = 8.3 Hz, 2H), 6.87 (d, J = 8.3
Hz, 2H); 13C NMR (101 MHz, CDCl3): δ 13.3, 44.2, 47.2, 55.3
(3C), 100.0, 106.7 (2C), 114.0 (2C), 118.0, 127.6, 129.1 (2C),
131.6, 135.6, 137.7, 159.8, 160.8 (2C), 170.9; HRMS (ESI):
calcd. for C22H24N3O4 394.17596 [M+H]+ found 394.17613
[M+H]+.
4-(1-(4-Methoxybenzyl)-5-methyl-2-oxo-2,3-dihydro-1H-
imidazo[1,5-a]imidazol-7-yl)benzonitrile (13).
Following the general procedure with 4-cyanophenylboronic
acid (65 mg, 0.45 mmol), the mixture was refluxed for 1.5
hours. The crude product was purified by flash
chromatography on silica gel (75:25 dichloromethane / ethyl
acetate).
Brown solid (65 mg; 61%); mp: 137-139 °C; IR (neat, cm-1): 844,
1
1296, 1509, 1605, 1720, 2215; H NMR (400 MHz, CDCl3): δ
Ethyl 4-(1-(4-methoxybenzyl)-5-methyl-2-oxo-2,3-dihydro-1H-
imidazo[1,5-a]imidazol-7-yl)benzoate (10).
2.38 (s, 3H), 3.75 (s, 3H), 4.51 (s, 2H), 4.88 (s, 2H), 6.73 (d, J =
8.1 Hz, 2H), 6.88 (d, J = 8.1 Hz, 2H), 7.46 (d, J = 7.7 Hz, 2H), 7.58
(d, J = 7.7 Hz, 2H); 13C NMR (101 MHz, CDCl3):δ 13.4, 44.5,
47.2, 55.4, 110.0, 114.3 (2C), 116.7, 119.2, 126.8, 128.5 (2C),
128.4 (2C), 132.2 (2C), 133.0, 138.4, 138.8, 159.5, 171.1; HRMS
Following
the
general
procedure
with
4-
ethoxycarbonylphenylboronic acid (80 mg, 0.45mmol), the
mixture was refluxed for 2 hours. The crude product was
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 7
Please do not adjust margins

Please do not adjust margins
RSC Advances
Page 8 of 10
ARTICLE
Journal Name
(ESI): calcd. for C21H18N4O2 359.15007 [M+H]+ found 359.15025 MHz, CDCl3): δ 2.38 (s, 3H), 3.74 (s, 3H), 4.51 (s,V2ieHw )A,rti4cl.e8O3nl(inse,
[M+H]+.
2H), 6.65 (d, J = 8.5 Hz, 2H), 6.77 (d, J = 8D.5OHI: z10, .210H3)9,/7C.54R1A2(5d5,2J0A=
7.7 Hz, 1H), 7.51 – 7.44 (m, 2H), 7.63 (s, 1H); 13C NMR (101
MHz, CDCl3): δ 13.3, 44.2, 47.2, 55.3, 113.8 (2C), 116.5, 123.4
(q, JC-F = 3.7 Hz), 123.9 (q, JC-F = 273 Hz, CF3), 125.0 (q, JC-F = 3.7
Hz), 126.6, 128.3 (2C), 128.5, 130.5 (q, J = 32.2 Hz), 131.5,
132.3, 134.6, 138.3, 159.4, 170.9; HRMS (ESI): calcd. for
C21H19F3N3O2 402.14226 [M+H]+ found 402.14239 [M+H]+.
1-(4-Methoxybenzyl)-5-methyl-7-phenyl-1H-imidazo[1,5-
a]imidazol-2(3H)-one (14).
Following the general procedure with phenylboronic acid (54
mg, 0.45 mmol), the mixture was refluxed for 1.5 hours .The
crude product was purified by flash chromatography on silica
gel (95:5 dichloromethane / ethyl acetate).
3-(1-(4-Methoxybenzyl)-5-methyl-2-oxo-2,3-dihydro-1H-
imidazo[1,5-a]imidazol-7-yl)benzonitrile (18).
Brown solid (74 mg; 75%); mp: 126-128 °C; IR (neat, cm-1):
1
769, 1031, 1252, 1332, 1615, 1700; H NMR (400 MHz, CDCl3):
δ 2.35 (s, 3H), 3.71 (s, 3H), 4.42 (s, 2H), 4.83 (s, 2H), 6.66 (d, J = Following the general procedure with 3-cyanophenylboronic
8.8 Hz, 2H), 6.8 (d, J = 8.8 Hz, 2H), 7.25 – 7.32 (m, 1H), 7.36 (q, acid (65 mg, 0.45 mmol), the mixture was refluxed for 1.5
J = 7.7 Hz, 4H). 13C NMR (101 MHz, CDCl3): δ 13.3, 44.1, 47.2, hours,the crude product was purified by flash chromatography
55.3, 114.0 (2C), 118.0, 127.1, 127.6 (2C), 128.4 (2C), 128.7 on silica gel (75:25 dichloromethane / ethyl acetate).
(2C), 129.2, 131.6, 133.7, 137.8, 159.2, 170.9. HRMS (ESI): Brown solid (60 mg; 56%); mp: 147-149 °C; IR (neat, cm-1): 805,
1
calcd. for C20H20N3O2 334.15488 [M+H]+; found 334.15500 1242, 1512, 1605, 1726, 2224; H NMR (400 MHz, CDCl3): δ
[M+H]+.
2.38 (s, 3H), 3.74 (s, 3H), 4.51 (s, 2H), 4.85 (s, 2H), 6.73 (d, J =
8.2 Hz, 2H), 6.86 (d, J = 8.2 Hz, 2H), 7.40 (t, J = 7.6, 1H), 7.52 (d,
J = 7.6 Hz, 1H), 7.56 (d, J = 7.6 Hz, 1H), 7.58 (s, 1H); 13C NMR
(101 MHz, CDCl3): δ 13.3, 44.4, 47.2, 55.4, 112.6, 114.37 (2C),
116.0, 118.8, 126.7, 128.4 (2C), 129.2, 130.4, 131.6, 132.5,
132.6, 135.0, 138.6, 159.3, 170.8; HRMS (ESI): calcd. for
C21H19N4O2 359.15012 [M+H]+ found 359.15025 [M+H]+.
1-(4-Methoxybenzyl)-5-methyl-7-(m-tolyl)-1H-imidazo[1,5-
a]imidazol-2(3H)-one (15).
Following the general procedure A with m-tolylboronic acid
(61 mg, 0.45 mmol), the mixture was refluxed for 1.5 hours.
The crude product was purified by flash chromatography on
silica gel (75:25 dichloromethane / ethyl acetate).
1-(4-Methoxybenzyl)-5-methyl-1H-imidazo[1,5-a]imidazol-
2(3H)-one (19).
Brown solid (82 mg; 79%); mp: 142-143 °C; IR (neat, cm-1):
1
825, 1246, 1513, 1637, 1721, 2920; H NMR (400 MHz, CDCl3)
δ 2.32 (s, 3H), 2.35 (s, 3H), 3.72 (s, 3H), 4.43 (s, 2H), 4.84 (s, Following the general procedure with 2-tolylboronic acid, 2-
2H), 6.68 (d, J = 8.0 Hz, 2H), 6.54 (d, J = 8.0 Hz, 2H), 7.16 (d, J = methoxyphenylboronic acid or 2-(trifluoromethyl)
7.4 Hz, 1H), 7.20 (d, J = 7.6 Hz, 1H), 7.20 (s, 1H), 7.21 – 7.25 (m, phenylboronic acid (1.5 eq, 0.45 mmol), the mixture was
1H); 13C NMR (101 MHz, CDCl3) δ 13.3, 21.5, 44.2, 47.20, 55.3, refluxed for 1.5 hours. The crude product was purified by flash
114.01 (2C), 118.1, 125.8, 127.6, 127.9, 128.27, 129.0 (2C), chromatography on silica gel (75:25 dichloromethane / ethyl
129.3, 131.5, 133.5, 137.8, 138.07, 159.3, 170.9; HRMS (ESI): acetate).
calcd. For C21H22N3O2 348.17050 [M+H]+ found 348.17065 White solid; (yield See table N°3 above). mp: 98-100 °C; IR
[M+H]+.
(neat, cm-1): 845, 1027, 1176, 1243, 1512, 1609, 1719, 2927;
1H NMR (400 MHz, CDCl3): δ 2.32 (s, 3H), 3.81 (s, 3H), 4.41 (s,
2H), 4.75 (s, 2H), 6.06 (s, 1H), 6.86 (d, J = 8.3 Hz, 2H), 7.29 (d, J
= 8.3 Hz, 2H); 13C NMR (101 MHz, CDCl3): δ 13.6, 45.2, 47.6,
55.4, 103.2, 114.4 (2C), 126.6, 130.0 (2C), 136.5, 138.1, 160.0,
170.0; HRMS (ESI): calcd. for C14H16N3O2 258.12369 [M+H]+
found 258.12370 [M+H]+.
1-(4-Methoxybenzyl)-5-methyl-7-(3-nitrophenyl)-1H-
imidazo[1,5-a]imidazol-2(3H)-one (16).
Following the general procedure with 3-nitrophenylboronic
acid (74 mg, 0.45 mmol), the mixture was refluxed for 1.5
hours. The crude product was purified by flash
chromatography on silica gel (95:5 dichloromethane / ethyl
acetate).Brown solid (83 mg, 74%); mp: 178-180 °C; IR (neat,
(E)-1-(4-Methoxybenzyl)-5-methyl-7-styryl-1H-imidazo[1,5-
a]imidazol-2(3H)-one (20).
cm-1) 810, 1033, 1112, 1245, 1329, 1512, 1727, 2925; H NMR
1
(400 MHz, CDCl3): δ 2.39 (s, 3H), 3.71 (s, 3H), 4.54 (s, 2H), 4.91 Following
the
general
procedure
with
trans-2-
(s, 2H), 6.6 (d, J = 8.0 Hz, 2H), 6.8 (d, J = 8.0 Hz, 2H), 7.4 (t, J = phenylvinylboronic acid (62 mg, 0.45 mmol), the mixture was
8.0 Hz, 1H), 7.7 (d, J = 8.0 Hz, 1H), 7.9 (dd, J = 8.0, 2.0 Hz, 1H), refluxed for 2 hours. The crude product was purified by flash
8.2 (d, J = 2.0 Hz, 1H); 13C NMR (101 MHz, CDCl3): δ 13.3, 44.4, chromatography on silica gel (75:25 dichloromethane / ethyl
47.2, 55.4, 114.2 (2C), 116.1, 121.6, 122.9, 126.6, 128.3 (2C), acetate).
129.3, 132.7, 134.1, 135.5, 138.7, 148.3, 159.4, 170.9; HRMS Brown solid (72 mg; 67%); mp: 192–194 °C; IR (neat, cm-1):
1
(ESI): calcd. for C20H19N4O4 379.14010 [M+H]+ found 379.14008 918, 1176, 1246, 1511, 1614, 1729; H NMR (400 MHz, CDCl3):
[M+H]+.
δ 2.37 (s, 3H), 3.78 (s, 3H), 4.43 (s, 2H), 4.98 (s, 2H), 6.65 (d, J =
15,8Hz, 1H), 6.92 (d, J = 8,3Hz, 2H), 7.13 (d, J = 15,8Hz, 1H),
1-(4-Methoxybenzyl)-5-methyl-7-(3-(trifluoromethyl)phenyl)- 7.18-7.27 (m, 1H), 7.28 – 7.32 (m, 6H); 13C NMR (101 MHz,
1H-imidazo[1,5-a]imidazol-2(3H)-one (17).
Following the general procedure
CDCl3):δ 13.4, 44.3, 47.3, 55.4, 114.5 (2C), 116.3, 117.5, 125.2,
3- 126.0 (2C), 126.8, 127.2, 128.5 (2C), 128.6 (2C), 133.0, 138.0,
with
(trifluoromethyl)phenylboronic acid (85 mg, 0.45 mmol), the 138.8, 159.6, 170.5; HRMS (ESI): calcd. for C22H22N3O2
mixture was refluxed for 1.5 hours. The crude product was 360.17047 [M+H]+ found 360.17065 [M+H]+.
purified by flash chromatography on silica gel (75:25
dichloromethane / ethyl acetate).
White solid (88 mg; 74%); mp: 156-158 °C; IR (neat, cm–1): 804,
1034, 1103, 1175, 1266, 1305, 1512, 1729, 2928; 1H NMR (400
8 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 9 of 10
RSC Advances
Please do not adjust margins
Journal Name
ARTICLE
7-(Furan-3-yl)-1-(4-methoxybenzyl)-5-methyl-1H-imidazo[1,5-
a]imidazol-2(3H)-one (21).
Berteina-Raboin, S. Massip, J-M. Leger, C. Jarry, E. Essassi, G.
View Article Online
Guillaumet, Eur. J. Org. Chem.2012, 2572; (d) A. El Akkaoui,
DOI: 10.1039/C5RA25520A
M-A. Hiebel, A. Mouaddib, S. Berteina-Raboin; G. Guillaumet,
Tetrahedron. 2012, 68, 9131; (e) A. Tikad, M. Akssira, S.
Massip, J-M. Leger, C. Jarry, G. Guillaumet, S. Routier, Eur. J.
Org. Chem. 2012, 4523; (f) S. Grosse, C. Pillard, F. Himbert, S.
Massip, J-M. Leger, C. Jarry, P. Bernard, G. Guillaumet, Eur. J.
Org. Chem. 2013, 4146; (g) Z. Tber, M.A. Hiebel, A. El
Hakmaoui, M. Akssira, G. Guillaumet, S. Berteina-Raboin. J.
Org. Chem. 2015, 80, 6564.
Following the general procedure with 3-furanylboronic acid
(50 mg, 0.45 mmol),the mixture was refluxed for 2 hours. The
crude product was purified by flash chromatography on silica
gel (75:25 dichloromethane / ethyl acetate).
Brown solid (44 mg; 46%); mp: 167-169 °C; IR (neat, cm-1);
1021, 1176, 1246, 1513, 1581, 1724; 1H NMR (400 MHz,
CDCl3): δ 2.34 (s, 3H), 3.75 (s, 3H), 4.43 (s, 2H), 4.84 (s, 2H),
6.47 (s, 1H), 6.77 (d, J = 7.8 Hz, 2H), 7.01 (d, J = 7.8 Hz, 2H),
7.40 (d, J = 5.0 Hz, 2H); 13C NMR (101 MHz, CDCl3): δ 13.3, 44.0,
47.3, 55.4, 108.8, 111.3, 114.2 (2C), 118.3, 127.4, 128.8 (2C),
132.0, 138.1, 140.0, 143.2, 159.4, 170.4; HRMS (ESI): calcd. for
C18H18N3O3 324.13425 [M+H]+ found 324.13426 [M+H]+.
6
7
(a) N. Miyaura, T. Yanagi, A. Suzuki, Synth. Commun. 1981,
11, 513; (b) A. Suzuki, Angew. Chem. Int. Ed. 2011, 50, 6722;
(c) J-P. Corbet, G. Mignani, Chem. Rev. 2006, 106, 2651; (d) S.
Kotha, K. Lahiri, Eur. J. Org. Chem. 2007, 1221.
(a) P.J Gilligan, R. Bakthavatchalam, Heterocycles, 2003, 60,
1329; (b) M. Bahnous, C. Mouats, Y. Fort, P. Gros,
Tetrahedron Lett. 2006, 47, 1949; (c) C. J. Serpell, N.L. Kilah,
L. Nathan, P.J. Costa, F. Vitor, P.D. Beer, Ang. Chem. Int. Ed.
2010, 49, 5322; (d) M. Bahnous, A. Bouraiou, M. Chelghoum,
S. Bouacida, T. Roisnel, F. Smati, C. Bentchouala, P.Gros, A.
Belfaitah, Bioorg. Med. Chem. Lett. 2013, 23, 1274.
(a) E.S. Dawson, J.W. Darrow, E. Sugg, T. P. Lybrand, L.J. Miller,
J. Med. Chem. 2006, 49, 850; (b) X. Hui, D. Ng, S.N. Savinov, B.
Dey, P.D. Kwong, R. Wyatt, A.M. Smith, W.A. Hendrickson, J.
Med. Chem. 2007, 50, 4898.
1-(4-Methoxybenzyl)-5-methyl-7-(thiophen-3-yl)-1H-
imidazo[1,5-a]imidazol-2(3H)-one (22).
Following the general procedure with 3-thienylboronic acid (57
mg, 0.45 mmol), the mixture was refluxed for 2 hours. The
crude product was purified by flash chromatography on silica
gel (75:25 dichloromethane / ethyl acetate).
8
9
White solid (70 mg; 65%); mp:161-163 °C; IR (neat, cm-1): 863,
1031, 1175, 1248, 1513, 1632, 1723; 1H NMR (400 MHz,
CDCl3): δ 2.33 (s, 3H), 3.72 (s, 3H), 4.42 (s, 2H), 4.83 (s, 2H),
6.71 (d, J = 8.4 Hz, 2H), 6.88 (d, J = 8.4 Hz, 2H), 7.14 (d, J = 3.7
Hz, 2H), 7.33 – 7.29 (m, 1H); 13C NMR (101 MHz, CDCl3): δ 13.3,
44.0, 47.2, 55.3, 113.1, 114.1 (2C), 122.2, 125.7, 127.6, 128.5,
129.0 (2C), 131.7, 134.2, 137.6, 159.3, 170.6; HRMS (ESI):
calcd. for C18H18N3O2S 340.11139 [M+H]+ found 340.11142
[M+H]+.
(a) M. Takashi; S.W. Rodney, O. Yoshiyuki, K. Makoto, O.
Takako, Sakakibara, Minoru, Bioorg. Med. Chem. Lett. 2005
,
15, 2611; (b) Y. Yanqin, W. Jing. Z. Jifu, L. Shenghai, Z. Suobo,
J. Membrane Sci. 2014, 467, 48; (c) B.C. Aakeroy, T.K.
Wijethunga, J. Desper, New J. Chem. 2015, 39, 822;
10 (a) J. Yin, S. L. Buchwald, Org. Lett. 2000, 2, 1101; (b) E.
Garnier, J. Audoux, E. Pasquinet, F. Suzenet, D. Poullain, B.
Lebret, G. Guillaumet, J. Org. Chem. 2004, 69, 7809; (c) B. P.
Fors, S. L. Buchwald, J. Am. Chem. Soc. 2010, 132, 15914; (d)
C. Salomé, M. Schmitt, J-J. Bourguignon, Tetrahedron Lett.
2012, 53, 1033; (e) K. Sugimoto, K. Tamura, N. Toyooka, Y.
Matsuya, Heterocycles. 2014, 88, 755; (f) S. Pallabi; S.
Gitarthi, G. Sanjib, B.C. Romesh, RSC Advances, 2015, 5,
23210.
11 (a) G. Eng, J. Wu, W. M. Dai, Tetrahedron Lett. 2007, 48, 401;
(b) K. Chen, C. Risatti, M. Bultman, M. Soumeillant, J.
Simpson, B. Zheng, D. Fanfair, M. Mahoney, B. Mudryk, R.
Fox, J. Org. Chem. 2014, 79, 8757; (c) Y. Matsuda, M.
Kitajima, H. Takayama, Org. Lett. 2008, 10, 125; (d) K.
Nagata, D. Sano, Y. Shimizu, M. Miyazaki, T. Kanemitsu, T.
Acknowledgements:
We acknowledge the OMJ (Office Mediterranéen de la
Jeunesse) for financial support of Mohammed Loubidi.
Notes and references
1
(a) Z.A. Filmwala, S. M.Bhalekar, J. P. D'Souza, P. S
Fernandes, Ind. J. Heterocycl. Chem. 2002, 11, 225; (b) S.
Grosse, V. Mathieu, C. Pillard, S. Massip, M. Marchivie, C.
Jarry, P. Bernard, R. Kiss, G. Guillaumet, Eur. J. Med. Chem.
2014, 84, 718; (c) B. Huan, X. Liang, L. Cuicui, W.Chen,T. Liu,
X. Li, Y. Sun,L. Fu, H. Liu, E. De Clercq, C. Pannecouque, P.
Zhan. Eur. J. Med. Chem. 2015, 93, 330.
Itoh, Tetrahedron: Asymmetry 2009
, 20, 2530; (e) P.
2 (a) Y. Wang, A. Benn, N. Flinn, T. Monk, M. Ramjee, J. Watts,
M. Quibell, Bioorg. Med. Chem. Lett. 2005, 15, 1327. (b) A.T.
Baviskar, C. Madaan, R. Preet, P. Mohapatra, V. Jain, A.
Agarwal, S.K. Guchhait, C. N. Kundu, U. C. Banerjee, P.V.
Bharatam, J. Med. Chem. 2011, 54, 5013;
3 (a) N. Takehiko, I. Yoshiyuki, Can. Pat. Appl. CA2066094 Chem.
Abstr. 1992, 119, 117246; (c) H. M. Elabdellaoui, J. M.
Ostresh, R. A. Houghten, U.S. Pat. Appl. Pub. US2001019783,
chem. Abstr. 2001, 134, 237828; (c) M. Elabdellaoui, J.
Ostresh, R. Houghten, U.S. Pat. Appl. Pub. US6545032, Chem.
Abstr. 2003, 138, 287973.
Subramanian, K. Kapliappan, Eur. J. Org. Chem. 2014, 5986;
(f) M. Dazhuang, S. Xuesong, H. Guozhen, T. Yao, J.
Zengqiang, H. Shiqing, Tetrahedron 2015, 71, 431; (g) H.
Jaeuk, T. Bodakuntla, K. Guhyun, K. Choogik, S. SungYong,
Dyes and Pigments, 2015, 114, 78.
12 K. Swapna, S. N. Murthy, Y. V. D. Nageswar, Eur. J. Org.
Chem.2010, 6678.
13 L. Light, J. Chem. Soc., 1922, 121, 2626.
14 R. Ferraccioli, A. Forni, Eur. J. Org. Chem. 2009, 3161.
4
(a) M. Elabdellaoui, J. Ostresh, R. Houghten, Tetrahedron
Lett. 2001, 42, 623.
5
(a) S. Grosse,C. Pillard, S. Massip, J-M Leger, C. Jarry, S. Bourg,
P. Bernard, G. Guillaumet, Eur. J. Org. Chem. 2012, 14943; (b)
A. Ben-Yahia, M. Nass, S. El Kazzouli, E. Essassi, G.
Guillaumet, Eur. J. Org. Chem. 2012, 7075; (c) I. Bassoude , S.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 9
Please do not adjust margins

RSC Advances
Page 10 of 10
View Article Online
DOI: 10.1039/C5RA25520A
A pathway to new 7-bromo-1-(4-methoxybenzyl)-5-methyl-imidazo[1,5-a]imidazol-2-one
was reported. The synthetic potential of this scaffold was demonstrated by displacing bromine
by Suzuki–Miyaura cross-coupling reactions. A large panel of boronic acids (aryl, heteroaryl
or vinyl) were easily introduced, giving access to a broad and diversified library of 1-(4-
methoxybenzyl)-5-methyl-7-(substituted)-imidazo[1,5-a]imidazol-2-ones.
N
N
Suzuki-Miyaura
cross-coupling
N
O
N
O
N
NH
3 steps
N
N
Br
PMB
R
PMB
R = aryl, heteroaryl or vinyl
18 examples
49-88%