Fast assembly of 1 H -imidazo[1,2- a ]imidazol-5-amines via groebke-blackburn-bienaymé reaction with 2-aminoimidazoles

Article abstract of DOI:10.1055/s-0032-1317986

A novel microwave-assisted protocol allowing the successful application of 2-aminoimidazoles in the Groebke-Blackburn-Bienaymé reaction for the facile construction of the 1H-imidazo[1,2-a]imidazol-5-amine core was developed. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0032-1317986

LETTER
▌351
letter
Fast Assembly of 1H-Imidazo[1,2-a]imidazol-5-amines via Groebke–
Blackburn–Bienaymé Reaction with 2-Aminoimidazoles
1H-Imidazo[1,2-a]imidazol-5-amines
Olga P. Pereshivko,1 Vsevolod A. Peshkov,1 Denis S. Ermolat’ev, Erik V. Van der Eycken*
Laboratory for Organic & Microwave-Assisted Chemistry (LOMAC), Department of Chemistry, University of Leuven (KU Leuven),
Celestijnenlaan 200F, 3001 Leuven, Belgium
Fax +32(16)327990; E-mail: erik.vandereycken@chem.kuleuven.be
Received: 30.09.2012; Accepted after revision: 14.12.2012
formed (Table 1, entry 3). Finally, elevating the reaction
temperature to 110 °C allowed the desired product 4a to
be obtained in only 12% yield together with 50% yield of
imine 5a (Table 1, entry 4). A considerable improvement
in the reaction outcome was achieved when switching to
the nonpolar solvent toluene;10 under these conditions,
1H-Imidazo[1,2-a]imidazol-5-amine 4a was obtained in
48% yield (46% isolated yield) together with only 15% of
the undesired imine 5a (Table 1, entry 5). A further
change of the parameters of the [Yb(OTf)3]-catalyzed re-
action or the use of [Sc(OTf)3] did not provide any sub-
stantial improvement of the 4a yield (Table 1, entries 6–
10). We then turned our attention to the application of p-
toluenesulfonic acid (TsOH), which has already been ef-
ficiently employed by several groups in the Groebke–
Blackburn–Bienaymé reaction.11 Carrying out the model
reaction with 10 mol% TsOH·H2O in toluene at 110 °C
under microwave irradiation gave the desired 1H-imid-
azo[1,2-a]imidazol-5-amine 4a in a good isolated yield of
52% (Table 1, entry 11). Further screening (Table 1, en-
tries 12 and 13) revealed that the best catalyst loading was
20 mol%, which allows 4a to be obtained in an improved
yield of 69%. It is also important to stress that reactions
run under conventional heating resulted in rather poor
yields of 4a even after an extended reaction time of
24 hours (Table 1, entries 14 and 15).
Abstract: A novel microwave-assisted protocol allowing the
successful application of 2-aminoimidazoles in the Groebke–
Blackburn–Bienaymé reaction for the facile construction of the
1H-imidazo[1,2-a]imidazol-5-amine core was developed.
Key words: multicomponent reactions, annulation, heterocycles,
fused-ring systems
Isocyanide-based multicomponent reactions have been
shown to be an efficient and operationally simple tool for
the generation of great structural complexity and diversi-
ty.2 The three-component Passerini and four-component
Ugi reactions are probably the most attractive, owning to
their exceptionally broad scope, functional group toler-
ance and the possibility of performing a variety of post-
condensation transformations.3 The three-component
Groebke–Blackburn–Bienaymé variation of the Ugi reac-
tion involves the Lewis or Brønsted acid catalyzed con-
densation of a 2-aminoazine or 2-aminoazole with an
aldehyde and an isocyanide. Since its independent discov-
ery by three research groups in 1998,4 the Groebke–
Blackburn–Bienaymé reaction has been established as a
general approach to a wide range of azine- and azole-
fused aminoimidazoles.5,6 In a continuation of our long-
standing interest in the chemistry of polysubstituted 2-
aminoimidazoles7,8 we were keen to explore them as sub-
strates in this process because, to the best of our knowl-
edge, only 2-aminobenzoimidazoles have been studied so
far.9
With these results at hand, we decided to evaluate the
scope and limitations of our procedure (Table 2).12,13 We
tested various 1,5-disubstituted 2-aminoimidazoles 1a–k
in combination with benzaldehyde (2a) and tert-butyl iso-
cyanide (3a). Running reactions under the developed op-
timal conditions (Table 1, entry 11) with some minor
workup variations13 we were able to obtain 1H-imid-
azo[1,2-a]imidazol-5-amines 4a–k in reasonable yields
ranging from 17 to 69% (Table 2, entries 1–11). We then
screened several aromatic aldehydes 2b–f in combination
with 1a and 3a (Table 2, entries 12–16). The application
of aldehydes bearing electron-withdrawing substituents in
the aromatic ring gave the best results, allowing the isola-
tion of the desired 1H-imidazo[1,2-a]imidazol-5-amines
4n–p in very good yields ranging from 73 to 77% (Table
2, entries 14–16). Heteroaromatic picolinaldehyde (2g)
and aliphatic butyraldehyde (2h) were also found to be ap-
plicable, delivering the expected products 4p and 4q in
good yields of 41 and 54%, respectively (Table 2, entries
17 and 18). Carrying out the reactions with 1,1,3,3-tetra-
We started our investigation with a model reaction of 1-
benzyl-5-phenyl-1H-imidazol-2-amine (1a) with benzal-
dehyde (2a) and tert-butyl isocyanide (3a; Table 1). Typ-
ically Groebke–Blackburn–Bienaymé reactions are
conducted in a polar protic solvent such as methanol.
However, carrying out our model reaction in methanol
with 5 mol% HClO4 at room temperature for 24 hours4c
generated only 7% of imine 5a and no desired 1H-imid-
azo[1,2-a]imidazol-5-amine product 4a could be detected
(Table 1, entry 1). Analogous reactions carried out under
microwave irradiation at 80 °C for 30 min also yielded
only small quantities of imine 5a (Table 1, entry 2).
Switching to 10 mol% [Yb(OTf)3] as catalyst improved
the yield of imine 5a but again no traces of 4a were
SYNLETT 2013, 24, 0351–0354
Advanced online publication: 16.01.2013
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9
3
6
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5
2
1
4
1
4
3
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2
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DOI: 10.1055/s-0032-1317986; Art ID: ST-2012-B0834-L
© Georg Thieme Verlag Stuttgart · New York

352
O. P. Pereshivko et al.
LETTER
Table 1 Optimal Parameters for the Synthesis of 1H-Imidazo[1,2-a]imidazol-5-amine 4aa
Bn
Bn
Bn
Ph
Ph
N
N
N
N
C
catalyst
N
Ph
NH2
Ph
Ph
+ O
+
+
N
t-Bu
N
conditions
N
N
Ph
1a
2a
3a
5a
HN
4a
t-Bu
Entry
Catalyst (mol%)
Conditions
Solvent
Yield (%)b
4a
5a
Time (min)
Temp (°C)
Heating method
1
2
HClO4 (5)
MeOH
MeOH
MeOH
MeOH
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
24 h
30
25
80
conventional
MW
0
7c
28c
55c
50
15
68
17
13
11
HClO4 (5)
0
3
Yb(OTf)3 (10)
Yb(OTf)3 (10)
Yb(OTf)3 (10)
Yb(OTf)3 (10)
Yb(OTf)3 (10)
Yb(OTf)3 (20)
Yb(OTf)3 (10 + 10)
Sc(OTf)3 (10)
30
80
MW
0
4
30
110
110
80
MW
12
5
30
MW
48, 46d
6
6
30
MW
7
30
130
110
110
110
110
110
110
110
110
MW
44
8
30
MW
43
9
25 + 15
30
MW
47
e
10
11
12
13
14
15
MW
45d
52d
69d
62d
22
–
e
TsOH·H2O (10)
30
MW
–
e
TsOH·H2O (20)
30
MW
–
e
TsOH·H2O (30)
Yb(OTf)3 (10)
TsOH·H2O (20)
30
MW
–
24 h
24 h
conventional
conventional
24
26f
25f
a All reactions were carried out on a 0.3 mmol scale with 1a/2a/3a ratio = 1:1.2:1.5.
b Unless otherwise specified, yields were calculated from the 1H NMR spectra of mixtures of 4a and 5a obtained directly by flash chromato-
graphy of the reaction mixture with no aqueous workup.
c Isolated yield obtained directly by flash chromatography of the reaction mixture with no aqueous workup.
d Isolated yield after the aqueous workup and flash chromatography.
e Not determined (5a decomposed in the presence of 1 M HCl during the aqueous workup).
f Yield determined by 1H NMR spectroscopic analysis of the reaction mixture using 3,4,5-trimethoxybenzaldehyde as internal standard.
methylbutyl isocyanide (3b) provided products 4r and 4s This fact could probably be ascribed to the steric
in slightly diminished yields compared to the analogous hindrance exerted by the substituent at the 4-position of
reactions with tert-butyl isocyanide (3a; Table 2, entries the 2-aminoimidazole core during the ring-closure step
19 and 20 vs 1 and 7).
(Figure 1).
Cyclohexyl isocyanide (3c) applied in combination with In conclusion, we have developed a novel microwave-as-
1a and 2a delivered 1H-imidazo[1,2-a]imidazol-5-amine sisted protocol for the Groebke–Blackburn–Bienaymé re-
4t in a relatively poor yield of 29% (Table 2, entry 21).
action optimized specifically for the use of 1,5-
disubstituted 2-aminoimidazoles, giving an access to 1H-
imidazo[1,2-a]imidazol-5-amines. The scope and limita-
tions of the process were studied by employing various al-
dehydes, isocyanides and 2-aminoimidazoles. A small
library of 1H-imidazo[1,2-a]imidazol-5-amines having
four points of diversity was prepared with yields ranging
from 17 to 77%.
Unfortunately we were unable to isolate any significant
amount of product from reactions conducted with 1a and
2a used in a combination with other isocyanides such as
benzyl isocyanide (3d) or aromatic 2-naphthyl isocyanide
(3e; Figure 1).
Another identified limitation is that, except for 1,5-disub-
stituted 2-aminoimidazoles, no other substitution pattern
could be successfully applied in our protocol (Figure 1).
Synlett 2013, 24, 351–354
© Georg Thieme Verlag Stuttgart · New York

LETTER
1H-Imidazo[1,2-a]imidazol-5-amines
353
Table 2 Scope of the Groebke–Blackburn–Bienaymé Protocola
R2
R2
R2
R1
R1
TsOH⋅H2O
N
N
N
N
(20 mol%)
C
R3
R1
R3
+
NH2
N
+
O
N
+
R4
N
R3
toluene, 110°C
30 min, MW
N
N
1
2
3
5
R4
HN
(in most cases decom-
poses during work up)
4
Entry
R1, R2 (1)
R3 (2)
R4 (3)
4
Yield (%)b
1
2
Ph, Bn (1a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
t-Bu (3a)
4a
4b
4c
4d
4e
4f
69
35
31
26
18
17
49
36
24
36
27
45
54
73
75
77
41
54
45
39
29
Ph, piperonyl (1b)
Ph, 2-BrC6H4CH2 (1c)
t-Bu (3a)
3
t-Bu (3a)
4
Ph, 3,4-(MeO)2C6H3CH2 (1d)
Ph, cyclohexyl (1e)
Ph, cyclododecyl (1f)
4-ClC6H4, cyclopropyl (1g)
4-ClC6H4, Me (1h)
4-ClC6H4, Bn (1i)
4-PhC6H4, cyclobutyl (1j)
4-MeSC6H4, Me (1k)
Ph, Bn (1a)
t-Bu (3a)
5
t-Bu (3a)
6
t-Bu (3a)
7
t-Bu (3a)
4g
4h
4i
8
t-Bu (3a)
9
t-Bu (3a)
10
11
12
13
14
15
16
17
18
19
20
21
t-Bu (3a)
4j
t-Bu (3a)
4k
4l
4-MeC6H4 (2b)
4-FC6H4 (2c)
t-Bu (3a)
Ph, Bn (1a)
t-Bu (3a)
4m
4n
4o
4p
4q
4r
4s
Ph, Bn (1a)
4-F3CC6H4 (2d)
4-NCC6H4 (2e)
4-O2NC6H4 (2f)
pyridin-2-yl (2g)
Pr (2h)
t-Bu (3a)
Ph, Bn (1a)
t-Bu (3a)
Ph, Bn (1a)
t-Bu (3a)
Ph, Bn (1a)
t-Bu (3a)
Ph, Bn (1a)
t-Bu (3a)
Ph, Bn (1a)
Ph (2a)
1,1,3,3-tetramethylbutyl (3b)
1,1,3,3-tetramethylbutyl (3b)
cyclohexyl (3c)
4-ClC6H4, cyclopropyl (1g)
Ph, Bn (1a)
Ph (2a)
4t
Ph (2a)
4u
a All reactions were carried out on a 0.3 mmol scale with 1a/2a/3a ratio = 1:1.2:1.5.
b Isolated yield.
..
R2
isocyanides
(failed in combination with 1a and 2a)
2-aminoimidazoles
(failed in combination with 2a and 3a)
H
N
N
R3
R1
F
N
C
Me
N
Pr
C
N
R
N
N
N
NH2
Bn
NH2
R4
substituent
N
Bn
N
3d
3e
at the 4-position
hinders the ring closure
Me
1m
1l
Figure 1 Unsuccessful substrates
scholarship. D.S.E. is grateful to the Fund for Scientific Research
(FWO), Flanders for a postdoctoral fellowship. The authors thank
Ir. B. Demarsin for valuable help with HRMS.
Acknowledgment
Support was provided by the Fund for Scientific Research (FWO),
Flanders and by the Research Fund of the University of Leuven (KU
Leuven). V.A.P. is grateful to the EMECW (Triple I) for a doctoral
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 351–354

354
O. P. Pereshivko et al.
LETTER
Savaliya, B.; De Weerdt, A.; De Coster, D.; Shah, A.; Van
der Eycken, E. V.; De Vos, D. E.; Vanderleyden, J.; De
Keersmaecker, S. C. J. J. Med. Chem. 2011, 54, 472.
(f) Ermolat’ev, D. S.; Bariwal, J. B.; Steenackers, H. P. L.;
De Keersmaecker, S. C. J.; Van der Eycken, E. V. Angew.
Chem. Int. Ed. 2010, 49, 9465. (g) Pereshivko, O. P.;
Peshkov, V. A.; Ermolat’ev, D. S.; Van Hove, S.; Van
Hecke, K.; Van Meervelt, L.; Van der Eycken, E. V.
Synthesis 2011, 1587.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
ungIifoop
r
t
References and Notes
(1) The authors contributed equally to this work.
(2) For selected reviews covering different aspects of
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(12) Microwave-Assisted Groebke–Blackburn–Bienaymé
Reaction; Typical Procedure for 1-Benzyl-N-tert-butyl-
2,6-diphenyl-1H-imidazo[1,2-a]imidazol-5-amine (4a):
To a microwave vial equipped with a magnetic stir bar
containing 1a (75 mg, 0.3 mmol) and p-toluenesulfonic acid
hydrate (11 mg, 0.06 mmol), anhydrous toluene (1 mL), 2a
(38 mg, 0.36 mmol) and 3a (37 mg, 0.45 mmol) were
consecutively added. The reaction vessel was sealed and
irradiated in the cavity of a CEM-Discover microwave
reactor at a set temperature of 110 °C for 30 min. Upon
completion of the reaction, the vial was cooled with a stream
of air. The resulting reaction mixture was diluted with
EtOAc (50 mL), thoroughly washed with 1 M HCl
(2 × 50 mL) and sat. aq Na2CO3 (50 mL), dried over
Na2SO4, and concentrated under reduced pressure. The
crude product was dissolved in EtOAc (5 mL) and subjected
to flash chromatography [silica (25 g); EtOAc–heptane, 3:7]
to give pure 4a (87 mg, 69%). 1H NMR (300 MHz, CDCl3):
δ = 8.07–7.95 (m, 2 H), 7.41–7.26 (m, 7 H), 7.25–7.10 (m,
6 H), 6.94 (s, 1 H), 5.22 (s, 2 H), 2.90 (br s, 1 H), 1.12 (s,
9 H); 13C NMR (CDCl3, 75 MHz): δ = 145.5, 137.4, 136.3,
136.2, 133.3, 129.5, 128.9, 128.7, 128.62, 128.56, 128.47,
128.0, 127.4, 127.3, 126.0, 120.1, 102.5, 55.6, 47.0, 30.3;
HRMS (EI): m/z calcd for C28H28N4: 420.2314; found:
420.2281.
(3) For selected reviews on post-condensation transformations,
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2010, 23.
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(a) Mandair, G. S.; Light, M.; Russell, A.; Hursthouse, M.;
Bradley, M. Tetrahedron Lett. 2002, 43, 4267.
(13) CAUTION! The acidic aqueous workup was necessary in
most cases to decompose imine 5, which was otherwise
difficult to separate from the desired product 4 (Scheme 1).
See the Supporting Information for details.
(b) Nenadjenko, V. G.; Reznichenko, A. L.; Balenkova, E.
S. Russ. Chem. Bull., Int. Ed. 2007, 56, 560. (c) Guchhait, S.
K.; Madaan, C. Synlett 2009, 628.
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R2
R2
R1
R1
H+
N
N
R3
N
NH2
+
O
R3
2
N
N
5
1
Scheme 1
Synlett 2013, 24, 351–354
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