Three-component mannich-like reaction of 2-aminoimidazole

Article abstract of DOI:10.1071/CH11358

A three-component reaction of 2-aminoimidazole with various aldehydes and amines is described that generates 4-substituted 2-aminoimidazoles containing a new chiral centre, a new CC bond and a new CN bond. The reactions can be conducted in water and requi

Full text of DOI:10.1071/CH11358

CSIRO PUBLISHING
Aust. J. Chem. 2011, 64, 1617–1620
Full Paper
http://dx.doi.org/10.1071/CH11358
Three-Component Mannich-like Reaction
of 2-Aminoimidazole
A
A B
,
Sudhir R. Shengule and Peter Karuso
A
Department of Chemistry and Biomolecular Sciences, Macquarie University,
NSW 2109, Australia.
B
Corresponding author. Email: peter.karuso@mq.edu.au
A three-component reaction of 2-aminoimidazole with various aldehydes and amines is described that generates
4-substituted 2-aminoimidazoles containing a new chiral centre, a new C–C bond and a new C–N bond. The reactions
can be conducted in water and require only sodium carbonate as reagent.
Manuscript received: 1 September 2011.
Manuscript accepted: 13 October 2011.
Published online: 22 November 2011.
Introduction
Natural products have played a pre-eminent role in drug devel-
opment[1] and, more recently, as templates for focussed combi-
natorial libraries.[2] Similarly, multicomponent reactions that are
atom-efficient and convergent approaches to diversity-orientated
synthesis have been widely sought for the generation of diversity
libraries.[3] In this communication, we report the first three-
component Mannich-like reaction of 2-aminoimidazole (2-AI)
that shows promise for the generation of natural-product-like
libraries.
2-Aminoimidazole is a common structural motif in marine
natural products and has itself been isolated from the sponge
Reneira cratera.[4] Numerous examples of natural products
bearing the 2-AI nucleus can be found, for example the oroidin
(1) family of alkaloids of which .100 are currently known,
many with powerful biological activity.[5] For example,
Palau’amine (2) has been shown to have potent anticancer
activity.[6] Another example is ageladine A (3), which has
powerful antiangiogenic activity.[7] We have recently reported
a concise synthesis of 3 using 2-AI in a biomimetic Pictet–
Spengler reaction as the key step (Scheme 1).[8]
Scheme 1. Biomimetic synthesis of ageladine A using the Pictet–Spengler
reaction as the key step.
favoured at low pH and C-alkylation at high pH but complex
mixtures were always formed.
In order to increase the scope of this reaction, we envisaged a
three-component version of the process in which two new bonds
as well as a chiral centre are formed simultaneously (Scheme 2),
presumably with the intermediacy of an imine formed from the
aldehyde and primary amine. Multicomponent reactions are
convergent processes where three (or more) starting materials
are condensed in a cascade of elementary equilibria that termi-
nates in an irreversible step.[9] Although a multicomponent
(Mannich) Pictet–Spengler reaction has not previously been
reported for 2-AI, precedent for this approach can be found in
two early reports. The first, by Kato et al. in 1952,[10] reported
that 4-methylimidazole and formaldehyde reacted in the pres-
ence of dimethylamine to form 4(5)-substituted imidazoles, and
Forsyth[11] reported the formation of mixtures of mono-, di-
and tri-substituted imidazoles from piperidine, formaldehyde
and 2-methylimidazole. Forsyth[11] found that N-alkylation was
Results and Discussion
Initially, we attempted a three-component reaction between
2-AI, butyl amine and acetaldehyde in the presence of scandium
triflate, the conditions we used for intramolecular Pictet–
Spengler reaction in the total synthesis of ageladine A.[8] This
reaction failed to yield the three-component adduct, so we
decided to first try to react activated imines with 2-AI
(Scheme 3). Reaction of 2-AI with N-Tosyl-benzylimine under
neutral or acidic conditions led to no observable reaction but
when sodium carbonate was used as a base, a low (18 %) yield of
the transimination product 5a was observed (Table 1). This
could be increased to ,50 % by using methanol as solvent and
caesium carbonate as base. Using highly activated imines
(e.g. 30-nitrophenyl) gave yields over 60 % for 5b. Disappoint-
ingly, no Mannich-like products were observed.
Journal compilation Ó CSIRO 2011
www.publish.csiro.au/journals/ajc

1618
S. R. Schengule and P. Karuso
δMe1.71(d)
δ
Hα4.56(q)
N
δC5123.3
NH2
N
5
H
2
4
N
H
δH47.02(s)
δC4115.2
4b
Scheme 2. Multicomponent Mannich reaction of 2-aminoimidazoles with
amines and aldehydes. The heavy bonds indicate new bonds formed and the
asterisk the new chiral centre.
PPM
110
115
120
125
Scheme 3. Reaction of 2-aminoimidazlone (2-AI) with activated imines
leads to transimination.
Table 1. Reactions of 2-aminoimidazole with activated imines to form
transimination products (given in parantheses)
RA
XA
Solvent
Base
Time [h] Yield [%]
Tosyl H (5a)
Tosyl H (5a)
Tosyl H (5a)
Tosyl H (5a)
Tosyl H (5a)
H2O
H2O
–
24
24
24
24
8
0
18
32
27
48
61
56
Na2CO3
7.1
4.6
1.7 PPM
H2O/EtOH (9:1) Na2CO3
H2O/MeCN (9:1) Na2CO3
MeOH
Cs2CO3
Cs2CO3
Cs2CO3
Fig. 1. Heteronuclear Multiple Bond Correlation (HMBC) spectrum of 4b
showing correlations between (a) H5 and C4 (123 ppm); (b) Ha and C5 and
C4; and (c) the Ca-Me with C4.
Butyl 3-NO2 (5b) MeOH
Butyl 2-NO2 (5c) MeOH
8
8
AR, X as per Fig. 3.
Table 2. Three-component Mannich-like reaction of 2-aminoimidazole
(2-AI) with different aldehydes and amines
The results obtained here were quite surprising, as in our
experience with the Pictet–Spengler reaction (intramolecular
Mannich reaction) of 2-AI, we found that the C4(5) position of
the 2-AI was more nucleophilic than the guanidine nitrogens.[8]
These results suggested a balance needed to be struck between
the fixed nucleophilicity of the 2-AI and the electrophilicity
of the imine. While screening less activated imines, we found
that the imine formed between acetaldehyde and benzylamine,
when stirred overnight with 2-AI in water, gave a low (10 %)
yield of the desired product (4b). Encouraged by this result, we
attempted a three-component version by mixing 2-AI, benzyl-
amine and acetaldehyde in water with sodium carbonate as base.
After 8 h stirring, the reaction resulted in the formation of the
expected three-component product 4b, albeit in low yield
(15 %), along with unreacted 2-AI (56 %). No N- or multiply
alkylated products were observed. Characterization of the prod-
uct by 2D NMR spectroscopy confirmed the exclusive forma-
tion of the 4-substituted product (3JCH couplings between Ha
and C5, and the methyl with C4; Fig. 1). The yield increased to
22 % (Table 2) when water/ethanol (9:1) was used as solvent but
the reaction did not proceed in non-aqueous solvents. Lewis acid
triflates (Sc, La, In, Yb) rapidly catalyzed the formation of imine
(5) but resulted in no three-component products. At elevated
temperatures, brown intractable mixtures were produced.
In terms of substrate scope, we found that the reaction
required water as the primary solvent and that a small amount
of ethanol improved the yield by reducing the precipitation of
the intermediate imine. However, higher proportions of organic
RA RA1
Product Yield of
B [%]
2-AI
recovered
[%]
Yield of 4 based
on recovered
2-AI [%]
4
H
Benzyl
4a
4b
4c
4d
4e
4f
20
22
15
19
19
13
18
23
15
17
56
64
61
52
66
56
48
74
68
52
45
61
38
40
56
30
35
88
47
35
Me Benzyl
Et
Benzyl
Butyl
Hexyl
Cyclohexyl
Benzyl
Butyl
Pr
4g
4h
4i
Hexyl
Cyclohexyl
4j
AR, R1 as per Scheme 2.
B 2-AI with 2 equiv. Na2CO3, 2 equiv. aldehyde and 1 equiv. amine, stirred
overnight in 10 % aqueous ethanol at room temperature.
solvent led to lower yields. Given the requirement for aqueous
conditions, aromatic amines and aldehydes proved problematic
owing to the insolubility of the intermediate imine.
Conclusion
Although this new reaction produced only moderate yields, it is
reasonably general and can be run under mild and green con-
ditions (Table 2). Notably though, aromatic aldehydes and

Three-Component Mannich
1619
anilines did not yield the three-component products. This may
be owing to solubility issues associated with the imine in
aqueous mixtures.
0.92 (t, J 7.36, 3H). dC (100 MHz, CD3OD) 150.2, 132.5, 130.9,
130.6, 130.2, 121.8, 116.3, 56.8, 50.8, 25.3, 10.3. m/z (HRMS)
231.1604 [M þ H]þ; C13H19N4 requires 231.1610.
There are several natural products bearing the 2-AI nucleus
substituted at the 4-position. This three-component reaction of
2-AI will not only help provide access to these natural products
but may also be useful in the generation of libraries of natural-
product-like 2-AIs. The reaction is highly regiospecific and
shows promise as a diversity-generating reaction, and is the first
example of a three-component Mannich reaction of 2-AI. In
addition, the reaction could also be directed to other pathways
such as the Povarov reaction.[12] These studies are currently in
progress.
4-(1-(Butylamino)propyl)-1H-imidazol-2-amine 4d
White solid. dH (400 MHz, CD3OD) 7.03 (s, 1H), 4.21 (dd,
J 10.9, 4.7, 1H), 2.84–3.01 (m, 2H), 1.93–2.13 (m, 2H),
1.57–1.73 (m, 2H), 1.34–1.44 (m, 2H), 0.93 (m, 6H). dC
(100 MHz, CD3OD) 150.2, 121.4, 116.5, 56.6, 46.8, 29.2,
25.2, 20.7, 13.7, 10.3. m/z (HRMS) 197.1770 [M þ H]þ;
C10H21N4 requires 197.1766.
4-(1-(Hexylamino)propyl)-1H-imidazol-2-amine 4e
White solid. dH (400 MHz, CD3OD) 7.03 (s, 1H), 4.21 (dd,
J 10.8, 4.8, 1H), 3.00–2.85 (m, 2H), 2.11–1.95 (m, 2H),
1.73–1.59 (m, 2H), 1.41–1.26 (m, 6H), 0.92 (t, J 7.4, 3H),
0.89 (t, J 6.8, 1H). dC (100 MHz, CD3OD) 150.3, 121.5, 116.4,
56.6, 47.1, 32.3, 27.2, 25.2, 23.3, 14.1, 10.4. m/z (HRMS)
225.2085 [M þ H]þ; C12H25N4 requires 225.2079.
Experimental
General Experimental Procedures
Chloroform, dichloromethane, ethanol and methanol were
obtained from Froline (Australia). All other reagents were
obtained from Aldrich (USA). Merck silica gel 60 (230–400
mesh) was used for column chromatography. NMR spectra were
recorded in 5-mm 507-PP Pyrex tubes (Wilmad, USA) on either
a DPX-400 400 MHz or DRX-600K 600 MHz spectrometer
(Bruker, Germany). Chemical shifts of 1H and 13C NMR were
referenced to the solvents peaks: dH 3.30 and dC 49.0 ppm for
CD3OD. High-resolution mass spectra (HRMS) were measured
on Waters Q-TOF Ultima tandem quadrupole–time-of-flight
instrument at the mass spectrometry laboratory, University of
Illinois at Urbana–Champaign.
4-(1-(Cyclohexylamino)propyl)-1H-imidazol-
2-amine 4f
White solid. dH (400 MHz, CD3OD) 7.05 (s, 1H), 4.36 (dd,
J 10.9, 4.7, 1H), 3.04–2.94 (m, 1H), 2.21–2.14 (m, 1H),
2.07–1.93 (m, 3H), 1.89–1.79 (m, 2H), 1.72–1.64 (m, 1H),
1.44–1.14 (m, 5H), 0.91 (t, J 7.5, 3H). dC (100 MHz, CD3OD)
151.4, 121.6, 116.3, 56.7, 53.3, 30.9, 29.8, 25.9, 25.5, 25.4, 25.3,
10.2. m/z (HRMS) 223.1925 [M þ H]þ; C12H23N4 requires
223.1923.
General Method for the Preparation of 4a–j
4-(1-(Benzylamino)butyl)-1H-imidazol-2-amine 4g
2-AI hemisulfate (0.37 mmol) was stirred with sodium carbon-
ate (0.75 mmol) in water/ethanol (9:1) at room temperature for
5 min. Amine (0.75 mmol) was added to the reaction mixture,
followed by the dropwise addition of the aldehyde (0.75 mmol)
over 5 min. After 10 min, a precipitate was formed but stirring
was continued for an additional 8–12 h, after which the solvent
was removed under reduced pressure to yield a brown solid,
which was subjected to column chromatography over silica gel
using a gradient of 5:95–15:85 (methanol/dichloromethane
saturated with ammonia) to afford 4-substituted imidazoles 4
(13–23 %) and unreacted 2-AI (48–74 %). All the compounds
were characterized and stored as their TFA salts.
dH (400 MHz, CD3OD) 7.38–7.46 (m, 5H), 7.04 (s, 1H), 4.37
(dd, J 9.3, 6.3, 1H), 4.15 (m, 2H), 1.96–2.07 (m, 2H), 1.24–1.35
(m,2H), 0.95(t, J7.62, 3H). dC (100 MHz, CD3OD)150.2,132.3,
130.9, 130.6, 130.2, 121.6, 116.4, 55.1, 50.6, 33.7, 20.0, 13.5.
m/z (HRMS) 245.1769 [M þ H]þ; C14H21N4 requires 245.1766.
4-(1-(Butylamino)butyl)-1H-imidazol-2-amine 4h
White solid. dH (400 MHz, CD3OD) 7.03 (s, 1H), 4.28 (dd,
J 10.2, 5.3, 1H), 2.83–3.0 (m, 2H), 1.92–2.05 (m, 2H), 1.56–1.72
(m, 2H), 1.25–1.45 (m, 4H), 0.90–0.99 (m, 6H). dC (100 MHz,
CD3OD) 150.3, 121.8, 116.3, 55.0, 46.7, 33.7, 29.2, 20.7, 20.0,
13.7, 13.5. m/z (HRMS) 211.1931 [M þ H]þ; C11H23N4 requires
211.1923.
4-((Benzylamino)methyl)-1H-imidazol-2-amine 4a
White solid. dH (400 MHz, CD3OD) 7.42–7.50 (m, 5H), 6.97
(s, 1H), 4.25 (s, 2H), 4.22 (d, J 0.69, 2H). dC (100 MHz, CD3OD)
149.8, 132.1, 131.0, 130.7, 130.3, 118.9, 116.5, 52.0, 41.5. m/z
(HRMS) 203.1297 [M þ H]þ; C11H15N4 requires 203.1297.
4-(1-(Hexylamino)butyl)-1H-imidazol-2-amine 4i
White solid. dH (400 MHz, CD3OD) 7.03 (s, 1H), 4.29 (dd,
J 10.1, 5.5, 1H), 3.00–2.83 (m, 2H), 2.03–1.92 (m, 2H), 1.73–
1.59 (m, 2H), 1.39–1.24 (m, 8H), 0.95 (t, J 7.16, 3H), 0.89 (t, J
6.79, 3H). dC (100 MHz, CD3OD) 150.3, 121.7, 116.4, 55.0,
47.0, 33.7, 32.3, 27.2, 23.3, 20.0, 14.1, 13.5. m/z (HRMS)
239.2242 [M þ H]þ; C13H27N4 requires 239.2236.
4-(1-(Benzylamino)ethyl)-1H-imidazol-2-amine 4b
White solid. dH (400 MHz, CD3OD) 7.39–7.47 (m, 5H), 7.02
(s, 1H), 4.56 (q, J 6.8, 1H), 4.17 (m, 2H), 1.71 (d, J 6.87, 3H). dC
(100 MHz, CD3OD) 150.0, 132.2, 130.9, 130.6, 130.2, 123.3,
115.2, 50.6, 50.4, 17.0. dN (60.8 MHz, CD3OD) 134.0 (N3),
132.7 (N1), 59.7 (CH2 –NH–CH). m/z (HRMS) 217.1452 [M þ
H]þ; C12H17N4 requires 217.1453.
4-(1-(Cyclohexylamino)butyl)-1H-imidazol-2-amine 4j
White solid. dH (400 MHz, CD3OD) 7.06 (s, 1H), 4.43 (dd,
J 10.7, 5.0, 1H), 3.03–2.94 (m, 1H), 2.22–2.14 (m, 1H),
2.06–1.78 (m, 5H), 1.72–1.64 (m, 1H), 1.41–1.17 (m, 7H),
0.95 (t, J 7.39, 3H). dC (100 MHz, CD3OD) 150.3, 121.7,
116.2, 56.6, 51.8, 34.1, 30.9, 29.8, 26.0, 25.4, 25.3, 19.9,
13.5. m/z (HRMS) 237.2078 [M þ H]þ; C13H25N4 requires
237.2079.
4-(1-(Benzylamino)propyl)-1H-imidazol-2-amine 4c
White solid. dH (400 MHz, CD3OD) 7.52 (s, 5H), 7.03 (s,
1H), 4.26 (dd, J 11.0, 4.5, 1H), 4.14 (m, 2H), 1.95–2.16 (m, 2H),

1620
S. R. Schengule and P. Karuso
N-(2-Nitrobenzylidene)-1H-imidazol-2-amine 5c
References
[1] D. J. Newman, M. Cragg, J. Nat. Prod. 2007, 70, 461. doi:10.1021/
NP068054V
[2] R. Breinbauer, I. R. Vetter, H. Waldmann, Angew. Chem. Int. Ed. Engl.
2002, 41, 2878. doi:10.1002/1521-3773(20020816)41:16,2878::
AID-ANIE2878.3.0.CO;2-B
[3] A. Ulaczyk-Lesanko, D. G. Hall, Curr. Opin. Chem. Biol. 2005, 9, 266.
doi:10.1016/J.CBPA.2005.04.003
[4] G. Cimino, S. De Stefano, L. Minale, Comp. Biochem. Physiol. 1974,
Yellow solid. dH (400 MHz, CD3OD) 9.38 (s, 1H), 8.29 (dd,
J 7.7, 1.3, 1H), 8.05 (dd, J 8.0, 1.2, 1H), 7.77 (t, J 8.2, 1H), 7.70
(t, J 8.0, 1H), 7.07 (s, 2H). dC (100 MHz, CD3OD) 154.3, 149.0,
131.9, 130.6, 128.7, 128.4, 127.6, 126.3, 123.1. m/z (HRMS)
217.0721 [M þ H]þ; C10H9N4O2 requires 217.0720.
N-(3-Nitrobenzylidene)-1H-imidazol-2-amine 5b
Orange solid. dH (400 MHz, CD3OD) 9.08 (s, 1H), 8.78
(s, 1H), 8.35–8.24 (m, 2H), 8.72 (t, J 8.9, 1H), 7.06 (s, 2H). dC
(100 MHz, CD3OD) 156.6, 147.7, 136.4, 133.3, 128.8, 124.4,
121.3. m/z (HRMS) 217.0723 [M þ H]þ; C10H9N4O2 requires
217.0720.
47B, 895.
[5] A. A. Mourabit, P. Potier, Eur. J. Org. Chem. 2001, 237. doi:10.1002/
1099-0690(200101)2001:2,237::AID-EJOC237.3.0.CO;2-V
[6] R. B. Kinnel, H. P. Gehrken, R. Swali, G. Skoropowski, P. J. Scheuer,
J. Org. Chem. 1998, 63, 3281. doi:10.1021/JO971987Z
[7] M. Fujita, Y. Nakao, S. Matsunaga, M. Seiki, Y. Itoh, J. Yamashita,
R. W. M. Van Soest, N. Fusetani, J. Am. Chem. Soc. 2003, 125, 15700.
doi:10.1021/JA038025W
[8] S. R. Shengule, P. Karuso, Org. Lett. 2006, 8, 4083. doi:10.1021/
OL061584Y
[9] I. Ugi, A. Do¨mling, W. Ho¨rl, Endeavour 1994, 18, 115. doi:10.1016/
S0160-9327(05)80086-9
N-Benzylidene-1H-imidazol-2-amine 5a
dH (400 MHz, CD3OD) 9.00 (s, 1H), 7.94 (dd, J 7.91, 1.59,
2H), 7.55–7.42 (m, 3H), 7.07 (s, 2H). dC (100 MHz, CD3OD)
159.6, 149.8, 134.6, 130.6, 127.5, 127.4. m/z (HRMS) 172.0870
[M þ H]þ; C10H10N3 requires 172.0869.
[10] T. Kato, T. Morikawa, Y. Suzuki, Yakugaku Zasshi 1952, 72, 1177.
[11] F. B. Stocker, J. L. Kurtz, B. L. Gilman, D. A. Forsyth, J. Org. Chem.
1970, 35, 883. doi:10.1021/JO00829A003
Accessory Publication
1H and 13C NMR spectra for all compounds are available on the
Journal’s website.
[12] L. S. Povarov, Russ. Chem. Rev. 1967, 36, 656.
Acknowledgements
The authors thank Macquarie University for financial support. SRS is the
grateful recipient of a Macquarie-funded international PhD scholarship
(iMURS).