Concise and diversity-oriented route toward polysubstituted 2-aminoimidazole alkaloids and their analogues

Article abstract of DOI:10.1002/anie.201004256

Alkaloids of the naamine family were synthesized from diverse propargylamines in just two steps (see scheme: R¹=Me, R ²=substituted benzyl, R³=Ar). Thus, the addition to a propargylamine of a carbodiimide generated in situ

Full text of DOI:10.1002/anie.201004256

Angewandte
Chemie
DOI: 10.1002/anie.201004256
Heterocycle Synthesis
Concise and Diversity-Oriented Route toward Polysubstituted
2-Aminoimidazole Alkaloids and Their Analogues
Denis S. Ermolatꢀev, Jitender B. Bariwal, Hans P. L. Steenackers, Sigrid C. J. De Keersmaecker,
and Erik V. Van der Eycken*
2-Aminoimidazole is emerging as an important pharmaco-
phore. It is widely found in biologically active marine-sponge
alkaloids (Scheme 1).[1] In particular, polysubstituted 2-ami-
hydroamination of propargylic cyanamides is rather limited
by the diversity and availability of the starting electron-rich
secondary benzylamines as well as by the harsh reaction
conditions.[7] Accordingly, the development of straightfor-
ward and general procedures for the synthesis of diversely
substituted 2-aminoimidazoles from readily available precur-
sors is highly warranted. Herein, we report a rapid and highly
efficient silver(I)-mediated synthesis of 1,4,5-trisubstituted 2-
aminoimidazoles from secondary propargylamines.
We envisioned that propargylguanidine 2 could be
assembled from propargylamine 1 by using modern guanyl-
ation procedures (Scheme 2).[8] The subsequent intramolecu-
lar p-philic metal-catalyzed 5-exo-dig heterocyclization[9] of
propargylguanidine 2 into the protected 2-iminoimidazoline 3
followed by deprotection and isomerization would provide
the target 1,4,5-trisubstituted 2-aminoimidazole 4.
Scheme 1. Examples of polysubstituted 2-aminoimidazole marine-
sponge alkaloids.
noimidazoles have recently been reported as potent modu-
lators of the formation and dispersion of bacterial biofilms,[2]
human b-secretase (BACE1) inhibitors,[3] and tubulin-binding
agents.[4] Although a variety of synthetic methods[1,5,6] for the
preparation of highly functionalized 2-aminoimidazole core
structures have been developed owing to the rising demand in
natural product synthesis and medicinal chemistry, most of
them involve long experimental procedures with many
protection/deprotection steps and the use of unstable pre-
cursors, such as a-aminoketones,[6a] a-bromoaldehydes,[6b] and
organomagnesium[6c] and organolithium[6d] compounds.
A recently reported synthesis of polysubstituted 2-di-
alkylaminoimidazoles through the lanthanide-mediated
Scheme 2. Synthesis of 1,4,5-substituted 2-aminoimidazoles from
secondary propargylamines.
To the best of our knowledge, there is only one reported
example of the formation of a 2-iminoimidazole from a
secondary propargylamine and a thiourea.[10] It was obtained
from a secondary propargylamine and a thiourea in the
presence of HgO. Importantly, as we reported recently, the
microwave-assisted copper(I)-catalyzed three-component
coupling of an aldehyde, an alkyne, and a primary amine
(A3 coupling) provides direct access to diversely functional-
ized secondary propargylamines 1.[11]
Initially, we focused on the guanylation of the sterically
hindered propargylamines 1a–h (Table 1, entries 1–8) with
N,N’-bis-Boc-protected thiourea[12] 5 (1.35 equiv) in the
presence of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
(EDCI; 2 equiv) and the Hꢀnig base (3 equiv; Table 1,
route A). The resulting propargylguanidines 2a–h underwent
cyclization in the presence of various catalysts. The desired
Boc-protected 2-iminoimidazolines 3a–h were formed in
[*] Dr. D. S. Ermolat’ev, Dr. J. B. Bariwal, Prof. Dr. E. V. Van der Eycken
Laboratory for Organic and Microwave-Assisted Chemistry
Katholieke Universiteit Leuven
Celestijnenlaan 200F, 3001 Leuven (Belgium)
Fax : (+32)16-327-990
E-mail: erik.vandereycken@chem.kuleuven.be
Homepage: http://www.chem.kuleuven.be/research/organ/lomac/
H. P. L. Steenackers, Dr. S. C. J. De Keersmaecker
Centre of Microbial and Plant Genetics
Katholieke Universiteit Leuven
Kasteelpark Arenberg 20, 3001 Leuven (Belgium)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201004256.
Angew. Chem. Int. Ed. 2010, 49, 9465 –9468
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
9465

Communications
Table 1: Synthesis of the protected 2-iminoimidazolines from secondary propargylamines.[12]
of propargylamine 1 to carbodi-
imide A then gives the protected
propargylguanidine intermediate 2.
Silver(I)-catalyzed cyclization and
subsequent proton transfer to inter-
mediate C finally provides the pro-
tected 2-iminoimidazoline 3. The
resulting insoluble AgSMe can be
converted readily into AgNO3 and
reused.[13] Remarkably, the pres-
ence of Boc or Cbz protecting
groups facilitates the key steps of
the process: 1) the activation of
thiourea toward methylsulfide elim-
ination; 2) the activation of the
carbodiimide toward the addition
of the propargylamine; 3) the acti-
vation of the guanidine functional-
ity toward the intramolecular
hydroamination of the alkyne.
The Boc groups were removed
by treatment with TFA/CH2Cl2
(1:2) at room temperature, and the
desired 2-aminoimidazoles 4a–f
were isolated as the free bases in
high yields (Table 2). 2-Aminoimi-
dazoles 4a–f were found to effec-
tively inhibit biofilm formation by
pathogenic Salmonella Typhimu-
rium and Pseudomonas aeruginosa
bacteria without a significant influ-
ence on planktonic growth (Table 2,
entries 3, 5, and 6).[13] These results
provide the first evidence of anti-
biofilm activity[2] of N-substituted 2-
aminoimidazoles against Gram-
negative bacteria.
Entry
3
X
R1
R2
R3
Yield [%][a]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
3a
3b
3c
3d
3e
3 f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Cbz
Cbz
Boc
Boc
Boc
Boc
Boc
Cbz
Boc
Boc
Cbz
Boc
Cbz
Boc
Me
Bn
Bn
Bn
PMB
c-C8H15
c-C12H23
nBu
3,4-DMB
Bn
Bn
Bn
H
cPr
nPr
iPr
p-FC6H4
nAm
iBu
iBu
H
c-C6H11
Ph
p-Tol
Ph
c-C6H11
cPr
p-BnOC6H4CH2
iBu
iBu
nPr
iBu
iPr
H
Ph
Ph
p-Tol
tBuC6H4
Ph
Ph
p-Tol
Me
100 (98)[b]
98 (94)[b]
86 (87)[b]
97 (91)[b]
84 (81)[b]
88 (87)[b]
77 (68)[b]
98 (79)[b]
84
Ph
99
82
80
cPent
p-PentOC6H4
Bn
PMP
cPentCH2
PMP
Ph
Ph
Ph
Ph
p-Tol
Ph
Bn
85
(S)-1-CHMeC6H5
cBu
Me
tBu
c-C7H13
Bn
3-MeOC6H4CH2CH2
Bn
79[c]
83
87
86
78
95
99
98
84
3s
3t
3u
3v
p-Tol
p-FC6H4
[a] Yield of the isolated product prepared by route B. [b] Yield of the isolated product prepared by route A
1
after two steps. [c] The yield was determined by H NMR spectroscopy; d.r. 65:35. Bn=benzyl, Boc=
tert-butoxycarbonyl, Cbz=carbobenzyloxy, DIPEA=N,N’-diisopropylethylamine, DMB=dimethoxy-
benzyl, PMB=p-methoxybenzyl, PMP=p-methoxyphenyl.
quantitative yield within 20 min when AgNO3 (15 mol%) in
MeCN was used. Comparable results were obtained with
AgOTf or Hg(OTf)2 (5–10 mol%), whereas other catalysts,
such as AuCl3, CuCl, CuBr, and Cu(OTf)2 (Tf = trifluorome-
thanesulfonyl) were not efficient.[13] Our attempts to carry out
guanylation and cyclization simultaneously with the AgI
catalyst (15 mol%) failed, probably as a result of the
formation of insoluble silver sulfide in the presence of 5.
Surprisingly, when we attempted the guanylation[14] of
propargylamines 1 with protected S-methylisothioureas 6
(1.25 equiv) in the presence of AgNO3 (1.4 equiv) and Et3N
(2 equiv) in MeCN, the corresponding Boc- and Cbz-pro-
tected 2-iminoimidazolines 3a–v were obtained in high yields
in a single step within 5–20 minutes at room temperature
(Table 1, route B). Remarkably, sterically hindered propar-
gylamines underwent efficient cyclization (Table 1, entries 6,
7, 14, 17, and 18) as did an N-aryl propargylamine (entry 22).
We presumed that the reaction proceeds through a
carbodiimide mechanism (Scheme 3).[15] In the first step, the
protected S-methylisothiourea 6 undergoes silver(I)-pro-
moted methylsulfide elimination in the presence of a base
to form a reactive carbodiimide intermediate A. The addition
Next, we applied our protocol to the total synthesis of
1,4,5-trisubstituted 2-aminoimidazole alkaloids of the naa-
mine family (Scheme 4). The starting N-methylpropargyl-
amines 11a–f were readily accessed through a microwave-
assisted copper(I)-catalyzed A3-coupling reaction[11] followed
Scheme 3. Proposed mechanism for the one-pot synthesis of protected
2-iminoimidazolines 3 from propargylamines 1.
9466 www.angewandte.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2010, 49, 9465 –9468

Angewandte
Chemie
Table 2: Deprotection[a] of bis-Boc-protected 2-iminoimidazolines 3 and
inhibitory activity of the products against bacterial biofilm formation.
by palladium(0)-catalyzed deallylation in the presence of 1,3-
dimethylbarbituric acid (DMBA). Silver(I)-promoted cyclo-
guanylation of the propargylamines and subsequent removal
of the Boc and Bn protecting groups (see the Supporting
Information) provided the target naamines A, C, E–G (13a–
e) and leucettamine A (13 f) in high overall yields (Scheme 4).
In summary, we have described a novel short and efficient
synthesis of diverse 2-aminoimidazoles from readily available
polysubstituted secondary propargylamines and thioureas.
Both the guanylation and the cyclization steps can be carried
out either in a stepwise manner with a carbodiimide activator
and an AgI catalyst or in a one-pot process with a recoverable
AgI salt as a promoter and catalyst. This protocol was
successfully applied to the total synthesis of all trisubstituted
2-aminoimidazole naamine alkaloids. Furthermore, we dem-
onstrated the potential of polysubstituted 2-aminoimidazoles
as inhibitors of bacterial biofilm formation. The synthesis of
other 2-aminoimidazole alkaloids is currently under develop-
ment.
Entry
4
Yield
IC50 [mm]
[%][b] S. Typhimurium PA14
ATCC14028
1
2
3
4a 85
4b 95
4c 78
42.4
74.4
18.3
377.1
109.0
17.4
Received: July 13, 2010
Published online: October 20, 2010
4
5
4d 80
4e 75
100.3
20.1
85.6
19.8
Keywords: alkaloids · 2-aminoimidazoles · cyclization ·
.
heterocycles · natural products
[1] For a general review of the synthesis and activity of 2-amino-
imidazole alkaloids, see: a) S. M. Weinreb, Nat. Prod. Rep. 2007,
24, 931 – 948; b) H. Hoffmann, T. Lindel, Synthesis 2003, 1753 –
1783.
[2] For the anti-biofilm activity of 2-aminoimidazoles, see: a) R. W.
Huigens III, J. J. Richards, G. Parise, T. E. Ballard, W. Zeng, R.
Deora, C. Melander, J. Am. Chem. Soc.
2007, 129, 6966 – 6967; b) S. A. Rogers, C.
Melander, Angew. Chem. 2008, 120, 5307 –
5309; Angew. Chem. Int. Ed. 2008, 47,
5229 – 5231; c) T. E. Ballard, J. J. Richards,
A. L. Wolf, C. Melander, Chem. Eur. J.
2008, 14, 10745 – 10761.
6
4 f 92
10.3
27.4
[a] Reaction conditions: 3 (0.2 mmol), TFA (2.0 mL), CH2Cl2 (4.0 mL), 1–
3 h, room temperature. [b] Yield of the isolated product. TFA=trifluoro-
acetic acid.
[3] a) M. S. Malamas, J. Erdei, I. Gunawan, J.
Turner, Y. Hu, E. Wagner, K. Fan, R.
Chopra, A. Olland, J. Bard, S. Jacobsen,
R. L. Magolda, M. Pangalos, A. J. Robi-
chaud, J. Med. Chem. 2010, 53, 1146 – 1158;
b) M. S. Malamas, J. Erdei, I. Gunawan, K.
Barnes, M. Johnson, Y. Hui, J. Turner, Y.
Hu, E. Wagner, K. Fan, A. Olland, J. Bard,
A. J. Robichaud, J. Med. Chem. 2009, 52,
6314 – 6323.
[4] a) R. S. Coleman, E. L. Campbell, D. J.
Carper, Org. Lett. 2009, 11, 2133 – 2136;
b) M. Nodwell, A. Pereira, J. L. Riffell, C.
Zimmermann, B. O. Patrick, M. Roberge,
R. J. Andersen, J. Org. Chem. 2009, 74,
995 – 1006.
[5] For a recent review of the chemistry and
biology of 2-aminoimidazoles from marine
sponges and their derivatives, see: J. D.
Sullivan, R. L. Giles, R. E. Looper, Curr.
Bioact. Compd. 2009, 5, 39 – 78.
[6] For examples of the synthesis of 2-amino-
Scheme 4. Short total synthesis of alkaloids of the naamine family. MW=microwave
irradiation. See the Supporting Information for groups corresponding to R1–4
imidazole alkaloids, see: a) N. S. Aberle, G.
Lessene, K. G. Watson, Org. Lett. 2006, 8,
.
Angew. Chem. Int. Ed. 2010, 49, 9465 –9468
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 9467

Communications
419 – 421; b) D. S. Ermolat’ev, V. L. Alifanov, V. B. Rybakov,
3350; b) H. C. Shen, Tetrahedron 2008, 64, 3885 – 3903; c) H. C.
Shen, Tetrahedron 2008, 64, 7847 – 7870; d) R. A. Widenhoefer,
X. Han, Eur. J. Org. Chem. 2006, 4555 – 4563; e) T. E. Mꢀller, M.
Beller, Chem. Rev. 1998, 98, 675 – 703.
E. V. Babaev, E. Van der Eycken, Synthesis 2008, 2083 – 2088;
c) P. B. Koswatta, C. J. Lovely, Chem. Commun. 2010, 46, 2148 –
2150; d) S. Nakamura, I. Kawasaki, M. Kunimura, M. Matsui, Y.
Noma, M. Yamashita, S. Ohta, J. Chem. Soc. Perkin Trans. 1
2002, 1061 – 1066.
[10] G. L. Eilrich, W. D. Dixon (Monsanto), US-3904395, 1975.
[11] J. B. Bariwal, D. S. Ermolat’ev, E. V. Van der Eycken, Chem.
Eur. J. 2010, 16, 3281 – 3284.
[12] B. R. Linton, A. J. Carr, B. P. Orner, A. D. Hamilton, J. Org.
Chem. 2000, 65, 1566 – 1568.
[7] R. L. Giles, J. D. Sullivan, A. M. Steiner, R. E. Looper, Angew.
Chem. 2009, 121, 3162 – 3166; Angew. Chem. Int. Ed. 2009, 48,
3116 – 3120.
[8] For
a
general review of the synthesis of polysubstituted
[13] See the Supporting Information for details.
[14] D. Ma, C. Xia, J. Jiang, J. Zhang, W. Tang, J. Org. Chem. 2003, 68,
442 – 451.
guanidines, see: A. R. Katritzky, B. V. Rogovoy, ARKIVOC
2005, 5, 49 – 87.
[9] For reviews on the synthesis of heterocycles by the transition-
metal-catalyzed cyclization of acetylenic compounds, see: a) E.
Jimꢁnez-Nfflæez, A. M. Echavarren, Chem. Rev. 2008, 108, 3326 –
[15] D. S. Ermolatꢂev, PhD thesis, Katholieke Universiteit Leuven
(Belgium), 2008.
9468 www.angewandte.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2010, 49, 9465 –9468