Synthesis of differentially substituted 2-aminoimidazolidines via a microwave-assisted tandem staudinger/Aza-wittig cyclization

Article abstract of DOI:10.1021/jo400481b

A new route for the construction of 2-aminoimidazolidines including analogues of the α₂ adrenergic agonist drug clonidine is elaborated. The key step is an intramolecular microwave-assisted Staudinger/aza-Wittig cyclization of an in situ generated urea intermediate (formed by the reaction of β-amino azide and isocyanate) upon treatment with Bu₃P or polymer-supported phosphine reagent, allowing the introduction of various substituents at the N1 and the 2-amino function. Furthermore, a useful one-pot Staudinger/aza-Wittig/Buchwald-Hartwig protocol leading to bicyclic guanidines has been elaborated.

Full text of DOI:10.1021/jo400481b

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Note
Synthesis of differentially substituted 2-aminoimidazolidines via
a microwave-assisted tandem Staudinger/aza-Wittig cyclization
Rakesh Kumar, Denis Semyonovich Ermolat'ev, and Erik V. Van der Eycken
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo400481b • Publication Date (Web): 03 May 2013
Downloaded from http://pubs.acs.org on May 3, 2013
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Synthesis of differentially substituted 2-aminoimidazolidines via a microwave-
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assisted tandem Staudinger/aza-Wittig cyclization
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[a]
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Rakesh Kumar, Denis S. Ermolat’ev,* and Erik V. Van der Eycken
*
Laboratory for Organic & MicrowaveꢀAssisted Chemistry
(LOMAC), Department of Chemistry, University of Leuven
(KU Leuven), Celestijnenlaan 200F, Bꢀ3001, Leuven, Belgium.
E-mails: erik.vandereycken@chem.kuleuven.be
denis.ermolatev@chem.kuleuven.be
Abstract: A new route for the construction of 2ꢀaminoimidazolidines including analogues of the
α2 adrenergic agonist drug clonidine is elaborated. The key step is an intramolecular microwaveꢀ
assisted Staudinger/azaꢀWittig cyclization of an in situ generated urea intermediate (formed by
the reaction of βꢀamino azide and isocyanate) upon treatment with Bu3P or polymerꢀsupported
phosphine reagent, allowing the introduction of various substituents at the N1 and the 2ꢀamino
function. Furthermore, a useful oneꢀpot Staudinger/azaꢀWittig/BuchwaldꢀHartwig protocol
leading to bicyclic guanidines has been elaborated.
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The cyclic guanidine structure (2ꢀaminoimidazolidine) represents an important structural motif
prevalent in a myriad of natural products and pharmacologically active molecules.1ꢀ2 In
particular, the 2ꢀaminoimidazolidine core is an integral part of many drugs, therapeutic leads
(e.g. potent DNA minor groove binder)2a,b and bioactive natural products. For instance, the
centrally acting α2ꢀadrenergic agonist drugs clonidine (antihypertensive/anaesthetic) and
brimonidine (antiglaucoma) contain the 2ꢀaminoimidazolidine core as the active pharmacophore
in their structure (Figure 1). Similarly, natural compounds such as the antibiotics of the
Streptothricin family and the antitumour agent NA22598A1 contain the 2ꢀaminoimidazolidine
scaffold (Figure 1). Besides this, 2ꢀaminoimidazolidines and their bicyclic analogues have found
numerous applications3ꢀ4 as e.g. in catalytic deprotonation processes (due to their superbasic
nature), in asymmetric catalysis or as sensors for anion recognition.
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Owing to the immense potential, the development of novel synthetic methodologies for
the construction of 2ꢀaminoimidazolidines is challenging. Moreover these structures show a high
basicity.4 The common approaches4ꢀ7 for their synthesis utilize assembled amine/diamine
precursors,[4,5] modification/cyclization of the guanidine core6 etc.. Other strategies7 include the
reaction of olefins with cyanimides (using NBS),7a cycloguanidation of olefins (using metal
catalyst),7b,c Tiemann rearrangement7d etc.. However, a majority of the above protocols are either
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limited in terms of diversity regarding the N1 and 2ꢀamino substitution pattern, or utilize
multistep protectionꢀdeprotection.
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Recently, the Staudinger/azaꢀWittig reaction has received much attention for the synthesis of
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substituted N-containing heterocycles.8 In this context, the reaction of
βꢀamino azides 1 with
isocyanates 2 seems an attractive proposition to access differentially substituted 2ꢀ
aminoimidazolidines (possible reaction pathways are depicted in Scheme 1). Path 1 would
proceed through the formation of the iminophosphorane A, followed by the carbodiimide
intermediate B and finally intramolecular cyclization to the desired compound 3. However,
isocyanate can lead to a side reaction with the NHꢀgroup of A, besides formation of the desired
carbodiimide B. To avoid this problem, the protection of the NHꢀgroup would be indispensable.
Shipman et al.9 explored a similar strategy using protected ꢀamino azide (R1 = Boc, Cbz, etc.)
β
with isocyanates. We envisioned that, reaction of 1 with 2 would generate intermediate C (Path
2). Staudinger reaction of C with a suitable phosphine reagent would lead to intermediate D
which on heating is expected to undergo cyclization to afford the desired guanidine 3. To the
best of our knowledge, such a tandem route involving a Staudinger/azaꢀWittig cyclization of an
in situ formed urea intermediate C has so far not been reported. This approach should also avoid
the necessity to protect the secondary amine 1 (Path 1).
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Our ongoing interest in the synthesis of 2ꢀaminoimidazole derivatives as novel antibiofilm
compounds10 encouraged us to explore this new approach towards the related 2ꢀ
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aminoimidazolidines. We herein disclose our results starting from
βꢀamino azides and
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isocyanates employing a tandem Staudinger/azaꢀWittig cyclization without any protectionꢀ
deprotection manipulations. The protocol allows a facile access to a various substitution pattern
on N1 as well as on the 2ꢀamino function. Initially, the Staudinger/azaꢀWittig cyclization was
performed using 2ꢀazidoꢀNꢀbenzylethanamine (1a) and benzyl isocyanate (2a) as substrates
(Table 1). A mixture of 1a (0.71 mmol), 2a (0.71 mmol) in dry toluene (1 mL) was heated at 100
oC to form the urea intermediate. Thereafter, Bu3P (1 equiv.) was added, and the resulting
o
mixture was further heated at 100 C for 20h (Table 1, entry 1). This condition afforded the
desired product 3a without any side product.11 However, 3a could not be isolated efficiently
through column chromatography over silica gel due to the superbasic nature of this compound
which was also amalgamated with Bu3P=O. Attempt to purify the highly polar 3a by reversed
phase preparative HPLC (ACN/H2O with 0.1% HCOOH) resulted in the corresponding formate
salt 3a'.12
Finally, we were able to purify 3a (93%, Table 1, entry 1) using neutral alumina as
stationary phase. Subsequently, a detailed optimization study was conducted to evaluate the
effect of temperature, time and phosphine reagent (Table 1). The reaction resulted in a
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comparable yield when performed at 120 C (Table 1, entries 1 and 2). However at higher
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temperature (140 C) some decomposition of the product was observed (Table 1, entry 3).
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Interestingly, cyclization could not be completed at lower temperature as below 100 C some
open chain intermediates were detected by NMR (Table 1, entries 4, 5 and 6). Replacement of
benzyl isocyanate by the corresponding isothiocyanate also provided 3a in a comparative yield
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of 82% (Table 1, entry 7). Screening of other phosphine reagents such as PPh3, (oꢀtol)3P, 1,4ꢀ
bis(diphenylphosphino)butane (DPPB) or stericaly hindered (tꢀBu3)P, provided 3a in
significantly lower yields than nꢀBu3P (Table 1, entries 8ꢀ11). Furthermore, shortening the
reaction time (using nꢀBu3P) from 20h to 5h or 10h decreased the yield of 3a (Table 1, entry 12).
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To our satisfaction the application of microwave irradiation (120 C) dramatically enhanced the
reaction rate as 3a could be accessed within 25 min (5 min for the first step and 20 min for the
cyclization step) in 95% yield (Table 1, entry 15).
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The utility of our optimized microwave conditions (Table 1, entry 15) was further ascertained
through the tandem synthesis of other 2ꢀaminoimidazolidines bearing electronꢀ donating as well
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as electron withdrawing substituents either on the parts derived from the
isocyanate (Table 2).
βꢀamino azide or the
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In particular, aliphatic as well as cyclic coupling partners could be successfully employed (Table
2, 3e, 3f, 3h and 3l). Importantly, chiral imidazolidine derivatives, finding huge potential in
asymmetric catalysis,3cꢀe,5d could be easily accessed by incorporating the chirality of the parent
isocyanate or β−amino azide (Table 2, see products; 3b, 3g and 3kꢀ3n).
Then, we turned our attention to the synthesis of biologically important clonidine
derivatives. Employing the optimized conditions, the reaction of 1a with 2,6ꢀdichlorophenyl
isocyanate (2j) provided the product 3p in 82% yield (NMR basis) (Table 2). However,
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particularly in this example, the complete removal of Bu3P=O proved to be difficult, although the
corresponding benzyl analogs 3n and 3o (using 2ꢀchlorobenzyl isocycanate and 2,4ꢀ
dichlorobenzyl isocycanate) could be isolated in good yields (Table 2). To solve the purification
problem we investigated the possibility to use polymerꢀsupported phosphine reagent.
Satisfactorily the reaction between 1a and 2j, when performed with (nBu)2PhP crossꢀlinked
polystyrene, finally provided 3p in an excellent yield of 94% (Table 3) without the need of
column purification. The generality of this protocol was extended with the synthesis of various
clonidine analogues (Table 3, 3qꢀ3r) and other 2ꢀaminoimidazolidines (Table 3, 3s, 3a).
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Interestingly, the above approach was also found to be applicable for the first concise
synthesis of nonꢀsymmetrical {6,5}ꢀbicyclic guanidines13 via a hitherto unknown tandem
Staudinger/azaꢀWittig/BuchwaldꢀHartwig coupling strategy (Scheme 2). Notably, the Buchwaldꢀ
Hartwig step using CuI could not provide complete conversion, even after a long reaction time,
whereas reaction with a Pd catalyst was found quite effective. The resulting guanidine
framework has important applications3,13 in organocatalysis, anion recognition and
supramolecular chemistry. Moreover, the known synthetic methodologies for such a scaffold
predominantly rely on the use of multistep procedures using harsh reaction conditions and
expensive starting materials.13
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CONCLUSIONS
In conclusion, a new route to 2ꢀaminoimidazolidines via a tandem Staudinger/azaꢀWittig reaction
has been elaborated. A various substitution pattern at the N1 as well as the amino function could
be introduced. Interestingly, the application of a polymerꢀsupported phosphine reagent allowed
the easy access to clonidine analogues without the need of purification. Furthermore, a novel
Staudinger/azaꢀWittig/BuchwaldꢀHartwig tandem protocol was elaborated for the synthesis of
bicyclic guanidines.
EXPERIMENTAL SECTION
General experimental methods. All the reagents (isocyanates and phosphine reagents) and
solvents used for isolation/purification of final compounds were purchased from commercial
sources and used as such. Anhydrous toluene (stored over molecular sieves) was used. For thinꢀ
layer chromatography, preꢀcoated TLC plates (0.2 mm, Aluminium oxide N/UV254) were used.
Column chromatography was performed using neutral alumina (Brockmann 1, 50ꢀ200 ꢁm).
All microwave irradiation experiments were carried out in a CEM Discover© monomode
microwave operating at a frequency of 2.45 GHz. The reactions were carried out in 10ꢀmL glass
tubes, sealed with Teflon septum. The temperature of reactions in microwave experiments was
measured by an inbuilt infrared temperature probe. H (300 MHz) and 13C (75.5 MHz) NMR
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spectra were recorded on a 300 MHz spectrometer using tetramethylsilane as internal reference.
In addition, the 1H NMR spectra of compound 3c at different temperature was recorded on a 400
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MHz spectrometer (see, supporting information). The following abbreviations were used to
designate chemical shift multiplicities: s = singlet, bs = broad singlet, d = doublet, dd = double
doublet, t = triplet, m = multiplet, q = quartet. The 13C NMR spectra are proton decoupled. Mass
spectra were recorded at ion source temperature of 150ꢀ250°C, as required. High resolution EIꢀ
mass spectra (using double focusing magnetic sector as mass analyzer) were performed with a
resolution of 10,000.
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Synthesis of starting β-amino azides (1aꢀ1e): βꢀAmino azides were synthesized from bromo
ethanol (8.55 mmol) using an earlier reported procedures.14 The NMR spectral data are given
below:
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2-Azido-N-benzylethanamine14 (1a): Colorless oil (1.09 g, yield 73%), H NMR (300 MHz,
CDCl3): δ (ppm) 7.33ꢀ7.23 (m, 5H), 3.81(s, 2H), 3.43 (t, J = 5.4 Hz, 2H), 2.83 (t, J = 5.8 Hz,
2H), 1.53 (bs, 1H). 13C NMR (75.5 MHz, CDCl3): δ (ppm) 139.9, 128.4, 128.0, 127.0, 53.5,
51.4, 47.9. HRMSꢀEI: m/z [M]+ for C8H10N, calculated 120.0813; observed 120.0809.
1
(R)-2-Azido-N-(1-phenylethyl)ethanamine (1b): Colorless oil (1.08 g, yield 67%), H NMR
(300 MHz, CDCl3): δ (ppm) 7.35ꢀ7.21 (m, 5H), 3.80 (q, J = 6.6 Hz, 1H), 3.42ꢀ3.28 (m, 2H),
2.72ꢀ2.56 (m, 2H), 1.68 (bs, 1H), 1.37 (d, J = 6.5 Hz, 3H). 13C NMR (75.5 MHz, CDCl3): δ
(ppm) 145.2, 128.5, 127.0, 126.5, 58.0, 51.6, 46.4, 24.4. HRMSꢀEI: m/z [M]+ for C9H12N,
calculated 134.0970; observed 134.0972.
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2-Azido-N-(4-methoxybenzyl)ethanamine (1c): Light yellow oil (1.27 g, yield 72%), H NMR
(300 MHz, CDCl3): δ (ppm) 7.25 (d, J = 8.4 Hz, 2H), 6.88 (d, J = 8.6 Hz, 2H), 3.79 (s, 3H), 3.75
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(s, 2H), 3.43 (t, J = 5.6 Hz, 2H), 2.82 (t, J = 5.8 Hz, 2H), 1.60 (bs, 1H). C NMR (75.5 MHz,
CDCl3): δ (ppm) 158.7, 132.0, 129.2, 113.8, 55.2, 52.9, 51.4, 47.8. HRMSꢀEI: m/z [M]+ for
C9H12NO, calculated 150.0919; observed 150.0924.
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2-Azido-N-(2-bromobenzyl)ethanamine (1d): Light yellow oil (1.16 g, yield 53%), H NMR
(300 MHz, CDCl3): δ (ppm) 7.55 (d, J = 7.7 Hz, 1H), 7.40 (d, J = 6.6 Hz, 1H), 7.31ꢀ7.26 (m,
1H), 7.15ꢀ7.10 (m, 1H), 3.89 (s, 2H), 3.45 (t, J = 5.4 Hz, 2H), 2.83 (t, J = 5.8 Hz, 2H), 1.80 (bs,
1H). 13C NMR (75.5 MHz, CDCl3): δ (ppm) 138.8, 132.8, 130.1, 128.7, 127.5, 123.9, 53.3, 51.4,
47.7. HRMSꢀEI: m/z [M]+ for C7H8N, calculated 106.0657; observed 106.0645.
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1
N-(2-Azidoethyl)cycloheptanamine (1e): Light yellow oil (0.79 g, yield 51%), H NMR (300
MHz, CDCl3): δ (ppm) 3.43 (t, J = 5.4 Hz, 2H), 2.80 (t, J = 5.8 Hz, 2H), 2.67ꢀ260 (m, 1H), 1.86ꢀ
1.78 (m, 2H), 1.69ꢀ1.35 (m, 11H). 13C NMR (75.5 MHz, CDCl3): δ (ppm) 58.7, 51.8, 46.1, 34.9,
28.2, 24.3. HRMSꢀEI: m/z [M]+ for C8H16N, calculated 126.1283; observed 126.1273.
CAUTION: Although the organic azides have not shown any explosive hazard under the
developed experimental conditions, appropriate safety measures (e.g. face shield and leather
gloves) must always be taken at all times.
Representative procedure for the preparation of N,1-Dibenzyl-4,5-dihydro-1H-imidazol-2-
amine (Table 2, 3a). To a solution of 2ꢀazidoꢀNꢀbenzylethanamine (1a, 0.71 mmol) in dry
toluene (1 mL) benzyl isocyanate (2a, 0.71 mmol) was added and the resulting reaction mixture
was irradiated at a ceiling temperature of 120 °C (maximum power 250 W) for 5 min. After
cooling of the reaction mixture to ambient temperature, nꢀBu3P (0.78 mmol) was added dropwise
under argon atmosphere and the reaction mixture was allowed to stir for 20 min. Thereafter the
reaction vial was filled with argon, sealed and irradiated at a ceiling temperature of 120 °C
(maximum power 250 W) for 20 min. The solvent was evaporated under reduced pressure and
the obtained residue was subjected to column chromatography over neutral alumina using 1ꢀ5%
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MeOH in DCM as eluent to afford 3a as a white sticky solid in 95% yield (179 mg); H NMR
(300 MHz, CDCl3): δ (ppm) 9.85 & 8.87 (bs, 1H), 7.60ꢀ7.57 (m, 2H), 7.24ꢀ7.15 (m, 8H), 4.67 (s,
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4H), 3.40ꢀ3.34 (m, 2H), 3.24ꢀ3.18 (m, 2H). 13C NMR (75.5 MHz, CDCl3): δ (ppm) 157.6, 136.9,
134.1, 128.8, 128.4 (3), 128.2, 127.6, 49.3, 46.9, 46.0, 40.8. HRMSꢀEI: m/z [M]+ for C17H19N3,
calculated 265.1579; observed 265.1579.
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The above procedure was also followed for synthesis of various other 2ꢀaminoimidazolidines15
(Table 2, 3b-3p).
(S)-N-Benzyl-1-(1-phenylethyl)-4,5-dihydro-1H-imidazol-2-amine (3b): Viscous liquid (166
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mg, yield 84%), H NMR (300 MHz, DMSOꢀd6): δ (ppm) 9.41 & 8.80 (bs, 1H), 7.41ꢀ7.29 (m,
10H), 5.49ꢀ5.47 (m, 1H), 4.51 (2H, s), 3.75ꢀ3.66 (m, 1H), 3.60ꢀ3.50 (m, 2H), 3.29ꢀ3.20 (1H, m),
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1.56 (d, J = 6.7 Hz, 3H). C NMR (75.5 MHz, DMSOꢀd6): δ (ppm) 156.9, 138.7, 137.1, 128.6,
128.3, 127.9, 127.4, 127.2, 126.8, 51.2, 45.3, 42.6, 16.6. HRMSꢀEI: m/z [M]+ for C18H21N3,
calculated 279.1735; observed 279.1720.
N-Benzyl-1-(4-methoxybenzyl)-4,5-dihydro-1H-imidazol-2-amine (3c): White solid (201 mg,
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yield 96%), m.p. 145ꢀ149°C, H NMR (300 MHz, CDCl3): δ (ppm) 9.83 & 8.84 (bs, 1H), 7.61
(d, J = 6.2 Hz, 2H), 7.26ꢀ7.20 (m, 3H), 7.13 (d, J = 8.4 Hz, 2H), 6.77 (d, J = 8.4 Hz, 2H), 4.73 (s,
2H), 4.64 (s, 2H), 3.74 (s, 3H), 3.47ꢀ3.42 (m, 2H), 3.28ꢀ3.23 (m, 2H). 13C NMR (75.5 MHz,
CDCl3): δ (ppm) 159.5, 157.5, 137.0, 129.9, 128.4 (2), 127.6, 126.1, 114.2, 55.3, 48.7, 46.8,
46.0, 40.8. HRMSꢀEI: m/z [M]+ for C18H21N3O, calculated 295.1685; observed 295.1684.
N-Benzyl-1-(2-bromobenzyl)-4,5-dihydro-1H-imidazol-2-amine (3d): Viscous colourless
liquid (217 mg, yield 89%), 1H NMR (300 MHz, CDCl3): δ (ppm) 9.75 & 9.07 (bs, 1H), 7.63 (d,
J = 7.8 Hz, 2H), 7.52 (d, J = 7.7 Hz, 1H), 7.28ꢀ7.11 (m, 6H), 4.88 (s, 2H), 4.74 (s, 2H), 3.55ꢀ3.46
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(m, 2H), 3.32ꢀ3.26 (m, 2H). C NMR (75.5 MHz, CDCl3): δ (ppm) 157.6, 136.9, 133.5, 133.1,
130.7, 130.0, 128.5, 128.4, 128.1, 127.6, 124.2, 49.1, 46.9, 46.2, 41.0. HRMSꢀEI: m/z [M]+ for
C17H18BrN3, calculated 343.0684; observed 343.0647.
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N-Benzyl-1-cycloheptyl-4,5-dihydro-1H-imidazol-2-amine (3e): White sticky solid (167 mg,
yield 87%), 1H NMR (300 MHz, CDCl3): δ (ppm) 9.58 & 8.32 (bs, 1H), 7.59 (d, J = 7.1 Hz, 2H),
7.31ꢀ7.22 (m, 3H), 4.70 (s, 2H), 4.44ꢀ4.40 (m, 1H), 3.56ꢀ3.54 (m, 2H), 3.49ꢀ3.47 (m, 2H), 1.79ꢀ
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1.47 (m, 12H). C NMR (75.5 MHz, CDCl3): δ (ppm) 157.1, 137.1, 128.5, 128.2, 127.6, 54.9,
45.9, 42.8, 41.0, 32.2, 27.5, 24.2. HRMSꢀEI: m/z [M]+ for C17H25N3, calculated 271.2048;
observed 271.2036.
1-Benzyl-N-heptyl-4,5-dihydro-1H-imidazol-2-amine (3f): Viscous colourless liquid (169 mg,
yield 87%), 1H NMR (300 MHz, CDCl3): δ (ppm) 9.06 & 8.87 (bs, 1H), 7.32ꢀ7.25 (m, 5H), 4.76
(s, 2H), 3.57ꢀ3.47 (m, 4H), 3.39ꢀ3.33 (m, 2H), 1.70ꢀ1.65 (m, 2H), 1.27ꢀ1.23 (m, 8H), 0.87 (t, J =
6.7 Hz, 3H). 13C NMR (75.5 MHz, CDCl3): δ (ppm) 157.7, 134.5, 128.8, 128.4, 128.2, 49.4,
47.0, 43.9, 40.9, 31.7, 29.2, 29.0, 26.6, 22.6, 14.1. HRMSꢀEI: m/z [M]+ for C17H27N3, calculated
273.2205; observed 273.2208.
(R)-1-Benzyl-N-(1-phenylethyl)-4,5-dihydro-1H-imidazol-2-amine (3g): White solid (180 mg,
yield 91%), m.p. 85ꢀ88°C, 1H NMR (300 MHz, CDCl3): δ (ppm) 9.39 & 8.75 (bs, 1H), 7.73 (d, J
= 7.2 Hz, 2H), 7.23ꢀ7.17 (m, 8H), 5.29ꢀ5.24 (m, 1H), 4.91ꢀ4.79 (m, 2H), 3.51ꢀ3.42 (m, 1H),
3.35ꢀ3.13 (m, 3H), 1.71 (d, J = 6.5 Hz, 3H). 13C NMR (75.5 MHz, CDCl3): δ (ppm) 157.1,
142.7, 134.4, 128.8, 128.5, 128.3, 128.1, 127.5, 126.8, 54.4, 49.6, 47.0, 40.9, 23.1. HRMSꢀEI:
m/z [M]+ for C18H21N3, calculated 279.1735; observed 279.1737.
N-Cyclopentyl-1-(4-methoxybenzyl)-4,5-dihydro-1H-imidazol-2-amine (3h): White solid
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(157 mg, yield 81%), m.p. 214ꢀ218°C, H NMR (300 MHz, CDCl3): δ (ppm) 8.88 & 8.42 (bs,
1H), 7.20 (d, J = 8.4 Hz, 2H), 6.86 (d, J = 8.4 Hz, 2H), 4.72 (s, 2H), 4.24ꢀ4.20 (m, 1H), 3.79 (s,
3H), 3.60ꢀ3.55 (m, 2H), 3.41ꢀ3.35 (m, 2H), 1.85ꢀ1.55 (m, 8H). 13C NMR (75.5 MHz, CDCl3): δ
(ppm) 159.5, 157.3, 129.8, 126.6, 114.1, 56.1, 55.3, 49.0, 47.0, 40.9, 32.5, 23.9. HRMSꢀEI: m/z
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[M]+ for C16H23N3O, calculated 273.1841; observed 273.1849.
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N,1-Bis(4-methoxybenzyl)-4,5-dihydro-1H-imidazol-2-amine (3i): Off white sticky solid (208
mg, yield 90%), 1H NMR (300 MHz, CDCl3): δ (ppm) 9.76 & 8.74 (bs, 1H), 7.57 (d, J = 8.4 Hz,
2H), 7.13 (d, J = 8.6 Hz, 2H), 6.79ꢀ6.75 (m, 4H), 4.69 (s, 2H), 4.63 (s, 2H), 3.75 (s, 3H), 3.73 (s,
3H), 3.52ꢀ3.47 (m, 2H), 3.31ꢀ3.25 (m, 2H). 13C NMR (75.5 MHz, CDCl3): δ (ppm) 159.5, 159.0,
157.4, 129.9, 129.8, 129.1, 126.1, 114.2, 113.8, 55.2(2), 48.7, 46.8, 45.5, 40.9. HRMSꢀEI: m/z
[M]+ for C19H23N3O2, calculated 325.1790; observed 325.1798.
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1-(4-Methoxybenzyl)-N-(4-methylbenzyl)-4,5-dihydro-1H-imidazol-2-amine (3j): Viscous
liquid (189 mg, yield 86%), 1H NMR (300 MHz, CDCl3): δ (ppm) 9.77 & 8.78 (bs, 1H), 7.49 (d,
J = 7.7 Hz, 2H), 7.13 (d, J = 8.1 Hz, 2H), 7.03ꢀ7.01 (m, 2H), 6.77 (d, J = 8.1 Hz, 2H), 4.66 (s,
2H), 4.61 (s, 2H), 3.74 (s, 3H), 3.46ꢀ3.40 (m, 2H), 3.26ꢀ3.21 (m, 2H), 2.26 (s, 3H). 13C NMR
(75.5 MHz, CDCl3): δ (ppm) 159.4, 157.6, 137.2, 133.9, 129.9, 129.1, 128.4, 126.1, 114.1, 55.2,
48.8, 46.8, 45.8, 40.9, 21.1. HRMSꢀEI: m/z [M]+ for C19H23N3O, calculated 309.1841; observed
309.1845.
(S)-N-(4-Methoxybenzyl)-1-(1-phenylethyl)-4,5-dihydro-1H-imidazol-2-amine (3k): Pale
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yellow solid (187 mg, yield 85%), m.p. 89ꢀ93°C, H NMR (300 MHz, CDCl3): δ (ppm) 9.67 &
8.71 (bs, 1H), 7.53 (d, J = 8.1 Hz, 2H), 7.26ꢀ7.28 (m, 5H), 6.77 (d, J = 8.2 Hz, 2H), 5.83 (q, J =
6.4 Hz, 1H), 4.69 (s, 2H), 3.72 (s, 3H), 3.55ꢀ3.41 (m, 3H), 3.17ꢀ3.11 (m, 1H), 1.52 (d, J = 6.6
Hz, 3H). 13C NMR (75.5 MHz, CDCl3): δ (ppm) 159.0, 157.2, 138.1, 129.7, 129.1, 128.7, 128.1,
127.1, 113.8, 55.2, 52.2, 45.4, 42.6, 40.8, 16.2. HRMSꢀEI: m/z [M]+ for C19H23N3O, calculated
309.1841; observed 309.1849.
(S)-N-Butyl-1-(1-phenylethyl)-4,5-dihydro-1H-imidazol-2-amine (3l): Light yellow oil (139
mg, yield 80%), 1H NMR (300 MHz, CDCl3): δ (ppm) 8.93 & 8.83 (bs, 1H), 7.33ꢀ7.27 (m, 5H),
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5.88 (q, J = 6.5 Hz, 1H), 3.60ꢀ3.47 (m, 5H), 3.22ꢀ3.15 (m, 1H), 1.70ꢀ1.61 (m, 2H), 1.55 (d, J =
6.7 Hz, 3H), 1.42ꢀ1.20 (m, 2H), 0.89 (t, J = 7.3 Hz, 3H). 13C NMR (75.5 MHz, CDCl3): δ (ppm)
157.2, 138.4, 128.7, 128.1, 127.1, 52.0, 43.6, 42.7, 40.7, 31.2, 19.8, 16.2, 13.8. HRMSꢀEI: m/z
[M]+ for C15H23N3, calculated 245.1892; observed 245.1892.
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N-((R)-1-Phenylethyl)-1-((S)-1-phenylethyl)-4,5-dihydro-1H-imidazol-2-amine (3m): White
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solid (179 mg, yield 86%), m.p. 248ꢀ251°C, H NMR (300 MHz, CDCl3): δ (ppm) 9.23 & 8.69
(bs, 1H), 7.75 (d, J = 6.9 Hz, 2H), 7.30ꢀ7.15 (m, 8H), 6.21 (q, J = 6.6 Hz, 1H), 5.29ꢀ5.23 (m,
1H), 3.51ꢀ3.28 (m, 3H), 3.15ꢀ3.06 (m, 1H), 1.68 (d, J = 6.6 Hz, 3H), 1.47 (d, J = 6.6 Hz, 3H).
13C NMR (75.5 MHz, CDCl3): δ (ppm) 156.6, 142.9, 138.4, 128.7, 128.5, 128.0, 127.3, 127.2,
126.8, 54.4, 52.1, 42.6, 40.8, 23.2, 16.0. HRMSꢀEI: m/z [M]+ for C19H23N3, calculated 293.1892;
observed 293.1901.
(S)-N-(2-Chlorobenzyl)-1-(1-phenylethyl)-4,5-dihydro-1H-imidazol-2-amine (3n): Light
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yellow solid (169 mg, yield 76%), m.p. 86ꢀ90°C, H NMR (300 MHz, CDCl3): δ (ppm) 9.30 &
8.83 (bs, 1H), 7.50ꢀ7.47 (m, 1H), 7.32ꢀ7.25 (m, 6H), 7.19ꢀ7.14 (m, 2H), 5.81 (q, J = 6.5 Hz, 1H),
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4.83ꢀ4.69 (m, 2H), 3.55ꢀ3.44 (m, 3H), 3.30ꢀ3.21 (m, 1H), 1.56 (d, J = 6.7 Hz, 3H). C NMR
(75.5 MHz, CDCl3): δ (ppm) 157.6, 138.2, 133.9, 133.2, 129.9, 129.4, 129.1, 128.8, 128.2,
127.1, 127.0, 52.7, 44.6, 43.3, 40.9, 16.8. HRMSꢀEI: m/z [M]+ for C18H20ClN3, calculated
313.1346; observed 313.1349.
N-(2,5-Dichlorobenzyl)-1-(4-methoxybenzyl)-4,5-dihydro-1H-imidazol-2-amine (3o): Off
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white solid (204 mg, yield 79%), m.p. 150ꢀ153°C, H NMR (300 MHz, CDCl3): δ (ppm) 9.49 &
8.88 (bs, 1H), 7.51 (d, J = 8.2 Hz, 1H), 7.28 (s, 1H), 7.19ꢀ7.12 (m, 3H), 6.82 (d, J = 8.4 Hz, 2H),
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4.74 (s, 2H), 4.66 (s, 2H), 3.77 (s, 3H), 3.53ꢀ3.48 (m, 2H), 3.42ꢀ3.37 (m, 2H). C NMR (75.5
MHz, CDCl3): δ (ppm) 159.6, 157.8, 134.1 (2), 132.7, 130.9, 129.9, 129.2, 127.2, 125.9, 114.2,
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55.3, 48.9, 47.2, 44.2, 41.0. HRMSꢀEI: m/z [M]+ for C18H19Cl2N3O, calculated 363.0905;
observed 363.0902.
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Representative procedure for the preparation of 1-Benzyl-N-(2,6-dichlorophenyl)-4,5-
dihydro-1H-imidazol-2-amine (Table 3, 3p) using polymer-supported phosphine reagent
[(nBu)2PhP Polystyrene]. To a solution of 2ꢀazidoꢀNꢀbenzylethanamine (1a, 0.14 mmol) in dry
toluene (1 mL), 2,6ꢀdichlorophenyl isocyanate (2j, 0.14 mmol) was added and the resulting
reaction mixture was irradiated at a ceiling temperature of 120 °C (maximum power 250 W) for
5 min. After cooling of the reaction mixture to ambient temperature, dry toluene (1.5 mL)
followed by (nBu)2PhP polystyrene (0.25 g, 0.66 mmol/g) were added under argon atmosphere.
Thereafter the reaction vial was filled with argon, sealed and irradiated under microwave at a
ceiling temperature of 120 °C (maximum power 250 W) for 20 min. The resin was filtered off
and washed with DCM. The obtained filtrate was passed through a small bed of neutral alumina
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to give 3p as a viscous liquid in 94% yield (42 mg); H NMR (300 MHz, CDCl3): δ (ppm) 7.49
(d, J = 7.1 Hz, 2H), 7.38ꢀ7.27 (m, 5H), 6.85 (t, J = 7.7 Hz, 1H), 4.64 (s, 2H), 3.82 (bs, 1H), 3.36ꢀ
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3.38 (m, 4H). C NMR (75.5 MHz, CDCl3): δ (ppm) 155.0, 145.5, 137.3, 129.4, 128.4, 128.2,
127.3, 122.5, 48.5, 45.7, 40.2. HRMSꢀEI: m/z [M]+ for C16H15Cl2N3, calculated 319.0643;
observed 319.0615.
The above procedure was also followed for synthesis of various other 2ꢀaminoimidazolidines
(Table 3, 3a, 3q-3s).
1-(2-Bromobenzyl)-N-(2,6-dichlorophenyl)-4,5-dihydro-1H-imidazol-2-amine (3q): Viscous
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liquid (51 mg, yield 92%), H NMR (300 MHz, CDCl3): δ (ppm) 7.71 (d, J = 7.5 Hz, 1H), 7.56
(d, J = 7.7 Hz, 1H), 7.33ꢀ7.14 (m, 4H), 6.85 (t, J = 7.7 Hz, 1H), 4.78 (s, 2H), 3.84 (bs, 1H), 3.44ꢀ
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3.46 (m, 4H). C NMR (75.5 MHz, CDCl3): δ (ppm) 154.9, 145.3, 136.4, 132.6, 130.1, 129.4,
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128.8, 128.2, 127.7, 123.7, 122.6, 48.1, 46.3, 40.3. HRMSꢀEI: m/z [M]+ for C16H14BrCl2N3,
calculated 396.9748; observed 396.9723.
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1-Benzyl-N-(3-chlorophenyl)-4,5-dihydro-1H-imidazol-2-amine (3r): Viscous liquid (39 mg,
yield 97%), 1H NMR (300 MHz, CDCl3): δ (ppm) 7.36ꢀ7.25 (m, 5H), 7.19ꢀ7.14 (m, 1H), 7.00 (s,
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1H), 6.93ꢀ6.85 (m, 2H), 4.53 (s, 2H), 4.22 (bs, 1H), 3.36ꢀ3.34 (m, 2H), 3.30ꢀ3.32 (m, 2H). C
NMR (75.5 MHz, CDCl3): δ (ppm) 155.8, 152.6, 137.3, 134.3, 130.0, 128.5, 128.2, 127.3, 123.1,
121.5 (2), 48.6, 45.8, 40.3. HRMSꢀEI: m/z [M]+ for C16H16ClN3, calculated 285.1033; observed
285.1010.
1-Cycloheptyl-N-cyclopentyl-4,5-dihydro-1H-imidazol-2-amine (3s): Brown sticky solid (32
mg, yield 92%), 1H NMR (300 MHz, CDCl3): δ (ppm) 8.75 & 8.25 (bs, 1H), 4.66ꢀ4.59 (m, 1H),
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4.22ꢀ4.13 (m, 1H), 3.64ꢀ3.52 (m, 4H), 2.09ꢀ2.04 (m, 2H), 1.90ꢀ1.46 (m, 18H). C NMR (75.5
MHz, CDCl3): δ (ppm) 156.6, 56.1, 54.4, 42.8, 41.0, 32.4, 32.0, 27.8, 23.9 (2). HRMSꢀEI: m/z
[M]+ for C15H27N3, calculated 249.2205; observed 249.2197.
General Microwave-assisted tandem protocol for the preparation of bicyclic guanidines (3t
and 3u, Scheme 2): To a solution of 2ꢀazidoꢀNꢀ(2ꢀbromobenzyl)ethanamine (0.14 mmol) in dry
toluene (1 mL), isocyanate (0.14 mmol) was added and the resulting reaction mixture was
irradiated at a ceiling temperature of 120 °C (maximum power 250 W) for 5 min. After cooling
of the reaction mixture to ambient temperature, dry toluene (1.5 mL) followed by (nBu)2PhP
polystyrene (0.25 g, 0.66 mmol/g) were added under argon atmosphere. Thereafter the reaction
vial was filled with argon, sealed and irradiated under microwave at a ceiling temperature of
120 °C (maximum power 250 W) for 20 min to obtain the corresponding 2ꢀaminoimidazolidine.
After cooling, Pd(dba)2 (10 mol%), Sꢀphos (20 mol%) and KOtBu (2.0 equiv.) were added to the
reaction mixture. Thereafter the reaction vial was filled with argon, sealed and irradiated at a
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ceiling temperature of 120 °C (maximum power 250 W) for 25 min. After completion of the
reaction, the resin was filtered off and washed with DCM. The obtained filtrate was evaporated
under reduced pressure. The obtained residue was subjected to column chromatography over
neutral alumina using 0.5ꢀ2% MeOH in DCM as eluent to afford bicyclic guanidines 3t and 3u.
10-benzyl-2,3,5,10-tetrahydroimidazo[2,1-b]quinazoline (3t): White solid (27 mg, yield
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72%), m.p. 95ꢀ99°C, H NMR (300 MHz, CDCl3): δ (ppm) 7.32ꢀ7.19 (m, 5H), 7.16ꢀ7.08 (m,
2H), 6.99ꢀ6.94 (m, 1H), 6.80 (d, J = 8.2 Hz, 1H), 5.34 (s, 2H), 4.29 (s, 2H), 3.86 (t, J = 8.4 Hz,
2H), 3.60 (t, J = 8.4 Hz, 2H). 13C NMR (75.5 MHz, CDCl3): δ (ppm) 158.2, 137.0, 136.0, 128.7,
128.6, 127.2, 126.5, 126.3, 122.2, 119.3, 113.8, 52.8, 48.6, 48.5, 47.9. HRMSꢀEI: m/z [M]+ for
C17H17N3, calculated 263.1422; observed 263.1398.
10-heptyl-2,3,5,10-tetrahydroimidazo[2,1-b]quinazoline (3u, Scheme 2): Off white sticky
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solid (25 mg, yield 65%), H NMR (300 MHz, CDCl3): δ (ppm) 7.33ꢀ7.27 (m, 1H), 7.11ꢀ7.03
(m, 2H), 6.97 (d, J = 8.2 Hz, 1H), 4.30 (s, 2H), 4.11 (t, J = 7.7 Hz, 2H), 3.91 (t, J = 8.6 Hz, 2H),
3.63 (t, J = 8.6 Hz, 2H), 1.78ꢀ1.68 (m, 2H), 1.48ꢀ1.40 (m, 2H), 1.31ꢀ1.28 (m, 6H), 0.89 (t, J = 6.3
Hz, 3H). 13C NMR (75.5 MHz, CDCl3): δ (ppm) 156.5, 135.4, 129.0, 126.9, 123.4, 118.8, 113.6,
51.2, 47.5, 45.8, 31.7, 29.1, 26.9, 26.4, 22.6, 14.0. HRMSꢀEI: m/z [M]+ for C17H25N3, calculated
271.2048; observed 271.2050.
Reversed Phase Preparative HPLC leading to N,1-dibenzylimidazolidin-2-amine, formate
salt (3a'): To a solution of 2ꢀazidoꢀNꢀbenzylethanamine (1a, 0.71 mmol) in dry toluene (1 mL)
benzyl isocyanate (2a, 0.71 mmol) was added and the resulting reaction mixture was heated at
100 °C (oil bath) for 3 h. After cooling of the reaction mixture to ambient temperature, nꢀBu3P
(0.71 mmol) was added dropwise under argon atmosphere and the reaction mixture was allowed
to stir for 20 min. Thereafter the reaction vial was filled with argon, sealed and heated at 100 °C
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for 20 h. The solvent was evaporated under reduced pressure and the obtained residue was
subjected to reversed phase preparative HPLC (ACN/H2O with 0.1% HCOOH). Evaporation of
solvent finally led to the formation of corresponding formate salt 3a' as a colourless oil (197 mg,
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54
55
56
57
58
59
60
1
yield 89%); H NMR (300 MHz, CDCl3): δ (ppm) 10.43ꢀ9.58 (bs, 1H), 8.44 (s, 1H), 7.33ꢀ7.12
13
(m, 10H), 4.52 (4H, s), 3.45ꢀ3.40 (m, 2H), 3.30ꢀ3.24 (m, 2H). C NMR (75.5 MHz, CDCl3): δ
(ppm) 167.7, 158.2, 136.9, 134.3, 128.9, 128.5, 128.2, 128.0, 127.7, 127.6, 48.8, 47.2, 46.1, 41.0.
HRMSꢀEI: m/z [M]+ for C17H19N3, calculated 265.1579; observed 265.1558.
ACKNOWLEDGEMENTS
The authors wish to thank the FWO [Fund for Scientific Research ꢀ Flanders (Belgium)] and the
Research Fund of the University of Leuven (KU Leuven) for financial support. RK is grateful to
the FWO for obtaining a visiting postdoctoral fellowship and DE for obtaining a postdoctoral
fellowship
.
SUPPORTING INFORMATION
1
13
Copies of H and C NMR spectra of all the synthesized compounds. This material is available
free of charge via the internet at http://pubs.acs.org/.
REFERENCES
(1) For excellent reviews on the chemistry and biology of guanidine derivatives, see: (a)
Berlinck, R. G. S.; TrindadeꢀSilva, A. E.; Santos, M. F. C. Nat. Prod. Rep. 2012, 29, 1382. (b)
Berlinck, R. G. S.; Burtoloso, A. C. B.; TrindadeꢀSilva, A. E.; Romminger, S.; Morais, R. P.;
Bandeira, K.; Mizuno, C. M. Nat. Prod. Rep. 2010, 27, 1871. (c) Berlinck, R. G. S.; Burtoloso,
A. C. B.; Kossuga, M. H. Nat. Prod. Rep. 2008, 25, 919. For an excellent review on biological
activities of guanidine compounds, see: (d) Saczewski, F.; Balewski, L. Expert Opin. Ther. Pat.
2009, 19, 1417.
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1
2
3
4
5
6
7
8
9
(2) (a) Nagle, P. S.; Rodriguez, F.; Nguyen, B.; Wilson, W. D.; Rozas, I. J. Med. Chem. 2012,
55, 4397; (b) Nagle, P. S.; Rodriguez, F.; Kahvedz ić, A.; Quinn, S. J.; Rozas, I. J. Med. Chem.
2009, 52, 7113. (c) Rodriguez, F.; Rozas, I.; Ortega, J. E.; Erdozain, A. M.; Meana, J. J.;
Callado, L. F. J. Med. Chem. 2009, 52, 601. (d) Rodriguez, F.; Rozas, I.; Ortega, J. E.; Meana, J.
J.; Callado, L. F. J. Med. Chem. 2007, 50, 4516. (e) Treder, A. P.; Andruszkiewicz, R.; Zgoda,
W.; Ford, C.; Hudson, A. L. Bioorg. & Med. Chem. Lett. 2009, 19, 1009. (f) Ji, Z.; Wang, M.;
Zhang, J.; Wei, S.; Wu, W. J. Antibiot. 2007, 60, 739.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(3) (a) Kumamoto, T. Superbases for Organic Synthesis: Guanidines, Amidines, Phosphazenes
and Related Organoctalysts, (Ed: Ishikawa, I.), John Wiley & Sons Press: West Sussex, U.K.,
2009, pp. 295ꢀ313. (b) Li, L.; Chen, W.; Yang, W.; Pan, Y.; Liu, H.; Tan, C.ꢀH.; Jiang, Z.
Macromolecules 2012, 45, 2249. (c) Li, L.; Chen, W.; Yang, W.; Pan, Y.; Liu, H.; Tan, C.ꢀH.;
Jiang, Z. Chem. Commun. 2012, 48, 5124. (d) Liu, H.; Leow, D.; Huang, K.ꢀW.; Tan, C.ꢀH. J.
Am. Chem. Soc. 2009, 131, 7212. (e) Corey, E. J.; Michael, G. J. Org. Lett. 1999, 1, 157. For
reviews, see: (f) Best, M. D.; Tobey, S. L.; Anslyn, E. V. Coord. Chem. Rev. 2003, 240, 3. (g)
Blondeau, P.; Segura, M.; PerezꢀFernandez, R.; de Mendoza, J. Chem. Soc. Rev. 2007, 36, 198.
(4) (a) Isobe, T.; Fukuda, K.; Tokunaga, T.; Seki, H.; Yamaguchi, K.; Ishikawa, T. J. Org. Chem.
2000, 65, 7774. (b) Isobe, T.; Fukuda, K.; Ishikawa, T. J. Org. Chem. 2000, 65, 7770.
(5) (a) Baltzer, C. M.; McCarty, C. G. J. Org. Chem. 1973, 38, 155. (b) Yu, Y.; Ostresh, J. M.;
Houghten, R. A. J. Org. Chem. 2002, 67, 3138. (c) Heinelt, U.; Schultheis, D.; Jäger, S.;
Lindenmaier, M.; Pollex, A.; Beckmann, H. S. G. Tetrahedron 2004, 60, 9883. (d) Kitani, Y.;
Kumamoto, T.; Isobe, T.; Fukuda, K.; Ishikawa, T. Adv. Synth. Catal. 2005, 347, 1653. (e) Shen,
H.; Wang, Y.; Xie, Z. Org. Lett. 2011, 13, 4562. (f) Farajollah, M.; Navabe, N.; Sadat, H. S.
Chin. J. Chem. 2011, 29, 1055. (g) O’Donovan, D. H.; Rozas, I. Tetrahedron Lett. 2012, 53,
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2
3
4
4532 and references cited therein.
5
6
7
8
(6) (a) Kim, M.; Mulcahy, J. V.; Espino, C. G.; Du Bois, J. Org. Lett. 2006, 8, 1073. (b)
Tsuchiya, S.; Sunazuka, T.; Hirose, T.; Mori, R.; Tanaka, T.; Iwatsuki, M.; Ohmura, S. Org. Lett.
2006, 8, 5577. (c) Albrecht, C.; Barnes, S.; Bockemeier, H.; Davies, D.; Dennis, M.; Evans, D.
M.; Fletcher, M. D.; Jones, I.; Leitmann, V.; Murphy, P. J.; Rowles, R.; Nash, R.; Stephenson, R.
A.; Horton, P. N.; Hursthouse, M. B. Tetrahedron Lett. 2008, 49, 185.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
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42
43
44
45
46
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48
49
50
51
52
53
54
55
56
57
58
59
60
(7) (a) Zhou, L.; Chen, J.; Zhou, J.; Yeung, Y.ꢀY. Org. Lett. 2011, 13, 5804. (b) Zhao, B.; Du,
H.; Shi, Y. Org. Lett. 2008, 10, 1087. (c) Muñiz, K.; Streuff, J.; Hövelmann, C. H.; Núñez, A.
Angew. Chem. Int. Ed. 2007, 46, 7125. (d) Yamamoto, Y.; Mizuno, H.; Tsuritani, T.; Mase, T.
Tetrahedron Lett. 2009, 50, 5813.
(8) For reviews on Staudinger/azaꢀWittig reaction, see: (a) Palacios, F.; Alonso, C.; Aparicio, D.;
Rubiales, G.; de los Santos, J. M. Tetrahedron 2007, 63, 523. (b) Eguchi, S. ARKIVOC 2005, ii,
98. (c) Loos, P.; Riedricha, M.; Arndt, H.ꢀD. Chem. Commun. 2009, 1900. (d) Attanasi, O. A.;
Bartoccini, S.; Favi, G.; Filippone, P.; Perrulli, F. R.; Santeusanio, S. J. Org. Chem. 2012, 77,
9338. (e) Molina, P.; Vilaplana, M. J. Synthesis, 1994, 1197. (f) Fresneda, P. M.; Molina, P.
Synlett 2004, 1. (g) Fresneda, P. M.; Molina, P.; Delgado, S. Tetrahedron 2001, 57, 6197.
(9) This is the only literature precedent for the synthesis of 2ꢀaminoimidazolidines starting from
β
ꢀamino azides, Nalli, S. M.; Clarkson, G. J.; Franklin, A. S.; Bellone, G.; Shipman, M. Synlett
2008, 2339.
(10) (a) 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. (b) Steenackers, H. P.; Ermolat'ev, D.
S.; 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.
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(11) After completion of the reaction, toluene was evaporated and the crude mixture was
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subjected for H NMR revealing the exclusive formation of 3a along with Bu3P=O as byꢀ
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product. Reaction via Path 1 (Scheme 1) resulted in the formation of some unidentified side
products.
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(12) After reversed phase preparative HPLC we obtained an oily compound with EIꢀMS peak at
265 (same as that of the expected 3a). The peaks at δ 8.44 ppm (IH NMR) and δ 167.7 ppm (13C
& DEPTꢀ135) indicated a HCOO functionality and the compound was confirmed to be the
corresponding formate salt 3a' (for NMR spectra see, supporting information). On the other
hand, without using HCOOH in the eluent, no sharp peak shape of product 3a could be obtained
in the HPLC chromatogram.
(13) For an excellent review on bicyclicꢀguanidines, see: (a) Coles, M. P. Chem. Commun. 2009,
3659. (b) Cotton, F. A.; Murillo, C. A.; Wang, X.; Wilkinson, C. C. Inorg. Chem. 2006, 45,
5493. (c) Bleda, J. A.; Fresneda, P. M.; Orenes, R.; Molina, P. Eur. J. Org. Chem. 2009, 2490.
(14) Demko, Z. P., Sharpless, K. B. Org. Lett. 2001, 3, 4091.
(15) Generally, 2ꢀaminoimidazolidines exist in two tautomeric forms.
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