MCRs reshaped into a switchable microwave-assisted protocol toward 5-aminoimidazoles and dihydrotriazines

Article abstract of DOI:10.1016/j.tet.2013.11.035

A tunable microwave-assisted protocol for the synthesis of two biologically relevant families of heterocycles has been designed. Via a simple switch of reaction conditions, the same starting materials can be engaged in either an improved synthesis of the dihydrotriazine scaffold or a novel, first-in-class MCR to render the challenging 5-aminoimidazole nucleus in a single step. An additional first-in-class MCR is also reported utilizing guanidines to afford 2,5-aminoimidazoles.

Full text of DOI:10.1016/j.tet.2013.11.035

Tetrahedron 70 (2014) 54e59
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
MCRs reshaped into a switchable microwave-assisted protocol
toward 5-aminoimidazoles and dihydrotriazines
,
Christan E. Bell a, Arthur Y. Shaw b, Fabio De Moliner b, Christopher Hulme b
*
a Department of Chemistry and Biochemistry, The University of Arizona, Tucson, AZ 85721, USA
b College of Pharmacy, Department of Pharmacology and Toxicology, BIO5 Oro Valley, 1580 E. Hanley Blvd., The University of Arizona, Oro Valley,
AZ 85737, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A tunable microwave-assisted protocol for the synthesis of two biologically relevant families of het-
erocycles has been designed. Via a simple switch of reaction conditions, the same starting materials can
be engaged in either an improved synthesis of the dihydrotriazine scaffold or a novel, first-in-class MCR
to render the challenging 5-aminoimidazole nucleus in a single step. An additional first-in-class MCR is
also reported utilizing guanidines to afford 2,5-aminoimidazoles.
Received 5 September 2013
Received in revised form 8 November 2013
Accepted 13 November 2013
Available online 20 November 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Imidazole
Multicomponent reaction
Strecker
Trimethylsilyl cyanide
1. Introduction
Multicomponent reactions (MCRs) are a valuable synthetic tool
for the efficient assembly of structurally diverse molecules in one
Imidazoles are one of the most common ring systems in het-
erocyclic chemistry, with a significant amount of scientific litera-
ture covering their preparations, properties, and a broad range of
applications in many different fields. For example, in marine nat-
ural products, imidazoles are common structural motifs that offer
significant synthetic challenges and represent key moieties re-
sponsible for observed biological activities.1 Indeed, the imidazole
ring constitutes a privileged structure in medicinal chemistry and
can be found in a large number of therapeutic agents, such as an-
giotensin II inhibitors, anti-inflammatory, and anticancer agents,
to cite just a few.2 This motif is also commonly employed in ma-
terial science, where it is widely used to generate high
temperature-resistant polymers and liquid crystals.3 In particular,
5-aminoimidazoles exhibit a distinctly attractive utility profile. This
scaffold is found, inter alia, in pharmaceuticals for the treatment of
cancer, HIV, and hepatitis B, with many other applications also re-
ported.4 Consequently, the utility is reflected in the numerous re-
ported syntheses of this nucleus.5 However, lengthy procedures,
poor yields, and access to limited substitution patterns make these
methodologies unsuitable for high-throughput synthesis and li-
brary generation.
synthetic operation6,7 and we were thus attracted by the possibility
of developing new MCR methodology to efficiently synthesize di-
verse arrays of 5-aminoimidazoles. Indeed, the well-known ad-
vantages of MCRs, e.g., high efficiency, generality, and step and
atom economy,8 are ideal to address the limitations of existing
methods to prepare this chemotype.
2. Results and discussion
Initially it was envisioned the most convenient strategy to the 5-
aminoimidazole 6, could feasibly utilize the versatile reactivity of
isonitriles.9 Akin to the GroebkeeBlackburneBienayme (GBB)
ꢀ
condensation10 that render bicyclic systems 4 (Scheme 1), it was
postulated that the replacement of the heterocyclic input 3 with an
amidine 5 would be sufficient to afford the desired chemotype 6.
* Corresponding author. Tel.: þ1 520 626 5322; e-mail addresses: cbell@email.
arizona.edu (C.E. Bell), shaw@pharmacy.arizona.edu (A.Y. Shaw), demoline@phar-
macy.arizona.edu (F. De Moliner), hulme@pharmacy.arizona.edu (C. Hulme).
ꢀ
Scheme 1. GroebkeeBlackburneBienayme MCR.
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.11.035

C.E. Bell et al. / Tetrahedron 70 (2014) 54e59
55
However, after preliminary investigation of acid-catalyzed pro-
motion of this MCR, production of 6 was observed in only nominal
yields <5% (Scheme 1).11
(Table 2, entry 1). Stoichiometry of the reactants was further
studied, and doubling the amount of TMSCN employed (4 equiv)
resulted in a distinct drop in the yield of 12a (entry 2). Conversely,
an analogous increase in benzaldehyde (4 equiv) afforded a satis-
factory 55% yield of 12a (entry 3). Subsequently, various desiccants
were evaluated (entries 4e6), resulting in only slightly lower yields
of 12a.
Subsequently, it was hypothesized that 6 could be synthesized
from aldehydes 2, amidines 5, and a cyanide source 8 (Scheme 2),
somewhat similar to a ‘Strecker variant’ of the GBB MCR where
trimethylsilyl cyanide (TMSCN) proved a fruitful replacement for
classical isonitriles, affording bicyclic structures 4 in good yield
(R1¼H).12 Mechanistically, aldehyde 2 and amidine 5 were expected
to form the corresponding Schiff base 7, which is prone to in-
terception by nucleophilic attack of cyanide 8 in a Strecker-like
fashion.13 Thereafter, intermediate 9 undergoes intramolecular
cyclization to the five-membered ring 10.14 After tautomerization
to free amine 11, and on the basis of prior published reactivity
observations of 4 (R1¼H),15 11 was thought susceptible to further
reaction with a second equivalent of aldehyde 2 to generate 5-
aminoimidazole 12, endowing the final product with a further di-
versity point.
Table 2
Survey of stoichiometry and desiccating agents
Entry
Equiv 2a
Equiv TMSCN
Desiccant
Yield 12a [%]
1
2
3
4
5
6
2
2
4
4
4
4
2
4
2
2
2
2
Na2SO4
Na2SO4
Na2SO4
MgSO4
5 A MS
CaCl2
36
8
55
38
48
51
ꢁ
Thus with an optimized and expeditious route to 12a in place,
which to the best of our knowledge compared favorably to existing
routes, the scope of the process was evaluated. Ten compounds
were prepared (Table 3) from a pool of six aromatic aldehydes and
four aromatic amidines. Note that aliphatic aldehydes proved in-
compatible with this method, the only other reaction failure being
observed with 4-nitrophenylbenzaldehyde (entry 2, 12b). Note that
this was somewhat surprising as based on relative electrophilicity
one would have expected the substrate to be highly reactive. Indeed
the substrate has been reported to react in high yield in TMSCN-
mediated Strecker reactions.22 For the amidine component, aro-
matic inputs were highly compatible, while aliphatic congeners
were not evaluated due to their scarce commercial availability
and lack synthetic accessibility. Of note, benzamidine and 3-
nitrobenzamidine hydrochloride are commercially available, and
other amidines were prepared by means of a reported procedure.23
In summary, the new imidazole-forming MCR is an example of a 3-
component-4-center reaction.
Scheme 2. Proposed mechanism of 5-aminoimidazole 12 formation.
Thus, TMSCN was employed in conjunction with benzaldehyde
2a and benzamidine 5a, coupled with relatively mild microwave
irradiation (Table 1).16,17 Initially, this failed to produce the desired
5-aminoimidazole 12a (Table 1, entries 1 and 2), interestingly
affording the dihydrotriazine 13a as the sole product.18 This finding
was not completely new, as preparation of dihydrotriazines via
similar methodology was reported over 40 years ago.19 Encourag-
ingly, at elevated temperatures (150 ꢀC and 180 ꢀC) 12a was ob-
served in modest yields, although 13a remained the major product.
Nevertheless, this expedited route to 13a was not undesirable, since
the dihydrotriazine core is known to display antiparasitic and an-
timicrobial activity.20
Table 3
Exploration of the reactivity domain
Table 1
Original MCR protocol to 12a and 13a
Entry
R1
R2
Yield 12 [%]
1
2
3
4
5
6
7
8
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
3-Nitrophenyl
3-Nitrophenyl
4-Methoxyphenyl
4-Methoxyphenyl
4-Chlorophenyl
4-Chlorophenyl
4-Chlorophenyl
12a, 55
12b, 0
4-Nitrophenyl
4-Bromophenyl
4-Methoxyphenyl
Phenyl
4-Methoxyphenyl
Phenyl
3-Thiophene
4-Bromophenyl
2-Methylphenyl
3-Fluorophenyl
Entry
Temp [ꢀC]
Yield 12a
Yield 13a [%]
12c, 69
12d, 55
12e, 26
12f, 47
12g, 55
12h, 61
12i, 57
12j, 68
12k, 66
1
2
3
4
50
100
150
180
0
0
20
25
53
52
36
31
9
10
11
Having developed an efficient single-step MCR that simulta-
neously generates two medicinally relevant scaffolds, the task of
identifying conditions capable of enabling complete control over
what appeared to be two distinct chemical pathways was un-
dertaken. Sodium sulfate has been previously used to facilitate
Strecker-type reactions,21 and interestingly when added to the re-
action, an improvement in 5-aminoimidazole 12a yield (36%) was
seen with complete suppression of dihydrotriazine 13a formation
Post-condensation modification of MCR adducts is a useful
strategy to enhance diversity,6b,24 and the imino group embedded
in 12 clearly offers functionalization opportunities. Simple hydro-
lysis of 12a under acidic conditions affords the 5-aminoimidazole
14 in 87% yield (Scheme 3).25

56
C.E. Bell et al. / Tetrahedron 70 (2014) 54e59
Table 6
Small library of dihydrotriazines
Scheme 3. Hydrolysis of 5-iminoimidazoles.
Entry
R1
Phenyl
2-Phenylethyl
2,3-Dimethoxyphenyl
4-Nitrophenyl
Cyclopropyl
3-Hydroxyphenyl
2-Methylphenyl
R2
Yield 13 [%]
1
Phenyl
Phenyl
Phenyl
Phenyl
3-Nitrophenyl
4-Methoxyphenyl
4-Chlorophenyl
13a, 73
13b, 56
13c, 89
13d, 0
13e, 61
13f, 88
13g, 51
Interestingly, a second new MCR, a 3-component-5-center re-
2
3
4
5
6
7
action, was also developed from guanidine 15 using the conditions
employed for the one-pot formation of 12. As such, exposure of
guanidine to aldehyde, TMSCN, and desiccant, with concomitant
microwave irradiation, delivered the 2,5-diaminoimidazole 16 in
one pot, with yields ranging from 30% to 39% (entries 1e4, Table 4).
The 2,5-diaminoimidazole core is another member of the imidazole
family found in biologically active compounds.26
3. Conclusions
Methodology is described herein leading to three chemotypes,
namely 5-aminoimidazoles, 2,5-aminoimidazoles, and dihydro-
triazines. By altering reaction conditions, either scaffold can be
exclusively obtained from the same amidine and aldehyde starting
materials. Overall, a novel, first-in-class, 3-component-4-center
MCR from reaction of aldehydes, amidines, and TMSCN has been
established, enabling an operationally friendly new portal to the 5-
aminoimidazole core. An extension introduces a first-in-class, 3-
component-5-center MCR affording 2,5-diaminoimidazoles from
guanidine 15. This new efficient protocol strategically positions
a versatile imino group offering functionalization opportunities,
exemplified by the preparation of 12. Alternatively, the dihydro-
triazine moiety 13 can be accessed in the absence of TMSCN. Op-
portunities also exist for design of additional secondary
modifications with subsequent biological evaluation of new prod-
ucts.28 Supplementary data containing all 1H and 13C spectra, ad-
ditional optimization tables, and crystal structures of 13a and 13b
are available online.
Table 4
Small collection of 2,5-diaminoimidazoles
Entry
R
Yield 16 [%]
1
2
3
4
Phenyl
16a, 39
16b, 30
16c, 35
16d, 37
3-Fluorophenyl
3-(Trifluoromethyl)-phenyl
3-Thiophene
With protocols in-hand favoring the exclusive formation of the
imidazole core, switching pathways to deliver dihydrotriazines 13
was achieved by removal of TMSCN from the reaction. Interestingly,
Zavatskii et al. conducted only nominal studies on the scope of this
reaction (Table 5) and MAOS (microwave-assisted organic synthe-
sis) was not available in 1969.19 Thus, irradiation at 100 ꢀC (40 min)
was determined to be optimal for formation of 13a (entry 3, Table 5,
73%). Additional irradiation (w60 min) resulted in negligible im-
provements in yield with enhanced side-product formation, ne-
gating the slight yield advantage (entry 4). The methodology also
proved optimal in polar aprotic solvents such as DMF and DMSO
(entries 1e5), while the polar protic solvent iso-propanol afforded
reduced yields (57%, entry 6).
4. Experimental section
4.1. General
1H and 13C NMR were recorded on a Varian 400 spectrometer at
400 and 100 MHz, respectively. 1H NMR and 13C NMR data are
reported as follows: chemical shift in parts per million (ppm) (d),
multiplicity (s¼singlet, d¼doublet, t¼triplet, m¼multiplet). Cou-
pling constants are measured in Hertz (Hz). HPLCeMS analyses
were performed on a Shimadzu-2020 LCeMS instrument using the
following conditions: Restek Ultra C18 column (reverse phase,
Table 5
Dihydrotriazine synthesis optimization
3
mm, 50ꢁ2.1 mm); a linear gradient from 10% water and 90%
acetonitrile to 95% acetonitrile and 5% water over 4.0 min; flow
rate of 1 mL/min; UV photodiode array detection from 200 to
300 nm. High-resolution mass spectra (HRMS) were acquired with
a 9.4 T Bruker FT/ICR-MS instrument. Melting points were mea-
sured on an MEL-TEMP II apparatus in an open glass capillary tube
and are uncorrected. The products were purified either by Tele-
dyne Isco CombiFlash Rf and n-hexane/EtOAc solvent systems or
by HPLC system (reverse phase) using the conditions mentioned
above. All reagents and solvents were obtained from commercial
sources and used without further purification. All microwave ir-
radiation experiments were carried out in a CEM-Discover SP-D
microwave apparatus, operating at a frequency of 2.45 GHz with
continuous irradiation power from 0 to 300 W with utilization of
the standard absorbance level of 220 W maximum power. The
reactions were carried out in 10 mL glass tubes, sealed with Teflon
septum and placed in the microwave cavity. The reaction was ir-
radiated at a required ceiling temperature using maximum power
Entry
Solvent
Temp [ꢀC]
t [min]
Yield 13a [%]
1
2
3
4
5
6
7
DMF
DMF
DMF
DMF
DMSO
i-PrOH
Toluene
50
100
100
100
100
100
100
20
20
40
60
40
40
40
48
64
73
75
68
57
19
The preparation of dihydrotriazines (13ae13g, Table 6) high-
lights the range of inputs that may be used in this MCR. Note that X-
ray structural assignment of 13b unambiguously confirmed the
observed substitution pattern.27 In summary, the microwave-
assisted protocol proved more general and efficient than earlier
published routes.19

C.E. Bell et al. / Tetrahedron 70 (2014) 54e59
57
for the stipulated time. Then it was cooled to rt with gas jet
cooling.
obtained (101 mg, 47% yield). Rf¼0.68 (silica gel, 1:1 hexanes/
EtOAc); 1H NMR (400 MHz, DMSO-d6)
12.79 (br, s, 1H), 9.16 (br, s,
d
1H), 8.97 (s, 1H), 8.53 (d, J¼7.9 Hz, 1H), 8.18e8.25 (m, 1H), 8.14 (d,
J¼8.1 Hz, 2H), 7.94 (d, J¼8.3 Hz, 2H), 7.78 (t, J¼8.0 Hz,1H), 7.23e6.96
(m, 4H), 3.80 (s, 3H), 3.85 (s, 3H); 13C NMR (100 MHz, DMSO-d6)
4.2. General procedure for the synthesis of scaffold 12, ex-
emplified for 12a
d
161.9, 158.9, 155.2, 148.8, 144.9, 141.7, 132.2, 131.9, 130.8, 130.4,
In a sealed vessel, benzamidine (60 mg, 0.5 mmol) and sodium
sulfate (284 mg, 2 mmol) were dissolved in 2.5 mL anhydrous
130.1, 128.6, 126.0, 123.2, 122.8, 120.0, 114.8, 114.5, 55.8, 55.6;
[MþH]þ¼429; HRMS: m/z calculated for C24H21N4O4 [MþH]þ:
429.1485; found 429.1486.
DMF. Benzaldehyde (204
mL, 2 mmol) and TMSCN (133 mL,
1 mmol) were then added. The solution was microwave irradiated
at 150 ꢀC for 10 min. The solvent was removed in vacuo, and the
crude product was purified by column chromatography employ-
ing either a Teledyne Isco chromatographic system (Hex/EtOAc)
or an HPLC purification system (reverse phase, water/acetoni-
trile). Note: when compounds of generic structure 12 were pu-
rified by HPLC, acetonitrile traces were sometimes observed in
the 1H NMR spectra (s, 2.10 ppm) and could not be removed de-
spite prolonged rotary evaporation and oven-drying under
vacuum.
4.2.6. N-Benzylidene-2-(4-methoxyphenyl)-4-phenyl-1H-imidazol-
5-amine (12g). An orange oil was obtained (97 mg, 55% yield).
Rf¼0.19 (silica gel, 4:1 hexanes/EtOAc); 1H NMR (400 MHz,
DMSO-d6)
d
12.43 (br, s, 1H), 9.19 (br, s, 1H), 8.17 (d, J¼7.4 Hz, 2H),
8.06 (d, J¼8.4 Hz, 2H), 7.96 (d, J¼6.9 Hz, 2H), 7.56e7.43 (m,
5H), 7.28 (t, J¼7.4 Hz, 1H), 7.06 (d, J¼8.5 Hz, 2H), 3.82 (s, 3H); 13C
NMR (100 MHz, DMSO-d6)
d 160.3, 155.1, 145.0, 137.3, 131.0,
129.3, 128.9, 128.6, 127.7, 127.1, 123.2, 114.6, 55.7; [MþH]þ¼354;
HRMS: m/z calculated for C23H20N3O [MþH]þ: 354.1528; found
354.1530.
4.2.1. N-Benzylidene-2,4-diphenyl-1H-imidazol-5-amine
(12a). A
yellow powder was obtained (89 mg, 55% yield). Mp 224e225 ꢀC;
Rf¼0.43 (silica gel, 7:3 hexanes/EtOAc); 1H NMR (400 MHz, DMSO-
4.2.7. 2-(4-Methoxyphenyl)-4-(thiophen-2-yl)-N-(thiophen-2-
ylmethylene)-1H-imidazol-5-amine (12h). A yellow solid was ob-
tained (112 mg, 61% yield). Mp 118e120 ꢀC; Rf¼0.15 (silica gel, 4:1
d6)
d
12.60 (s, 1H), 9.24 (s, 1H), 8.19 (d, J¼7.7 Hz, 2H), 8.14 (d,
J¼7.8 Hz, 2H), 7.99 (d, J¼6.9 Hz, 2H), 7.51 (m, 7H), 7.42 (t, J¼7.3 Hz,
hexanes/EtOAc); 1H NMR (400 MHz, DMSO-d6)
d 12.50 (br, s, 1H),
1H), 7.32 (t, J¼7.3 Hz, 1H); 13C NMR (100 MHz, DMSO-d6)
d
154.5,
9.18 (br, s, 1H), 8.00 (d, J¼7.7 Hz, 2H), 7.77e7.46 (m, 4H), 7.22e7.15
144.9, 144.8, 135.9, 131.9, 131.4, 130.2, 129.8, 129.0, 128.9, 128.7,
128.6, 125.7, 124.6, 124.1, 120.0; [MþH]þ¼324; HRMS: m/z calcu-
lated for C23H18N4 [MþH]þ: 324.1422; found 324.1421.
(m, 1H), 7.15e7.09 (m, 1H), 7.09e7.03 (m, 2H), 3.81 (s, 3H); 13C NMR
(100 MHz, DMSO-d6)
d 160.4, 147.8, 145.1, 144.3, 143.8, 132.5, 131.7,
130.7, 128.8, 127.6, 127.4, 123.8, 123.0, 122.0, 114.6, 110.0, 55.8;
[MþH]þ¼366; HRMS: m/z calculated for C19H16N3OS2 [MþH]þ:
366.0657; found 366. 0657.
4.2.2. N-(4-Bromobenzylidene)-4-(4-bromophenyl)-2-phenyl-1H-
imidazol-5-amine (12c). A yellow solid was obtained (167 mg, 69%
yield). Mp 102e110 ꢀC; Rf¼0.35 (silica gel, 4:1 hexanes/EtOAc); 1H
4.2.8. N-(4-Bromobenzylidene)-4-(4-bromophenyl)-2-(4-
chlorophenyl)-1H-imidazol-5-amine (12i). An orange oil was ob-
tained (287 mg, 57% yield). Rf¼0.36 (silica gel, 4:1 hexanes/
NMR (400 MHz, DMSO-d6) d 12.68 (br, s, 1H), 9.15 (br, s, 1H), 8.13 (d,
J¼9.2 Hz, 2H) 8.11 (d, J¼9.2 Hz, 2H), 7.92 (d, J¼8.0 Hz, 2H), 7.70 (d,
J¼8.1 Hz, 2H), 7.68 (d, J¼8.1 Hz, 2H), 7.50 (d, J¼7.6 Hz, 2H), 7.42 (t,
J¼7.3 Hz, 1H); 13C NMR (100 MHz, DMSO-d6) 154.5, 144.9, 144.8,
135.9, 131.9, 131.4, 130.2, 129.8, 129.0, 128.9, 128.7, 128.6, 125.7,
124.6, 124.2, 120.0; [MþH]þ¼482; HRMS: m/z calculated for
EtOAc); 1H NMR (400 MHz, DMSO-d6)
d 12.76 (br, s, 1H), 9.15
(br, s, 1H), 8.26e8.04 (m, 4H), 7.87e8.00 (m, 2H), 7.65e7.82 (m,
4H), 7.65e7.53 (m, 2H); 13C (100 MHz, DMSO-d6)
d
155.1,
144.2, 136.2, 133.9, 132.4, 131.9, 130.6, 129.3, 129.2, 129.1,
C
22H16Br2N3 [MþH]þ: 479.9633; found 479.9638, 481.9634, and
127.8, 124.8, 120.6; [MþH]þ¼516; HRMS: m/z calculated for
483.9635.
C
22H15Br2ClN3 [MþH]þ: 513.9243; found 513.9242, 515.9245, and
517.9245.
4.2.3. N-(4-Methoxybenzylidene)-4-(4-methoxyphenyl)-2-phenyl-
1H-imidazol-5-amine (12d). A dark orange viscous oil was obtained
(106 mg, 55% yield). Rf¼0.35 (silica gel, 4:1 hexanes/EtOAc); 1H
4.2.9. 2-(4-Chlorophenyl)-N-(2-methylbenzylidene)-4-(o-tolyl)-1H-
imidazol-5-amine (12j). A yellow solid was obtained (131 mg, 68%
yield). Mp 197e199 ꢀC; Rf¼0.54 (silica gel, 4:1 hexanes/EtOAc);
NMR (400 MHz, DMSO-d6)
d 12.42 (s, 1H), 9.14 (s, 1H), 8.13 (d,
J¼8.6 Hz, 2H), 8.11 (d, J¼8.6 Hz, 2H), 7.92 (d, J¼8.4 Hz, 2H), 7.49 (t,
1H NMR (400 MHz, DMSO-d6)
d 12.78 (br, s, 1H), 9.42 (br, s, 1H),
J¼7.5 Hz, 2H), 7.39 (t, J¼7.3 Hz, 1H), 7.13e7.03 (m, 4H), 3.84 (s, 3H),
8.08 (m, 2H), 7.87 (d, J¼7.9 Hz, 1H), 7.63e7.51 (m, 2H),
3.82 (s, 3H); 13C NMR (100 MHz, DMSO-d6)
d 161.7, 158.7, 154.5,
7.45 (d, J¼6.7 Hz, 1H), 7.41e7.15 (m, 6H), 2.54 (s, 3H), 2.39
144.5, 144.0, 130.7, 130.3, 129.1, 128.9, 128.4, 125.9, 125.1, 123.2,
(s, 3H); 13C (100 MHz, DMSO-d6)
d 152.9, 145.2, 142.9,
114.8, 114.4, 55.8, 55.6; [MþH]þ¼384; HRMS: m/z calculated for
137.9, 136.9, 134.4, 133.0, 131.0, 130.3, 130.1, 129.6, 129.2, 128.8,
C
24H22N3O2 [MþH]þ: 384.1634; found 384.1637.
128.2, 126.9, 126.7, 126.1, 125.4, 20.4, 19.1; [MþH]þ¼386; HRMS:
m/z calculated for
386.1345.
C
24H21ClN3 [MþH]þ: 386.1346; found
4.2.4. N-Benzylidene-2-(3-nitrophenyl)-4-phenyl-1H-imidazol-5-
amine (12e). An orange solid was obtained (48 mg, 26% yield). Mp
240e241 ꢀC; Rf¼0.40 (silica gel, 4:1 hexanes/EtOAc); 1H NMR
4.2.10. 2-(4-Chlorophenyl)-N-(3-fluorobenzylidene)-4-(3-
fluorophenyl)-1H-imidazol-5-amine (12k). A yellow solid was ob-
tained (130 mg, 66% yield). Mp 78e79 ꢀC; Rf¼0.50 (silica gel, 4:1
(400 MHz, DMSO-d6) d 12.97 (br, s, 1H), 9.23 (br, s, 1H), 9.00 (s, 1H),
8.56 (d, J¼7.9 Hz, 1H), 8.27e8.14 (m, 3H), 7.99 (d, J¼7.2 Hz, 2H), 7.80
(t, J¼8.0 Hz, 1H), 7.63e7.44 (m, J¼6.7 Hz, 5H), 7.33 (t, J¼7.3 Hz, 1H);
hexanes/EtOAc); 1H NMR (400 MHz, DMSO-d6)
d 12.75 (br, s, 1H),
13C NMR (100 MHz, DMSO-d6)
d
156.4, 148.8, 142.6, 137.1, 132.1,
9.21 (br, s, 1H), 8.13 (d, J¼8.5 Hz, 2H), 8.09e7.96 (m, 2H), 7.82 (d,
131.3, 130.9, 129.4, 129.0, 128.8, 127.6, 127.3, 123.5, 120.2;
[MþH]þ¼369; HRMS: m/z calculated for C22H17N4O2 [MþH]þ:
369.1273; found 369.1270.
J¼7.6 Hz, 1H), 7.75 (d, J¼9.5 Hz, 1H), 7.64e7.48 (m, 4H), 7.34 (t,
J¼8.7 Hz,1H), 7.14 (t, J¼8.9 Hz,1H); 13C (100 MHz, DMSO-d6)
d 163.6
(d, J¼25.0 Hz), 161.2 (d, J¼23 Hz), 154.8, 143.8, 137.9 (d, J¼7.6 Hz),
133.4, 129.8 (d, J¼8.0 Hz), 129.4 (d, J¼8.5 Hz), 127.7, 127.5, 126.3,
123.5 (d, J¼2.9 Hz), 121.6 (d, J¼2.9 Hz), 116.5 (d, J¼21.7 Hz), 112.8 (d,
J¼21.7 Hz), 112.4 (d, J¼21.0 Hz), 111.8 (d, J¼23.4 Hz); [MþH]þ¼394;
4.2.5. N-(4-Methoxybenzylidene)-4-(4-methoxyphenyl)-2-(3-
nitrophenyl)-1H-imidazol-5-amine (12f). An orange viscous oil was

58
C.E. Bell et al. / Tetrahedron 70 (2014) 54e59
HRMS: m/z calculated for C22H15ClF2N3 [MþH]þ: 394.0844; found
123.8 (m), 123.5 (m), 123.4, 123.1, 123.0; [MþH]þ¼555; HRMS: m/z
calculated for C26H16F9N4 [MþH]þ: 555.1153; found 555.1149.
394.0846.
4.3. Synthesis of 2,4-diphenyl-1H-imidazol-5-ammonium
chloride 14
4.4.4. 4-(Thiophen-2-yl)-N2,N5-bis(thiophen-2-ylmethylene)-1H-im-
idazole-2,5-diamine (16d). A red foam was obtained (68 mg, 37%).
Rf¼0.17 (silica gel, 8:2 hexanes/EtOAc); 1H NMR (400 MHz, DMSO-
Imidazole 12a (103 mg, 0.319 mmol) was dissolved in 5 mL
EtOAc. Therefore, 10 drops of concentrated HCl were added to the
solution, and a yellow precipitate was immediately observed. The
reaction mixture was heated at 50 ꢀC in an oil bath for 4 h and then
cooled to room temperature. The precipitate was collected on
a fritted filter and washed with DCM. A yellow powder was ob-
tained (75 mg, 87% yield). Mp 180 ꢀC; 1H NMR (400 MHz, DMSO-
d6) d 12.99 (br, s, 1H), 9.34 (s, 1H), 9.11 (br, s, 1H), 8.06e7.81 (m,
2H), 7.79e7.71 (m, 1H), 7.65 (br, s, 1H), 7.54 (br, s, 2H), 7.27 (dd,
J¼8.6, 4.9 Hz, 1H), 7.19 (dd, J¼8.6, 4.9 Hz, 1H), 7.08 (dd, J¼8.6,
4.9 Hz, 1H); 13C (100 MHz, DMSO-d6)
d 154.7, 149.2, 148.1, 144.1,
142.2, 136.2, 132.9, 132.7, 131.1, 129.3, 128.9, 127.5, 123.7;
[MþH]þ¼369; HRMS: m/z calculated for C17H13N4S3 [MþH]þ:
369.0224; found 369.0222.
d6)
d
8.06 (d, J¼7.7 Hz, 2H), 7.72 (d, J¼7.8 Hz, 2H), 7.52 (m, 5H), 7.30
(t, J¼7.4 Hz, 1H); 13C (100 MHz, DMSO-d6)
d
138.3, 136.9, 130.9,
4.5. General procedure for the synthesis of 13, exemplified for
13a
129.6, 129.2, 129.0, 127.1, 126.4, 126.1, 125.1, 112.6; [MþH]þ¼236;
HRMS: m/z calculated for C15H14N3 [MþH]þ: 236.1822; found
236.1821.
In a sealed vessel, benzamidine (120 mg, 1 mmol) and benzal-
dehyde (101 mL, 1 mmol) were dissolved in 1.5 mL anhydrous DMF.
4.4. General procedure for the synthesis of 16, exemplified for
16a
The solution was microwave irradiated at 100 ꢀC for 40 min.
The solvent was removed in vacuo, and the crude product was
purified by column chromatography employing a Teledyne Isco
chromatographic system (Hex/EtOAc). Note: Notwithstanding
multiple attempts to remove them by chromatographic techniques,
recrystallization from different solvents and scavenging, small
traces of the starting aldehydes were sometimes detectable in the
final compounds.
In a sealed vessel, guanidine hydrochloride (48 mg, 0.5 mmol)
and sodium sulfate (284 mg, 2 mmol) were suspended in 2.5 mL
anhydrous DMF. Benzaldehyde (408
m
L, 2 mmol) and TMSCN
(133
m
L, 1 mmol) were added, and the solution was microwave
irradiated at 150 ꢀC for 10 min. The solvent was removed in
vacuo, and the crude product was purified by column chroma-
tography employing a Teledyne Isco chromatographic system
(Hex/EtOAc).
4.5.1. 2,4,6-Triphenyl-1,2-dihydro-1,3,5-triazine
(13a). A white
crystalline solid was obtained (110 mg, 71% yield). Rf¼0.41 (silica
gel, 1:1 hexanes/EtOAc); mp 177e178 ꢀC; 1H NMR (400 MHz,
4.4.1. N2,N5-Dibenzylidene-4-phenyl-1H-imidazole-2,5-diamine
DMSO-d6)
d
9.17 (br, s, 1H), 8.16 (br, s, 4H), 7.58e7.15 (m, 11H), 6.10
160.0,159.2,144.5,138.0,
(16a). A yellow oil was obtained (68 mg, 39% yield). Rf¼0.79 (silica
(br, s,1H); 13C NMR (100 MHz, DMSO-d6)
d
gel, 4:1 hexanes/EtOAc); 1H NMR (400 MHz, DMSO-d6)
d
12.93 (br,
133.5, 132.6, 130.5, 129.0, 128.7, 128.5, 128.4, 127.9, 127.2, 126.6,
68.8; [MþH]þ¼312; HRMS: m/z calculated for C21H18N3 [MþH]þ:
312.1422; found 312.1422.
s, 1H), 9.29 (s, 1H), 9.16 (br, s, 1H), 8.20 (d, J¼7.5 Hz, 2H), 8.07e8.00
(m, 2H), 7.98 (d, J¼6.7 Hz, 2H), 7.64e7.40 (m, 8H), 7.28 (t, J¼7.4 Hz,
1H); 13C (100 MHz, DMSO-d6)
d 161.6, 149.5, 137.2, 136.0, 132.6,
131.2, 129.5, 129.5, 129.4, 129.0, 128.7, 127.2, 126.8; [MþH]þ¼351;
HRMS: m/z calculated for C23H19N4 [MþH]þ: 351.1531; found
351.1533.
4.5.2. 2-Phenethyl-4,6-diphenyl-1,2-dihydro-1,3,5-triazine (13b). A
white crystalline solid was obtained (95 mg, 56% yield). Rf¼0.39
(silica gel, 1:1 hexanes/EtOAc); mp 155e156 ꢀC; 1H NMR (400 MHz,
DMSO-d6)
d
8.27 (br, s, 1H), 8.13 (d, J¼7.1 Hz, 4H), 7.56e7.42 (m, 6H),
4.4.2. N2,N5-Bis(3-fluorobenzylidene)-4-(3-fluorophenyl)-1H-imid-
azole-2,5-diamine (16b). An orange viscous oil was obtained
(60 mg, 30% yield). Rf¼0.68 (silica gel, 8:2 hexanes/EtOAc); 1H
7.33e7.21 (m, 4H), 7.21e7.08 (m, 1H), 5.13 (t, J¼5.5 Hz, 1H),
2.89e2.76 (m, 2H), 2.15e2.00 (m, 2H); 13C NMR (100 MHz, DMSO-
d6)
d 160.5, 159.28, 141.8, 133.3, 132.0, 129.8, 128.4, 128.3, 127.8,
NMR (400 MHz, DMSO-d6)
d
13.07 (br, s, 1H), 9.21 (s, 1H), 9.06 (s,
127.5, 127.4, 125.7, 109.3, 68.7, 66.2, 29.5; [MþH]þ¼340; HRMS: m/z
1H), 7.96 (m, 2H), 7.82 (d, J¼7.8 Hz, 1H), 7.74 (m, 2H), 7.68 (d,
calculated for C23H22N3 [MþH]þ: 340.1735; found 340.1734.
J¼9.9 Hz, 1H), 7.60e7.41 (m, 3H), 7.37 (m, 1H), 7.29 (m, 1H),
7.10e7.00 (m, 1H); 13C NMR (100 MHz, DMSO-d6)
d
164.1 (d,
4.5.3. 2-(2,3-Dimethoxyphenyl)-4,6-diphenyl-1,2-dihydro-1,3,5-
triazine (13c). A white crystalline solid was obtained (166 mg, 89%
yield). Rf¼0.42 (silica gel, 1:1 hexanes/EtOAc); mp 170e171 ꢀC; 1H
J¼11.5 Hz), 164.0, 161.8 (d, J¼12.3), 161.6, 160.9, 155.3, 149.4, 139.5
(d, J¼7.3 Hz), 138.3 (d, J¼7.5 Hz), 131.6 (d, J¼8.6), 131.5 (d,
J¼8.8 Hz), 131.1 (d, J¼8.8 Hz), 125.9 (d, J¼3.0 Hz), 125.2 (d,
J¼2.5 Hz), 122.9, 119.5 (d, J¼22.0 Hz), 118.2 (d, J¼22.0 Hz), 115.2 (d,
J¼23.0 Hz), 114.4 (d, J¼22.0 Hz), 113.9 (d, J¼22.0 Hz), 113.2 (d,
J¼22.5 Hz); [MþH]þ¼405; HRMS: m/z calculated for C23H16F3N4
[MþH]þ: 405.1249; found 405.1251.
NMR (400 MHz, DMSO-d6) d 8.85 (s, 1H), 8.26e8.18 (m, 2H), 8.11 (d,
J¼6.7 Hz, 2H), 7.70e7.33 (m, 6H), 7.15e6.88 (m, 3H), 6.47 (s, 1H),
3.88 (s, 3H), 3.82 (s, 3H); 13C NMR (100 MHz, DMSO-d6)
d
160.4,
158.8, 153.0, 146.0, 138.1, 137.9, 132.5, 130.4, 128.9, 128.7, 128.3,
127.8, 127.7, 124.6, 119.6, 113.0, 64.8, 61.4, 56.3; [MþH]þ¼372;
HRMS: m/z calculated for C23H22N3O2 [MþH]þ: 372.1634; found
372.1637.
4.4.3. N2,N5-Bis(3-(trifluoromethyl)benzylidene)-4-(3-(tri-
fluoromethyl)phenyl)-1H-imidazole-2,5-diamine (16c). An orange
viscous oil was obtained (97 mg, 35% yield). Rf¼0.36 (silica gel, 8:2
4.5.4. 2-Cyclopropyl-4,6-bis(3-nitrophenyl)-1,2-dihydro-1,3,5-
triazine (13e). A yellow solid was obtained (112 mg, 61% yield).
Rf¼0.42 (silica gel, 1:1 hexanes/EtOAc); mp 154e155 ꢀC; 1H NMR
hexanes/EtOAc); 1H NMR (400 MHz, DMSO-d6)
d 13.24 (br, s, 1H),
9.31 (s, 1H), 9.13 (s, 1H), 8.75 (s, 1H), 8.31 (s, 1H), 8.27 (m, 2H), 8.22
(d, J¼7.7 Hz,1H), 8.12 (d, J¼7.6 Hz,1H), 7.87 (d, J¼7.7 Hz,1H), 7.79 (d,
J¼7.8 Hz, 1H), 7.77e7.67 (m, 2H), 7.63 (t, J¼7.8 Hz, 1H), 7.56 (d,
(400 MHz, DMSO-d6)
d
9.23 (br, s,1H), 8.90 (s, 2H), 8.57 (d, J¼7.8 Hz,
2H), 8.38 (d, J¼7.9 Hz, 2H), 7.80 (t, J¼7.9 Hz, 2H), 4.80 (d, J¼6.7 Hz,
J¼7.8 Hz, 1H); 13C NMR (100 MHz, DMSO-d6)
d 160.7, 154.9, 149.6,
137.9, 136.7, 133.6, 133.29, 130.8, 130.7, 130.5, 130.4, 130.2, 130.1,
130.1, 129.7 (m), 128.8 (m), 127.6 (m), 126.1, 125.8, 125.8, 125.1 (m),
1H), 1.43e1.22 (m, 1H), 0.57e0.49 (m, 4H); 13C NMR (100 MHz,
DMSO-d6) d 181.5, 168.4, 148.2, 147.8, 136.6, 134.5, 133.6, 130.7,
130.0, 127.9, 125.7, 122.6, 121.8, 70.1, 17.8, 12.5, 1.5; [MþH]þ¼366;

C.E. Bell et al. / Tetrahedron 70 (2014) 54e59
59
HRMS: m/z calculated for C18H16N5O4 [MþH]þ: 366.1124; found
Morris, L.; Taylor, D. Science 2010, 329, 1168; (d) Kondaskar, A.; Kondaskar, S.;
Kumar, R.; Fishbein, J. C.; Muvarak, N.; Lapidus, R. G.; Sadowska, M.; Edelman,
M. J.; Bol, G. M.; Vesuna, F.; Hosmane, R. S. ACS Med. Chem. Lett. 2011, 2, 252; (e)
Nguyen-Ba, N.; Lee, N.; Chan, L.; Zacharie, B. Bioorg. Med. Chem. Lett. 2000, 10,
2223.
5. (a) Imidazole and Benzimidazole Synthesis; Grimmett, R. M., Ed.; Academic:
London, UK, 1997; (b) Shealy, Y. F. J. Pharm. Sci. 1970, 59, 1533; (c) Barrans, J. J.
Compt. Rend. Soc. Biol. 1964, 258, 6185; (d) Mutha, S. C.; Ketcham, R. J. Org. Chem.
1969, 34, 3661; (e) McLaughlin, M.; Mohareb, R. M.; Rapoport, H. J. Org. Chem.
2003, 68, 50.
366.1127.
4.5.5. 3-(4,6-Bis(4-methoxyphenyl)-1,2-dihydro-1,3,5-triazin-2-yl)
phenol (13f). A white solid was obtained (171 mg, 88% yield).
Rf¼0.14 (silica gel, EtOAc); mp 207e209 ꢀC; 1H NMR (400 MHz,
DMSO-d6)
d 9.39 (br, s, 1H), 8.25e7.98 (m, 4H), 7.24e7.09 (m, 2H),
7.05e6.99 (m, 4H), 6.92e6.86 (m, 2H), 6.68 (d, J¼8.0 Hz,1H), 6.04 (s,
6. (a) Ruijter, E.; Scheffelaar, R.; Orru, R. V. A. Angew. Chem. 2011, 123, 6358; Angew.
Chem., Int. Ed. 2011, 50, 6234; (b) Hulme, C.; Gore, V. Curr. Med. Chem. 2003, 10,
1H), 3.84e3.80 (m, 6H); 13C NMR (100 MHz, DMSO-d6)
d
163.5,
€
162.1,157.9,146.2,129.8,129.7,117.3,115.2,114.0,113.6, 55.81, 55.78;
[MþH]þ¼388; HRMS: m/z calculated for C23H22N4 [MþH]þ:
388.1583; found 388.1581.
51; (c) Balkenhohl, F.; von dem Bussche-Hunnefeld, C.; Lansky, A.; Zechel, C.
Angew. Chem. 1996, 108, 2436; Angew. Chem., Int. Ed. 1996, 35, 2288.
7. (a) Xu, Z.; De Moliner, F.; Cappelli, A. P.; Hulme, C. Angew. Chem. 2012, 124, 8161;
Angew. Chem., Int. Ed. 2012, 51, 8037; (b) Gunawan, S.; Ayaz, M.; De Moliner, F.;
Frett, B.; Kaiser, C.; Patrick, N.; Xu, Z.; Hulme, C. Tetrahedron 2012, 68, 5606; (c)
Gunawan, S.; Petit, J.; Hulme, C. ACS Comb. Sci. 2012, 14, 160; (d) De Moliner, F.;
Hulme, C. Org. Lett. 2012, 14, 1354.
4.5.6. 4,6-Bis(4-chlorophenyl)-2-(o-tolyl)-1,2-dihydro-1,3,5-triazine
(13g). A white solid was obtained (100 mg, 51% yield). Rf¼0.87
(silica gel, 1:1 hexanes/EtOAc); mp 188e189 ꢀC; 1H NMR (400 MHz,
€
€
8. (a) Domling, A. Chem. Rev. 2006, 106, 17; (b) Domling, A.; Wang, W.; Wang, K.
Chem. Rev. 2012, 112, 3083.
9. Ayaz, M.; De Moliner, F.; Dietrich, J.; Hulme, C. In Evolution of Isocyanide
Chemistry; Nenajdenko, V., Ed.; Wiley-VCH: Weinheim, Germany, 2012.
10. (a) Groebke, K.; Weber, L.; Mehlin, F. Synlett 1998, 661; (b) Bienayme, H.;
DMSO-d6)
(d, J¼6.8 Hz, 2H), 7.30 (d, J¼6.4 Hz, 1H), 7.21 (br, s, 3H), 6.38 (s, 1H),
2.51 (s, 3H); 13C NMR (100 MHz, DMSO-d6)
159.4, 157.5, 141.0,
137.0, 136.2, 135.2, 134.8, 131.7, 130.6, 129.3, 129.2, 128.6, 127.9,
127.8, 126.5, 126.1, 66.7, 18.8; [MþH]þ¼394; HRMS: m/z calculated
for C22H18Cl2N3 [MþH]þ: 394.0800; found 394.0804.
d
8.99 (s, 1H), 8.18 (br, s, 4H), 7.62 (d, J¼6.7 Hz, 2H), 7.45
ꢀ
d
Bouzid, K. Angew. Chem. 1998, 110, 2349; Angew. Chem., Int. Ed. 1998, 37, 2234;
(c) Blackburn, C.; Guan, B.; Fleming, P.; Shiosaki, K.; Tsai, S. Tetrahedron Lett.
1998, 39, 3635.
11. Note: acetic acid and Sc(OTf)3 were evaluated. During the course of this work,
nanoclay (K10) catalysis was reported Rai, V. K.; Singh, S.; Singh, P.; Yadav, L. S.
Synthesis 2010, 23, 4051.
12. Schwerkoske, J.; Masquelin, T.; Perun, T.; Hulme, C. Tetrahedron Lett. 2005, 46,
8355.
Acknowledgements
13. Strecker, S. Ann. Chem. Pharm. 1850, 23, 360.
14. Baldwin, J. E.; Thomas, R. C.; Kruse, L. I.; Silberman, L. J. Org. Chem. 1977, 42,
The authors thank Dr. Sue Roberts for X-ray analyses and Dr.
David Bishop for proofreading, editing, and preparing the final
version of the text and figures. The National Institute of Health
(NIH) is gratefully acknowledged for funding (P41GM086190).
3846.
15. Masquelin, T.; Bui, H.; Brickley, B.; Stephenson, G.; Schwerkoske, J.; Hulme, C.
Tetrahedron Lett. 2006, 47, 2989.
16. Wang, J.; Liu, X.; Feng, X. Chem. Rev. 2011, 111, 6947.
17. A screen of alternate cyanide sources is included in Experimental section.
18. Unambiguous X-ray structural assignment was achieved for 13a. Crystallo-
graphic data for 13a are available at CCDC 916049.
Supplementary data
19. Cherkasov, V. M.; Kapran, N. A.; Zavatskii, V. N. Chem. Heterocycl. Compd. 1969,
5, 266.
20. (a) Kidwai, M.; Mothsra, P.; Mohan, R.; Biswas, S. Bioorg. Med. Chem. Lett. 2005,
15, 915; (b) Maeda, S.; Kita, T.; Meguro, K. J. Med. Chem. 2009, 52, 597; (c) Ma,
X.; Tan, S.; Khoo, C.; Sim, H.; Chan, L.; Chui, W. Bioorg. Med. Chem. Lett. 2011, 21,
5428.
21. (a) Jarusiewicz, J.; Choe, Y.; Yoo, K. S.; Park, C. P.; Jung, K. W. J. Org. Chem. 2009,
74, 2873; (b) Dave, R. H.; Hosangadi, B. D. Tetrahedron 1999, 55, 11295.
22. Dekamin, M. G.; Mokhtari, Z. Tetrahedron 2012, 3, 922.
23. (a) Dalai, V. N.; Belov, S.; Nizamov, S.; Rauch, K.; Finsinger, D.; de Meijere, A. Eur.
J. Org. Chem. 2006, 2753.
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2013.11.035.
References and notes
1. (a) Seiple, I. B.; Su, S.; Young, I. S.; Nakamura, A.; Yamaguchi, J.; Jørgenson, L.;
€
Rodriguez, R. A.; O’Malley, D. P.; Gaich, T.; Kock, M.; Baran, P. S. J. Am. Chem. Soc.
2011, 133, 14710; (b) Boger, D. L.; Cai, H. Angew. Chem. 1999, 111, 470; Angew.
Chem., Int. Ed. 1999, 38, 448; (c) Baran, P. S.; O’Malley, D. P.; Zografos, A. L.
Angew. Chem. 2004, 116, 2728; Angew. Chem., Int. Ed. 2004, 43, 2674.
24. (a) Sunderhaus, J. D.; Martin, S. F. Chem.dEur. J. 2009, 15, 1300; (b) Basso, A.;
Banfi, L.; Riva, R. Eur. J. Org. Chem. 2010, 1831.
ꢀ
2. (a) Kamijo, S.; Yamamoto, Y. Chem. Asian J. 2007, 2, 568; (b) Molina, P.; Tarraga,
25. Belowich, M. E.; Stoddart, J. F. Chem. Soc. Rev. 2012, 41, 2003.
26. (a) Woo, P. W. K.; Kostlan, C. R.; Sircar, J. C.; Dong, M. K.; Gilbertsen, R. B. J. Med.
Chem. 1992, 35, 1451; (b) Jordan, F.; Wu, A. J. Med. Chem. 1978, 21, 877.
27. X-ray structural assignment was also achieved for 13b. This unambiguously
confirmed the substitution pattern of dihydrotriazine 13. Crystallographic data
are available at CCDC 916050.
ꢀ
A.; Oton, F. Org. Biomol. Chem. 2012, 10, 1711.
3. (a) Anderson, E. B.; Long, T. E. Polymer 2010, 51, 2447; (b) Zhang, J.; Chen, X. C.
Chem. Commun. 2006, 1689.
4. (a) Newlands, E. S.; Stevens, M. F. G.; Wedge, S. R.; Wheelhouse, C.; Brock, R. T.
Cancer Treat. Rev. 1997, 23, 35; (b) Fung, J.; Lai, C.; Seto, W.; Yuen, M. J. Anti-
microb. Chemother. 2011, 66, 2715; (c) Karim, Q. A.; Karim, S. S. A.; Frohlich, J. A.;
Grobler, A. C.; Baxter, C.; Mansoor, L. E.; Kharsany, A. B. M.; Sibeko, S.; Milsana,
K. P.; Omar, Z.; Gengiah, T. N.; Maarschalk, S.; Arulappan, N.; Mlotshwa, A.;
28. Four additional optimization tables are included within the attached experi-
mental data.