Cyanoguanidine as a versatile, eco-friendly and inexpensive reagent for the synthesis of 2-aminobenzoxazoles and 2-guanidinobenzoxazoles

Article abstract of DOI:10.1016/j.tetlet.2018.03.036

An effective, easy-to-handle, safe and inexpensive protocol is reported for the synthesis of 2-aminobenzoxazoles under Lewis acid activation, utilising cyanoguanidine as the cyanating reagent. An optimized procedure for the synthesis of 2-guanidinobenzoxazole and novel derivatives is also described.

Full text of DOI:10.1016/j.tetlet.2018.03.036

Accepted Manuscript
Cyanoguanidine as a versatile, eco-friendly and inexpensive reagent for the
synthesis of 2-aminobenzoxazoles and 2-guanidinobenzoxazoles
Oleksandr Grytsai, Tetiana Druzhenko, Luc Demange, Cyril Ronco, Rachid
Benhida
PII:
S0040-4039(18)30350-2
https://doi.org/10.1016/j.tetlet.2018.03.036
TETL 49805
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
8 February 2018
7 March 2018
15 March 2018
Please cite this article as: Grytsai, O., Druzhenko, T., Demange, L., Ronco, C., Benhida, R., Cyanoguanidine as a
versatile, eco-friendly and inexpensive reagent for the synthesis of 2-aminobenzoxazoles and 2-
guanidinobenzoxazoles, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.03.036
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Cyanoguanidine as a versatile, eco-friendly and inexpensive reagent for the synthesis of 2-
aminobenzoxazoles and 2-guanidinobenzoxazoles
Oleksandr Grytsai,#a Tetiana Druzhenko,#a Luc Demange,a,b Cyril Ronco*a and Rachid Benhida*a,c
aInstitut de Chimie de Nice UMR7272, Université Côte d’Azur, CNRS, Nice, France.
bDépartement de Chimie, Université Paris Descartes, Sorbonne Paris Cité, UFR des Sciences Pharmaceutiques, 4 avenue de
l'Observatoire & UFR Biomédicale des Saints Pères, 45 rue des Saints Pères, Paris, France.
cMohammed VI Polytechnic University, UM6P, Ben Guerir, Morocco.
* Corresponding authors:
E-mail addresses: cyril.ronco@unice.fr (C. Ronco); rachid.benhida@unice.fr (R. Benhida)
Phone numbers: 0033 492076517 (C. Ronco); 0033 492076143 (C. Ronco);
Abstract
An effective, easy-to-handle, safe and inexpensive protocol is reported for the synthesis of 2-aminobenzoxazoles
under Lewis acid activation, utilising cyanoguanidine as the cyanating reagent. An optimized procedure for the
synthesis of 2-guanidinobenzoxazole and novel derivatives is also described.
1. Introduction
2-Aminobenzoxazoles are heterocyclic compounds, which play important roles in medicine, biology and
material science. This scaffold has been used for the design of hepatitis C virus (HCV) ligands,1 antimicrobial,2
anti-inflammatory3,4 and anti-cancer agents,5,6 as well as for the marketed anti-insomnia drug suvorexant.7 In
addition, their photophysical properties have been exploited for the preparation of fluorescent dyes.8 Several
methods have been already reported for the synthesis of 2-aminobenzoxazoles. Historically, the conventional
route consists of coupling 2-aminophenol derivatives with cyanogen bromide.9 However, this approach suffers
from the high toxicity of cyanogen bromide, whose production and use might be strongly restricted in the future
because of increasing safety regulations. Therefore, other synthetic methodologies have been recently explored,
based on reagents such as di(imidazole1-yl)methanimine,10 N-cyano-N-phenyl-p-toluenesulfonamide,11
isothiocyanates followed by cyclodesulfurization12 and carbon disulfide at reflux.13 However all these reagents
require preliminary preparation steps, such as the use of cyanogen bromide with imidazole for the preparation of
di(imidazole1-yl)methanimine, or are limited by similar safety restrictions, such as the highly explosive and
toxic carbon disulfide.14 Therefore, despite this apparent variety of reagents to access 2-aminobenzoxazoles,
there is still a need for an efficient, straightforward and safe method to produce these highly important
heterocycles.
2. Results and Discussion
To the best of our knowledge, the synthesis of heterocycles using cyanoguanidine as a cyanating agent has not
been reported. Thus, in continuation of our studies directed towards the development of new and eco-friendly
synthetic methodologies of bioactive molecules,15 we report herein an effective, easy-to-handle, safe and
inexpensive protocol for the synthesis of 2-aminobenzoxazoles (Scheme 1).

Scheme 1. Selective synthesis of either 2-aminobenzoxazoles or 2-guanidinobenzoxazoles from o-
aminophenols.
Cyanoguanidine is a non-toxic, readily available and inexpensive chemical.16 This reagent has been described for
the synthesis of 2-guanidinobenzoxazole.17 From a mechanistic point of view, the cyano group can be activated
by Lewis or Brønsted acids to facilitate nucleophilic attack of the aniline group. Subsequent ring closure and
aromatization via ammonia condensation affords the 2-guanidinobenzoxazoles. We hypothesized that, under
defined hydrolysis conditions, the amidine group of the guanidine can be cleaved to yield the corresponding 2-
aminobenzoxazoles, along with a stable urea molecule. By adapting the reaction conditions, we aimed to
perform these two reaction steps in one-pot, with selective hydrolysis of 2-guanidinobenzoxazole over
cyanoguanidine.
We started our study by the survey of various reaction conditions, i.e. Lewis or Brønsted acids, mode of
activation (classical heating versus microwave activation), using the cyclocondensation of 2-aminophenol 1a
with cyanoguanidine as a model reaction (Table 1).
Table 1. Survey of the reaction conditions
Entry
Reactant
Solvent
Time (h)
T (°C)
65
Results (%)
n.r.a
1
2
3
4
5
6
7
16
16
16
16
16
16
48
p-TSA
SnCl2
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
65
Traces of 3a
65
n.r.a
Ti(OiPr)4
65
100%b (2a), (58%)c
95%b (3a), (57%)c
90%b (mixture of 2a/3a, 50/50 )
60%b (mixture of 2a/3a, 30/70)
BF3·Et2O
AlCl3
1,4-Dioxane
1,4-Dioxane
65
FeCl3
1,4-Dioxane
H2O
65
Yb(OTf)3
100

8
Sc(OTf)3
None
H2O
H2O
48
16
100
25%b (mixture of 2a/3a, 80/20)
9
100
n.r.a
Traces of 2a
10
11
12
140 (MW)
140 (MW)
140 (MW)
None
H2O
H2O
1
1
Sc(OTf)3
10%b (mixture of 2a/3a, 80/20)
None
10% aq. NaOH
1
n.r.a
Reagents and conditions: 2-aminophenol (1.0 mmol), cyanoguanidine (1.3 mmol), reactant (1.0 mmol), solvent
(5.0 mL). MW: microwave irradiation. a n.r.: no reaction. b Conversion based on LCMS analyses. c Isolated yield.
Depending on the applied conditions, very different behaviour in terms of reactivity and selectivity were
observed. For example, Brønsted acid and base, as well as mild Lewis acids such as SnCl2, Ti(OiPr)4, Yb(OTf)3
and Sc(OTf)3 led to no or poor conversion, with various ratios of 2a/3a being formed (Table 1, entries 1-3 and 7-
8). Conversely, the use of strong Lewis acids provided interesting results. First, 2a could be obtained by a one-
pot procedure through formation of the heterocycle and subsequent cleavage of the amidine using boron
trifluoride (Entry 4). The desired product was isolated in 58% yield after purification by silica gel
chromatography. Second, treatment with aluminum chloride selectively led to the intermediate guanidine 3a in
57% yield after work-up and purification (Entry 5). These encouraging results prompted us to select these two
reagents for further optimization of each reaction
Table 2. Optimization of the reaction conditions for the synthesis of 2-aminobenzoxazole 2a
Reactant
Entry
Solvent
T (°C)
Results
(equiv.)
1
2
3
4
5
65
100%a (2a), 58%b
BF3·Et2O (1)
1,4-Dioxane
Methanol
DMF
Partial conversion,
BF3·Et2O (1)
BF3·Et2O (1)
BF3·Et2O (1)
BF3·Et2O (1)
65
65
65
65
mixture of 2a and 3a
100%a (2a in mixture with by-products)
100%a (2a in mixture with by-products)
100%a (2a in mixture with by-products)
n-BuOH
ClCH2CH2Cl

6
7
BF3·Et2O (1)
BF3·Et2O (1)
BF3·Et2O (0.1)
BF3·Et2O (2)
BF3·Et2O (1)
BF3·Et2O (1)
THF
65
65
65
65
80
90
100%a (2a in mixture with by-products)
DME
100%a (2a in mixture with by-products)
10%a of 2a, 90%b of 1a
8
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
100%a (2a in mixture with by-products)
100%a (2a), 90%b
9
10
11
100%a (2a), 37%b
Reagents and conditions: 2-aminophenol (1.0 mmol), cyanoguanidine (1.3 mmol), reactant (1.0 mmol), solvent
(5.0 mL). a Conversion after 16 h, based on LCMS analyses. b Isolated yield.
Replacement of 1,4-dioxane by other solvents resulted in the formation of varying amounts of side-products
(Table 2, entries 1-7). Furthermore, the stoichiometric role of the Lewis acid was demonstrated (Entry 8), as 10
mol% BF3·Et2O loading provided only 10% conversion. Conversely, the use of excess (2 equiv.) induced the
formation of side-products (Entry 9). Finally, we evaluated the temperature effects, and after a careful screening,
80 °C was determined to be optimal, providing the desired product in 90% isolated yield. Increasing the
temperature to 90 °C resulted in significant amounts of non-identified side-products and an isolated yield of only
37%.
o
The optimized procedure (i.e. BF3·Et2O in dioxane at 80 C) was then applied to a selection of commercially
available substituted o-aminophenols (1a-g, Table 3) in order to explore the reaction scope. We successfully
obtained the expected 2-aminobenzoxazoles 2d-g with good yields. However, it is worth noting that yields were
slightly decreased when using 2-amino-4-nitrophenol (2b, 55%) or 3-amino-4-nitrophenol (2c, 48%), due to the
lower reactivity of nitro derivatives.
Table 3. Substrate scope for the synthesis of 2-aminobenzoxazoles (2a-g)
Entry
Substrate
Product
Isolated
Yield (%)
1
2
90
55

3
4
48
73
5
6
83
75
7
74
Reagents and conditions: 1a-g (1 mmol), cyanoguanidine (1.3 mmol), BF3·Et2O (1.0 mmol), dioxane (5 mL), 80
oC.
Table 4. Optimization of the reaction conditions for the synthesis of 2-guanidinobenzoxazole 3a
Reactant
Entry
Solvent
Time (h)
T (oC)
Isolated Yield (%)
(equiv)
1
2
57%
57%
n.r.a
69%
AlCl3 (1)
1,4-Dioxane
16
65
AlCl3 (1)
AlCl3 (1)
THF
16
16
65
65
3
MeOH
4
AlCl3 (1)
AlCl3 (2)
Al(OTf)3 (1)
H2SO4
THF
THF
THF
96
60
5
60
96
60
60
70%
6
68%
27%
7 b
8 c
2
6
90
90
EtOH/H2O,
1/1
EtOH/H2O,
4/1
19%
HCl
Reagents and conditions: 2-aminophenol (1.0 mmol), cyanoguanidine (1.3 mmol), reactant (1.0 mmol), solvent
a
b
c
(5.0 mL). n.r.: no reaction. Following reference17 procedure on a 5 mmol scale. Following reference18
procedure on a 5 mmol scale.
Although a large-scale protocol (1 mol scale) for the synthesis of unsubstituted 2-guanidinobenzoxazole has
been already described,17 no efficient, reproducible and generalizable procedure affording substituted 2-
guanidinobenzoxazoles on a millimolar scale with high yields has been disclosed. The synthesis of the 2-

aminobenzoxazole ring is challenging because the strong acidic conditions required for the formation of this
heterocycle, simultaneously promote its reopening (e.g. through hydrolysis). Therefore, we decided to carry out
the reactions in dry solvents, 1,4-dioxane or THF (Table 4, entries 1-3), which resulted in a significant yield
improvement compared to the aqueous conditions protocols depicted in the literature (Entries 7, 8). The yields
were further enhanced by slightly decreasing the temperature to 60 °C, despite a slower reaction time (Entry 4).
It is notable that the kinetics could be partially restored by using 2 equivalents of aluminum salt (Entry 5),
leading to the expected product in 70% isolated yield. Lastly, since the use of Al(OTf)3 yielded 3a in similar
yields (Entry 6), we selected AlCl3 as the Lewis acid for economic reasons.
We next explored the scope of this reaction by applying the optimized procedure (i.e. AlCl3 in THF at 60 °C) to a
selection of commercially available substituted o-aminophenols (1a-g, Table 5) to afford the expected 2-
guanidinobenzoxazoles 3a-g in good yields (45-70%). To further investigate our methodology, we tested this
procedure on a 50-100 mmol scale for compounds 3a, 3b, 3c, 3e and 3f. Consistent and reproducible yields were
obtained for these five compounds delivering multi-gram amounts of the desired products.
Table 5. Substrate scope for the synthesis of 2-guanidinobenzoxazoles (3a-g)
Entry
Substrate
Product
Isolated
Yield (%)
1
70
61
2
3
54
4
5
45
52

6
7
58
52
Reagents and conditions: 1a-g (1 mmol), 8 (1.3 mmol), AlCl3 (2.0 mmol), THF (5 mL), 60 oC
3. Conclusion
In summary, we have successfully developed a facile, eco-friendly and efficient synthesis of 2-
aminobenzoxazoles from 2-aminophenols using inexpensive commercially available cyanoguanidine as a
cyanating reagent. Moreover, we report an unprecedented Lewis Acid catalyzed procedure for the synthesis of 2-
guanidinobenzoxazoles. This allowed the syntheses of novel 2-guanidinobenzoxazole derivatives, which were
not accessible using the procedures currently available in the literature. We believe that the simplicity and
versatility of our approach, will offer an effective alternative for the preparation of these scaffolds, which are
relevant for biological purposes.
4. Acknowledgements
The authors are grateful for the financial support from CNRS, Université Côte d’Azur and Ministry of Higher
Research and Education for the PhD grant to O.G., the Research fund from the Canceropôle PACA, ANR and
INCA.
Supplementary data
Supplementary data associated with this article can be found, in the online version, at https://doi.org/.
#: Equal contribution, *: co-first authors.
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Highlights
•
•
•
Under specific Lewis acid activation, cyanoguanidine acts as cyanating agent
Cyanoguanidine/BF3 allows safe and eco-friendly synthesis of 2-aminobenzoxazoles
AlCl3 activation broadens and optimizes the synthesis of 2-guanidinobenzoxazoles