A method for the synthesis of 2-aminobenzoxazoles

Article abstract of DOI:10.1016/j.tetlet.2011.12.001

A synthesis of 2-aminobenzoxazoles from the parent C-H compound is described. The procedure involves deprotonation at the 2-position of the benzoxazole and quenching the intermediate organolithium species with a halogen electrophile. The 2-halobenzoxazole is then treated in the same pot with an amine nucleophile to afford the desired product. The substrate scope and selectivity of the reaction are presented. The method is operationally simple and provides access to a variety of amine products bearing additional nucleophilic heteroatoms.

Full text of DOI:10.1016/j.tetlet.2011.12.001

Tetrahedron Letters 53 (2012) 730–732
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A method for the synthesis of 2-aminobenzoxazoles
⇑
Benjamin D. Sherry , Yeo-Chuin Justin Chen , Ian K. Mangion, Jingjun Yin
Department of Process Research, Merck and Co., Inc., PO Box 2000, Rahway, NJ 07065, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A synthesis of 2-aminobenzoxazoles from the parent C–H compound is described. The procedure involves
deprotonation at the 2-position of the benzoxazole and quenching the intermediate organolithium spe-
cies with a halogen electrophile. The 2-halobenzoxazole is then treated in the same pot with an amine
nucleophile to afford the desired product. The substrate scope and selectivity of the reaction are pre-
sented. The method is operationally simple and provides access to a variety of amine products bearing
additional nucleophilic heteroatoms.
Received 28 October 2011
Revised 30 November 2011
Accepted 1 December 2011
Available online 8 December 2011
Keywords:
Aminobenzoxazole
Amination
Ó 2011 Elsevier Ltd. All rights reserved.
Lithiation
Bromination
Introduction
2-mercaptobenzoxazole with S(IV) or P(V) (oxy)chlorides.5 Byprod-
ucts generated in the chlorination step often necessitate workup of
The 2-aminobenzoxazole subunit is found in a number of ther-
apeutically important molecules.1 As such, methods which allow
rapid access to a range of compounds containing this key structural
feature are of broad importance. Three general approaches are
most frequently used to construct the 2-aminobenzoxaole array:
(a) reaction between an aminophenol and a C(IV) electrophile;2
(b) oxidative coupling between a benzoxazole and an amine;3 (c)
formation of a 2-halogenated benzoxazole and subsequent amine
displacement.4
The merit of these methods is without debate however each
suffers from certain drawbacks inherent to the specific system. In
the reaction of aminophenols, the electrophile must often be gen-
erated in a parallel step, and amines bearing pendant nucleophiles
may not readily form the type of reactive electrophiles required.
Oxidative C–N bond formation is arguably the most direct
approach, but the scope of this transformation remains limited,
particularly in the coupling primary amines. Amine displacement
from a 2-halogenated precursor is attractive, but formation of the
2-halobenzoxazole can be tedious and require multiple operations.
Despite the drawbacks mentioned above, we were drawn to the
halide displacement method, particularly in the light of the reli-
ability with which this approach allows the coupling of primary
amines bearing additional heteroatoms. Generation of the 2-halo
precursor is generally accomplished through the reaction of a
the reaction prior to amine addition, resulting in a negative
environmental impact and increased time cycle for the overall
transformation. An alternative method which complements the
nucleophilic introduction of the halide would be metalation of
the C–H benzoxazole followed by quenching with an electrophilic
halogenating agent.6,7 The latter approach has not been rigorously
evaluated in the context of 2-aminobenzoxazole formation,8 and
may provide a more streamlined synthesis of these valuable
structures. This study describes our efforts to use electrophilic
halogenation of benzoxazoles as part of a practical synthesis of
2-aminobenzoxazoles.
Results and discussion
Optimization experiments were carried out with 5-chlorobenz-
oxazole and N-Boc-ethylenediamine (Table 1). Evaluation of the
base demonstrated that lithium hexamethyldisilazide led to the
highest conversion (entries 1–4). Of the electrophilic halogen
sources examined higher conversions were observed for iodinating
or brominating versus chlorinating agents (cf. entries 1, 7 and 9).
Elemental bromine efficiently quenched the lithium anion, but
led to increased levels of uncharacterized decomposition products
(entry 8). Employing NBS led to a small amount of unreacted start-
ing material (entry 9), but refinement around the reagent charges
and order of addition improved the conversion and resulted in a
high yield for the amination reaction (entry 10). The amination
requires no exogenous base, as lithium succinimide generated in
the bromination is well suited to act as a general base for the
amine addition. Ultimately the amination process requires two
⇑
Corresponding author. Tel.: +1 732 594 5349.
E-mail address: benjamin_sherry@merck.com (B.D. Sherry).
Present address: NERA Economic Consulting, 1166 Avenue of the Americas, 29th
Floor, New York, NY 10036, United States.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.12.001

B. D. Sherry et al. / Tetrahedron Letters 53 (2012) 730–732
731
Table 1
Reaction optimization
of the known propensity of 2-lithiated benzoxazoles to exist in
equilibrium with the ring opened 2-(isocyano)phenolate.6b Halo-
genation of the ring is therefore not unexpected, but what is
perhaps more interesting is why this pathway should predominate
in the fused aromatic case. Interestingly, changing the position of
the ring fusion restored the selectivity for bromination at the benz-
oxazole 2-position (entry 9).
Entry
Base
X–Y
2a (%)
1a (%)
Variation of the amine component was also evaluated. The
primary goal was to establish the selectivity for primary amine
alkylation in nucleophiles bearing additional heteroatoms
(Fig. 1). No selectivity in the alkylation reaction was observed
between primary and N-alkyl amines. Additionally, discrimination
between primary linear and branched amines proved challenging.
Good selectivity was seen for alkylation of a primary amine in the
presence of an aniline, phenol, and alcohol.
1
2
3
4
5
6
LHMDS
NHMDS
KHMDS
LiNH2
LHMDS
LHMDS
LHMDS
LHMDS
LHMDS
LHMDS
NCS
NCS
NCS
NCS
DCDMH
TClCA
I2
Br2
NBS
NBS
77
58
59
nd
48
15
85
89
86
93
18
18
21
89
16
14
nd
nd
6
7b
8c
9
10d
nd
Conclusion
General conditions: 1.25 equiv base, 10 vol THF, À20 °C; then 1.20 equiv X–Y and
warm to rt; then 1.20 equiv amine. Notes:
a
Starting material and product amounts were determined by quantitative HPLC.
Amine addition run with 1.2 equiv TEA at 60 °C.
Amine addition run with 1.2 equiv TEA.
1.5 equiv base, 14 vol THF, 1.5 equiv NBS, 1.6 equiv amine and inverse addition
In conclusion
a practical method has been developed to
b
2-aminobenzoxazoles via a 2-halobenzoxazole generated by elec-
trophilic bromination. The chemistry is operationally simple
requiring three separate reagent charges and two vessels to obtain
the 2-aminobenzoxazole from the parent C–H compound without
any intermediate isolations. This method should find utility in
the preparation of benzoxazole structures which bear multiple
nucleophilic sites on the amine component.
c
d
of anion to NBS slurry. Abbreviations: DCDMH, 1,3-dichloro-5,5-dimethylhydantoin;
TCICA, trichloroisocyanuric acid; nd, not detected.
vessels and is comprised of three distinct chemical steps: lithiation
with LHMDS, bromination with NBS and amine displacement of
the 2-bromo compound.
Experimental
The optimized conditions were then used to evaluate the sub-
strate scope of the benzoxazole component with ethanolamine as
the nucleophile (Table 2). The reaction performed well for a variety
of 5-substituted benzoxazoles, regardless of the electronic nature
of the substituent (entries 1–5). Substitution at the 4- and 6-posi-
tion was also well tolerated (entries 6 and 7). One limitation of the
methodology was established in the reaction of a fused aromatic
substrate (entry 8). Competing halogenation of the aromatic C–H
bond adjacent to oxygen was observed leading to a mixture of
amine products. This observation can be rationalized in the light
A 500 mL 3-neck round bottom flask equipped with a septum,
thermocouple, 125 mL addition funnel, inert gas inlet and
magnetic stir bar was purged with nitrogen for 10 min. Hexameth-
yldisilazane (42 mL, 0.20 mol) and THF (78 mL) were charged
against positive nitrogen pressure. The addition funnel was
charged with
a hexane solution of n-butyllithium (78.0 mL,
195 mmol). The amine solution was cooled to À52 °C and n-butyl-
lithium was added over 84 min, resulting in a temperature increase
to 12.5 °C over the course of the addition. The resulting lithium
Table 2
Benzoxazole substrate scope
Entry
1
Product
#
3
Yielda (%)
80
Entry
6
Product
#
7
Yielda (%)
85
2
3
4
5
71
84
7
8
8
9
80
21
4
5
2
6
84
84
9
10
65
General conditions: 1.2 equiv LHMDS (1 M THF solution), 1.22 equiv NBS, 1.4 equiv ethanolamine, final 0.3 M starting material concentration in THF. Notes:
a
Yields are of isolated material after silica gel chromatography.

732
B. D. Sherry et al. / Tetrahedron Letters 53 (2012) 730–732
Figure 1. Selectivity of primary amine nucleophiles. General conditions: 1.2 equiv LHMDS (1 M THF solution), 1.22 equiv NBS, 1.4 equiv amine, final 0.3 M starting material
concentration in THF. Notes: yields are of isolated material after silica gel chromatography.
hexamethyldisilazide solution was removed from the cooling bath
and aged for 30 min.
(100 MHz, DMSO-d6): d = 163.5, 146.8, 145.0, 127.7, 119.5, 115.0,
109.4, 59.3, 45.0 ppm.
To a 500 mL 3-neck round bottom flask equipped with a sep-
tum, thermocouple, inert gas inlet and magnetic stir bar was
charged 5-chlorobenzoxazole (20.00 g, 130 mmol). The gray solid
was dissolved in THF (100 mL) and the resulting colorless solution
was cooled to À25 °C. The freshly prepared lithium hexamethyldi-
silazide solution was added via cannula over 80 min. The temper-
ature of the anion solution was maintained between À25 and
À15 °C during the addition. The resulting dark brown solution
was aged for 90 min between À25 and À15 °C.
Acknowledgements
This work was supported by the Merck Future Talent Program
(Y.-C.J.C.). The authors wish to thank Cheng Chen for valuable
assistance during the preparation of this manuscript.
References and notes
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Claisen adapter, septum, thermocouple, inert gas inlet, stir shaft
bearing, and blade was charged THF (100 mL) and N-bromosuccin-
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1H), 3.56 (q, J = 5.7 Hz, 2H), 3.35 ppm (q, J = 5.8 Hz, 2H). 13C NMR
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