Tert-Butyl Nitrite Mediated Synthesis of 1,2,4-Oxadiazol-5(4 H)-ones from Terminal Aryl Alkenes

Article abstract of DOI:10.1021/acs.orglett.9b01430

tert-Butyl nitrite (TBN) mediated synthesis of 3-aryl-1,2,4-oxadiazol-5(4H)-ones has been accomplished using terminal aryl alkenes via a biradical reaction intermediate. Three consecutive sp² C-H bond functionalizations of styrenes afforded 3-phenyl-1,2,4-oxadiazol-5(4H)-ones via the formation of new C?N, C?O, C-O, and two C-N bonds. Both of the N atoms originate from TBN, while the carbonyl oxygen is from the water (moisture) the other oxygen from the N?O part of the TBN.

Full text of DOI:10.1021/acs.orglett.9b01430

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
tert-Butyl Nitrite Mediated Synthesis of 1,2,4-Oxadiazol-5(4H)‑ones
from Terminal Aryl Alkenes
Prasenjit Sau, Amitava Rakshit, Tipu Alam, Hemant Kumar Srivastava,* and Bhisma K. Patel*
Department of Chemistry, Indian Institute of Technology Guwahati, North Guwahati 781039, India
S
* Supporting Information
ABSTRACT: tert-Butyl nitrite (TBN) mediated synthesis of
3-aryl-1,2,4-oxadiazol-5(4H)-ones has been accomplished
using terminal aryl alkenes via a biradical reaction
intermediate. Three consecutive sp2 C−H bond functionaliza-
tions of styrenes afforded 3-phenyl-1,2,4-oxadiazol-5(4H)-
ones via the formation of new CN, CO, C−O, and two
C−N bonds. Both of the N atoms originate from TBN, while
the carbonyl oxygen is from the water (moisture) the other oxygen from the NO part of the TBN.
Scheme 1. C−H Functionalization of Alkene to 1,2,4-
itrogen-containing heterocyclic frameworks are ubiqui-
Ntous and found in many naturally occurring and
synthetic compounds exhibiting remarkable biological and
medicinal properties.1 Among the N-containing heterocycles,
1,2,4-oxadiazol-5(4H)-one is an integral constituent of many
pharmaceutically and biologically active molecules (Figure
1).2a−d Thus, considerable attention has been devoted to
exploring newer routes and especially one-pot synthetic
strategies for these N-heterocycles and their derivatives. In
this regard, only a few methods are available for the synthesis
of 3-phenyl-1,2,4-oxadiazol-5(4H)-one.3 However, all of the
existing strategies involve condensation of amidoximes with
carboxylic acid esters or carbonyldiimidazole. The amidoximes
often need additional reaction steps for their preparation, thus
affecting the overall efficacy. Therefore, it is pertinent to design
an efficient and reliable strategy for the synthesis of 3-phenyl-
1,2,4-oxadiazol-5(4H)-one and its derivatives.
Oxadiazole
heterocycles in a single operation.5 Recently, Maiti et al.
reported a radical intermediate generated in the reaction of
The oxidative C−H bond functionalizations are reliable and
valuable tools in synthetic organic chemistry, providing
sustainable synthetic methodologies with minimum steps and
waste.4 Amidst the significant C−H bond functionalization
process, the derivatization of alkenes using tert-butyl nitrite is a
powerful yet simple route for the creation of N-containing
t
styrene with BuONO in which the nitroalkane radical was
trapped with the help of a scavenger such as TEMPO (Scheme
1a).6 During the oxysulfenylation of aromatic terminal alkenes
reported by Gao et al. utilizing ammonium iodide, DMSO, and
alcohol, a radical pathway was associated with the generation
of a methylthiyl radical (MeS•) from DMSO (Scheme 1b).7
Taking a cue from above, we were inquisitive to examine
whether the reaction of styrene with tert-butyl nitrite in the
presence of DMSO will offer similar difunctionalized product
or a complete different reactivity would be observed leading to
the formation of some other product (Scheme 1c).
With this assumption, we commenced our investigation by
reacting styrene (1) with tert-butyl nitrite (tBuONO) (a, 3.0
equiv) and Sc(OTf)3 catalyst (10 mol %) at 80 °C using
DMSO as the solvent. Fortuitously, the reaction provided 3-
phenyl-1,2,4-oxadiazol-5(4H)-one (1a) in 47% yield, the
Figure 1. Representative examples of clinically relevant 1,2,4-
oxadiazoles.
Received: April 25, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01430
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Scheme 2. Substrate Scope for Synthesis of 1,2,4-
Oxadiazoles from Aryl Alkenes
Scheme 3. Proposed Reaction Pathway for the Formation of
1a
a,b
transformation. By increasing the tert-butyl nitrite loading
from 3 to 4 equiv, the yield of the product 1a improved to 67%
(Table S1, entry 8). No significant improvement in the
product yield was noticed when 5 equiv of TBN was employed
in the reaction (Table S1, entry 9). Increasing the reaction
temperature to 100 °C or decreasing it to 60 °C decreased the
product yield to 51% and 57%, respectively. The optimized
conditions were found to be using 4 equiv of TBN at 80 °C in
DMSO.
a
Reaction conditions: alkene (1−18) (0.25 mmol), tert-butyl nitrite
b
c
(a) (1 mmol) at 80 °C in DMSO. Yield after 6 h. Gram-scale
reaction.
The scope of the methodology was examined with a variety
of aromatic terminal aryl alkenes (Scheme 2) under the
optimized reaction condition. Styrenes bearing moderately
electron-donating substituents on the aromatic ring such as m-
Me (2), p-Me (3), p-tBu (4), and p-CH2Cl (5) yielded the
corresponding 1,2,4-oxadiazoles 2a, 3a, 4a, and 5a in 64−69%
yields (Scheme 2). The single-crystal X-ray diffraction
measurement reconfirmed the structure of the product 3a
(Figure S1). Vinyl arenes possessing moderately electron-
withdrawing groups such as p-Br (6), o-Br (7), p-Cl (8), m-Cl
(9), o-Cl (10), p-F (11), and m-F (12) on the aromatic ring
provided the corresponding 1,2,4-oxadiazoles 6a (71%), 7a
(65%), 8a (74%), 9a (69%), 10a (67%), 11a (75%), and 12a
(74%) in moderate yields (Scheme 2). However, vinyl arenes
having strong electron-withdrawing substituents such as p-OAc
(13), p-CO2Me (14), and m-nitro (15), also reacted smoothly,
affording the corresponding 1,2,4-oxadiazoles 13a (79%), 14a
(77%), and 15a (75%) in modest yields (Scheme 2). Other
aromatic terminal alkenes such as 2,4-dimethylstyrene (16), 4-
phenyl styrene (17), and 2-vinylpyridine (18) underwent the
structure of which was ascertained by standard spectroscopic
investigations (Scheme 1c). The synthesis of 1,2,4-oxadiazole
was realized via the snapping of a vinylic CC bond with
concurrent construction of three C−N and two C−O bonds. It
was observed that here the two N atoms in the oxadiazole
moiety originated from TBN while the oxygen can originate
either from the TBN, water, or oxygen.
Encouraged by the above outcome, further optimization of
the reaction was carried out by varying various reaction
parameters. At first, polar aprotic solvents such as DMSO,
DMF, DMA, CH3CN, and DCE were tested (Table S1, entries
1−5). Among the solvents examined, DMSO was found to be
an effective solvent providing the product in 47% yield. When
Cu(OTf)3 (10 mol %) was used in lieu of Sc(OTf)3 (10 mol
%) under otherwise identical conditions, a diminished product
yield (41%) was observed (Table S1, entry 6). Interestingly,
the reaction proceeds better in the absence of any catalyst,
giving the product 1a in 59% yield (Table S1, entries 7). This
result suggested that the catalyst has no role in the
B
DOI: 10.1021/acs.orglett.9b01430
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Letter
a
Scheme 4. Energy Profile Diagram of the Reaction
a
Relative energy (blue color), activation barrier (italic bold) and stabilization gained (italic normal) are given in kcal/mol and calculated at M06/6-
31+G(d,p) level of DFT. The “tertiary-butyl” radical is shown as “t-Bu” for clarity in representation. The biradical path (shown in green color) is
preferred over the cationic path (shown in red color). The cross sign in red color (X) indicates the unfavorable reaction with higher activation
barrier and lower stabilization. Selected interatomic distances of the transition states are given in angstroms.
reactions successfully to produce the 1,2,4-oxadiazoles 16a,
17a, and 18a in 62%, 81%, and 73% yields, respectively, as
shown in Scheme 2. During the synthesis of 1,2,4-oxadiazoles,
similar yields were obtained from styrenes irrespective of the
nature of the substituents (electron-donating or electron-
withdrawing) present in the aryl rings. The possible reason for
this could be the higher reactivity of the reaction intermediate.
However, employing aliphatic alkenes such as pent-1-ene
(19a) but-1-ene (20a), and allylbenzene (21a) in the reaction
failed to react with tert-butyl nitrite, which might be due to the
instability of the radical produced during the reaction (Scheme
2). A successful demonstration of a gram-scale reaction using
styrene (1) (12 mmol, 1.25 g) and tert-butyl nitrite (a) (48
mmol, 4.94 g) under the standard reaction conditions giving
the product 1a in 55% isolated yield conveyed the synthetic
potential of this strategy.
To illustrate a probable reaction pathway for this one-pot
synthesis of 1,2,4-oxadiazole, some control experiments were
carried out. At first, to ascertain the origin of keto oxygen in
the product 1a, the reaction between styrene (1) and tert-butyl
nitrite (a) was performed in the presence of H218O under
otherwise identical conditions. Incorporation of 18O-labeled
product suggested that the oxygen from water (moisture from
DMSO) is the possible source of oxygen in keto group of the
product and the other oxygen is originating from TBN (see the
Supporting Information). To confirm the radical nature of this
transformation, a reaction was performed in the presence of a
radical scavenger 2,2,6,6-tetramethylpiperidine-1-oxyl
(TEMPO, 1 equiv) under otherwise identical conditions.
The desired product (1a) was obtained in <3%, suggesting the
radical nature of the reaction. From the HRMS analysis of the
reaction mixture at various time points, many possible reaction
intermediates were detected, based on which a reaction
mechanism can be inferred (Scheme 3).
The thermal decomposition of tert-butyl nitrite generates a
•NO radical, which under aerobic condition is oxidized to a
nitro radical (•NO2).8 Subsequently, the attack of •NO2 radical
at the nonbenzylic terminal sp2-carbon generates the nitro-
•
•
alkane radical intermediate A. Although both NO and NO2
radicals coexist in the medium, only the later attacks at the
terminal carbon and the former at the benzylic position to
generate an intermediate (B) (path a, Scheme 3),5a and no
reverse attack (path b, Scheme 3) was observed in the
literature.5a To understand this, DFT calculations were carried
out and modeled the reaction profile at the M06/6-31+G(d)
level of theory. The activation barrier for the attack of •NO2 at
the terminal carbon is around 6 kcal/mol lower compared to
the attack of •NO radical (Scheme 4). Moreover, •NO2 attack
C
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Letter
leads to the generation of a comparatively stable intermediate
(A). Formation of C-nitroso intermediate B through the
TS(A−B) is a quick reaction with an activation barrier of only
0.41 kcal/mol and stabilization of more than 38 kcal/mol. The
intermediate B rearranges to an α-nitroxime C through TS(B−
C), and this has an activation barrier of 59.45 kcal/mol and
stabilization of more than 80 kcal/mol. From the intermediate
C, the reaction may either proceed via a biradical path through
TS(C−D1) and TS(D1−D) to generate the intermediate D or
via a cationic path through TS(C−C′) to form the
intermediate C′. As evident from Scheme 4, the activation
barrier for the formation of C′ (53.66 kcal/mol) is much
higher compared to the barrier for the formation of D1 (12.40
kcal/mol). The formation of a biradical species is a two-step
process. The first step is the abstraction of one hydrogen atom
from the hydroxyl group by a tert-butoxy radical to give
intermediate D1, while the second step is the abstraction of
one hydrogen atom from the nitro group by another tert-
butoxy radical to form the biradical intermediate D. Both of
these steps have a lower activation barrier and higher
stabilization and may proceed easily to form a biradical species
D. This biradical species cyclizes to a four-membered 4H-1,2-
oxazete (E) intermediate through TS(D−E), and the process
has an activation barrier of 21.13 kcal/mol and stabilization of
33.82 kcal/mol. On the other hand, the formation of
intermediates C′ and C″ through TS(C−C′) and TS(C′−
C″) via a cationic path shows much higher activation barrier,
and also the stabilization is lower compared to the barrier.
Thus, the biradical path is preferred over the cationic path. As
of aryl arenes reacted successfully with TBN to generate the
heterocycle in good yields. However, the method is not
successful for aliphatic terminal alkenes. On the basis of
control experiments and detection of intermediates and from
the DFT calculations a biradical reaction pathway has been
suggested. This work is not only important from a mechanistic
point of view but has a potential opportunity for easy access to
many biologically active compounds.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01430.
Experimental procedures; spectral and analytical data of
all products; DFT calculations (PDF)
Accession Codes
CCDC 1911236 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
*E mail: hemants@iitg.ac.in.
*E mail: patel@iitg.ac.in.
ORCID
•
•
expected, all of the steps from NO2 attack followed by NO
attack, rearrangement, attack of two tert-butoxy radicals, and
ring closure to generate intermediate E are favorable with
reasonable activation barriers, and they lead to the generation
of stable intermediates. Formation of a similar four-membered
ring has been proposed in the literature.9 Because of the ring
strain, the four-membered ring intermediate E undergoes ring-
Hemant Kumar Srivastava: 0000-0001-6589-6854
Bhisma K. Patel: 0000-0002-4170-8166
Notes
The authors declare no competing financial interest.
•
opening reaction with NO through transition TS(E−F) to
generate intermediate F (Scheme S1). The activation barrier
for this reaction is 28.64 kcal/mol, and stabilization is more
than 100 kcal/mol. This reactive radical intermediate F
undergoes cyclization through TS(F−G) to intermediate G.
Formation of G is also a favorable reaction with an activation
barrier of 29.49 kcal/mol and stabilization of more than 80
kcal/mol. Dehydration of intermediate G to intermediate H
through TS(G−H) seems a slow reaction with an activation
barrier of 98.14 kcal/mol. However, the reaction is feasible as
the stabilization is much more than the activation barrier for
the formation of H (Scheme S1). This is possibly the rate-
determining step. Now the intermediate H is hydrolyzed by
moisture available in the solvent/atmosphere through TS(G−
H) to form the intermediate I. The activation barrier and
stabilization for this transformation is 56.70 and 67.46 kcal/
mol, respectively. Finally, the intermediate I undergoes
ketonization through TS(I−1a) to form the desired and stable
product (1a). All of the steps are given in Scheme 4, and
Scheme S1 is feasible and leads to a stable complex formation
as the activation barrier is always lower than the stabilization.
Generation of intermediates A, B, C, and F has been identified
by the HRMS analysis of reaction mixtures, thereby supporting
the proposed pathway (see the Supporting Information).
In summary, an efficient protocol for the synthesis of 3-
phenyl-1,2,4-oxadiazol-5(4H)-ones from aromatic terminal
alkenes using tert-butyl nitrite has been developed. A range
ACKNOWLEDGMENTS
■
B.K.P. acknowledges the support of this research by the
Department of Science and Technology (DST/SERB) (EMR/
2016/007042), T.A. and A.R. thank IIT Guwahati for
fellowships. H.K.S. thanks DST/SERB SB/S2/RJN/004-2015
and Param-Ishan supercomputing facility at IIT Guwahati.
CIF, IIT Guwahati, is highly acknowledged.
DEDICATION
■
Dedicated to Professor H. Ila on the occasion of her 75th
birthday.
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