tert-Butyl Nitrite Mediated Different Functionalizations of Internal Alkenes: Paths to Furoxans and Nitroalkenes

Article abstract of DOI:10.1002/adsc.201800668

tert-Butyl nitrite (TBN) reacts differently with various internal alkenes leading to interesting and useful products. Synthesis of 1,2,5-oxadiazole-N-oxides (furoxans) has been achieved from internal alkenes using tert-butyl nitrite (TBN), quinoline and K₂S₂O₈. Under an identical reaction condition α,β-unsaturated carboxylic acids and cyclic and acyclic internal alkenes both afforded nitroalkenes as the sole product via decarboxylative and direct nitration path respectively. (Figure presented.).

Full text of DOI:10.1002/adsc.201800668

Title: tert-Butyl Nitrite Mediated Differential Functionalizations of
Internal Alkenes: Paths to Furoxans and Nitroalkenes
Authors: Bhisma Patel, Bilal Mir Ahmad, Sarangthem Joychandra
Singh , and Ritush Kumar
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201800668
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10.1002/adsc.201800668
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
tert-Butyl Nitrite Mediated Different Functionalizations of
Internal Alkenes: Paths to Furoxans and Nitroalkenes
Bilal Ahmad Mir,a Sarangthem Joychandra Singh,a Ritush Kumar,a and Bhisma K.
Patela,*
aDepartment of Chemistry, Indian Institute of Technology Guwahati, North Guwahati 781 039, Assam, India
Fax: (+91)361-26909762, E-mail: patel@iitg.ac.in
Received:((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
drugs.[5] Selected furoxan derivatives possessing
potential pharmaceutical applications are shown in
Abstract: tert-Butyl nitrite (TBN) reacts differently
with various internal alkenes leading to interesting and
useful products. Synthesis of 1,2,5-oxadiazole-N-oxides
(furoxans) has been achieved from internal alkenes
using tert-butyl nitrite (TBN), quinoline and K2S2O8.
Under an identical reaction condition α,β-unsaturated
carboxylic acids and cyclic and acyclic internal alkenes
both afforded nitroalkenes as the sole product via
decarboxylative and direct nitration path respectively.
Figure 1.[2i,3a,5c,6]
Figure 1. Some representative bioactive furoxans.
Keywords: tert-Butyl nitrite (TBN); furoxans;
nitroalkenes; isoxazolines; internal alkenes
Furoxan (or 1,2,5-oxadiazole 2-oxide) is
a
heterocycle of the isoxazole family and is an
important scaffold in medicinal chemistry.[1]
Derivatives of furoxans or furoxan N-oxides are of
significant importance in organic synthesis, since
they are an integral part of several potential
therapeutic agents such as furoxans-praziquantel,[2a]
N-acyl derivatives of furoxans,[2b] furoxans-
Existing strategies for furoxan synthesis involve
dehydration of α-nitro oximes,[7a] dimerization of
nitrile N-oxides,[7b] oxidation of α-dioximes,[7c]
pthalimide,[2c]
furoxanyl-N-acylhydraxones,[2d]
[7d]
acid,[2e]
acid,[2f]
furoxan-
furoxans
reaction of styrenes with NOBF4.
However, any
furoxanylacyl-salicyclic
farnesylthiosalicylic
tert-butyl nitrite mediated synthesis of furoxans from
internal alkenes is still unexplored. In this regard,
synthesis of furoxans from easily accessible and
biologically demanding internal alkenes bearing an
allylic stereogenic centre may generate potential
applications as both stereogenic centre[8a] and furoxan
moiety[8b,c] are important parts of many biologically
active compounds, thus are expected to receive
amodiaquine,[2g]
furoxans-phenylsulfonyl,[2h]
4-
furoxanyl nitrone,[2i] furoxan-chalcones,[2j] furoxan-
fenoterol,[2k] furoxan-oleanolic acid,[2l] furoxans-
dibenzoyl,[2m] furoxan-ibuprofen,[2n] etc. Moreover,
furoxan derivatives have drawn phenomenal
biological and pharmaceutical interests, some of
which are reported to have antioxidant,[3a]
vasodilator,[3a]
leishmanicidal,[3b]
anticancer,[3c]
antibacterial,[2i] antimalarial,[2l] antihistaminic,[3d] and
anti HIV[3e] activities. Furoxan derivatives are known
to release nitric oxide (NO) in the presence of thiol
co-factors, thus activating the soluble guanylate
cyclase.[1,4] Consequently, many research groups
pursued studies on the development of furoxan-based
considerable
interest
from
biological
and
pharmaceutical point of view.
Alkenes which are simple organic molecules have
been widely applied in organic synthesis for the
construction of a diverse array of complex molecules.
One of the finest approaches to build such class of
1
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10.1002/adsc.201800668
Advanced Synthesis & Catalysis
molecules in a single operation is via the direct 1,2-
difunctionalization of alkenes. In this context, tert-
butyl nitrite (TBN) has emerged as a versatile reagent
in organic synthesis.[9a] Therefore, it has been
employed for the oxidative nitration,[9b] [Scheme 1
(i)], stereoselective nitration[9c] [Scheme 1 (ii)],
aerobic oxynitration[9d] [Scheme 1 (iii)] of terminal
olefins [(Scheme 1)], metal free nitration of 2-
oxindoles[9e] and phenols,[9f] metal free synthesis of
isatins,[9g] synthesis of quinoxaline N-oxides,[9h]
substituted pyrazole N-oxides,[9i] cyclization of o-
explored FeCl3 (2.5 mol%) catalyst, and base 1,4-
diazabicyclo[2.2.2]octane (DABCO) (1 equiv.) in
1,2-dichloroethane (DCE) (1.5 mL) at 85 °C for 5.0 h.
A new product (1a) was isolated in 33% yield after
column chromatographic separation (Table 1, entry
1). Spectroscopic (1H and 13C NMR) analysis of the
product (1a) revealed the disappearance of both
alkene protons at 6.40 ppm. However, appearance of
a doublet at 1.23 ppm and a multiplet at 3.27 ppm
suggests that the PhCH(CH3)- part is intact thereby
confirming di-functionalization across the double
bond of (1). Further, HRMS analysis of the product
indicates loss of two protons and addition of two NO
groups. Finally, the exact structure of the product was
confirmed by X-ray crystallographic analysis of one
of its derivative (8a) as shown in Figure 2. Fascinated
by the formation of this interesting furoxan skeleton,
this reaction was further screened by varying various
other Lewis acid catalysts. Among the catalysts
screened such as AlCl3 (37%), Fe(OTf)3 (39%) and
Sc(OTf)3 (44%) (Table 1, entries 2-4), it was
observed that Sc(OTf)3 provided better yield (44%).
alkynylanilines[9j]
decarboxylative
and
TEMPO
mediated
nitration
of ,-unsaturated
carboxylic acids [(Scheme 1 (iv)].[9k] Recently our
group has reported a tert-butyl nitrite-mediated
domino synthesis of isoxazolines and isoxazoles
respectively from styrenes and phenylacetylenes
[Scheme 1(v)].[9l] However, tert-butyl nitrite-
mediated difunctionalization of any internal olefin is
less explored so far. Thus, treatment of an internal
alkene with TBN may lead to the formation of similar
isoxazoline[9l] or a completely different reactivity may
drive the formation of some other product? Therefore, However, the use of other bivalent metal catalysts
we were curious to investigate the reaction of various
internal alkenes with TBN.
such as Cu(OTf)2 and Zn(OTf)2 provided the desired
product (1a) in lesser yields 19% and 17%
respectively (Table 1, entries 5-6). Interestingly, the
use of organic base quinoline (Table 1, entry 9) in
lieu of DABCO, DBU, DMAP (Table 1, entries 4, 7,
8) provided the product (1a) in an improved yield
(56%). Reaction carried out in the absence of
Sc(OTf)3 catalyst was detrimental to product
formation (Table 1, entry 10), suggesting the
involvement of Sc(OTf)3 in facilitating the reaction.
When the reaction was performed in the absence of
base under otherwise identical condition the yield of
(1a) decreased to 39% (Table 1, entry 11). These
results suggest the active involvement of both catalyst
and base in this reaction. In order to further improve
the product yield, various oxidant/additive
combinations were employed in lieu of a single
oxidant. It was found that the use of additive Oxone®
along with TBN improved the product yield upto
59% (Table 1, entry 12). By changing the additive
from Oxone® to potassium persulphate (K2S2O8) the
product yield improved upto 62% (Table 1, entry 13).
Surprisingly, when the reaction was carried out in the
absence of Sc(OTf)3 catalyst, but in the presence of
TBN, K2S2O8 and quinoline the yield of (1a)
improved to 64% (Table 1, entry 14). This
observation suggests that the reaction is neither
mediated by a redox process nor by a Lewis acid
catalyst. However, when the reaction was carried out
in the absence of base the product formation (1a)
dropped to 29% (Table 1, entry 15). In the presence
of K2S2O8 (1 equiv.) alone i.e in the absence of any
catalyst and base the reaction gave 51% yield (Table
1, entry 16). When the reaction was carried out at 100
oC the yield remained unchanged (64 %) of (1a)
(Table 1, entry 17) but a decrease in the reaction
temperature to 70 oC provided reduced yield (52%) of
S
cheme 1. tert-Butylnitrite mediated functionalization of
olefins.
Our initial investigation started by reacting an
internal alkene (1) with tert-butyl nitrite (a). Alkene
(E)-1,3-diphenyl-1-butene (1) was chosen as the
model substrate as this core unit contains an allylic
carbon stereogenic centre which represents
a
privileged and biologically important molecular
scaffold.[8a] Initially, alkene (1) was treated with tert-
butyl nitrite (a) (2 equiv.) in the presence of well
2
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10.1002/adsc.201800668
Advanced Synthesis & Catalysis
Table 1. Screening of reaction conditions.[a]
Entry
1
2
3
4
5
6
7
8
Catalyst (mol %)
FeCl3 (2.5)
AlCl3 (2.5)
Fe(OTf)3 (2.5)
Sc(OTf)3 (2.5)
Cu(OTf)2 (2.5)
Zn(OTf)2 (2.5)
Sc(OTf)3 (2.5)
Sc(OTf)3 (2.5)
Sc(OTf)3 (2.5)
Base (equiv.)
DABCO (1)
DABCO (1)
DABCO (1)
DABCO (1)
DABCO (1)
DABCO (1)
DBU (1)
Solvent (1.5 mL)
DCE
Additive (equiv.) Yield %[b]
33
37
39
44
19
17
44
27
56
23
39
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DMAP (1)
Quinoline (1)
Quinoline (1)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
Sc(OTf)3 (2.5)
Sc(OTf)3 (2.5)
Sc(OTf)3 (2.5)
Quinoline (1)
Quinoline (1)
Quinoline (1)
Oxone® (1)
K2S2O8 (1)
K2S2O8 (1)
K2S2O8 (1)
K2S2O8 (1)
K2S2O8 (1)
K2S2O8 (1)
K2S2O8 (1)
K2S2O8 (1)
K2S2O8 (1)
K2S2O8 (1)
K2S2O8 (1)
K2S2O8 (1)
K2S2O8 (2)
59
62
64
29
Sc(OTf)3 (2.5)
51
Quinoline (1)
Quinoline (1)
Quinoline (1)
Quinoline (1)
Quinoline (1)
Quinoline (1)
Quinoline(1)
Quinoline (2)
Quinoline (1)
64[c]
52[d]
73
DCE
CH3CN
DMSO
DMF
AcOH
21
43
51
27
76
60
CH3CN
CH3CN
[a]Reaction conditions: 1 (0.50 mmol), K2S2O8 (0.50 mmol), base (0.50 mmol), tert-butylnitrite (1.0 mmol) at 85 C.
°
[b]Yield after 5.0 h. [c]Temperature 100 °C. [d]Temperature 70 °C.
the product (Table 1, entry 18). Subsequently
screening of other solvents such as CH3CN, DMSO,
DMF, AcOH, solvent CH3CN was found to give the
best yield 73% (Table 1, entries 19-22) under
otherwise identical condition. Since most of the
reagents are liquid at room temperature the reaction
was attempted under a neat condition, unfortunately
the reaction was unclean giving multitude of products
and reducing the isolated yield to 27% (Table 1, entry
23). A marginal improvement in the yield (76%) of
the product was observed by increasing the quinoline
amount to 2 equivalents (Table 1, entry 24).
However, a twofold loading of K2S2O8 was found to
be counterproductive for the reaction giving only
60% yield (Table 1, entry 25). After a series of
screening, it was found that this bis-functionalization
is best achieved using alkene (1) (0.5 mmol), TBN (2
equiv.), quinoline (1 equiv.), K2S2O8 (1 equiv.) at 85
°C for 5.0 h.
(1-9) with TBN (a). This reaction proceeded well
with a variety of alkenes bearing electron-donating as
well as electron-withdrawing groups in their phenyl
rings. Phenyl rings of these alkenes possessing
moderately electron-donating groups such as 4-Me
(2) 4-tBu (3), 4-Ph (4), gave their corresponding
products (2a, 57%), (3a, 55%), (4a, 59%), in
moderate yields (Scheme 2). Alkene substrates
having moderately electron-withdrawing groups such
as 4-Cl (5), 4-Br (6), 4-F (7) in the phenyl rings
provided their corresponding products (5a, 71%), (6a,
73%), (7a, 75%) in good yields as shown in (Scheme
2). Alkenes possessing strongly electron-withdrawing
group such as 3-NO2 (8) also resulted in the
formation of furoxan (8a) in good yield (79%).
Internal alkene having tri-methyl (9) substitution in
its phenyl ring reacted successfully and provided the
corresponding furoxan (9a, 51%) in a relatively lesser
yield (Scheme 2). The lower yield of product
obtained for the substrate (9) is possibly due to the
steric hindrances due to ortho substitutions.
After establishing the optimized reaction
condition for furoxan (1a) formation from internal
alkene (1) as shown in (Table 1), we explored the
reaction between various (E)-1,3-diphenyl-1-butenes
3
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10.1002/adsc.201800668
Advanced Synthesis & Catalysis
To demonstrate the applicability of the reaction in
large scale, internal alkene (1) (5 mmol, 1.04 g) was
reacted with TBN (10 mmol) and K2S2O8 (5 mmol)
the product was obtained in 51% yield. Interestingly,
when TBN and K2S2O8 were added in four equal lots
over a period of 4 h the yield of the product (1a)
improved up to 64% (Scheme 2).
Scheme 3. Substrate scope for furoxan synthesis from
trans-stilbenes. Reaction conditions: (10-13) (0.50 mmol),
K2S2O8 (0.50 mmol), quinoline (0.50 mmol), tert butyl
nitrite (1.0 mmol) in CH3CN (1.5 mL) at 85 C for 5 h.
Isolated yields.
Scheme 2. Substrate scope for furoxan synthesis. Reaction
conditions: (1-9) (0.50 mmol), K2S2O8 (0.50 mmol),
quinoline (0.50 mmol), tert butyl nitrite (1.0 mmol) in
°
°
CH3CN (1.5 mL) at 85 C for 5 h. Isolated yields.[a] TBN
and K2S2O8 was added in 4 equal lots over a period of 4 h.
To check whether the reaction is proceeding via a
radical
path,
(E)-4,4'-(but-2-ene-1,3-
diyl)bis(bromobenzene) (6) was reacted with tert-
butylnitrite (a) in the presence of an equimolar
quantity
of
radical
scavenger
(2,2,6,6-
tetramethylpiperidin-1-yl)oxidanyl
(TEMPO).
Formation of (<2%) of the product (6a) (Scheme S1)
[see supporting information (SI)] suggests a
possible radical pathway for this transformation. On
the basis of the literature reports, intermediates
detected by HRMS analysis of the reaction mixtures a
plausible mechanism has been proposed for the
furoxan formation. Initially, the heterolytic cleavage
of tert- butyl nitrite produces a NO radical and a tert-
butoxy radical (Scheme 4). The NO radical under an
aerobic reaction condition gets converted to a NO2
radical.[11] Subsequently, the NO2 radical attacks at
the nonbenzylic carbon of the olefin (6) to generate a
nitroalkane benzyl radical intermediate (A) (Scheme
4). The radical intermediate (A) then reacts with the
NO• radical at its benzylic position to give a nitro-
nitroso intermediate (B). Alternatively, the
intermediate (A) loses a proton giving product (A´),
which has been detected by HRMS analysis of the
reaction aliquots. This pattern of preferential attack of
NO• at the benzylic position is consistent with our
isoxazoline synthesis involving a terminal alkene and
TBN.[9l] The intermediate (B) then undergo a CC
bond rotation which is perhaps facilitated by the co-
ordination of K+ with two of the oxygen atoms from
NO and NO2 groups forming an intermediate (C).
The nitroso intermediate (C) isomerizes to a bis-
Figure 2. ORTEP molecular diagram of (8a).[10]
In addition to these unsymmetrical benzylic
internal alkenes this method is equally amenable to
1,2-disubstituted symmetrical and unsymmetrical
stilbenes. When trans-stilbene (10) was treated with
TBN it provided corresponding furoxan (10a) in 67%
yield (Scheme 3). In addition, unsymmetrical trans-
stilbenes possessing moderately electron-donating 4-
Me (11) and electron-withdrawing 4-Cl (12)
substituents in one of the phenyl ring reacted
successfully providing their expected products (11a)
and (12a) in 55% and 51% yields respectively. A
heterocylic trans-stilbene (13) also reacted
successfully and provided the corresponding furoxan
(13a) in a good yield (75%). At present we are not
sure about the position of N-oxide as towards which
phenyl ring it is oriented but based on the mechanism
proposed in (Scheme 4), the N-oxide is expected to
be towards phenyl side in (11a), 4-Cl phenyl side in
(12a) and towards pyridine ring in (13a) (Scheme 3)
4
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10.1002/adsc.201800668
Advanced Synthesis & Catalysis
oxime type intermediate (D) in the presence of base,
from which furoxan (6a) is generated via the loss of a
water molecule (Scheme 4). Formation of
intermediates (B)/(D) have been detected by HRMS
analysis of the reaction mixture [Fig. S1, S2 see
supporting information (SI)].
intermediates, which have been used in the
preparation of a wide variety of biorelevant
compounds and pharmaceuticals.[13] Thus, the present
metal free decarboxylative nitration is an economical,
safer and greener approach for the synthesis of
nitroalkenes. The proposed mechanism for the
reaction is expected to be similar to the one proposed
by Prabhu et.al using TBN and CuCl[12d] and Maiti
using TEMPO and TBN[9k] as shown in (Scheme 8).
Scheme 4. Plausible mechanism for 1,2,5-oxadiazole-N-
oxide synthesis.
Scheme 5. Nitration of α,β-unsaturated carboxylic acids.
Reaction conditions: (14-19) (0.50 mmol), K2S2O8 (0.50
mmol), quinoline (0.50 mmol), tert-butyl nitrite (1.0
mmol) in CH3CN (1.5 mL) at 85 °C for 5 h. Isolated yields.
Further, to check whether this strategy of furoxan
synthesis is applicable to other internal alkenes such
as α,β-unsaturated acids or not? trans-cinnamic acid
(14) was reacted with TBN (a) under an identical
reaction condition. The reaction proceeded well and
provided product (14a) in good yield (77%).
Encouraged by the above differential reactivity of
tert-butyl nitrite (TBN) with two classes of alkenes,
one leading to furoxans and the other decarboxylative
nitration giving nitroalkenes, this strategy was then
applied to alicyclic alkenes to see the type of product
it would result. To our delight alicyclic alkenes such
as cyclohexene (20), cycloctene (21) and
cycloctadiene (22) yielded nitroalkenes under an
identical reaction condition affording products (20a,
74%), (21a, 76%) and (22a, 73%) respectively in
good yields as shown in (Scheme 6). Surprisingly,
none of the substrates (20-22) gave any trace of their
furoxan products. Here the reaction stops at the
mono-nitration stage, however, for the furoxan
synthesis generation of vicinal nitro-nitroso
intermediate is essential (Scheme 4). All the
substrates in Scheme 2 and (Scheme 3) form stable
benzyl radical after initial mono nitration (Scheme 4),
but in alicyclic alkenes formation of such stable
benzylic radical is not possible as a result none of the
substrates gave furoxan as their products.
Nevertheless formation of similar nitro alkenes have
been reported using TBN in the presence of TEMPO
but only from terminal alkenes.[9c] Acyclic trans-
alkenes such as prop-2-ene-1,1,3-triyltribenzene (23)
and 3-(4-bromophenyl)prop-2-ene-1,1-diyl)dibenzene
(24) provided their 3-nitroproducts (23a) and (24a) in
51% and 57% yields respectively rather than the
expected 2-nitroproducts. The structure of the product
(23a) is 3-nitro and not 2-nitro has been confirmed by
1
Spectroscopic (IR, H and 13C NMR) analysis of the
isolated product (14a) showed the absence of COOH
group. The HRMS analysis of the new product
revealed the loss of a COOH group and incorporation
of a NO2 group. Here, perhaps tert-butyl nitrite (a) is
serving as a decarboxylative nitrating agent because
their corresponding ester did not yield any trace of
the nitroalkene (nor even furoxan). To explore the
generality of this strategy, the reaction of electron-
donating such as 4-Me (15), 4-OMe (16) and
electron-withdrawing such as 4-Cl (17), 4-Br (18),
and 3-NO2-4-Cl (19) substituents present in the aryl
ring of the cinnamic acids all afforded β-nitration
products (15a, 79%), (16a, 81%), (17a, 85%), (18a,
83%) and (19a, 76%) (Scheme 5) in good yields.
Prior to this report there are reports on
decarboxylative nitration using HNO3,[12a-c] tBuONO
in combination with CuCl[12d] and TEMPO.[9k] Few
other methods such as Henry reaction involving
nitroalkanes,[12e] and direct nitration of alkenes using
[12f]
AgNO2
have also been reported for the synthesis
of nitroalkenes. Although few decarboxylative
nitration are reported, which have been achieved
either using metal catalyst or the use of harsh reaction
conditions such as high temperature, highly acidic
conditions or stoichometric amounts of metal
nitrates.[12] It may be mentioned here that the nitro-
olefins are a distinguished class of synthetic
5
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10.1002/adsc.201800668
Advanced Synthesis & Catalysis
X-ray crystallographic analysis (Figure S3).[14]
Similarly the structure of (24a) is ascertained by
NOE experiments (SI). Interestingly, under the
present reaction condition terminal alkene viz. allyl
cyclopentane (25) afforded the isoxazoline product
(25a, 59%) (Scheme 7). This result is not surprising
since we have recently reported the formation of
isoxazoline from terminal alkenes using TBN,
quinoline in the presence of catalyst Sc(OTf)3.[9l]
unexpected 3-nitroprop-1-ene-1,1,3-triyl)tribenzene
(23a) is shown in [Scheme 8 (iii)].
Scheme 6. Nitration of alicyclic alkenes.
Reaction conditions: (20-22) (0.50 mmol), K2S2O8 (0.50
mmol), quinoline (0.50 mmol), tert-butyl nitrite (1.0
mmol) in CH3CN (1.5 mL) at 85 °C for 5 h. Isolated yields.
Scheme 8. Plausible mechanism for synthesis of
nitroolefins.
In conclusion we have demonstrated the
differential reactivity of various alkenes with tert-
butyl nitrite (TBN). Internal benzylic alkenes such as
(E)-1,3-diphenyl-1-butene gave furoxan as the
exclusive product in the presence of K2S2O8, base and
TBN. While α,β-unsaturated esters are inert to TBN
but α,β-unsaturated acids under an identical condition
undergo a rapid decarboxylation giving nitroalkenes.
On the other hand, acyclic internal alkenes yielded
nitro alkenes as the sole product, whereas terminal
aliphatic alkenes gave isooxazolines as their product.
In the furoxan formation, TBN is serving as a NO2
cum NO synthon and as a decarboxylative nitrating
agent when the substrates are α,β-unsaturated acids.
Scheme 7. Nitration of acyclic alkenes.
Reaction conditions: (23-25) (0.50 mmol), K2S2O8 (0.50
mmol), quinoline (0.50 mmol), tert-butyl nitrite (1.0
mmol) in CH3CN (1.5 mL) at 85 °C for 5 h. Isolated yields.
[a]Using allylcyclopentane (1.0 mmol).
To account for the formation of nitroalkenes from
-unsaturated carboxylic acids and alicyclic
alkenes, the following mechanism has been proposed.
The carboxylic acid reacts with the base and form its
potassium salt (E) [Scheme 8 (i)]. The NO2 radical
generated via heterolytic cleavage of TBN and
subsequent oxidation reacts with (E) to form a radical
Experimental Section
General Procedure for the Synthesis of 4-Phenyl-3-(1-
phenylethyl)-1,2,5-oxadiazole 2-oxide (1a)
intermediate
(F),
which
upon
oxidative
decarboxylation gives (14a) [Scheme 8 (i)]. An
analogous mechanism has been proposed for the
formation of nitroalkenes from alicyclic alkenes. The
NO2 radical reacts with alicyclic alkene (20) to form
a radical intermediate (G) [Scheme 8 (ii)], one
electron oxidation of (G) gives rise to the carbocation
intermediate (H). In the presence of base, the
intermediate (H) loses a proton to give (20a)
[Scheme 8 (ii)]. Mechanism for the formation of the
To an oven-dried 25 mL round bottom flask fitted with a
reflux condenser were added (E)-but-1-ene-1,3-
diyldibenzene (104 mg, 0.5 mmol), K2S2O8 (135 mg, 0.5
mmol), quinoline (0.059 mL, 0.5 mmol), tert-butyl nitrite
(0.119 mL, 1.0 mmol) and acetonitrile (1.5 mL) Then the
°
reaction mixture was heated at 85 C for 5.0 h. After the
completion of the reaction excess solvent was evacuated
under reduced pressure. The reaction mixture was admixed
with ethyl acetate 20 mL and washed with water (2 x 10
6
This article is protected by copyright. All rights reserved.

10.1002/adsc.201800668
Advanced Synthesis & Catalysis
mL). The separated organic layer was dried over
anhydrous sodium sulphate (Na2SO4), and evaporated
under reduced pressure. The crude product so obtained was
purified by silica gel column chromatography using hexane
as the eluent to give pure 4-phenyl-3-(1-phenylethyl)-
1,2,5-oxadiazole 2-oxide (1a, 98 mg, 73% yield). The
identity and purity of the product was confirmed by
spectroscopic analysis.
C. Dias, E. I. Ferreira, Eur. J. Med. Chem. 2014, 82,
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Med. Chem. 2012, 55, 7583-7592; d) P. Hernandez, M.
Cabrera, M. L. Lavaggi, L. Celano, I. Tiscornia, T. R.
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General Procedure for the Synthesis of E-(2-
Nitrovinyl)benzene (14a)
To an oven-dried 25 mL round bottom flask fitted with a
reflux condenser were added trans-cinnamic acid (74 mg,
0.5 mmol), K2S2O8 (135 mg, 0.5 mmol), quinoline (0.059
mL, 0.5 mmol), tert-butyl nitrite (0.119 mL, 1.0 mmol) and
acetonitrile (1.5 mL). Then the reaction mixture was
°
heated at 85 C for 5.0 h. After the completion of the
reaction excess solvent was evacuated under reduced
pressure. The reaction mixture was admixed with ethyl
acetate 20 mL washed with water (2 x 10 mL). The
separated organic layer was dried over anhydrous sodium
sulphate (Na2SO4), and evaporated under reduced pressure.
The crude product so obtained was purified by silica gel
column chromatography using hexane as the eluent to give
pure E-(2-nitrovinyl)benzene (14a, 57 mg, 77% yield). The
identity and purity of the product was confirmed by
spectroscopic analysis.
General Procedure for the Synthesis of 1-
Nitrocyclohex-1-ene (20a)
To an oven-dried 25 mL round bottom flask fitted with a
reflux condenser were added cyclohexene (41 mg, 0.5
mmol), K2S2O8 (135 mg, 0.5 mmol), quinoline (0.059 mL,
0.5 mmol), tert-butyl nitrite (0.119 mL, 1.0 mmol) and
acetonitrile (1.5 mL) Then the reaction mixture was heated
°
at 85 C for 5.0 h. After completion of the reaction excess
solvent was evacuated under reduced pressure. The
reaction mixture was admixed with ethyl acetate 20 mL
and water (2 x10 mL) and the separated organic layer was
dried over anhydrous sodium sulphate (Na2SO4), and
evaporated under reduced pressure. The crude product so
obtained was purified by silica gel column chromatography
using hexane as the eluent to give pure 1-nitrocyclohex-1-
ene (20a, 47 mg, 74% yield). The identity and purity of the
product was confirmed by spectroscopic analysis.
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Acknowledgements
B.K.P. acknowledges the support of this research by the
Department of Science and Technology (DST/SERB)
(EMR/2016/007042), DST-FIST, and MHRD: 5-5/2014-TS-VII.
CIF, IIT Guwahati for instrumental facilities.
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8
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10.1002/adsc.201800668
Advanced Synthesis & Catalysis
UPDATE
tert-Butyl
Nitrite
Mediated
Different
Functionalizations of Internal Alkenes: Paths to
Furoxans and Nitroalkenes
Adv. Synth. Catal.Year, Volume, Page – Page
B. A. Mir, S. J. Singh, R. Kumar and B. K. Patel*
9
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