A three-component approach to isoxazolines and isoxazoles under metal-free conditions

Article abstract of DOI:10.1039/c9ob01909j

A 1,3-dipolar cycloaddition of 2-methylquinoline, tert-butyl nitrite (TBN) and alkynes or alkenes for the synthesis of biheteroaryls containing both isoxazoline/isoxazole and quinoline motifs has been developed. In this protocol, TBN serves as a convenient N-O source to convert 2-methylquinoline into intermediate nitrile oxides in situ.

Full text of DOI:10.1039/c9ob01909j

Organic &
Biomolecular Chemistry
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A three-component approach to isoxazolines and
isoxazoles under metal-free conditions†
Dahan Wang,a Feng Zhang,b Fuhong Xiao *a and Guo-Jun Deng
Cite this: Org. Biomol. Chem., 2019,
17, 9163
a
*
Received 31st August 2019,
Accepted 1st October 2019
A 1,3-dipolar cycloaddition of 2-methylquinoline, tert-butyl nitrite (TBN) and alkynes or alkenes for the
synthesis of biheteroaryls containing both isoxazoline/isoxazole and quinoline motifs has been developed.
In this protocol, TBN serves as a convenient N–O source to convert 2-methylquinoline into intermediate
nitrile oxides in situ.
DOI: 10.1039/c9ob01909j
rsc.li/obc
Isoxazoles and isoxazolines are important and prevalent five- alkynes using TBN as a convenient N–O source (Scheme 1, (a)).9
membered N,O-heterocycles and are present in many natural Subsequently, Hu’s group developed a Cu-catalyzed cascade
products, bioactive compounds and chiral ligands.1 They can sequence for the synthesis of fluoroalkylated isoxazoles from
also be used as versatile synthons for the diverse synthesis of commercially available amines and alkynes (Scheme 1, (b)).10
valuable molecules in organic synthesis.2 Consequently, Biheteroaryls are an important class of organic functional
several efficient and practical methods have been developed compounds. Meanwhile, the quinoline scaffold is particularly
for the construction of various isoxazole rings.3 Among these important as it can be found in a large variety of bioactive
methods, a well-established approach for the synthesis of iso- compounds.11 We and others have reported several unactivated
xazolines is the 1,3-dipolar cycloaddition of nitrile oxides with alkyl quinoline C(sp3)–H bond functionalization for the
unsaturated compounds (alkenes, enols or alkynes) under straightforward preparation of biheteroaryls.12 In 2015, Yang’s
terminal oxidant conditions (such as oxone, phenyliodine bis group described the reaction of Cu-catalyzed 2-methyl-
(trifluoroacetate) or t-BuOI).4 These methods have the dis- quinoline and aliphatic alkenes/alkynes to obtain isoxazolines/
advantage of the need for the preparation of precursors for isoxazoles by using potassium nitrate as a N–O source
cycloaddition to occur, because nitrile oxides are commonly (Scheme 1, (c)).13 Thus far, sustainable progress has been
generated by the elimination of HCl from hydroximinoyl chlor- made in the area of using cheap nitrates as a N–O source.14
ides in the presence of a base.5 Furthermore, hydroximinoyl Nevertheless, most of these reactions suffer from some limit-
chlorides are generally prepared from the corresponding aldox- ations, such as limited substrate scope, poor regioselectivity or
imes and electrophilic chlorine-containing sources.6 Thus it is the need for toxic metal catalysts. In this study, we describe a
still necessary to explore new strategies for the in situ for-
mation of nitrile oxides from simple starting materials under
mild reaction conditions.
As a versatile reagent, tert-butyl nitrite (TBN) has been
receiving more and more attention because of its advantages
such as commercial availability, low cost, good solubility in
organic solvents and ease of handling.7 In recent years,
various methods have been developed to introduce TBN into
more complex molecules as a N–O source.8 For example, in
2017, Patel reported a Sc-catalyzed domino synthesis of
isoxazolines and isoxazoles from terminal aryl alkenes and
aKey Laboratory of Environmentally Friendly Chemistry and Application of Ministry
of Education, Key Laboratory for Green Organic Synthesis and Application of Hunan.
Province, College of Chemistry, Xiangtan University, Xiangtan 411105, China.
E-mail: fhxiao@xtu.edu.cn, gjdeng@xtu.edu.cn
bCollege of Science, Hunan Agricultural University, Changsha 410128, China
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c9ob01909j
Scheme 1 Synthesis of isoxazolines and isoxazoles from TBN.
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cascade access to 3-(quinolin-2-yl)isoxazoles: the quinoline-2- dinitrobenzoic acid was the most effective and afforded 3aa in
carbaldehyde oxime, in situ generated through nucleophilic 88% yield (entries 14–16). When the reaction was conducted at
addition of 2-methylquinoline and TBN, undergoes formal 1,3- 100 °C, the yield of 3aa decreased to 63% (entry 17).
dipolar cycloaddition with alkenes or alkynes to form the
With this cycloaddition procedure in hand, the substrate
target biheteroaryls under metal free conditions (Scheme 1, scope with respect to 2-methylquinoline was explored
(d)). This present protocol is distinct from those of previous (Table 2). The model reaction of 2-methylquinoline (1a) with
studies (Scheme 1, (a–c)) owing to its metal-free nature, which phenylacetylene (2a) and TBN gave the desired product 3aa in
should make it more practical and useful from a drug develop- 85% isolated yield. A series of functional groups at the C6-posi-
ment perspective as the metal-contamination problem is tion of quinolines, such as methyl, halogen, oxethyl and
avoided. Being suitable for arylenes, styrenes and 2-methyl- acetyl, were tolerated under the optimal reaction conditions,
benzothiazoles is another added benefit of this method rela- and the desired products 3ba–3ha were obtained in high
tive to Yang’s work.
yields. 2-Methylquinolines with a chloro group at the C-4, C-6
Our studies began with a three-component cycloaddition of and C-7 positions all smoothly coupled with 2a and gave the
2-methylquinoline (1a) with phenylacetylene (2a) and TBN in desired products in 71%, 87% and 85% yields, respectively.
the presence of NH4I at 110 °C for 1.5 h, and selected results 2-Methylquinolines with methoxy at the C8-position were also
are shown in Table 1. The reaction was carried out to afford tolerated well, giving the corresponding product 3ja in 88%
the desired product 3aa in 35% yield (entry 1). Lower yields yield. Apart from 2-methylquinolines, other methylquinolines
were obtained when other iodide-containing additives were such as 4-methylquinoline (1l), 2-methylquinoxaline (1m),
screened for the transformation (entries 2–4). Further solvent 1-methylisoquinoline (1n) and 2-methyl-1,8-naphthyridine (1o)
screening showed that DMAc is the best reaction medium for could also be used in this direct cycloaddition, giving the
this cycloaddition (entries 5–8). Interestingly, the use of 0.5 corresponding products in moderate to good yields.
equiv. NCS (N-chlorosuccinimide) promoted the yield of 3aa to 3-Methylbenzo[f]quinoline (1p) was also used as a substrate
58% (entry 9), while NBS (N-bromosuccinimide) proved to be for this kind of reaction. Next, we turned our attention to
ineffective (entry 10). To improve the reaction yield, several acids evaluate the substrate scope with respect to alkynes. Various
were screened for this kind of transformation. When acetic acid alkynes with different substituents were investigated for the
and trifluoroacetic acid (TFA) were added, the desired products synthesis of isoxazoles (Table 3). A range of para substituted
were obtained in 63% and 60% yields (entries 11 and 12), phenylacetylenes smoothly reacted with 1a to give isoxazoles
respectively. A slightly higher yield could be obtained using 3ab–3aj in moderate to good yields. The position of the substi-
benzoic acid (entry 13). Among the aromatic acids screened, 2,4- tuent on the benzene ring (ortho or meta) slightly affected the
reaction yields (3ak–3am). Furthermore, similar yields were
obtained when electron-deficient alkynes were used as sub-
Table 1 Optimization of reaction conditionsa
Table 2 Substrate scope with respect to methyl aza-heterocyclesa
Additive Additive
Yieldb
Solvent (%)
Entry
A
B
Acid
1
2
3
4
NH4I
NaI
NIS
DMAc
DMAc
DMAc
DMAc
35
17
20
22
I2
5
6
7
8
NH4I
NH4I
NH4I
NH4I
NH4I
NH4I
NH4I
NH4I
NH4I
NH4I
NH4I
NH4I
NH4I
DMSO 18
CH3CN 10
DMF
23
21
58
34
63
60
69
88
74
68
63
NMP
9
NCS
NBS
NCS
NCS
NCS
NCS
NCS
NCS
NCS
DMAc
DMAc
DMAc
DMAc
DMAc
10
11
12
13
14
15
16
17c
AcOH
TFA
Benzoic acid
2,4-Dinitrobenzoic acid DMAc
4-Nitrobenzoic acid
Salicylic acid
DMAc
DMAc
2,4-Dinitrobenzoic acid DMAc
a Conditions: 1a (0.2 mmol), 2a (0.4 mmol), TBN (0.6 mmol), additive a Conditions: 1 (0.2 mmol), 2a (0.4 mmol), TBN (0.6 mmol), NH4I
A (0.15 mmol), additive B (0.1 mmol), acid (0.2 mmol), DMAc (0.5 mL), (0.15 mmol), NCS (0.1 mmol), 2,4-dinitrobenzoic acid (0.2 mmol),
110 °C, 1.5 h, under air. b GC yield base on 1a. c 100 °C.
9164 | Org. Biomol. Chem., 2019, 17, 9163–9168
DMAc (0.5 mL), 110 °C, 1.5 h, under air.
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Table 3 Substrate scope with respect to alkynesa
Table 4 Substrate scope with respect to alkenesa
a Conditions: 1a (0.2 mmol), 4 (0.4 mmol), TBN (0.6 mmol), NH4I
(0.15 mmol), NCS (0.1 mmol), 2,4-dinitrobenzoic acid (0.2 mmol),
DMAc (0.5 mL), 110 °C, 1.5 h, under air.
Finally, 2-methylbenzothiazoles could also convert to the
corresponding products when the amount of NH4I was
increased to 0.3 mmol (Table 5). The reaction of 2-methyl-
benzothiazole (6a) and ethynylbenzene (2a) generated the
corresponding isoxazole (7aa) in 58% isolated yield. Methyl-
and fluoro-2-methylbenzothiazoles (7ab and 7ac) were also
smoothly reacted with 2a to afford the target products in mod-
erate yields. The reactions with substituted phenylacetylenes
proceeded smoothly to give the desired products (7ad and
a Conditions: 1a (0.2 mmol), 2 (0.4 mmol), TBN (0.6 mmol), NH4I
(0.15 mmol), NCS (0.1 mmol), 2,4-dinitrobenzoic acid (0.2 mmol),
DMAc (0.5 mL), 110 °C, 1.5 h, under air.
strates (2n–2p). Other aliphatic alkynes (2q–2t) were also found
to be suitable substrates and they can give the desired pro-
ducts in good yields. It is noteworthy that the aliphatic alkyne
bearing a free hydroxyl group afforded the desired product 3au
in good yield. To our delight, moderate yields were obtained
when heterocyclic aromatic alkynes such as 2-ethynylpyridine
(2w) and 2-ethynylthiophene (2v) were used. Non-terminal
alkynes (2x and 2y) also underwent cycloaddition to give the
corresponding products (3ax and 3ay5f,15) in moderate yields.
When 1,4-diethynylbenzene (2z) and octa-1,7-diyne (2aa) were
used as substrates, mono-cyclization products (3az and 3aaa)
were obtained.
Table 5 Substrate scope with respect to 2-methylbenzothiazolesa
Subsequently, alkenes also served as outstanding dipolaro-
philes in this system and afforded the corresponding isoxazo-
lines in moderate to good yields (Table 4). When styrene was
used in this strategy, the desired product 5aa could be
obtained in 76% yield. In general, electron-rich styrenes and
halo-substituted styrenes afforded the corresponding isoxazo-
lines 5ab–5ah in good yields. This 1,3-dipolar cycloaddition
also gave good yields for aliphatic alkenes (5ai, 5ak and 5al).
Gratifyingly, substrate 4j with an electron-withdrawing ester
group was successfully converted into 5aj in 59% yield.4c,d
Treatment of 1,1-disubstituted styrenes, such as 1,1-diphenyl-
ethylene (4m), prop-1-en-2-ylbenzene (4n) and isobutyl meth-
acrylate (4o), also gave cyclization products (5am–5ao) in good
yields. No desired product was obtained when (E)-1,2-diphenyl-
ethylene was used as a substrate.
a Conditions: 1a (0.2 mmol), 4 (0.4 mmol), TBN (0.6 mmol), NH4I
(0.3 mmol), NCS (0.1 mmol), 2,4-dinitrobenzoic acid (0.2 mmol),
DMAc (0.5 mL), 110 °C, 1.5 h, under air.
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7ae). To our delight, 2-methylbenzoxazole (7af) was also suit-
able for this cycloaddition procedure. A range of other methyl-
heterocycles such as 2-methylpyridine, 2-methylpyrazine
2-methyl-1H-benzo[d]imidazole, 2-methyl-1H-indole, 8-methyl-
quinoline, 3-methylquinoline, 2-methylthiazole and so forth
failed to afford the cyclization products.
The synthetic value of our method was further demon-
strated by the synthetic transformations of the obtained isoxa-
zoles (Scheme 2). For instance, the monochlorinated product
8a was obtained in 75% yield from isoxazole 3aa. Furthermore,
isoxazole 3aa was reduced by Mo(CO)6 to give β-aminoenones
8b in 93% yield through the ring-opening reaction. The incor-
poration of a bromo-substituent in product 3ea allows for
further synthetic modification through the Pd-catalyzed
Sonogashira coupling reaction which provides rapid access to
a broader range of functional molecules.
To elucidate our speculations on the reaction mechanism,
several control experiments were conducted (Scheme 3). The
transformation was almost completely inhibited and only
trace amounts of 3aa were detected when 3 equivalents of
2,6-di-tert-butyl-4-hydroxytoluene (BHT) were added to the
Scheme 4 Possible reaction mechanism.
reaction as a radical scavenger under standard conditions
(Scheme 3, (a)). This indicates that a radical pathway might be
involved in this reaction. It was assumed that the reaction
might proceed via cycloaddition of intermediate 9a with 2a,
affording the desired product 3aa in 51% yield (Scheme 3, (b)).
This result indicates that 9a was the possible intermediate to
obtain the final product, whereas 9a was not obtained under
the standard reaction conditions. But the dehydration product
nitrile 10a was detected by GC, showing that 9a might not be
stable at high temperature and under strong oxidant con-
ditions (Scheme 3, (c)).
On the basis of the aforementioned experimental results
and previously reported studies, possible reaction mechanisms
have been proposed (Scheme 4). Brønsted acid could promote
the isomerization of 2-methylquinoline 1a to intermediate A,
which reacts with TBN to generate a reactive intermediate B
and release a tert-butoxy radical. Subsequently, oxidation of
intermediate B generates 2-(nitrosomethyl)quinoline C, which
undergoes tautomerization to form oxime 9a. Then, oxime 9a
can be further oxidized by NCS (or I+ which was produced by
oxidizing iodine anions or TBN which is used in excess4b,8j) to
generate the nitrile oxides D which could be converted to the
desired isoxazole through 1,3-dipolar cycloaddition.6c,8j,15
In summary, we have developed an efficient and practical
1,3-dipolar cycloaddition for the synthesis of a variety of isoxa-
zolines and isoxazoles under metal-free conditions. In this
system, TBN serves as a convenient N–O source to convert
2-methylquinoline into nitrile oxides in situ. Functional groups
such as halogen, acetyl and ester groups were well tolerated
under the optimized reaction conditions. This method affords
a simple alternative approach to biologically important bihe-
teroaryls from readily available starting materials.
Scheme 2 Late modification of isoxazole. Reaction conditions: (a) 3aa
(0.2 mmol), NCS (1.5 eq.), DMF (0.5 mL), rt, 24 h. (b) 3aa (0.2 mmol), Mo
(CO)6 (0.2 mmol), CH3CN (1.5 mL), H2O (0.5 mL), Ar, 85 °C, 6 h. (c) 3ea
(0.2 mmol), 2a (0.28 mmol.), PdCl2 (5 mol%), CuI (5 mol%), PPh3
(10 mol%), Et3N (0.5 mL), Ar, 80 °C, 12 h.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
Support from the National Natural Science Foundation of
China (21602187, 21871226) and the Collaborative Innovation
Center of New Chemical Technologies for Environmental
Benignity and Efficient Resource Utilization is gratefully
acknowledged.
Scheme 3 Control experiments.
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