[2 + 2 + 1] Cycloaddition ofN-tosylhydrazones,tert-butyl nitrite and alkenes: a general and practical access to isoxazolines

Article abstract of DOI:10.1039/d1sc02352g

N-Tosylhydrazones have proven to be versatile synthons over the past several decades. However, to our knowledge, the construction of isoxazolines based onN-tosylhydrazones has not been examined. Herein, we report the first demonstrations of [2 + 2 + 1] cycloaddition reactions that allow the facile synthesis of isoxazolines, employingN-tosylhydrazones,tert-butyl nitrite (TBN) and alkenes as reactants. This process represents a new type of cycloaddition reaction with a distinct mechanism that does not involve the participation of nitrile oxides. This approach is both general and practical and exhibits a wide substrate scope, nearly universal functional group compatibility, tolerance of moisture and air, the potential for functionalization of complex bioactive molecules and is readily scaled up. Both control experiments and theoretical calculations indicate that this transformation proceedsviathein situgeneration of a nitronate from the coupling ofN-tosylhydrazone and TBN, followed by cycloaddition with an alkene and subsequent elimination of atert-butyloxy group to give the desired isoxazoline.

Full text of DOI:10.1039/d1sc02352g

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[2 + 2 + 1] Cycloaddition of N-tosylhydrazones,
tert-butyl nitrite and alkenes: a general and
practical access to isoxazolines†
Cite this: Chem. Sci., 2021, 12, 9823
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have been paid for by the Royal Society
of Chemistry
Liang Ma, Feng Jin, Xionglve Cheng, Suyan Tao, Gangzhong Jiang, Xingxing Li,
*
*
Jinwei Yang, Xiaoguang Bao
and Xiaobing Wan
N-Tosylhydrazones have proven to be versatile synthons over the past several decades. However, to our
knowledge, the construction of isoxazolines based on N-tosylhydrazones has not been examined.
Herein, we report the first demonstrations of [2 + 2 + 1] cycloaddition reactions that allow the facile
synthesis of isoxazolines, employing N-tosylhydrazones, tert-butyl nitrite (TBN) and alkenes as reactants.
This process represents a new type of cycloaddition reaction with a distinct mechanism that does not
involve the participation of nitrile oxides. This approach is both general and practical and exhibits a wide
substrate scope, nearly universal functional group compatibility, tolerance of moisture and air, the
potential for functionalization of complex bioactive molecules and is readily scaled up. Both control
experiments and theoretical calculations indicate that this transformation proceeds via the in situ
generation of a nitronate from the coupling of N-tosylhydrazone and TBN, followed by cycloaddition
with an alkene and subsequent elimination of a tert-butyloxy group to give the desired isoxazoline.
Received 28th April 2021
Accepted 19th June 2021
DOI: 10.1039/d1sc02352g
rsc.li/chemical-science
synthesis. Thus, the development of efficient approaches to the
construction of these valuable molecules has received
Introduction
increasing attention. State-of-the-art synthetic methods have
shown that the formation of isoxazolines proceeds primarily via
the [3 + 2] cycloaddition of olens with nitrile oxides generated
in situ. However, the formation of furoxan (a nitrile oxide dimer)
is an undesired side reaction that is difficult to avoid during
such syntheses. The nitrile oxides that are employed in these
procedures are typically derived from aldoximes11 or nitro
compounds,12 although the use of various additives (including
oxidants, bases, Grignard reagents and dehydrating agents) can
cause environmental, cost and safety issues, especially when
employed on an industrial scale. Consequently, alternative
synthetic methods have been examined, such as the intra-
molecular cyclization of b,g-unsaturated oximes,13 the iminoxyl
radical promoted formation of isoxazolines14 and others.15
Despite the signicant achievements to date, the methods that
have been reported oen have limited substrate scopes, espe-
cially with regard to the range of possible functional groups.
Thus, the development of new and versatile techniques for the
synthesis of isoxazolines remains challenging.
Recently, our group demonstrated the synthesis of isoxazo-
lines from diazo compounds bearing electron withdrawing
groups.15a,15d Unfortunately, these diazo compounds have to be
pre-synthesized using a process comprising several time-
consuming steps. More importantly, diazo compounds
without electron withdrawing substituents are usually unstable
and difficult to handle, which limits their synthetic value when
constructing complex structures. Consequently, the present
The electrophilicity of the carbonyl carbon and the acidity of the
a-hydrogen in ketones and aldehydes allow these compounds to
play important roles in synthetic chemistry.1 Over the past several
decades, N-tosylhydrazones, which are readily obtained from
ketones or aldehydes, have rapidly become a new type of versatile
synthon for transition metal-catalysed or metal-free reactions.2
Since the pioneering work by Barluenga,3m–3p a wide range of
transformations using N-tosylhydrazones has been established,
including coupling,3 insertion,4 cyclization,2e,5 olenation6 and
alkynylation7 reactions, and these are now standard methods in
organic synthesis. Although this unconventional manipulation of
carbonyl compounds provides powerful and indispensable
protocols for the facile construction of diverse molecular frame-
works, this rapidly evolving area is still far from mature and there
is ample opportunity for further development. As an example, the
use of N-tosylhydrazones in the synthesis of isoxazolines has not
been explored to date.
Isoxazolines8 are important structural motifs that are ubiq-
uitous in bioactive molecules, pharmaceuticals and chiral
ligands,9 and are also versatile intermediates10 in organic
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry,
Chemical Engineering and Materials Science, Soochow University, Suzhou 215123,
China. E-mail: xgbao@suda.edu.cn; wanxb@suda.edu.cn
† Electronic supplementary information (ESI) available: Experimental procedures,
spectroscopic data, NMR spectra. CCDC 2083541. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/d1sc02352g
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Scheme 2 Initial attempt for the synthesis of isoxazoline.
CuCl2. The desired isoxazoline 3aa was obtained in 10% yield
(Scheme 2). Although the yield was very low, the above results
demonstrated the feasibility of our design. The efficiency of this
isoxazoline formation reaction was enhanced by developing
a one-pot, two-step procedure using commercially available
aldehydes as starting materials. Aer exploring a wide range of
reaction parameters, we determined that the use of CuCl2
(10 mol%) and N,N,N,N,-tetramethylethylenediamine (TMEDA,
1.5 equiv.) gave 3aa in an 88% yield (Table 1, entry 1). It is
important to note that this [2 + 2 + 1] cycloaddition reaction was
Scheme 1 Reaction design: [2 + 2 + 1] cycloaddition to construct
isoxazoline based upon nitronates.
work employed N-tosylhydrazones as more stable surrogates for
unstable diazo compounds. These compounds were generated
in situ from readily obtainable commercial aldehydes and
TsNHNH2, thus providing a new platform for the construction
of isoxazolines. To illustrate the feasibility of this new approach,
we also propose a plausible mechanism herein, as shown in
Scheme 1. In this mechanism, the condensation of aldehydes
with TsNHNH2 generates N-tosylhydrazones I, which are easily
transformed to the diazo compounds II by adding a suitable
base. The loss of a diatomic nitrogen molecule from the diazo in
the presence of a transition metal catalyst affords the carbene
III. Subsequently, III reacts with tert-butyl nitrite (TBN) to
generate the nitronate IV, which then undergoes a [3 + 2]
cycloaddition with an alkene to afford the cycloadduct V.
Table 1 Synthesis of isoxazoline: effect of reaction parametersa
Entry Variation from the “standard conditions” catalyst Yieldb (%)
t
Finally, the elimination of BuOH delivers the desired isoxazo-
line. However, it is very challenging to realize the [2 + 2 + 1]
cycloaddition step in this process because the mechanism
involves several highly reactive intermediates that tend to
undergo undesired side reactions. As an example, the cyclo-
propanation reaction2e,5h between a carbene and an alkene is
a well-known process that can potentially interrupt the forma-
tion of the unstable nitronate. Typically, an electron with-
drawing group must be attached to the a-carbon to both form
and stabilize IV.16 Thus, a lack of suitable electron-withdrawing
groups may not permit the successful in situ generation of IV in
this transformation. Moreover, this nitronate is prone to
decomposition instead of the desired cycloaddition with an
alkene to deliver the cycloadduct V.
Herein, we report the rst-ever construction of isoxazolines
from N-tosylhydrazones. The most important features of this
methodology are the ability to use readily-available aldehydes
and alkenes, a wide substrate scope, signicant functional
group compatibility, the potential for the late-stage modica-
tion of bioactive molecules and scalability to the 20 mmol level.
This new approach to isoxazolines formation proceeds through
a pathway presumably involving unstable nitronates, in sharp
contrast to the classical [3 + 2] cycloaddition of nitrile oxides
with alkenes.
1
2
3
4
5
6
7
8
None
No CuCl2
No TMEDA
88
61
<1
84
54
31
53
81
72
79
68
76
77
83
56
58
<1
68
<1
<1
<1
<1
<1
16
76
84
87
Trace
Acetone instead of THF
MeCN instead of THF
EA instead of THF
Toluene instead of THF
CHCl3 instead of THF
DMF instead of THF
iPrONO instead of tBuONO
nBuONO instead of tBuONO
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
iBuONO instead of BuONO
CuCl instead of CuCl2
CuBr instead of CuCl2
CuI instead of CuCl2
Cu(OAc)2 instead of CuCl2
Cs2CO3 instead of TMEDA
DABCO instead of TMEDA
tBuOLi instead of TMEDA
K2CO3 instead of TMEDA
tBuOK instead of TMEDA
NaOH instead of TMEDA
K3PO4 instead of TMEDA
Na2CO3 instead of TMEDA
N2 instead of air
t
O2 instead of air
At 80 ꢀ
C
At room temperature
a
Reaction conditions: N-tosylhydrazones (0.65 mmol, generated in situ
from 4-bromobenzaldehyde 1a and TsNHNH2), ethyl acrylate 2a (0.50
mmol), CuCl2 (10 mol%), TMEDA (0.75 mmol), and TBN (2.0 mmol)
Results and discussion
b
in 4.0 mL THF at 65 ꢀC for 24 h. Isolated yields of the average of two
In an initial study, we examined the reaction of the diazo
experiments.
compound 1aa with TBN and ethyl acrylate, 2a, catalysed by
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able to tolerate both air and moisture. In addition, 3aa could the [2 + 2 + 1] cycloaddition reaction. This method also showed
still be obtained in a good yield even in the absence of CuCl2 broad compatibility with common functional groups, including
(entry 2). In sharp contrast, a control experiment showed that alkyl (3ac, 3at), halide (3af, 3ag, 3ar, 3as, 3ax, 3ay, 3ha), ether
TMEDA was indispensable to achieving optimal reaction effi- (3ad, 3au, 3aw, 3ba), amide (3an), cyano (3ak), nitro (3al, 3ap),
ciency (entry 3). Similar results were also observed when the sulfonyl (3aj) and triuoromethyl (3ah, 3aq) groups. Remark-
reaction was performed using a variety of nitrites or different ably, aldehydes with more reactive functional groups such as
copper catalysts (entries 10–16). Other bases, including repre- hydroxyl (3ao, 3av, 3aw, 3ay), thioether (3ae), amine (3ai) and
sentative inorganic and organic bases, were less effective than carboxyl (3am) groups, which are typically challenging to use as
TMEDA (entries 17–24), although the atmosphere under which substrates in known methods, reacted smoothly with TBN and
the reaction was performed had little effect on efficiency 2a to provide the corresponding products in satisfactory yields.
(entries 25 and 26). When the reaction was performed at 80 ꢀC Naphthyl-substituted aldehydes were also readily transformed
(entry 27), the yield was nearly identical to that obtained at into the desired products in high yields (3az, 3da). In addition,
ꢀ
65 C, while very little 3aa was produced at room temperature polysubstituted aldehydes were accommodated under the
(entry 28).
optimal conditions, giving the corresponding products in good
With the optimal catalyst and reaction conditions identied, yields (3ax, 3ay, 3ba, 3ga, 3ha). The example of 3fa is especially
we next assessed the scope of aldehyde that could be used in noteworthy, because the double bond in the alkyl chain was
this process (Table 2). Numerous mono-substituted benzalde- retained and therefore could be utilized for further modica-
hydes containing both electron-donating and electron- tions. Biologically active heterocycles, including benzo[b]thio-
withdrawing groups were all found to be viable substrates, phene (3ca), chromone (3ea), antipyrine (3ga) and pyrazole
delivering the desired products in moderate to excellent yields. (3ha), could be converted into the corresponding isoxazoline
The exact structure of 3ab was conrmed by single crystal X-ray products in good yields. Cyclopropanecarboxaldehyde also
diffraction (for details, see the ESI†). Of note, the position of the delivered the desired product 3ia in moderate yield.
substituent (para-, meta- or ortho-) had no signicant effect on
Subsequently, the scope of alkenes was evaluated, as illus-
trated in Table 3. Not surprisingly, a variety of acrylates reacted
smoothly to afford the desired products in good yields. A wide
range of synthetically versatile functional groups, including
ester (4aa–4ae, 4aj, 4ja), triuoromethyl (4ae) and alkyne (4aj)
moieties, were accommodated under the present conditions.
For the reaction of acrylamide, including free amine (4af),
primary amine (4ah) and secondary amine (4ag and 4ai), the
target products were obtained in good yields. Interestingly, the
use of a triene also gave the corresponding isoxazoline 4ja,
albeit in a relatively low yield, and pentauorostyrene delivered
the desired product 4as in a reasonable yield under the stan-
dard conditions. This [2 + 2 + 1] cycloaddition reaction was also
found to be compatible with unactivated aliphatic alkenes (4aw,
4ay, 4ga, 4ka, 4ma–4oa). In addition, styrene derivatives
carrying both electron-donating and electron-withdrawing
groups afforded the corresponding isoxazoline products (4ak–
4ar) in acceptable yields. Under the identical conditions, the
reaction with diethyl vinylphosphonate resulted in the desired
product 4ea in a good yield. Silylated alkenes, including vinyl-
trimethylsilane (4ca) and vinylphenyldimethylsilane (4av), were
also viable substrates for this transformation. Notably, even
enamides (4au), enol esters (4la) and enol ethers (4az) were
smoothly transformed into the corresponding products in
synthetically useful yields. In addition, both internal alkenes
(4ga) and 1,1-disubstitued alkenes (4at, 4ha, 4ma) also under-
went smooth cyclization with satisfactory yields, and two spiro
products (4at and 4ha) were obtained in good yields. Biologi-
cally active heterocycles, including saccharin (4ka) and phtha-
Table 2 Evaluation of aldehydesa
limide (4na), remained intact during the [2
+ 2 + 1]
cycloaddition reaction. It is particularly noteworthy that this
protocol could generate a wide range of isoxazolines, including
those bearing less stable functional groups such as hydroxyl
(4ah, 4aw), NHBoc (4ay), free N–H (4af, 4ah), thioether (4da) and
acetal (4fa) moieties, which are typically challenging substrates
a
Reaction conditions: N-tosylhydrazones (0.65 mmol, generated in situ
from aldehyde 1 and TsNHNH2), ethyl acrylate 2a (0.50 mmol), CuCl2
(10 mol%), TMEDA (0.75 mmol), and TBN (2.0 mmol) in 4.0 mL THF
at 65 ꢀC for 24 h under air atmosphere. For details, see the ESI.
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Table 3 Evaluation of alkenesa
Table 4 Synthetic application for biologically important derivativesa
a
Reaction conditions: N-tosylhydrazones (0.65 mmol, generated in situ
from aldehydes 1 and TsNHNH2), alkenes 2 (0.50 mmol), CuCl2
(10 mol%), TMEDA (0.75 mmol), and TBN (2.0 mmol) in 4.0 mL THF
at 65 ꢀC for 24 h under air atmosphere.
bromobenzaldehyde, 1a, under the established conditions, and
were transformed into the corresponding isoxazolines in moderate
to good yields. These examples highlight the wide applicability of
this new method, and we therefore envision that this protocol
could have potential applications in drug development.
Another advantage of our cycloaddition approach is ready
scalability, as shown in Scheme 3. The reaction of 26 mmol 1a,
28 mmol TsNHNH2, 20 mmol 2a and 80 mmol TBN with
10 mol% CuCl2 at 65 ꢀC for 24 h, followed by ltration through
a pad of silica gel, afforded 3aa in 85% yield (Scheme 3a). Thus,
there was no signicant loss in efficiency compared with the
reaction on the 0.5 mmol scale. We also conducted further
transformations of the isoxazoline as shown in Scheme 3b. Both
reductive cleavage (13) and hydrolysis (14) proceeded smoothly
to give the corresponding high-value derivatives in good yields.
A variety of control experiments were performed to gain
preliminary insights into the possible mechanistic pathways
(Scheme 4). The addition of butylated hydroxytoluene (BHT)
a
Reaction conditions: N-tosylhydrazones (0.65 mmol, generated in situ
from 4-bromobenzaldehyde 1a and TsNHNH2), alkenes 2 (0.50 mmol),
CuCl2 (10 mol%), TMEDA (0.75 mmol), and TBN (2.0 mmol) in 4.0 mL
THF at 65 ꢀC for 24 h under air atmosphere.
in traditional nitrile oxide cycloadditions. The retention of
these versatile functional groups provides the option for further
modication of the corresponding isoxazolines products.
The excellent functional group tolerance exhibited by this
process prompted us to apply this methodology to bioactive and
pharmaceutical molecules (Table 4). The reactions of N-tosylhy-
drazones with suitable alkenes provided drug candidates such as
carbonic anhydrase inhibitors (5),8a anticancer agents (6)8c and
antibacterial agents (8)8g in one-pot processes with moderate
yields. Furthermore, various complex bioactive molecules (indo-
methacin 7, naproxen 9, pregnenolone 10, estrone 11, ezetemibe
12) reacted with the N-tosylhydrazone obtained from 4-
Scheme 3 Scale-up experiment and further transformations.
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Scheme 4 Probe for the possible mechanism.
only minimally inhibited the formation of isoxazoline 3aa,
indicating that radical intermediates were not involved in this
transformation (Scheme 4a). When oxime (15), a precursor of
nitrile oxide, was subjected to this cycloaddition reaction, only
a small amount of 3aa was obtained (Scheme 4b). In addition,
furoxan 16 in Scheme 4c was not detected during the reaction.
Because the proposed nitronate intermediate did not incorpo-
rate suitable electron-withdrawing groups, and was therefore
not sufficiently stable, it could not be isolated. Fortunately,
a trace amount of nitronate 17 was detected aer careful anal-
ysis using liquid chromatography-high resolution mass spec-
trometry (for details, see the ESI†). Together, these data indicate
that nitronates rather than nitrile oxides were involved in the
isoxazoline formation reaction.
Fig. 1 Energy profiles (in kcal molꢁ1) for the formation of isoxazolines
in the absence of the CuCl2 catalyst. Bond lengths are shown in A˚.
a concerted manner. The computational results also suggested
that the energy barrier to the formation of INT3 via TS2b is
1.6 kcal molꢁ1 lower than that associated with the intermolec-
ular [3 + 2] cycloaddition via TS2c. Thus, the formation of INT3
via TS2b should occur more readily. Finally, the elimination of
tBuOH via TS3c would be expected to give the desired product.
This process could be assisted by a water molecule acting as
a shuttle to transfer a proton via TS3b (Fig. 1). The possible
t
elimination of BuOH from nitronate INT2 to afford a nitrile
Computational studies were also performed to gain further
insight into the isoxazoline formation mechanism. The results
showed that, in the absence of CuCl2 as a catalyst, the nucleo-
philic substitution reaction between a diazo compound (INT1)
generated in situ from the N-tosylhydrazone and TBN produces
transition state TS1. Here, the C1/N1 distance is shortened to
oxide intermediate (INT4) was also considered. When a water
molecule is present to assist the process, the corresponding TS
is TS2a, and the activation energy calculated for this step is
1.7 kcal molꢁ1 higher than that for the intermolecular [3 + 2]
1
2
˚
˚
1.92 A, while the C /N distance is lengthened to 1.39 A
(Fig. 1). Subsequently, a nitronate (INT2) is afforded along with
the release of N2. It is noteworthy that, in the presence of the
copper catalyst, INT1 might coordinate with the CuCl2 to form
complex INT20. This species can subsequently release N2 via
TS10 to generate intermediate INT30 exergonically (Fig. 2).
Following this, the nucleophilic attack of TBN on INT30 via TS20
could afford intermediate INT40, aer which a nitronate (INT2)
is generated via TS30 along with the regeneration of CuCl2.
Similarly, employing CuCl as the catalyst could also promote
the formation of nitronate INT2 via analogous steps (Fig. S3 in
the ESI†). This nitronate could then undergo an intermolecular
[3 + 2] cycloaddition with an alkene (2a) to produce a cyclized
intermediate. Both regioselective cycloaddition pathways were
considered, and the corresponding transition states were
determined to be TS2b (Fig. 1) and TS2c (Fig. S2 in the ESI†),
respectively. In the case of TS2b, the C1/C2 and O1/C3
˚
distances are shortened to 2.12 and 2.34 A, respectively. Thus,
Fig. 2 Energy profile (in kcal molꢁ1) for the formation of nitronate with
the CuCl2 catalyst. Bond lengths are shown in A˚.
the ve-membered ring intermediate INT3 is generated in
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experiments. F. J. and X. B. carried out all computational work.
X. B. and X. W. conceived and directed the project and wrote the
paper. All the authors discussed the results and commented on
the manuscript.
Conflicts of interest
There are no conicts to declare.
Acknowledgements
This work was funded by the Priority Academic Program
Development of Jiangsu Higher Education Institutions (PAPD),
NSFC (grant numbers 21971175, 21572148, 21973068). We
thank Liwen Bianji (Edanz) (https://www.liwenbianji.cn) for
editing the language of a dra of this manuscript.
Scheme 5 Proposed catalytic cycle.
cycloaddition via TS2b. Thus, the formation of the nitrile oxide
intermediate is not suggested in this reaction, although the
subsequent intermolecular [3 + 2] cycloaddition with 2a via
TS3a should proceed to give the desired product. At present, we
suggest that the product is most likely obtained through inter-
mediate INT3 followed by the elimination of tBuOH.
Based on both our experimental results and density func-
tional theory (DFT) calculations, a plausible catalytic cycle was
proposed, as shown in Scheme 5. Initially, a condensation
reaction between the aldehyde and the TsNHNH2 generates the
N-tosylhydrazone A. A then produces the diazo compound B in
the presence of TMEDA, which is subsequently captured by TBN
to form the nitronate C, aided by CuCl2. Next, the [3 + 2]
cycloaddition of C with the alkene gives rise to the nitroso acetal
D.15a,15e,17 Finally, the release of a tert-butyloxy group from D
delivers the desired isoxazoline.
Notes and references
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derivatives, in Organic Reaction Mechanisms 1989, ed. A. C.
Knipe and W. E. Watts, John Wiley & Sons Ltd, 1991, ch. 1;
(b) B. A. Murray, Reactions of Aldehydes and Ketones and
their Derivatives, in Organic Reaction Mechanisms 2015, ed.
A. C. Knipe, John Wiley & Sons Ltd, 2019, ch 1.
2 For selected reviews on this topic, see: (a) Y. Xia and J. Wang,
J. Am. Chem. Soc., 2020, 142, 10592; (b) D. Arunprasath,
B. D. Bala and G. Sekar, Adv. Synth. Catal., 2019, 361, 1172;
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H. Zhang, Chem. Soc. Rev., 2012, 41, 560; (h) J. Barluenga
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3 For recent examples on this topic, see: (a) Y. Yang, J. Tsien,
A. Ben David, J. M. E. Hughes, R. R. Merchant and T. Qin,
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Conclusions
A novel CuCl2-catalysed [2 + 2 + 1] cycloaddition strategy based on
the reaction of N-tosylhydrazones, TBN and alkenes has been
developed and characterized. This modular protocol offers
a practical and exible approach to the synthesis of isoxazolines,
and a vast array of aldehydes and alkenes have been found to be
suitable substrates. Thus, this method represents a highly valu-
able complement to classical nitrile oxide-based cycloaddition.
We believe that this technique may have potential uses in drug
discovery because the synthesis is both facile and compatible
with a wide range of functional groups. DFT calculations and
experimental work provided preliminary mechanistic insights,
and the proposed mechanism evidently involves the generation
of nitronates and subsequent cycloaddition with alkenes.
Further, more detailed investigations of the reaction mechanism
and synthetic applications are in progress in our laboratory.
Data availability
All data is in the ESI.† There is no more to deposit.
Author contributions
L. M. performed the experiments and prepared the ESI.† X. C.,
S. T., G. J., X. L. and J. Y. prepared some substrates and repeated
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9830 | Chem. Sci., 2021, 12, 9823–9830
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