Domino reaction between nitrosoarenes and ynenones for catalyst-free preparation of indanone-fused tetrahydroisoxazoles

Article abstract of DOI:10.1021/acs.orglett.9b00426

A catalyst-free domino reaction to synthesize highly functionalized indanone-fused tetrahydroisoxazole from easily accessed nitrosoarene and 1,6-ynenone with good chemo- A nd regioselectivity was disclosed. This unprecedented domino reaction represents a new strategy for multifunctionalization of an internal alkyne with nitrosoarene by formation of two rings and four bonds in a single operation.

Full text of DOI:10.1021/acs.orglett.9b00426

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Domino Reaction between Nitrosoarenes and Ynenones for
Catalyst-Free Preparation of Indanone-Fused Tetrahydroisoxazoles
†
†
‡
,†,‡
Shaotong Qiu, Renxiao Liang, Yongdong Wang, and Shifa Zhu*
†Key Laboratory of Functional Molecular Engineering of Guangdong Province and Guangdong Engineering Research Center for
Green Fine Chemicals, School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou,
5
‡
10640, China
Singfar Laboratories, Guangzhou, 510670, China
S Supporting Information
*
ABSTRACT: A catalyst-free domino reaction to synthesize highly
functionalized indanone-fused tetrahydroisoxazole from easily accessed
nitrosoarene and 1,6-ynenone with good chemo- and regioselectivity was
disclosed. This unprecedented domino reaction represents a new strategy for
multifunctionalization of an internal alkyne with nitrosoarene by formation
of two rings and four bonds in a single operation.
itroxy containing compounds are widely accepted as
Scheme 2. Overview of Multifunctionalization of Alkyne
N
powerful building blocks since these N−O containing
with Nitrosoarene
species can be transformed into important precursors for
agrochemical, pharmaceutical, and fine chemical industries.
1
Particularly nitroso species may be regarded as nucleophiles,
2
3
electrophiles, and even radical precursors in some cases
Scheme 1).
(
Scheme 1. Versatile Reactivity of Nitrosoarene
Recently, much attention has been drawn to multi-
funtionalization of alkynes with nitrosoarenes to synthesize
various molecules. For example, terminal alkynes reacted with
nitrosoarenes to afford indole derivatives via 1,4 diradical
4
intermediates. When a bulky 2,6-dihalonitrosoarene is used,
an α-styryl cation is produced, which is attacked by another
5
nitrosoarene to provide a dinitrone (Scheme 2a). Beside
terminal alkynes, the Liu group found that ynamide and
propiolate could also react with nitrosoarene to give 2-
oxoiminylamide and α-imidoyl nitrone with gold salt as the
6
,7
alkynes with nitroarenes still remains unsolved due to its
inherent low reactivity and undesired side reaction.
catalyst (Scheme 2b−c). As for the common internal alkyne,
fewer examples have been reported due to its relatively lower
reactivity compared with the terminal alkyne, ynamide and
propiolate. In 1922, Alessandri reported a solvent-evaporated
method to achieve dinitrones for 2 months. A higher reaction
temperature was tried to shorten the conversion time, while
the desired product was obtained in a decreased yield with a
As part of our continuous efforts in developing highly
10
efficient tandem reactions based on alkyne chemistry, here,
we devised a new kind of substrate of 1 with both an internal
alkyne and deficient CC bifunctional groups, in which the
internal alkyne was first attacked by two nitrosobenzenes to
form dinitrone dipoles, and triggered the subsequent [3 + 2]
8
large quantity of azoxyarenes detected, which indicated
nitrosoarene has a strong tendency to react with itself to
form the undesired byproduct (Scheme 2d). To our
9
Received: January 31, 2019
knowledge, the multifunctionalization of common internal
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00426
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
1
1,12
domino reaction
with the deficient alkene; thus, two rings
tetrahydroisoxazole 4a was also detected (entries 7 to 12).
Both structures of 3a and 4a were confirmed by X-ray
diffraction analysis (see the Supporting Information).
with four new bonds were built up rapidly in a single operation
Scheme 3). It was noted that in this process a highly
functionalized tetrahydroisoxazole was furnished.
(
13
Based on the optimized reaction condition (Table 1, entry
1
0), the substrate scope of this protocol was examined. As
shown in Scheme 4, the reaction could be scaled up to 10
Scheme 3. New Strategy for Multifunctionalization of
Internal Alkyne with Nitrosoarene
mmol, giving the product 3a in 60% yield. 1,6-Ynenones with
1
different substituent groups at R gave the desired products
3
b−i in good yields (60−80%). The reaction seemed
insensitive to both the electron property and steric hindrance
of the R group. An attempt to extend this reaction to
1
heterocycles also succeeded (3j), albeit the terminal alkenyl
failed to give the desired product (3k). When ynenones with
different capping aryl groups on the CC triple bond were
tested, they all gave the corresponding products smoothly (3l−
p, 52−74%). Besides, the substrate with a cyclopropyl capping
group also successfully gave the desired product in 41% yield
With this design in mind, the easily accessed 1,6-ynenone 1a
was selected as a model substrate. Initial efforts were made to
systematically screen the suitable conditions to convert alkyne
1a and nitrosobenzene 2a into the target product (Table 1).
(
3q), while linear hexyl substituted 1r resulted in a sharp
a
decrease in reaction yield (3r). Furthermore, ynenones bearing
different R substituents at the phenylene ring could also be
Table 1. Optimization of Reaction Conditions
3
effectively converted into the target products (3s−u, 59−
75%). To further study the robustness of this reaction system,
nitrosobenzenes containing different functionalized groups
were also investigated. As our expectation, nitrosobenzenes
with both electronic-withdrawing and -donating groups were
all compatible with our protocol (3v−x). Additionally, it was
found that electronic-deficient nitrosobenzene performed
slightly better than the electron-rich one.
c
yield (%)
b
entry
catalyst
solvent
T (°C)
3a
4a
5a
To broaden the generality of this transformation, electron-
deficient alkenes were tested to conduct the intermolecular
reactions. As shown in Scheme 5, neither isoxazole 7 nor 8 was
detected in the standard condition. Major azoxybenzene 5a
was furnished, which was consistent with the previous results
mentioned above (Scheme 2d).
To better understand the reaction mechanism, control
reactions were then carried out (Scheme 6). Initially,
azoxybenzene 5a was isolated and added into the reaction
system under standard conditions to test whether 5a was
involved as an intermediate. However, no desired product was
detected even after 24 h of heating (eq 1). When 1.5 equiv of
TEMPO was added, the reaction seemed to be depressed
partially. The desired product 3a was isolated only in 17%
yield, which indicated that a radical process might be involved
(eq 2).
Based on the results in hand, a possible reaction mechanism
was proposed (Scheme 7). First, the internal alkyne of the
ynenone was attacked by two nitrosobenzenes to form
dinitrone intermediate A, which underwent [2 + 3] dipolar
cycloaddition to give the final product 3 or 4. There might
exist two reaction pathways (paths a and b), as either nitrone
in intermediate A could react with the CC double bond. For
path a, indanone-fused tetrahydroisoxazole 3 was formed
preferably due to less steric hindrance in the cycloaddition
process. As for path b, naphthalenone-fused tetrahydroisox-
azole B was produced. Furthermore, with the attack of an
external nitrosobenzene, an O-bridged intermediate C might
be generated, followed by release of one nitrosoarene molecule
to furnish the desired product 4.
1
2
3
4
5
6
7
8
IPrAuNTf2
AgNTf2
Pd(OAc)2
PtCl2
DCE
DCE
DCE
DCE
DCE
DCE
DCE
MeCN
CHCl3
CHCl3
CHCl3
CHCl3
80
80
80
80
80
80
80
80
80
80
100
60
15
nd
nd
20
30
32
36
62
66
nd
nd
nd
nd
nd
nd
<5
5
5
9
6
<5
trace
trace
trace
nd
trace
nd
32
28
24
25
Rh (OAc)
2
4
CuCl2
−
−
−
−
−
−
9
d
e
1
1
1
0
69
d
,
,
f
1
2
56
40
30
22
d
g
h
a
Unless otherwise noted, the reaction was performed with 1a (0.25
mmol) and 2a (1.0 mmol) for 24 h, under a N atmosphere. 5 mol
b
2
c
1
%
. The yield was determined by H NMR using CH NO as an
3 2
d e f
internal standard. 100 mg 4 Å MS was added. Isolated yield. 100
g
h
°
C. 60 °C. 40% 1a was recovered.
IPrAuNTf , AgNTf , and Pd(OAc) were tested as the
catalysts which are typically regarded as good catalysts for
alkynes activation in organic synthesis. As shown in Table 1,
IPrAuNTf gave 3a in 15% yield in DCE at 80 °C while
AgNTf and Pd(OAc) showed no catalytic activity (Table 1,
entries 1−3). PtCl , almost similar as IPrAuNTf , gave the
product 3a in 20% yield (entry 4). When Rh (OAc) or CuCl
was used, the yield of 3a was raised to 30% and 32%
respectively (entries 5−6). To our surprise, 3a could also be
observed in the absence of catalyst (entry 7). Therefore, the
reaction conditions without catalyst were then screened
2
2
2
2
2
2
2
2
2
4
2
(
entries 8−12). It was found that MeCN and CHCl were
3
better solvents (62% and 66%, entries 8−9). Additionally,
With the tetrahydroisoxazoles 3 in hand, further chemical
transformations were performed to demonstrate the potential
applications of these molecules (Scheme 8). Taking 3a as an
example, the nitrone of 3a could be easily trapped by in situ
generated benzyne, giving [2 + 3] annulation product 9 in 52%
when 4 Å MS was added, the yield of 3a was increased to 69%
(
entry 10). Variation of reaction temperature could not further
improve the reaction yield (entries 11−12) (see Supporting
Information for more details). Besides, naphthalenone-fused
B
DOI: 10.1021/acs.orglett.9b00426
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 4. Substrate Scopes
a
Unless otherwise noted, the reaction was performed with 1 (0.25 mmol) and 2 (1.0 mmol), in CHCl (2 mL) for 24 h, under a N atmosphere;
3
2
b
c
isolated yield. See ref 14. The reaction was conducted in 60 °C, 48 h.
Scheme 5. Intermolecular Trapping
Scheme 7. Proposed Reaction Mechanism
Scheme 6. Control Reactions
Scheme 8. Further Transformations of 3a
yield. In hot EtOH, water could attack the nitrone group of 3a,
providing 10 in 82% yield. It was noted that product 9
represented tetrafunctionalization of the CC triple bond of
substrate 1.
In summary, we have developed a catalyst-free method to
synthesize indanone-fused tetrahydroisoxazoles derivatives
from easily accessed nitrosoarenes and 1,6-ynenones. This
transformation was proposed to proceed through a challenging
multifunctionalization of an internal alkyne with a nitrosoarene
in which the reactivity of the alkyne is relatively lower and the
nitrosoarene has a strong tendency to react with itself. Control
C
DOI: 10.1021/acs.orglett.9b00426
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
experiments showed that a radical process might be involved.
During the trapping process, the selectivity of [2 + 3]
annulation was controlled by the steric effect. In addition, the
reaction conditions were mild and efficient, enabling formation
of four bonds and construction of two rings.
(7) Singh, R. R.; Liu, R. Chem. Commun. 2014, 50, 15864.
8) (a) Alessandri, L. Gazz. Chim. Ital. 1922, 52, 193. (b) Alessandri,
L. Gazz. Chim. Ital. 1924, 54, 426.
9) (a) Ohe, K.; Uemura, S.; Sugita, N.; Masuda, H.; Taga, T. J. Org.
Chem. 1989, 54, 4169. (b) Chen, C.; Tsai, Y.; Liu, R. Angew. Chem.,
Int. Ed. 2013, 52, 4599. (c) Choi, M.; Viji, M.; Kim, D.; Lee, H. Y.;
Sim, J.; Kwak, Y.; Lee, K.; Lee, H.; Jung, J. Tetrahedron 2018, 74,
4182.
(
(
ASSOCIATED CONTENT
Supporting Information
■
*
S
(10) For selective examples of our researches on alkyne chemistry,
see: (a) Zhu, S.; Zhang, Q.; Chen, K.; Jiang, H. Angew. Chem., Int. Ed.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00426.
2
2
015, 54, 9414. (b) Liang, R.; Jiang, H.; Zhu, S. Angew. Chem., Int. Ed.
016, 55, 2587. (c) Zhu, D.; Ma, J.; Luo, K.; Fu, H.; Zhang, L.; Zhu,
S. Angew. Chem., Int. Ed. 2016, 55, 8452. (d) Chen, L.; Chen, K.; Zhu,
S. Chem. 2018, 4, 120. (e) Cao, T.; Kong, Y.; Luo, K.; Chen, L.; Zhu,
S. Angew. Chem., Int. Ed. 2018, 57, 8702. (f) Chen, L.; Liu, Z.; Zhu, S.
Org. Biomol. Chem. 2018, 16, 8884. (g) Zhu, D.; Chen, L.; Zhang, H.;
Ma, Z.; Jiang, H.; Zhu, S. Angew. Chem., Int. Ed. 2018, 57, 12405.
Optimization of reaction conditions; experimental
procedures and data; X-ray analysis; copies of NMR
spectra (PDF)
Accession Codes
(11) For [2 + 3] cycloaddition, see: (a) Confalone, P. N.; Huie, E.
M. Org. React. 1988, 36, 1. (b) Chakraborty, B.; Luitel, G. P. J. Hetero.
Chem. 2015, 52, 726.
CCDC 1838424 and 1891232 contain 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
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
(
12) For a domino reaction, see: (a) Alba, A.-N.; Companyo, X.;
́
Viciano, M.; Rios, R. Curr. Org. Chem. 2009, 13, 1432. (b) Volla, C.
M. R.; Atodiresei, I.; Rueping, M. Chem. Rev. 2014, 114, 2390.
(
13) (a) Pinho e Melo, T. M. V. D. Curr. Org. Chem. 2005, 9, 925.
(
b) Grunanger, P., Vita-Finzi, P., Dowling, J. E., Eds. The Chemistry
of Heterocyclic Compounds. Isoxazoles. Part 2, Vol. 170. In The
Chemistry of Heterocyclic Compounds; John Wiley & Sons: 2009.
̈
AUTHOR INFORMATION
Corresponding Author
■
(
c) Pevarello, P.; Amici, R.; Brasca, M. G.; Villa, M.; Varasi, M.
Targets in Heterocyclic Systems 1999, 3, 301.
14) The terminal alkenyl seemed to be active to PhNO, resulting in
*E-mail: zhusf@scut.edu.cn.
(
ORCID
a complex mixture in this attempt. For selective examples of a
terminal alkenyl reacted with PhNO, see refs 3a, d.
Shifa Zhu: 0000-0001-5172-7152
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We appreciate financial support from the Ministry of Science
and Technology of the People’s Republic of China
■
(
2016YFA0602900), NSFC (21871096, 21672071), Guang-
dong Science and Technology Department (2018B030308007,
018A030310359, 2016A030310433), and Science and
2
Technology Program of Guangzhou (201707010316).
REFERENCES
■
(
1) For a selective example of using nitroso compounds as
nucleophile, see: Gawade, S. A.; Huple, D. B.; Liu, R. J. Am. Chem.
Soc. 2014, 136, 2978.
(
2) For selective examples of using nitroso compounds as
electrophiles, see: (a) Momiyama, N.; Yamamoto, H. Org. Lett.
002, 4, 3579. (b) Yamamoto, Y.; Momiyama, N.; Yamamoto, H. J.
2
Am. Chem. Soc. 2004, 126, 5962. (c) Momiyama, N.; Yamamoto, H. J.
Am. Chem. Soc. 2005, 127, 1080. (d) Han, R.; Qi, J.; Gu, J.; Ma, D.;
Xie, X.; She, X. ACS Catal. 2013, 3, 2705.
(3) For selective examples of using nitroso compounds as radical
precursors, see: (a) Kang, J. Y.; Bugarin, A.; Connell, B. T. Chem.
Commun. 2008, 3522. (b) Liu, J.; Skaria, M.; Sharma, P.; Chiang, Y.;
Liu, R. Chem. Sci. 2017, 8, 5482. (c) Sharma, P.; Jadhav, P. D.; Skaria,
M.; Liu, R. Org. Biomol. Chem. 2017, 15, 9389. (d) Kawade, R. K.;
Liu, R. Angew. Chem., Int. Ed. 2017, 56, 2035.
(4) (a) Penoni, A.; Palmisano, G.; Broggini, G.; Kadowaki, A.;
Nicholas, K. M. J. Org. Chem. 2006, 71, 823. (b) Penoni, A.;
Palmisano, G.; Zhao, Y.; Zhao, Y.; Houk, K. N.; Volkman, J.;
Nicholas, K. M. J. Am. Chem. Soc. 2009, 131, 653.
(
5) Gornostaev, L. M.; Geets, N. V.; Bocharova, E. A.; Stashina, G.
́
A.; Firgang, S. I.; Smolyakovc, A. F. Russ. Chem. Bull. 2010, 59, 441.
6) Mukherjee, A.; Dateer, R. B.; Chaudhuri, R.; Bhunia, S.; Karad,
S. N.; Liu, R. J. Am. Chem. Soc. 2011, 133, 15372.
(
D
DOI: 10.1021/acs.orglett.9b00426
Org. Lett. XXXX, XXX, XXX−XXX