Hoveyda-Grubbs II Catalyst: A Useful Catalyst for One-Pot Visible-Light-Promoted Ring Contraction and Olefin Metathesis Reactions

Article abstract of DOI:10.1021/acs.orglett.8b00971

A one-pot reaction to synthesize functionalized 2H-azirines through visible-light-mediated ring contraction and olefin metathesis of isoxazoles is described. Hoveyda-Grubbs II catalyst was found to function as a photocatalyst for these transformations, al

Full text of DOI:10.1021/acs.orglett.8b00971

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Hoveyda−Grubbs II Catalyst: A Useful Catalyst for One-Pot Visible-
Light-Promoted Ring Contraction and Olefin Metathesis Reactions
Yun Ge,† Wangbin Sun,† Bingbing Pei,† Jia Ding,† Yaojia Jiang,*,† and Teck-Peng Loh*,†,‡,§
†Institute of Advanced Synthesis, School of Chemistry and Molecular Engineering, Jiangsu National Synergetic Innovation Center for
Advanced Materials, Nanjing Tech University, 30 South Puzhu Road, Nanjing 211816, P. R. China
‡Department of Chemistry, University of Science and Technology of China, Hefei, Anhui 230026, P. R. China
§Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
Singapore 637616
S
* Supporting Information
ABSTRACT: A one-pot reaction to synthesize functionalized
2H-azirines through visible-light-mediated ring contraction and
olefin metathesis of isoxazoles is described. Hoveyda−Grubbs
II catalyst was found to function as a photocatalyst for these
transformations, allowing these processes to be carried out in a
one-pot manner. This study offers a new entry for the
application of Grubbs catalysts as efficient photocatalysts and
the possibilities of carrying out other photoreactions and olefin
metathesis in a one-pot process.
lefin metathesis is an extremely useful reaction for the
have been used as latent initiators under UV-light irradiation.7
Herein, we demonstrate for the first time a one-pot reaction of
olefin metathesis and ring contraction of isoxazoles using
Hoveyda−Grubbs II catalyst to construct synthetically useful
functionalized 2H-azirines8 under visible-light irradiation
(Figure 2).
O
synthesis of both linear and cyclic alkenes.1 It has been
shown that ruthenium complexes such as Grubbs catalyst I (G-
I),2 Grubbs catalyst II (G-II),3 Hoveyda−Grubbs I (HG-I),4
and Hoveyda−Grubbs II (HG-II)5 are useful catalysts to effect
this important transformation (Figure 1). Therefore, the ability
Figure 2. One-pot ring contraction and olefin metathesis reaction.
Ring contraction of isoxazoles is a useful strategy for the
synthesis of 2H-azirines.9 This can normally be realized using
UV irradiation, high temperature, or iron-catalyzed processes
with well-defined substrates.10 Ohe and co-workers recently
have shown that transition metals can also efficiently mediate
the isomerization of isoxazoles.8 We first explored the
possibility of the ring contraction of 3-cyclohexyl-5-amino-
isoxazole 1a under visible light in the presence of Ru catalysts
(Table 1, entries 1−6). Interestingly, the desired product 3-
cyclohexyl-2H-azirine-2-carboxamide 2a was obtained when
HG-II catalyst was employed, while G-I and G-II catalysts
failed to promote the reaction. Surprisingly, other known
Figure 1. Ruthenium complex promoted reactions.
to carry out various transformations that can include olefin
metathesis in a one-pot manner using ruthenium complexes
will be useful in organic synthesis. Recently, there has been
great interest in the development of a new organic method
under visible-light promotion.6 We envisage that the ruthenium
complexes used in olefin metathesis may also be able to
function as photocatalysts since many ruthenium complexes
Received: April 2, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00971
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a,b
Table 1. Optimization of Reaction Conditions
Scheme 1. Ring Contraction of Isoxazoles
b
entry
catalyst
solvent
conditions
yield (%)
1
G-I
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DCE
green LED
green LED
green LED
green LED
green LED
green LED
blue LED
green LED
green LED
green LED
green LED
green LED
green LED
blue LED
white LED
dark
0
0
2
G-II
HG-I
3
58
65
5
4
HG-II
5
Ru(bpy)3Cl2·6H2O
Ru(bpy)3(PF6)2
Ru(bpy)3(PF6)2
HG-II
6
3
7
0
8
53
60
58
54
9
HG-II
CH2Cl2
toluene
MeOH
EtOH
10
11
12
13
14
15
16
17
18
HG-II
HG-II
c
HG-II
85/81
d
HG-II
EtOH
49
HG-II
EtOH
72
67
0
HG-II
EtOH
HG-II
EtOH
EtOH
180 °C
green LED
0
EtOH
0
a
Conditions: a mixture of 1a (0.1 mmol, 1 equiv), catalyst (1 mol %),
and solvent (1 mL) was sealed in a Schlenk tube under an argon
atmosphere, and the mixture was stirred until the 1a was consumed
b
completely. Yields were determined by 1H NMR vs an internal
c
d
standard. Isolated yield. 5 mol % of PCy3 was added. DCE =
dichloroethane.
a
Conditions: 0.2 mmol of 1 and 1 mol % of HG-II in EtOH (2 mL)
were stirred under irradiation of 36 W green LEDs at room
temperature. Isolated yields. 10 mmol scale.
b
c
ruthenium photocatalysts in the reaction displayed low
reactivities under either green LEDs or blue LEDs (Table 1,
entries 5−7). Further screening of the solvent effect revealed
that EtOH was the optimal solvent, affording the desired
product 2a in 81% isolated yield (Table 1, entry 12). It is worth
noting that when a small amount of PCy3 was added into the
reaction, the product was obtained in lower yield (49% instead
of 85%) (Table 1, entry 13). Considering that no reaction was
observed when G-I and G-II catalysts were used in the reaction,
it indicated that the nucleophilic PCy3 ligand might have
inhibited the reaction. Different wavelengths of visible light
were also tested. Product 2a was obtained under blue and white
LEDs in 72% and 67% yields, respectively (Table 1, entries 14
and 15). However, a control experiment carried out without a
light source resulted in no desired product (Table 1, entry 16).
This result showed that visible light is essential for the
transformation. Control experiments performed in the absence
of Ru catalyst or under a light source or high temperature
(Table 1, entries 17 and 18) also led to no desired product 2a.
With the optimized reaction conditions in hand, we
proceeded to examine the substrate scope of the reaction
(Scheme 1). Overall, numerous functional groups were
tolerated, and the corresponding products were obtained in
good to excellent yields. Alkyl-substituted substrates difficult to
prepare using reported methods can be successfully obtained
using our reaction conditions (2a−e). Bulky groups such as
tert-butyl (2d) and adamantyl (2e) also proceeded well under
the reaction conditions to give the corresponding products in
71% and 68% yields, respectively. It is worth noting that the
reaction of 1f can be scaled up to 10 mmol without a decrease
in yield, affording the 3-phenyl-2H-azirine-2-carboxamide 2f in
92% yield. The electronic effect was then studied in the
reaction. The aryl-substituted compounds with electron-
donating groups proceeded well (2g−i) and gave the desired
small rings in excellent yields (85−97%). The reaction using
electron-withdrawing aryl groups also underwent smooth
reaction but with decreased yields (2j−l). Different halogen
substituents (F, Cl, Br, and I) on the aryl group also worked
well under the standard conditions, affording the desired
products in good to excellent yields (2m−q). It is worth noting
that the chloro, bromo, and iodo functional groups are useful in
coupling reactions.11 A naphthalene substrate worked efficiently
to give the corresponding 2H-azirine in 95% yield (2r).
Heterocyclic compounds such as thienyl and furyl groups were
also well tolerated and generated the products in 85% and 81%
yields, respectively (2s and 2t). Conjugated double bonds
survived in the presence of Hoveyda−Grubbs II catalyst
reaction conditions, albeit in decreased yield (2u). Notably,
when R2 = alkyl, allyl, and aryl groups (2v−x), the reaction
proceeded smoothly to furnish 2H-azirine-2-carboxamides
bearing all-carbon quaternary centers. Rather than simple
primary carboxamides, secondary amides were found to be
obtained in excellent yield (2z, 2aa, and 2ab).
After establishing the catalytic system, we then turned our
attention to synthesize useful 2-allyl-2H-azirines12 through the
one-pot reaction of ring contraction and olefin metathesis of
isoxazoles under visible-light irradiation. The reactions
proceeded smoothly to give functionalized 2H-azirines in the
presence of conjugated alkenes 3 in dichloromethane with
increased catalyst loading in a one-pot manner (Scheme 2). In
the one-pot reaction, dichloromethane was used as solvent
B
DOI: 10.1021/acs.orglett.8b00971
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Organic Letters
Letter
a,b
Scheme 2. One-Pot Reaction of Isoxazoles
Scheme 3. Proposed Mechanism
the Ru complex in the excited state, giving intermediate A,
which subsequently undergoes N−O bond cleavage through an
SET process to afford B. The C−N bond then is formed by
radical addition to give intermediate C, which transfers one
electron to Ru to afford the corresponding 2H-azirine 2 and the
ground state Ru. On the other hand, the activated ruthenium
complex may directly insert into the N−O bond and afford
intermediate D (Scheme 3, path B),8b which subsequently leads
to four-membered ring E. After a reductive elimination process,
the small ring product 2 was obtained through C−N bond
formation. In either case, 2-vinyl-2H-azirine 2 then reacts with
alkene 3 to give the functionalized 2H-azirine 4 through an
olefin metathesis process.
To provide further understanding of the possible reaction
pathway, some control experiments were explored (Scheme 4).
We found that the amino group was essential to the reaction.
When the amino group was substituted with an electron-
withdrawing group, it failed to give the corresponding 2H-
azirines. On the other hand, with a benzyl-substituted substrate,
a
Conditions: 1 (0.2 mmol), 3 (2.0 mmol), and 2 × 5 mol % HG-II in
CH2Cl2 (2 mL) were stirred under irradiation of 36 W green LEDs at
room temperature. Isolated yields.
b
because halogenic solvents are common solvent used in olefin
metathesis reaction. Notably, increased catalyst loading is
essential for this one-pot transformation since using 1 mol % of
HG-II will cause the reaction to stop at the ring-contraction
step. This is probably the reason why substrates that bear an
allyl moiety in Scheme 1 (2w,ab) were transformed to the 2H-
azirines efficiently without homometathesis side reaction of the
terminal alkene side chain. Both methyl acrylate and vinyl
ketone 3 reacted efficiently under the reaction conditions (4a−
j). Unfortunately, styrene, acrylamide, and acrylonitrile were
not suitable for this one-pot catalytic system. Isoxazoles 1 with
different substitutents (Me, MeO, and halogens) on the phenyl
group gave moderate to good yields (4c−h). A naphthalene
substrate worked well with both the methyl acrylate and vinyl
ketone 3 to give the corresponding 2H-azrines in 70% and 62%
yields, respectively (4i and 4j). Heterocycles including thienyl
and furyl groups survived uner the reaction conditions and
resulted in promising yields (4k and 4l). Interestingly, a bulky
group was also incorporated successfully to afford 2-vinyl-2H-
azirine in 82% yield (4m). Next, we explored the one-pot
reaction of substrates having a double bond attached to the
amino group. The secondary vinyl amides could be obtained in
59% yield (4n). Notably, this one-pot reaction of isoxazoles
facilitates ring contraction first, followed by cross-metathesis
with an alkene cross-partner (see the Supporting Information).
Encouraged by the above results, we became interested in the
reaction mechanism. The well-known visible-light promoted
reactions normally proceeded through a single-electron-transfer
(SET) pathway in the presence of a ruthenium catalyst. Thus, a
possible radical reaction pathway was proposed for the visible
light-promoted ring contraction reactions (Scheme 3, path A).
Initially, HG-II is probably activated from the ground state to
the excited state under light irradiation. Both the nitrogen
atoms of the isoxazole ring and amino group coordinate with
Scheme 4. Mechanism Study
C
DOI: 10.1021/acs.orglett.8b00971
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the desired product was obtained in 90% yield (Scheme 4a,b).
If an amino group at the 2-position of isoxazole was replaced by
a methyl or phenyl group, the reaction was completely
suppressed (Scheme 4, c). These results showed that the
amino group may be coordinated with the ruthenium catalyst.
When the reaction was carried out in the presence of radical
trapping reagents such as 2,2,6,6-tetramethyl-1-piperidinyloxy
(TEMPO), 5,5-dimethyl-1-pyrroline N-oxide (DEMPO), and
butylated hydroxytoluene (BHT) (Scheme 4d), the desired
product was obtained in slightly decreased yields (72, 56, and
53%). Although the mechanism is not fully understood, path B
is preferred.
In summary, we have shown that Hoveyda−Grubbs II
catalyst can be used to catalyze a one-pot photochemical ring
contraction/olefin metathesis. Representative examples involv-
ing the visible-light-mediated one-pot ring contraction of
substituted isoxazoles followed by olefin metathesis has been
demonstrated. This study opens the door for the application of
Hoveyda−Grubbs catalysts as efficient photocatalysts and the
possibility of carrying out other photoreactions and olefin
metathesis in a one-pot manner.
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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.8b00971.
Experimental procedures and characterization data for
new compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
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16, 12928−12934. (d) Wang, D.; Unold, J.; Bubrin, M.; Frey, W.;
Kaim, W.; Buchmeiser, M. R. ChemCatChem 2012, 4, 1808−1812.
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(c) Okamoto, K.; Nanya, A.; Eguchi, A.; Ohe, K. Angew. Chem., Int. Ed.
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*E-mail: iamyjjiang@njtech.edu.cn.
*E-mail: teckpeng@ntu.edu.sg.
ORCID
Teck-Peng Loh: 0000-0002-2936-337X
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
The authors gratefully acknowledge funding from the National
Natural Science Foundation of China (21502089), Jiangsu
Province Funds Surface Project (BK 20161541), and the
Starting Funding of Research (39837107) from Nanjing Tech
University. We are also thankful for financial support by
SICAM Fellowship by Jiangsu National Synergetic Innovation
Center for Advanced Materials.
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