Copper-Catalyzed Aerobic Oxidative Azo-Ene Cyclization

Article abstract of DOI:10.1002/adsc.202100687

A copper-catalyzed aerobic oxidative azo-ene cyclization has been developed. The developed CuI/DMAP/O₂ system efficiently facilitates the aerobic oxidation of ene-containing hydrazides to azo compounds, which undergo azo-ene cyclizations for the synthesis of oxazolidinones. In addition, the present approach enables the synthesis of lactams, as well as a nitroso-ene cyclization. Preliminary mechanistic studies revealed that two carbonyl groups were essential for the successful azo-ene cyclization and that a concerted mechanism might be plausible for this azo-ene cyclization. (Figure presented.).

Full text of DOI:10.1002/adsc.202100687

Title: Cu-Catalyzed Aerobic Oxidative Azo-Ene Cyclization
Authors: Junsu Kim, Da Hye Lee, and Jinho Kim
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Advanced Synthesis & Catalysis
10.1002/adsc.202100687
COMMUNICATION
DOI: 10.1002/adsc.202((will be filled in by the editorial staff))
Copper-Catalyzed Aerobic Oxidative Azo-Ene Cyclization
a
a
a,
Junsu Kim, Da Hye Lee, and Jinho Kim *
a
Department of Chemistry, and Research Institute of Basic Sciences, Incheon National University, 119 Academy-ro,
Yeonsu-gu, Incheon 22012, Republic of Korea
Fax: (+82)-32-835-0762; e-mail: jinho@inu.ac.kr
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######.((Please
delete if not appropriate))
Abstract. A copper-catalyzed aerobic oxidative azo-ene
cyclization has been developed. The developed triggered by the oxidation of well-designed hydrazides
CuI/DMAP/O
The azo-ene cyclization has been generally
2
system efficiently facilitates the aerobic (Scheme 1). In 1979, Meier reported that the oxidation
oxidation of ene-containing hydrazides to azo compounds, of ethyl 2-acyl hydrazinecarboxylates by excess
which undergo azo-ene cyclizations for the synthesis of amounts of MnO generated the corresponding azo
2
oxazolidinones. In addition, the present approach enables the
synthesis of lactams, as well as a nitroso-ene cyclization.
Preliminary mechanistic studies revealed that two carbonyl
groups were essential for the successful azo-ene cyclization
and that a concerted mechanism might be plausible for this
azo-ene cyclization.
intermediates, then the following azo-ene cyclization
of the transient azo compounds produced lactams
[7]
(
Scheme 2 (a)). The use of stoichiometric oxidants
for the oxidation of acyl hydrazinecarboxylates was
[8]
achieved by Leblanc and co-workers (Scheme 2 (b)).
When
2,2,2-trichloroethyl
2-acyl
hydrazinecarboxylates were used as starting materials,
Keywords: aerobic oxidation; Cu-catalysis; azo-ene
cyclization; hydrazide; organic synthesis
the use of phenyliodine(III) bis(trifluoroacetate)
(
PIFA, 1.1 equiv) or Pb(OAc) (1.2 equiv) as oxidants
4
efficiently facilitated the oxidation of hydrazides and
azo-ene cyclization sequence. Recently, the Malkov
group developed an oxidative azo-ene cyclization to
synthesize oxazolidinones in the presence of catalytic
3
The ene reaction,[1] which is a pericyclic reaction
between an alkene having an allylic hydrogen (ene)
and multiple bonds (enophile), is of importance in
organic synthesis, because the ene reaction provides
facile and atom-efficient routes for the construction of
chemical bonds with concomitant allylic C-H bond
activation.[ Especially, the intramolecular ene
reaction (ene cyclization) is an efficient protocol for
amounts of Fe(OTf) and stoichiometric PIFA
2]
[3]
the synthesis of biologically important heterocycles.
A variety of multiple bonds including C=C, C=O, and
C=N bonds (or their precursors) have been efficiently
employed as enophiles for the synthesis of
[4]
heterocycles through C-C bond formation. However,
the utilization of azo compounds as enophiles (azo-ene
[
5]
cyclization) has been relatively less investigated,
although the azo-ene reaction can be used for the
synthesis of N-heterocycles bearing allylic amines
[6]
through the direct C-N bond formation.
Scheme 1. Mechanistic outline of the intramolecular
oxidative azo-ene cyclization.
Scheme 2. Representative examples of azo-ene cyclization.
1
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Advanced Synthesis & Catalysis
10.1002/adsc.202100687
(
Scheme 2 (c)).[9] Although the use of PIFA alone
Initially,
3-methylbut-2-en-1-yl
2-
showed acceptable reactivity, the cleaner and
accelerated azo-ene cyclization was observed by the
combination of PIFA and Fe(OTf)3. However, the use
of molecular oxygen as an oxidant in Malkov's report
benzoylhydrazinecarboxylate (1a) was selected as a
model substrate to explore the feasibility of our
envisioned Cu-catalyzed aerobic oxidative azo-ene
[14]
cyclization (Table 1). Gratifyingly, the use of CuI
and 4-(dimethylamino)pyridine (DMAP), which was
an efficient catalyst system for the aerobic oxidations
[9]
gave the azo-ene reaction product in low yield.
Aerobic oxidative transformations exhibit a number
of advantages over other oxidation reactions with
[11a]
of di-tert-butyl hydrazodicarboxylates,
generated
[10]
organic or inorganic oxidants. Compared to other
oxidants, molecular oxygen is inexpensive and readily
accessible. In addition, only water is produced as a
byproduct, therefore, no laborious purification
processes are required. Recently, we, and other groups,
have developed several reaction systems to carry out
the desired oxazolidinone (2a) in a quantitative yield
(entry 1). Among the copper catalysts screened, it was
observed that cuprous or cupric halides facilitated the
present azo-ene cyclization, albeit in slightly inferior
yields to CuI (entries 2–3). However, the azo-ene
cyclizations with other copper salts such as
[11,12]
aerobic oxidations of disubstituted hydrazines.
Cu(CH
3
CN)
4
PF
6
, Cu(OAc)
2
, and Cu(OTf) showed
2
Notably, our developed CuI/DMAP system was
poor reactivity (entries 4–6). It was revealed that the
use of DMAP is superior to other additives including
pyridine, 4-methoxypyridine (4-OMepy), and 1,10-
phenanthrolrine (1,10-phen) (entries 7–9). No
reasonable yields were observed in the use of other
solvents (entries 10–11). It is worth noting that the
present cyclization could also be carried out under air
(entry 12). The yield of 2a was lowered to a greater
effective for the oxidation of hydrazinedicarboxylates,
which have high oxidation potentials.[
11a,13]
Building
from our previous work, and inspired by the reports
described above, we envisioned that the aerobic
oxidative
hydrazinedicarboxylates containing an ene moiety
might be possible. Herein, we describe a Cu-catalyzed
aerobic oxidative azo-ene cyclization for the synthesis
of oxazolidinones (Scheme 2 (d)).
azo-ene
cyclization
of
Table 1. Optimization of the Cu-catalyzed aerobic oxidative
[
a]
azo-ene cyclization.
yield
entry
Cu
additive solvent
(
%)[b]
99
90
89
0
1
2
3
4
5
6
7
8
9
CuI
DMAP CH
DMAP CH
DMAP CH
DMAP CH
DMAP CH
DMAP CH
pyridine CH
4-OMepy CH
1,10-phen CH
3
3
3
3
3
3
3
3
3
CN
CN
CN
CN
CN
CN
CN
CN
CN
CuBr
CuBr
Cu(CH CN)
Cu(OAc)
2
3
4 6
PF
2
7
Cu(OTf)
CuI
2
10
4
CuI
14
15
12
33
CuI
1
1
0
1
CuI
DMAP
toluene
DMSO
CuI
DMAP
1 [
2
c]
CuI
DMAP CH
DMAP CH
DMAP CH
CN 28,90[d]
3
3
3
1
3
CuI
CN
CN 51,92[d]
8[e]
1 [
4
f]
CuI
[a]Reaction conditions: 1a (0.5 mmol), Cu (10 mol %), and
2
additive (20 mol %) in solvent (3.0 mL) under an O balloon
at 50 C for 3 h. Yield of 2a was determined by H NMR
1
Scheme 3. Substrate scope of substitution at the R position
o
[b]
1
in hydrazinecarboxylates 1. Reaction conditions: 1 (0.5
mmol), CuI (10 mol %), and DMAP (20 mol %) in CH
3.0 mL) under an O balloon at 50 C for 3 h. Isolated yield.
spectroscopy with 1,1,2,2-tetrachloroethane as internal
3
CN
[
c]
[d]
[e]
standard. Under air. For 15 h. At room temperature.
o
(
2
[
f]
The use of 5 mol % of Cu and 10 mol % of DMAP.
[
a]
o
At 70 C for 15 h.
2
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Advanced Synthesis & Catalysis
10.1002/adsc.202100687
extent at room temperature (entry 13). The catalyst
loading could be reduced to 5 mol % of CuI and 10
mol % of DMAP, however, increased reaction time
was required to obtain an acceptable product yield
oxazolidinones having naphthalene, furan, or thiophen
group were also efficiently synthesized by our method
(2o–2q). A pivaloyl group was tolerable in the
developed reaction conditions to derive a high yield
(2r). Interestingly, it was shown that alkoxy carbonyl
substrates showed excellent yields regardless of
alkoxy groups (2s–2u). The structure of the desired
product 2s was unambiguously characterized by X-ray
(
entry 14). Control experiments revealed that the use
of Cu, DMAP, and molecular oxygen was
[14]
indispensable for the successful azo-ene cyclization.
The use of hydrogen peroxide (1.0 equiv) as an
[
9,15]
[16]
oxidant
14u]nder molecular nitrogen produced 2a in
crystallography.
2
2% yield.[
Next, the substrate scope of the ene group was
investigated with the slight modification of the
optimized conditions (Scheme 4). Both substrate 3a
and substrate 3b, which were synthesized from crotyl
alcohol and trans-hex-2-enol respectively, showed
moderate yields even with higher catalyst loading,
whereas the derivatives of ethoxy carbonyl 3c and 3d
exhibited better reactivity. It was observed that the
oxazolidinones 4b and 4d were produced as 3:1 and
4:1 E/Z mixtures, respectively. The azo-ene
cyclization of hydrazides bearing other allylic alcohols
such as 4-phenyl-2-butenol, 4-methyl-2-pentenol, and
5-methyl-2-hexenol produced the corresponding
oxazolidinones in moderate to good yields (4e–4g).
Although the hydrazide derived from nerol showed
good reactivity, the azo-ene cyclization of the
hydrazide derived from geraniol was sluggish (4h and
With the optimized conditions in hand (Table 1,
entry 1), we next explored the scope of substitution at
1
the R position in hydrazinecarboxylates 1 (Scheme 3).
It was observed that the cyclization of 3-methylbut-2-
en-1-yl
2-benzoylhydrazinecarboxylates
having
electron donating groups on the phenyl moiety
produced the corresponding oxazolidinones in high
yields under the optimized conditions (2a–2e, 2h–2j,
and 2l–2n), however, that of 3-methylbut-2-en-1-yl 2-
benzoylhydrazinecarboxylates
bearing
electron
withdrawing groups required a longer reaction time at
elevated temperature (2f, 2g, and 2k). Other
4i). Interestingly, it was shown that the formation of a
six-membered ring was accessible through the present
azo-ene cyclization of 3j (4j). However, the azo-ene
cyclization of 3k for the synthesis of spiro
oxazolidinone produced 4k in 15% yield with
Scheme 5. Scale-up process for the aerobic oxidative azo-
ene cyclization.
Scheme 4. Substrate scope of ene group. Reaction
conditions: 3 (0.5 mmol), CuI (5 mol %), and DMAP (10
o
mol %) in CH
6
(
3
CN (3.0 mL) under an O
2
balloon at 50 C for
[
a]
h. Isolated yield. The use of CuI (10 mol %) and DMAP
20 mol %) at 70 C for 15 h. The use of CuI (10 mol %)
o
[b]
Scheme 6. Cu-Catalyzed aerobic oxidative synthesis of
lactams and nitroso-ene cyclization.
o
and DMAP (20 mol %) at 50 C for 3 h.
3
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Advanced Synthesis & Catalysis
10.1002/adsc.202100687
numerous unidentified side products.
2-en-1-yl 2-phenylhydrazinecarboxylate 10 was used
as a starting material in the developed reaction
conditions, the azo compound 12 was produced in 30%
yield along with other decomposition products, and no
We carried out the aerobic oxidative azo-ene
cyclization of 1a on a 20-fold scale to highlight the
practicality of the developed protocol (Scheme 5). By
reducing the catalyst loading and increasing the
reaction time, we were able to achieve the large scale
azo-ene cyclization with no significant decrease to
either the conversion or the yield.
[21]
cyclization product 11 was produced (Scheme 8 (a)).
Quantitative yield of azo compound 12 was obtained
in the reaction of 10 at room temperature after 2 hours
These results indicate that two carbonyl groups of
hydrazides, which makes the azo enophile electron-
deficient, was shown to be essential for the successful
azo-ene cyclization, and indirectly support that the azo
compound is a key intermediate during azo-ene
cyclization. The addition of 10 equivalent of water to
the optimized conditions did not generate the Prins-
type byproduct 13, and only a slight reduction to the
yield was observed (Scheme 8 (b)). Therefore, a
concerted mechanism might be the plausible
mechanism for the present azo-ene cyclization,
however, other possibilities such as stepwise
mechanism could not be completely ruled out at this
It was demonstrated that the developed CuI and
DMAP system facilitated the synthesis of lactams.
When
ethyl
2-(5-methylhex-4-
enoyl)hydrazinecarboxylate 5a and ethyl 2-(dec-4-
enoyl)hydrazinecarboxylate 5b were exposed to the
developed reaction conditions, the desired products 6a
and 6b were produced in high yields (83% and 90%,
respectively) (Scheme 6 (a)).[
17]
In addition, the
present protocol was able to be applied to the aerobic
[
6,18]
oxidative nitroso-ene cyclization.
Using slightly
modified reaction conditions (including reduced
catalyst loading, room temperature, and shorter
reaction time) enabled the aerobic oxidative nitroso-
ene cyclization of N-hydroxycarbamate 7 to produce
[2b]
stage.
Thus, we proposed that the overall
mechanism consist of a Cu-catalyzed aerobic
oxidation of the hydrazinecarboxylate followed by an
[19]
the desired product 8 in 77% yield (Scheme 6 (b)).
[22]
Cleavage of the N-N bond in the oxazolidinone
azo-ene cyclization.
products could be achieved by the previously reported
In conclusion, we have developed a novel aerobic
oxidative azo-ene cyclization for the synthesis of
oxazolidinones. Not only various ene groups but also
carbonyl substituents such as benzoyl, hetero-aroyl,
acyl, and alkoxy carbonyl could be employed to
produce the corresponding oxazolidinones. The
present approach was effective even on a larger scale,
and enabled the synthesis of lactams and also a nitroso-
ene cyclization. Preliminary mechanistic studies
revealed that two carbonyl groups were essential to
activate the azo enophile and that the azo-ene
cyclization likely occurs with a concerted mechanism.
Further studies to understand mechanistic details for
the present aerobic oxidative azo-ene reaction are
underway.
procedure (Scheme 7).[ In the presence of SmI
in
20]
2
MeOH, the N-N bond in the oxazolidinone 2a
underwent cleavage to afford 9 in 61% yield.
Scheme 7. Cleavage of the N-N bond.
Experimental Section
General Procedure for the Synthesis of Products 2: A 10
mL flame-dried test tube (O.D. 15 mm), which was
equipped with a magnetic stir bar and charged with the
hydrazide 1 (0.5 mmol), CuI (10 mol %, 0.05 mmol), and
DMAP (20 mol %, 0.1 mmol) was evacuated and backfilled
with oxygen (this process was repeated three times). After
acetonitrile (3.0 mL) was added, the reaction mixture was
o
stirred at 50 C. After 3 h, the mixture was quenched with a
4
saturated aqueous solution of NH Cl at room temperature
and diluted with DCM. Two layers were separated, and
aqueous layer was extracted with DCM. The combined
4
organic layer was dried over MgSO , filtered, and
Scheme 8. Mechanistic investigation for the aerobic
oxidative azo-ene cyclization. At room temperature for 2
h.
concentrated on rotary evaporator. The residue was purified
[
a]
by column chromatography to give products 2.
Acknowledgements
In order to obtain mechanistic insight into our
developed protocol, we tried to isolate the azo
compounds, which would be the presumed
intermediates of the cyclization. However, the azo
compounds were not observed during our optimization
and substrate scope study. Instead, when 3-methylbut-
This work was supported by the National Research Foundation of
Korea (NRF) grant funded by the Korea government (MSIT) (No.
2
021R1A2C4002062). This work was also supported by the
Incheon National University Research Grant in 2018. We are
thankful to Dr. H. J. Lee at the Western Seoul Center of Korea
4
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Advanced Synthesis & Catalysis
10.1002/adsc.202100687
Basic Science Institute for the technical support in the SC-XRD
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5
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Advanced Synthesis & Catalysis
10.1002/adsc.202100687
COMMUNICATION
Copper-Catalyzed Aerobic Oxidative Azo-Ene
Cyclization
Adv. Synth. Catal. Year, Volume, Page – Page
Junsu Kim, Da Hye Lee, and Jinho Kim*
6
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