Copper(I)-catalyzed aerobic oxidation of α-diazoesters

Article abstract of DOI:10.1021/acs.joc.0c01744

A practical Cu-catalyzed oxidation of α-diazoesters to α-ketoesters using molecular oxygen as an oxidant has been developed. Both electron-poor and electron-rich aryl α-diazoesters are suitable substrates and provide the α-ketoesters in good yields. In this oxidative system, α-diazo-β-ketoesters are also compatible as substrates but unexpectedly furnish α-ketoesters via C-C bond cleavage, rather than the vicinal tricarbonyl products.

Full text of DOI:10.1021/acs.joc.0c01744

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Article
Copper(I)-Catalyzed Aerobic Oxidation of #-Diazoesters
Changming Xu, Yongchang Wang, and Lei Bai
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01744 • Publication Date (Web): 06 Sep 2020
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The Journal of Organic Chemistry
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Copper(I)-Catalyzed Aerobic Oxidation of α-Diazoesters
Changming Xu,*a Yongchang Wang,a and Lei Bai*b
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aSchool of Chemical and Biological Engineering, Lanzhou Jiaotong University, Lanzhou 730070, China
bCollege of Chemistry and Chemical Engineering, Northwest Normal University, Lanzhou 730070, China
*E-mail: xucm@mail.lzjtu.cn; bailei@nwnu.edu.cn.
ABSTRACT: A practical Cu-catalyzed oxidation of α-diazoesters to α-ketoesters, using molecular oxygen as oxidant, has been
developed. Both electron-poor and electron-rich aryl α-diazoesters are suitable substrates and provide the α-ketoesters in good yields.
In this oxidative system, the substrates α-diazo-β-ketoesters are also compatible, but unexpectedly furnished α-ketoesters via C-C
bond cleavage, rather than the vicinal tricarbonyl products.
green and sustainable chemistry.9 In fact, the reactions of
INTRODUCTION
α-Diazoesters are an important type of reactant used in many
transformations, especially in the transition-metal catalyzed
preformed stable metal carbene compounds with oxygen are
known (Scheme 1, E).10
Scheme 1. Oxidation of α-Diazoesters to α-Ketoesters
carbene transfer reactions. During the past decades, many
impressive transformations based on metal carbene reactions
have been developed, such as cyclopropanation, X–H insertion
(X = C, N, O, S, etc.), ylide reaction, and 1,2-migration
reaction.1 Compared to these achievements, oxidative
dedinitrogenation of α-diazoesters as a useful protocol to
provide α-ketoesters, which are useful intermediates in a variety
of functional group transformations and important units in
many biologically active compounds,2 has received very little
attention., Traditional oxidation protocols typically employ
1a,
3
dimethyldioxirane (DMDO),
which is generated from
Oxone and acetone, or tert-butyl hypochlorite (tBuOCl)3c, 4 as
oxidants (Scheme 1, A). The major disadvantages of these
methods are lack of functional group tolerability and raise
safety concerns for large-scale production, due to the strong
oxidizing ability of oxidants. In 2006, Hu et al. reported a
dirhodium acetate catalyzed oxidative reaction of aryl
diazoacetate with H2O, delivering the corresponding aryl α-
ketoesters,
wherein
a
stoichiometric
amount
of
dehydrogenative reagent diethyl azodicarboxylate (DEAD) was
needed (Scheme 1, B).5 In addition, Stoltz and co-workers
found that dimethyl sulfoxide (DMSO) could also serve as
oxidant to achieve dedinitrogenation of aryl α-diazoesters, but
only the substrates bearing electron-donating functionality are
well tolerated (Scheme 1, C).6 Recently, pyridine-N-oxides
have also been employed as oxidants for this transformation
with a broad range of substrates under the transition-metal
catalyzed conditions.7-8 Notably, the α-diazo-β-ketoesters are
suitable substrates and provide the vicinal tricarbonyl
compounds in good yields (Scheme 1, D).8 Owing to its
abundant, natural, and environmental friendly character,
molecular oxygen is considered as an ideal oxidant in view of
However, the catalytic method of aerobic oxidation of α-
diazoesters has not achieved preparative significance so far, due
to the messy reaction systems and/or low yields of products α-
12
ketoesters.11,
Herein, we describe a highly efficient and
catalytic procedure for the aerobic oxidation of α-diazoesters to
α-ketoesters via copper carbene intermediate. It is noteworthy
that the α-diazo-β-ketoesters also delivered α-ketoesters via C-
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C bond cleavage rather than the assumed vicinal tricarbonyl
Page 2 of 6
Using optimized conditions, the scope of this aerobic
oxidation reaction was explored with a series of α-diazoesters
(Scheme 2). Generally, phenyl α-diazoesters with alkyl, benzyl,
allyl, or propargyl substituents at R2 all afforded moderate to
high yields of the desired α-ketoesters (2a-2g). Both electron-
withdrawing (F, Cl, Br and NO2) and electron-donating (MeO
and tBu) substituents at benzene ring were well tolerated to give
corresponding α-ketoesters with moderate yields (2h-2m).
Methyl 1-naphthyldiazoacetate also underwent smooth
conversion to give 2n in 52% yield. Surprisingly, the
replacement of the phenyl by a 2-pyridyl group (1o) or using
cyclic substrates (1p-1q) led to a full recovery of the starting
material. In addition, the reaction of ethyl diazoacetate (1r) was
messy. When ethyl benzyldiazoacetate (1s) or α-diazoketone 1t
was employed, no reaction occurred under standard conditions.
However, it was found that the 1,2-hydride migration reaction
of 1s occurred at an elevated temperature of 90 °C in toluene,12d
giving olefin 4 in 80% yield and with a 5:1 ratio of E/Z isomers
(Scheme 3).
1
2
3
4
5
6
7
8
products in this oxidative system, which stands in contrast to
the system of using pyridine-N-oxide as oxidant (Scheme 1, F).8
RESULTS AND DISCUSSION
Table 1. Optimization of Reaction Conditionsa
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Yieldb (%)
Entry
Catalyst
CuI
Conditions
2a
57
(E)-3
trace
15
(Z)-3
trace
25
1c
2c
3
MeCN, rt, 48 h
MeCN, 50 oC, 5 h
CuI
15
58
59
70
68
NR
0
CuI
MeCN, rt, 48 h
trace
trace
trace
trace
-
trace
trace
trace
trace
-
4d
CuI
MeCN, rt, 48 h
5
CuI
MeCN, 50 oC, 5 h
MeCN, 50 oC, 17 h
MeCN, 50 oC, 12 h
MeCN, 50 oC, 24 h
DCE, 50 oC, 18 h
toluene, 50 oC, 18 h
EtOAc, 50 oC, 7 h
THF, 50 oC, 28 h
DMF, 50 oC, 28 h
EtOAc, 50 oC, 4 h
EtOAc, 50 oC, 21 h
EtOAc, 50 oC, 5 h
EtOAc, 50 oC, 0.1 h
EtOAc, 50 oC, 52 h
Scheme 2. Substrate Scope of Oxidation of α-Diazoesters a
6e
7
8f
CuI
-
CuI
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58
9
CuI
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66
82
66
66
77
78
43
29
51
trace
trace
trace
trace
trace
trace
trace
31
trace
trace
trace
trace
trace
trace
trace
24
10
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12
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16
17
18
CuI
CuI
CuI
CuI
CuBr
CuCl
CuCl2
Cu(OTf)2
Cu(OAc)2
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29
trace
trace
aUnless otherwise noted, all the reactions were run with 1a (0.3 mmol)
and catalyst (20 mol%) under oxygen atmosphere (balloon) in 3.0 mL
b
c
d
solvent. Isolated yield. Reaction was run under open air. Reaction
e
was run under oxygen (6.0 atm). Reaction was run with 10 mol%
catalyst. fReaction was run under nitrogen. NR: No Reaction.
Our initial explorations focused on the reaction of ethyl
phenyldiazoacetate (1a) in the presence of copper salts. We
were delighted to find that aryl α-ketoester 2a was produced in
57% yield under air condition at room temperature when CuI
was used as the catalyst (Table 1, entry 1). Rising temperature
to 50 oC led to the formation of undesired alkenes (E)-3 and (Z)-
3 (Entry 2).13 To our gratification, by changing air to oxygen
balloon at 50 oC the yield of target product 2a was increased to
70% (Entries 3-5). Subsequently, it was also found that
reducing the catalyst loading to 10 mol% resulted in similar
yield, but the rate of reaction was slowed (Entry 6). Without
copper catalyst, the reaction did not proceed at all (Entry 7).
Furthermore, in the absence of oxygen no desired product 2a
was observed, however, the alkenes still formed in high total
yield (Entry 8). The screening of solvents showed that EtOAc
was the best choice (Entries 9-13), giving 2a in 82% yield
(Entry 11). Various copper salts were also screened, but no
better result was obtained (Entries 14–18). In the case of
Cu(OTf)2, the reaction was found to proceed significantly faster
than with other copper salts (Entry 17). Attempts to accelerate
the rate of this transformation using Cu(OTf)2 as catalyst proved
deleterious to the chemoselectivity of the reaction (see
supporting information Table S1).
aUnless otherwise noted, all the reactions were run with 1 (0.3 mmol)
and CuI (20 mol%) under oxygen (balloon) in 3.0 mL EtOAc at 50 oC.
NR: No Reaction.
Scheme 3. 1,2-Hydride Migration of 1s a,b
aReaction was run with 1s (0.3 mmol) and CuI (20 mol%) under oxygen
(balloon) in 3.0 mL toluene at 90 oC. bThe E/Z Ratio of 4 was
determined by 1H NMR of the reaction mixture.
To extend the scope of this oxidative reaction, we turned our
attention to the use of α-diazo-β-ketoesters (Scheme 4). When
the above optimized conditions were employed, the reaction of
ethyl benzoyldiazoacetate (5a) did not proceed at all. To our
surprise, rising temperature to 90 oC in DMF led to the
formation of α-ketoester 6a (2a) in 70% yield (see supporting
information Table S2 for the optimization of reaction
conditions), but not the assumed vicinal tricarbonyl compound
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7 or its hydrate 8. The control reactions showed that omission
reacts with molecular oxygen to form a peroxycopper
intermediate B,9 followed by an intramolecular cyclization to
yield the intermediate C. Subsequently, the reductive
elimination produces dioxirane D with regenerating Cu(I) for
the next catalytic cycle. Finally, another molecule of α-
diazoester 1a reacts with the dioxirane D to deliver two
molecules of α-ketoester 2a.3a The dioxirane D is also deemed
to result in the production of molecular I2 in our reaction
systems. The formation of byproducts 3 is attributed to the
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5
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7
8
of the CuI catalyst or O2 resulted in complete inactivity of this
transformation. A variety of aryl groups in the substrates were
tested, and electron-withdrawing (F and Cl) or electron-
donating (MeO) groups at the ortho, meta or para position of
the phenyl group can be equally applied with acceptable yields
(6b-6f). Notably, we also found this newly developed oxidative
cleavage protocol to be compatible with acyclic 2-diazo-1,3-
diketones, giving 1,2-diketones with moderate to high yields
(6g and 6h). Unfortunately, the reactions of aliphatic α-diazo-
β-ketoesters (5i and 5j) were messy. However, no reaction
occurred when diazomalonate 5k or cyclic 2-diazo-1,3-
diketone 5l was used.
reaction between copper carbene intermediate A and α-
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diazoester 1a.13c,
For α-diazo-β-ketoester 5a, loss of N2
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generates a carbene intermediate E, which subsequently
undergoes Wolff rearrangement to form ketene F.1a, 16 Next, the
ketene F produced carbene G via loss of CO,1a, 17 followed by
the generation of copper carbene A’, which was coordinated by
the released CO and can be observed using HRMS. It should be
noted that CO can also be found when the residual gas of the
gram-scale reaction B in Scheme 5 was detected using gas
chromatography (GC). Then the carbene A’ undergoes an
identical pathway to yield the α-ketoester 2a. The substrates
scope indicates that the benzoyl group in 2-diazo-1,3-
dicarbonyls seems to be necessary for this transformation,
which can be reasoned that the aryl is favored migrating group
in Wolff rearrangement.1a
Scheme 4. Substrate Scope of Oxidation of 2-Diazo-1,3-
dicarbonyls a
CONCLUSIONS
In summary, we have developed two convenient,
environmentally friendly, highly atom-economical and low-
cost procedures for displace dinitrogen of α-dizaocarbonyls
with oxygen by copper-catalyzed aerobic oxidation. Both aryl
α-diazoesters and benzoyl α-diazoesters, as well as 2-diazo-1,3-
diketones are suitable substrates for this transformation.
Notably, the latter two types of substrates undergo loss of CO
via C-C bond cleavage to produce α-ketoesters and 1,2-
diketones respectively, which provides a novel approach for
oxidative cleavage of 1,3-dicarbonyls2a-2c using oxygen and
may extend the Wolff rearrangement beyond known reactions.
aUnless otherwise noted, all the reactions were run with 5 (0.3 mmol)
and CuI (20 mol%) under oxygen (balloon) in 3.0 mL DMF at 90 oC.
NR: No Reaction.
To demonstrate the practicability of this methodology, gram-
scale experiments of model substrates 1a and 5a were
conducted (Scheme 5). It was found that both of these reactions
proceed at slower rates, which maybe result from the reduced
purity of oxygen in balloon with the release of nitrogen. In spite
of this, two oxidative reactions were successfully completed
and gave target product 2a (6a) with higher isolated yields
respectively.
Scheme 6. Possible Reaction Mechanisms
Scheme 5. Gram-scale Experiments
In order to shed light on the mechanism, the reaction systems
of substrate 1a under the conditions of entry 5 in Table 1 and
5a under the standard conditions were detected using high-
resolution mass spectrum (HRMS) to trap the active
intermediates. On the basis of the results presented above and
our preliminary mechanistic study, the possible reaction
pathways for aerobic oxidation are depicted in Scheme 6. First,
α-diazoester 1a reacts with catalyst CuI, generating copper
carbene intermediate A,14 which is supported by HRMS,
accompanied by nitrogen gas evolution. The subsequent adduct
EXPERIMENTAL SECTION
General information: Commercial reagents were used as
received, unless otherwise indicated. Nuclear magnetic
resonance (NMR) spectra were recorded using Bruker AV-500
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1
spectrometer. H and 13C NMR spectra were measured on a
NMR instrument (500 MHz and for 1H NMR, 125 MHz for 13C
NMR). Tetramethylsilane (TMS) served as the internal standard
acetate (50:1) as the eluent to give the desired products 6a-6h.
Compounds 6a-6c,23 6d,26 6e,23 6f,27 6g-6h2c are known.
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6
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8
for 1H NMR, and CDCl3 served as the internal standard for 13
C
The Procedure for the Oxidation of 1a on Gram-scale:
The catalyst CuI (0.2 g, 1.05 mmol) was put into a 100 mL two-
neck flask equipped with a rubber balloon filled with pure O2.
The flask was evacuated and then backfilled with oxygen three
times. Subsequently, ethyl phenyldiazoacetate (1a) (1.0 g, 5.26
mmol) in EtOAc (50 mL) was added to the flask. The reaction
NMR. High resolution mass spectra (HRMS) were obtained
using Thermo Scientific Q Exactive instrument by the ESI
(Quadrupole-Orbitrap) ionization sources. Gas chromatography
(GC) analysis was performed on Agilent 7890B GC (TCD
detector, Propak-Q column (50m×0.53mm×15um)). Reactions
were monitored using thin-layer chromatography (TLC). All
the solvents were dried before use.
o
mixture was heated to 50 C in oil bath and stirred for 80 h.
9
After cooling to room temperature, ethyl acetate (50 mL) and
water (50 mL) were added to the reaction mixture. The aqueous
layer was extracted by ethyl acetate (2×50 mL). The combined
organic phases were washed with brine and dried over
anhydrous sodium sulfate. The solvent was removed by rotary
evaporation and purified by a silica gel column chromatography
with petroether/ethyl acetate (50:1) as the eluent to give the
desired product 2a (0.82 g) in 87% yield.
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Materials: The α-diazoesters 1a-1p18, 1q19, 1s-1t18 and 2-
diazo-1,3-dicarbonyls 5a-5l19 were prepared according to the
literatures. The α-diazoester 1r was commercially available.
Compounds 1a-1s and 5a-5l are known and the NMR data are
identical to those previously reported.
General Procedure for the Oxidation of α-Diazoesters
with Oxygen: The catalyst CuI (12 mg, 0.06 mmol) was put
into a Schlenk tube equipped with a rubber balloon filled with
pure O2. The tube was evacuated and then backfilled with
oxygen three times. Subsequently, α-diazoesters 1 (0.3 mmol)
in ethyl acetate (3 mL) was added to the tube. The reaction
The Procedure for the Oxidation of 5a on Gram-scale:
The catalyst CuI (0.18 g, 0.92 mmol) was put into a 100 mL
two-neck flask equipped with a rubber balloon filled with pure
O2. The flask was evacuated and then backfilled with oxygen
three times. Subsequently, ethyl benzoyldiazoacetate (5a) (1.0
g, 4.58 mmol) in DMF (45 mL) was added to the flask. The
reaction mixture was heated to 90 oC in oil bath and stirred for
8 h. After cooling to room temperature, ethyl acetate (100 mL)
and water (100 mL) were added to the reaction mixture. The
organic phase was washed with water (9×80 mL) and dried over
anhydrous sodium sulfate. The solvent was removed by rotary
evaporation and purified by a silica gel column chromatography
with petroether/ethyl acetate (50:1) as the eluent to give the
desired product 6a (2a) (0.67 g) in 82% yield.
o
mixture was heated to 50 C in oil bath and stirred until
completion as indicated by TLC. After cooling to room
temperature, ethyl acetate (20 mL) and water (20 mL) were
added to the reaction mixture. The aqueous layer was extracted
by ethyl acetate (2×20 mL). The combined organic phases were
washed with brine and dried over anhydrous sodium sulfate.
The solvent was removed by rotary evaporation and purified by
a silica gel column chromatography with petroether/ethyl
acetate (50:1) as the eluent to give the desired products 2a-2n.
Compounds 2a-2c,20 2d,21 2e,2d 2f,21 2g,22 2h-2i,20 2j-2k,2d 2l,23
2m,24 2n,2d (Z)-3,13a-13b (Z)-4,25 (E)-425are known.
ASSOCIATED CONTENT
Supporting Information
Diethyl (E)-2,3-diphenylmaleate ((E)-3). Yellow oil, 14.6 mg,
15% yield. 1H NMR (500 MHz, CDCl3, TMS) δ ppm 7.47–7.32
(m, 10H), 4.00 (d, J = 7.0 Hz, 4H), 0.94 (t, J = 7.0 Hz, 6H).
13C{1H} NMR (125 MHz, CDCl3) δ ppm 168.2, 137.8, 135.7,
The Supporting Information is available free of charge on the ACS
Publications website at DOI:
Table S1, Table S2, copies of 1H, and 13C NMR spectra for products
(PDF)
+
128.8, 128.5, 128.3, 61.5, 13.8. HRMS (ESI) m/z: [M+H]
calcd for C20H21O4+ 325.1434, found 325.1434.
AUTHOR INFORMATION
Corresponding Author
*E-mail: xucm@mail.lzjtu.cn.
*E-mail: bailei@nwnu.edu.cn.
Diethyl (Z)-2,3-diphenylmaleate ((Z)-3). Yellow oil, 24.3 mg,
1
25% yield. H NMR (500 MHz, CDCl3) δ ppm 7.24–7.06 (m,
10H), 4.30 (q, J = 7.0 Hz, 4H), 1.30 (t, J = 7.0 Hz, 6H). 13C{1H}
NMR (125MHz, CDCl3) δ ppm 168.1, 138.8, 134.8, 129.9,
128.3, 128.2, 61.8, 14.2. HRMS (ESI) m/z: [M+H]+ calcd for
C20H21O4+ 325.1434, found 325.1435.
ORCID
Changming Xu: 0000-0001-9608-7013
Notes
The authors declare no competing financial interests.
General Procedure for the Oxidation of 2-Diazo-1,3-
dicarbonyls with Oxygen: The catalyst CuI (12 mg, 0.06
mmol) was put into a Schlenk tube equipped with a rubber
balloon filled with pure O2. The tube was evacuated and then
backfilled with oxygen three times. Subsequently, 2-diazo-1,3-
dicarbonyls 5 (0.3 mmol) in DMF (3 mL) was added to the tube.
The reaction mixture was heated to 90 oC in oil bath and stirred
until completion as indicated by TLC. After cooling to room
temperature, ethyl acetate (20 mL) and water (20 mL) were
added to the reaction mixture. The aqueous layer was extracted
by ethyl acetate (2×20 mL). The combined organic phases were
washed with brine and dried over anhydrous sodium sulfate.
The solvent was removed by rotary evaporation and purified by
a silica gel column chromatography with petroether/ethyl
ACKNOWLEDGMENT
We acknowledge financial support by the National Natural Sci-
ence Foundation of China (NSFC) (Grant No. 21662024),
Foundation of A Hundred Youth Talents Training Program of
Lanzhou Jiaotong University and the Young Teacher Research
Foundation of Northwest Normal University (Grant No. NWNU-
LKQN2019-15).
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