Photoinduced Oxidative Formylation of N,N-Dimethylanilines with Molecular Oxygen without External Photocatalyst

Article abstract of DOI:10.1021/acs.orglett.7b01230

A photoinduced oxidative formylation of N,N-dimethylanilines with molecular oxygen in the absence of an external photocatalyst was developed and provided the corresponding formamides in good yields under mild reaction conditions. Investigations indicated that both the starting material and product act as photosensitizers and that ¹O₂ coexists with O₂^?- during the reaction through energy transfer and single electron transfer process.

Full text of DOI:10.1021/acs.orglett.7b01230

Letter
pubs.acs.org/OrgLett
Photoinduced Oxidative Formylation of N,N‑Dimethylanilines with
Molecular Oxygen without External Photocatalyst
Shuai Yang,† Pinhua Li,*,† Zhihui Wang,† and Lei Wang*,†,‡
†Department of Chemistry, Huaibei Normal University, Huaibei, Anhui 235000, P. R. China
‡State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Shanghai 200032, P. R. China
S
* Supporting Information
ABSTRACT: A photoinduced oxidative formylation of N,N-dimethylanilines with molecular oxygen in the absence of an
external photocatalyst was developed and provided the corresponding formamides in good yields under mild reaction conditions.
Investigations indicated that both the starting material and product act as photosensitizers and that 1O2 coexists with O2•− during
the reaction through energy transfer and single electron transfer process.
ince MacMillan developed the direct asymmetric alkylation
of aldehydes by merging photoredox with organocatalysis
salt as the photosensitizer14 and the visible-light-induced and Ir-
catalyzed photoredox reactions of N,N-dimethylanilines with
oxygen were established.15 It is also worth noting that an auto-
oxidation of C(sp3)−H of glycine derivatives to oxalic acid
derivatives with molecular oxygen was reported.16 On the basis
of this understanding and our work,4b we report a photo-
induced oxidative formylation of N,N-dimethylanilines with
molecular oxygen without an external photocatalyst. The
reactions generated the corresponding formamides in good
yields under mild conditions.
First, the reaction conditions were optimized by using N,N-
dimethylaniline (1a) as the model substrate, as shown in Table
1. When the model reaction was carried out under the
irradiation of LEDs (420−425 nm) with molecular oxygen in
toluene at room temperature for 12 h, the oxidation product N-
methyl-N-phenylformamide (2a) was isolated in 56% yield
(Table 1, entry 1). It was found that the desired product 2a was
obtained in 65% and 59% yields with the irradiation of LEDs at
380−385 and 410−415 nm, respectively (Table 1, entries 2 and
3). When the wavelength of the light source was in the range of
450−455 nm or a white light was used, no reaction occurred,
and the starting material 1a was recovered (Table 1, entries 4
and 5). Thus, LEDs (380−385 nm) were the best light source
for the reaction. The ultraviolet−visible absorption spectra of
the substrates indicated that they have a stronger absorption
intensity at 380−385 nm than that at visible ranges (Figure S6,
S8, and S10 in SI). The effect of the solvent on the reaction was
examined, and DME is the best choice. When the model
reaction was performed in DME, an 87% yield of 2a was
generated (Table 1, entry 6). Other solvents, such as THF,
dioxane, PhCl, MeCN, acetone, 1,2-dichloroethane, and
CHCl3, exhibited less reactivity, providing 2a in 24−79% yields
S
under visible-light irradiation in 2008,1 visible light, as an
abundant and green energy source has been shown to induce a
number of organic transformations through single-electron
transfer, energy transfer, and hydrogen atom transfer process
and has received considerable attention.2 A variety of C−C and
C−heteroatom bond formations in the presence of a suitable
photosensitizer, including Ru, Ir, Au, Cu, and Ni complexes,
organic dyes, or semiconductor nanoparticles under visible-light
irradiation have been disclosed.3 To preserve the precious
metals (Ru, Au, and Ir complexes) and expensive organic dyes
(acridinium and pyrylium salts) that have been used as
photocatalysts, hypervalent iodine reagent catalyzed organic
reactions under visible-light irradiation without the use of a
photosensitizer have been reported.4 Further, Melchiorre
developed a visible-light-induced organic reaction that relied
on the formation of photon-absorbing electron donor−
acceptor complexes without an external photosensitizer.5
Most recently, Li and Hong described the direct trifluor-
omethylation of arenes and phosphonation of quinolinones
under photocatalyst-free and light-irradiation conditions.6
N-Methyl-N-arylformamides are widely used as organic
intermediates and formylation reagents in Vilsmeier reactions.7
Traditionally, they have been prepared by the reaction of N-
methylaniline with formic acid.8 There are a number of
modifications that have been developed in recent years. For
example, the Au-catalyzed N-formylation of amines with
paraformaldehyde,9 the boron-catalyzed N-methylation of N-
methylaniline using formic acid,10 and the formylation of
amines using CO2 and hydrosilanes11 were reported. Addition-
ally, the Pd-catalyzed oxidation of N,N-dimethylanilines12 and
the FeIII-catalyzed transformation of N,N-dimethylanilines with
H2O2 have been described.13
Most recently, the visible-light-induced oxidation of a
Received: May 4, 2017
benzylic C(sp3)−H to a ketone by oxygen with acridinium
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01230
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Letter
a
Table 1. Optimization of the Reaction Conditions
Scheme 1. Reaction of N-Alkyl-N-methylanilines 1
b
entry
light source
solvent
toluene
yield (%)
1
420−425 nm (1.5 W)
380−385 nm (1.5 W)
410−415 nm (1.5 W)
450−455 nm (1.5 W)
white light (18 W)
56
65
2
toluene
toluene
toluene
toluene
DME
3
59
4
NR
NR
87
5
6
380−385 nm (1.5 W)
380−385 nm (1.5 W)
380−385 nm (1.5 W)
380−385 nm (1.5 W)
380−385 nm (1.5 W)
380−385 nm (1.5 W)
380−385 nm (1.5 W)
380−385 nm (1.5 W)
380−385 nm (1.5 W)
380−385 nm (1.5 W)
380−385 nm (1.5 W)
380−385 nm (1.5 W)
380−385 nm (1.5 W)
in dark (no light)
7
THF
79
8
dioxane
PhCl
66
9
61
10
11
12
13
14
15
16
17
18
19
20
MeCN
acetone
1,2-dichloroethane
CHCl3
DMA
46
54
51
24
NR
NR
NR
NR
NR
NR
EtOH
DMF
DMSO
H2O
DME
c
380−385 nm (1.5 W)
DME
NR
a
Reaction conditions: N,N-dimethylaniline (1a, 0.30 mmol), solvent
(2.0 mL) at room temperature under light irradiation in air for 12 h.
Isolated yield, NR = no reaction. Under N2 atmosphere.
b
c
(Table 1, entries 7−13). It should be noted that no desired
product 2a was formed when the reaction was carried out in
DMA, EtOH, DMF, DMSO, or H2O (Table 1, entries 14−18).
In the absence of light or molecular oxygen, no reaction was
observed either (Table 1, entries 19 and 20).
any of the desired products 2v−x and only resulted in the
recovery of starting materials owing to the steric effect of a
more bulky group attached to nitrogen atom compared with
methyl group. When N,N-dimethyl-3-nitroaniline (1y) was
employed as substrate, a N-demethylated product N-methyl-3-
nitroaniline (2y) was obtained in 73% yield.17 As N,N-
dimethylbenzylamine (a N,N-dimethylalkylamine) was used,
no desired product was detected.
Next, several N-methyldiarylamines 3 as substrates were
surveyed, shown in Scheme 2. The oxidative formylation of N-
methyldiphenylamine, N-methyldi(p-tolyl)amine, and N-
methylbis(p-bromophenyl)amine with molecular oxygen gen-
erated the corresponding products 4a−c in 57−71% yields.
It was indicated that N-benzyl-N-methylaniline was an
ineffective substrate for the reaction (2x), but the oxidative
conversion of 2-(methyl(phenyl)amino)-1-phenylethanone
With the optimized conditions in hand, the generality of the
oxidative formylation of N-alkyl-N-methylanilines was explored.
The results are listed in Scheme 1. First, a variety of N,N-
dimethylanilines was examined under the standard conditions,
indicating a broad tolerance of substituted groups on the
aromatic rings. N,N-Dimethylanilines with an electron-donating
group, such as Me, t-Bu, or MeCONH at the para-position of
the aromatic rings, reacted with O2 to generate the
corresponding products 2b−d in 61−88% yields. Meanwhile,
N,N-dimethylanilines bearing an ester group, such as
benzoyloxy, n-butanoyloxy, and cyclopropanecarbonyloxy,
generated the desired products 2e−g in 91−96% yields. The
reactions of N,N-dimethylanilines with a m-methyl, or m,m-
dimethyl on the benzene rings afforded 2h and 2i in 57% and
75% yields, respectively. Furthermore, N,N-dimethylanilines
that possessed an electron-withdrawing group, including F, Br,
F3 CO, CN, MeCO, PhCO, HCO, EtO2 C, or
(Me)2CHCH2CH2O2C on the para-position of the benzene
rings, underwent the oxidative formylation with O2 to afford the
anticipated products 2j−r in 75−97% yields. Substitution at the
meta-aromatic position of N,N-dimethylanilines with Cl or Br
exhibited good reactivity and afforded the corresponding
products 2s and 2t in 95% and 92% yields, respectively. It
should be noted that an oxidative formylation of N,N-
dimethylnaphthalen-2-amine proceeded well, leading to 2u in
82% yield. However, N-ethyl-N-methylaniline, N-methyl-N-(n-
propyl)aniline, and N-benzyl-N-methylaniline failed to generate
Scheme 2. Formylation of N-Methyldiarylamines 3
B
DOI: 10.1021/acs.orglett.7b01230
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Letter
(5a) generated product 6a in 75% yield (Scheme 3). As the
analogues of 5a, 2-((4-bromophenyl) (methyl)amino)-1-(p-
(Scheme 4c), and 1-(2-(prop-2-yn-1-ylamino)phenyl)ethanone
(13) could be converted into 14 in 90% yield (Scheme 4d)
along with the cleavage of the carbon−carbon bonds. Under
LEDs (380−385 nm) irradiation, the reactions of 1-(2-
(benzylamino)phenyl)ethanone (15), diphenylmethane (17)
and diphenylmethanol (18) with oxygen afforded 16 in 80%
yield, and 10 in 89% and 90% yields, respectively (Scheme 4e−
g).19 The reaction could be performed on a gram scale,
treatment 10 mmol of 1a under the optimized conditions
afforded the corresponding 2a in 76% isolated yield.
Scheme 3. Oxidative Formylation of Substrates 5
When a radical scavenger 2,2,6,6-tetramethyl-1-piperidiny-
loxy (TEMPO) was added to the model reaction of 1a with air,
the oxidative carbonylation was completely inhibited along with
the formation of its adduct with TEMPO, which was detected
by HRMS (Figure S1), implying the formation of an
aminomethyl radical. On the other hand, 18O2-labeling
experiments were conducted, and the results are presented in
the SI. When the reaction of 1a was performed in the presence
of 18O2 instead of 16O2, a product 2a-18O was obtained in 81%
yield and confirmed by HRMS, and no unlabeled 2a was
observed (Figure S2). In addition, when 1a was carried out
under an air atmosphere (16O2) and with H218O (2.0 equiv),
the product 2a was isolated in 78% yield, and no 2a-18O was
detected (Figure S3). These results indicated that oxygen in 2a
comes from molecular oxygen.
tolyl)ethanone (5b), 2-((4-bromophenyl) (methyl)amino)-1-
(4-chlorophenyl)ethanone (5c), and 1-(4-bromophenyl)-2-
(methyl(phenyl)amino)ethanone (5d) were tolerated and
products 6b−d were obtained in 79−84% yields. Normally,
an alkyl radical near a carbonyl group would be formed first
because it is more stable. Then a free-radical rearrangement
would generate an aminomethyl radical for the next oxidative
formylation, providing the desired products.
The oxidative carbonylation of the other substrates was
further investigated, as indicated in Scheme 4. When the
To further explore the reaction mechanism, the following
experiments proved the important role of oxygen in the
reaction. When 5,5-dimethylpyrroline N-oxide (DMPO) and
2,2,6,6-tetramethylpiperidine (TEMP) were employed to
Scheme 4. Oxidation of Methylenes to Carbonyls
•−
1
capture O2 and O2, respectively, the resulting electron-spin
resonance (ESR) spectra were recorded, as shown in Figure S4.
There was no signal when DMPO was added into a solution of
1a in air-saturated DME in the absence of light irradiation
•−
(Figure S4a). However, a strong characteristic signal of an O2
adduct with DMPO was observed when the above solution was
irradiated with LEDs (380−385 nm), and a series of stronger
•−
characteristic signals of O2 were collected with prolonged
1
irradiation time (Figure S4b−d). A strong signal of the O2
adduct with TEMP was also observed when the above solution
was irradiated with LEDs (380−385 nm), but no signal was
1
recorded without light (Figure S5), implying that O2 coexists
•−
with O2 during the reaction.
Moreover, the ultraviolet−visible absorption spectra of
substrates 1 and their corresponding products 2 demonstrated
that they absorb light at 380−385 nm and act as photo-
sensitizers (Figure S6−10), thus avoiding the need for any
external photocatalyst. It should be noted that the obtained
formamides as products absorb a longer wavelength light,
which activates the molecular oxygen in the air more efficiently
and accelerates the reaction, so the entire oxidative formylation
is self-sustaining in an autocatalytic manner (Figure S11). As a
well-known photocatalyst, [Ru(bpy)3]Cl2·6H2O (1.0 mol %)
was added to the reaction of 1a, and a superior yield of 2a was
observed, thus indicating its positive effect as an 1O2-generating
photosensitizer.20 It is thought that the singlet oxygen 1O2 may
be generated from the interaction of molecular oxygen with a
photoexcited 1 and 2 via an energy-transfer process.
reactions of 1,3,3-trimethyl-2-methyleneindoline (7) and 1,1-
diphenylethylene (9) were performed under the optimized
reaction conditions, the corresponding terminal vinyl groups
were oxidized into ketones 8 and 10 in 88% and 96% yields,
respectively (parts a and b, respectively, of Scheme 4).18 To
expand the oxidation of methylenes to carbonyls, the reaction
of (2-(allylamino)phenyl)(phenyl)methanone (11) with O2
afforded N-(2-benzoylphenyl)formamide (12) in 82% yield
On the basis of these observations and the literature, a
possible mechanism for the photoreaction of 1 with O2 is
proposed in Scheme 5. To begin, substrate 1 is excited by light
(380−385 nm) to generate the excited species 1* and acts as a
photosensitizer, which then undergoes an energy-transfer
pathway with ground-state triplet oxygen 3O2 to afford a
C
DOI: 10.1021/acs.orglett.7b01230
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Organic Letters
Letter
Scheme 5. Possible Reaction Mechanism
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and an active secondary alcohol, providing the corresponding
carbonylative products. Investigations supported a mechanism
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photocatalysts upon excitation using LEDs (380−385 nm) to
photochemically promote ground-state oxygen (3O2) to
excited-state oxygen (1O2) via an energy-transfer process.
EPR results demonstrated the formation of O2 and O2,
which play an important role in the reaction. This protocol
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•−
1
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.7b01230.
Full experimental details and characterization data for all
products (PDF)
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: pphuali@126.com.
*E-mail: leiwang88@hotmail.com.
ORCID
Lei Wang: 0000-0001-6580-7671
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the National Natural Science
Foundation of China (21572078, 21372095) for financial
support.
D
DOI: 10.1021/acs.orglett.7b01230
Org. Lett. XXXX, XXX, XXX−XXX