Visible-Light-Mediated Efficient Metal-Free Catalyst for α-Oxygenation of Tertiary Amines to Amides

Article abstract of DOI:10.1021/acscatal.8b01897

A metal-free system has been discovered for the efficient α-oxygenation of tertiary amines to the corresponding amides using oxygen as an oxidant. This visible-light-mediated oxygenation reaction exhibited excellent substrates scope under mild reaction conditions and generated water as the only byproduct. The synthetic utility of this approach has been demonstrated by applying onto drug molecules. At the end, detailed mechanistic reactions clearly showed the role of oxygen and the photocatalyst.

Full text of DOI:10.1021/acscatal.8b01897

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Letter
Visible-Light-Mediated Efficient Metal-Free Catalyst
for #-Oxygenation of Tertiary Amines to Amides
Yu Zhang, Daniel Riemer, Waldemar Schilling, Jiri Kollmann, and Shoubhik Das
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b01897 • Publication Date (Web): 15 Jun 2018
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Visible-Light-Mediated Efficient Metal-Free Catalyst for α-
Oxygenation of Tertiary Amines to Amides
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Yu Zhang†, Daniel Riemer†, Waldemar Schilling, Jiri Kollmann, and Shoubhik Das*
Institut für Organische und Biomolekulare Chemie, GeorgꢀAugustꢀUniversität Göttingen, Tammannstraße 2,
37077 Göttingen, Germany
KEYWORDS: amides • amines • O2 • oxygenation • photocatalysts • metalꢀfree
ABSTRACT: A metalꢀfree system has been discovered for the efficient αꢀoxygenation of tertiary amines to the correꢀ
sponding amides using oxygen as an oxidant. This visibleꢀlightꢀmediated oxygenation reaction exhibited excellent subꢀ
strates scope under mild reaction conditions and generated only water as the byꢀproduct. The synthetic utility of this
approach has been demonstrated by applying onto drug molecules. At the end, detailed mechanistic reactions clearly
showed the role of oxygen and the photocatalyst.
H
O
Synthesis of tertiary amides is highly important in organic
N
O
O
chemistry due to their wide application as chemical raw
materials, synthetic intermediates, agrochemicals etc.[1ꢀ6]
In addition to these, there are many pharmaceutical
drugs containing this structural scaffold such as lenalidꢀ
omide, piperine, evodiamine, diazepam and many more
(Figure 1).[7ꢀ12] Traditionally, amides have been syntheꢀ
sized by the reaction of activated carboxylic acid derivaꢀ
tives with amines or by acidꢀcatalyzed rearrangement
reactions of ketoximes.[13] However, these reactions
often need toxic reagents in (over) stoichiometric amount
and generate (over) stoichiometric amount of toxic byꢀ
products. Except these, metalꢀcatalyzed linear amide
synthesis also has been achieved using Rh, Pd, Cu, Co,
Zn or Fe catalysts starting from aldehydes (1,3ꢀdienes or
alcohols) and amines. However, synthesis of cyclic amꢀ
ides is highly challenging using these methods.[14ꢀ23]
N
N
O
NH2
O
O
O
Piperine
N
Lenalidomide
O
N
N
Cl
N
H
H
N
Diazepam
Evodiamine
Figure 1: Examples of pharmaceuticals containing tertiary
amide unit.
(Figure 2).[26ꢀ30] Compared to these, oxygen is a green
oxidant and only generates water as byꢀproduct. Based
on this concept, several metalꢀbased catalysts using Ru,
Au, Fe or Cu have been discovered under harsh reaction
conditions.[31ꢀ33] Recently, Mizuno group reported the αꢀ
oxygenation of amines into amides with supported gold
nanoparticles which needed high temperature and exꢀ
pensive gold as catalyst.[34] In addition to these, rutheniꢀ
um catalyzed oxidantꢀfree amide synthesis from amine is
also reported however reactions needed longer reaction
time (48ꢀ89 h), high temperature (150°C) and limited to
only cyclic amides.[35]
In contrast, synthesis of amides directly from amines via
α−oxygenation has brought major attention to the scienꢀ
tific community due to the easy availability of amines.[24ꢀ
25]
Moreover, syntheses of cyclic amides directly from
amines is also easier. Usually, stoichiometric oxidants
t
such
as
iodosobenezne,
PhCO3 Bu,
tBuOOH,
RuO2/NaIO4 etc. have been used which generate stoiꢀ
chiometric amounts of toxic and harmful byꢀproducts
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Recently, visibleꢀlightꢀmediated organic synthesis has
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With these optimized reaction conditions in hand, we
further aimed to apply the present metalꢀfree system to
diverse tertiary amines (Scheme 1; entries 2b–20b). As
shown in Scheme 1, the present strategy is compatible
with various substituted tertiary amines, including Nꢀ
substituted piperidines, N,Nꢀdimethylbenzylamine, Nꢀ
substituted tetrahydroquinoline, Nꢀsubstituted tetrahyꢀ
droisoquinoline and in all of the cases corresponding
amide was isolated in an excellent yield (Scheme 1;
entries 2b–11b). Furthermore, Nꢀcontaining heterocyclic
substrate like 1ꢀbenzylpyrrolidine was converted to the
corresponding amide with satisfactory yield (Scheme 1;
entry12b).
1
2
3
4
5
6
7
8
achieved strong priority due to the enhancement of susꢀ
tainable chemistry route.[36] For this purpose, ruthenium
and iridiumꢀbased photocatalysts have shown wide apꢀ
plications.[37ꢀ38] However, they are highly expensive and
potentially toxic in nature. In contrast, metalꢀfree organic
dyes are cheap and easy to handle.[39ꢀ40] Overall, these
organic dyes as catalysts provide mild reaction condiꢀ
tions in a very costꢀeffective and environmentally friendly
way. Additionally, these organic dyes are capable of
activating O2 molecule which has been applied in organꢀ
ic reactions already such as C–H bond functionalization,
oxidation reactions etc.[41ꢀ46] Especially, König group
reported the photoꢀoxidation of methylbenzenes, styꢀ
renes and phenylacetic acids using flavin as catalyst,
which was a pioneering work but with limited scope of
amines.[47] Based on all the above information and to
develop our own interest in metalꢀfree catalysis, we deꢀ
scribe metalꢀfree catalytic system for the visibleꢀlightꢀ
mediated oxygenation of amines to directly synthesize
amides using oxygen as the oxidant.[48ꢀ52]
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Table 1. Optimization for the visibleꢀlightꢀinduced αꢀ
oxygenation of 1ꢀbenzylpiperidine (1a) to 1ꢀ
benzoylpiperidine (1b).[aꢀe]
Entry
1
Catalysts
Base
DBN
Solvent
DMSO
Yield [%]
78
iodosobenzene, tBuOOH,
RuO2/NaIO4, PhCO3tBu
Rose bengal
(Over) stoichiometric
byꢀproducts
(Ref. 26ꢀ30)
DBN
DBN
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
27
10
64
49
34
28
95
88
51
95c
96d
99e
2
3
Riboflavin
Fluorenone
O
R3
Expensive catalyst,
removal of transitionꢀ
metals
N
R2
R3
O
2 as the oxidant
R1
R1
DBU
N
R2
4
Rose bengal
Rose bengal
Ru, Au, Fe and Cu
(Ref. 31ꢀ35)
Na2CO3
NEt3
5
This work
O2 as the oxidant
Rose bengal
Rose bengal
Rose bengal
Rose bengal
Rose bengal
Rose bengal
Rose bengal
Rose bengal
Metalꢀfree, cheap,
commercially available,
nonꢀtoxic catalyst.
6
Rose bengal (3 mol%)
DBN, DMF, rt,
blue LED
DMAP
DBN
7
Figure 2: αꢀOxygenation of amines to amides.
8
DBN
DMA
9
At the outset of our reaction, 1ꢀbenzylpiperidine (1a) was
taken as a model substrate to optimize the reaction conꢀ
ditions under oxygen atmosphere. As shown in Table 1,
different metalꢀfree catalysts such as rose bengal, fluꢀ
orenone and riboflavin were screened with DMSO as
solvent and DBN as base under the irradiation of 12 W
blue LED for 16 h (Table 1, entries 1–3). To our delight,
rose bengal provided 78% yield of the corresponding
amide (1b). Subsequently, other bases such as DBU,
Na2CO3, Et3N, and DMAP were also applied but did not
improve the yield of the reaction (Table 1, entries 4–7).
However, changing to other polar solvents and concenꢀ
tration of the solution provided highest yield of 99% in
16h (Table 1, entries 8–13). It should be noted that the
reaction did not show similar activity under air and only
59% of the product was observed.
DBN
ACN
10
11
12
13
DBN
DMF
DBN
DMF
DBN
DMF
[a] General reaction conditions: O2 (balloon), 12 W blue LED, 0.3
mmol 1a, photocatalyst (3 mol%), 0.45 mmol DBN, 2.5 mL solvent,
room temperature, 16 h. [b] Yields were determined by GC analysis
using nꢀdodecane as an internal standard. [c] 2.0 mL DMF. [d] 1.5
mL DMF. [e] 1.0 mL DMF.
Inspired by the reactivity of benzylic amines, we sought
to replace the aromatic part with furan and thiophene
moieties which also exhibited high reactivity under optiꢀ
mized reaction conditions (Scheme 1; entries 13b–14b).
Different other heteroaromatic compounds such as Nꢀ
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substituted morpholine, and 4ꢀphenylpiperidine were
lieve this strategy can become highly important for the
oneꢀpot synthesis of pharmaceutical drugs and natural
products.
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also effectively explored under our system (Scheme 1;
entries 16b–19b). Furthermore, cinnamamide, a very
important and useful compound used as herbicide, inꢀ
secticide etc. was synthesized with good yield (Scheme
1; entry 17b).[53ꢀ57] After successfully investigating aroꢀ
matic and heteroaromatic amines, we became interested
to find out the potential of this metalꢀfree catalyzed sysꢀ
tem for the conversion of aliphatic amines. To our deꢀ
light, 1ꢀmethylpiperidine showed moderate reactivity
(Scheme 1; entry 20a). In all the cases, products were
easily isolated by column chromatography on silica gel.
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Reaction conditions: O2 (balloon), 12 W blue LED, 0.3 mmol subꢀ
strates, 4 mol% rose bengal, 1 mL DMF, 0.60 mmol DBN, 16–24 h.
All are isolated yields. [c] 24b was performed with 3.0 eq. DBN and
10 mol% rose bengal with molecular sieves (3 Å).
Scheme 2: Oneꢀpot syntheses of tertiary amides from
second amines.
Furthermore, we became interested in the direct syntheꢀ
ses of phthalimide derivatives as they are highly imꢀ
portant as drug intermediates such as thalidomide, amꢀ
photalide, taltrimide, talmetoprim etc.[60ꢀ61] It should be
noted that due to strong electronꢀwithdrawing effect of
phthalimide, affording Nꢀsubstituted phthalimides directly
from phthalimides are highly challenging. Inspired by this
information, we applied isoindoline derivatives and corꢀ
responding bromides to proceed in a oneꢀpot oxidation
reaction under our optimized reaction conditions. To our
delight, all these substrates showed good yields of the
desired phthalimides (Scheme 3; entries 26b–28b). In
addition to these, Nꢀethylmaleimide was also syntheꢀ
sized efficiently from 2,5ꢀdihydropyrrole and ethyl broꢀ
mide under mild conditions (Scheme 3; entry 29b).
Reaction conditions: O2 (balloon), 12 W blue LED, 0.3 mmol starting material,
photocatalyst (3–6 mol%), 0.45–0.60 mmol DBN, 1.0 mL DMF, room temperꢀ
ature, 16–48 h. All are isolated yields.
Scheme 1: Substrates scope for visible lightꢀmediated
oxygenation of tertiary amines.
Based on our experience with direct conversion of terꢀ
tiary amines to amides, we paid attention to a oneꢀpot
synthesis of tertiary amides from secondary amines
under metalꢀfree conditions.[58ꢀ59] We rationalized that
tertiary amines can be directly synthesized from secondꢀ
ary amines with halides and further oxidation to this
molecule under the optimized conditions should generꢀ
ate corresponding tertiary amides. In fact, several benꢀ
zylic and aliphatic bromides were reacted smoothly with
piperidine and showed high formation of the desired
tertiary amides (Scheme 2; entries 21b–25b). We beꢀ
Reaction conditions: O2 (balloon), 12 W blue LED, 0.3 mmol subꢀ
strates, 4–6 mol% rose bengal, 1 mL DMF, 0.45–0.75 mmol DBN,
16h–48 h. All are isolated yields.
Scheme 3: Oneꢀpot syntheses of phthalimides and maꢀ
leimide derivatives.
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In order to prove the synthetic practicability of the preꢀ
tetramethylꢀ1ꢀpiperidinyloxyl (TEMPO) were added to the
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reaction mixture, the yield dramatically decreased which
proved radical pathway. Application of benzoquinone as
quencher revealed the presence of superoxide radical
anion. Furthermore, addition of CuCl2 and catalase to
the reaction mixture showed lower yields which clearly
showed the involvement of single electron processes
and the presence of peroxide species in this photocataꢀ
lytic system.[66]
sent metalꢀfree αꢀoxygenation protocol, the oxidation of
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Table 2: Control experiments for the oxygenation of 1ꢀ
benzylpiperidine.
Reaction conditions: O2 (balloon), 12 W blue LED, 0.3 mmol subꢀ
strates, 6 mol% rose bengal, 1 mL DMF, 0.75 mmol DBN, 48 h. All
are isolated yields.
Entry Controlled parameter Yield [%]
1
2
3
4
5
Standard conditions
N2 atmosphere
No light
99
0
Scheme 4: Selective oxygenation of drug molecules[a]
0
drug molecules was performed. As shown in Scheme 4,
oxidation of meclizine and donepezil was performed
smoothly in our system with a good yield of the correꢀ
sponding amide (Scheme 4; entries 30-31b).[62ꢀ63] Finalꢀ
ly, we also investigated the applicability of our protocol
for the direct synthesis of natural products including (S)ꢀ
(−)ꢀ8ꢀoxoxylopinine and 17ꢀoxosparteine (Scheme 5;
entries 32b–33b).[64ꢀ65] In fact, both of these natural
products can be synthesized directly in a single step
using this metalꢀfree pathway.
No catalyst
2
No base
3
[a] Reaction conditions: O2 (balloon), 12 W blue LED, 0.3 mmol 1a,
3 mol% rose bengal, 0.45 mmol DBN, 1.0 mL solvent, 18 h. Yields
were determined by GC analysis using nꢀdodecane as an internal
standard.
Table 3: Quenching experiments for the oxygenation of
1ꢀbenzylpiperidine
Quenchers
BHT
Equivalents Yield [%] Conclusions
0.5
1.0
0.5
1.0
1.0
1.0
23
0
radical
BHT
radical
TEMPO
TEMPO
tertꢀbutanol
CuCl2
30
2
radical
radical
Reaction conditions: O2 (balloon), 12 W blue LED, 0.3 mmol subꢀ
strates, 4–6 mol% rose bengal, 1 mL DMF, 0.45–0.75 mmol DBN,
16h–48 h. All are isolated yields.
75
2
hydroxide radical
single electron
Scheme 5: One step syntheses of natural products. [a]
Benzoquiꢀ
none
Superoxide
radical
1.0
2
6
Considering the broad scope of this approach, we
sought to gather mechanistic information about the role
of the catalyst, base and light source in our reaction.
Control experiments showed no product formation in the
absence of light, photocatalyst or base (Table 2). Addiꢀ
tionally, the yield drastically dropped to 0% under nitroꢀ
gen atmosphere which clearly showed the significance of
O2 in this reaction. Furthermore, the effect of different
quenchers was investigated to recognize the reactive
oxygen species and possible intermediates (Table 3).
When 2,6ꢀdiꢀtertꢀbutylꢀ4ꢀmethylphenol (BHT) or 2,2,6,6ꢀ
Catalase
100mg
peroxide radical
Reaction conditions: O2 (balloon), 12 W blue LED, 0.3 mmol 1a,
3 mol% rose bengal, 0.45 mmol DBN, 1.0 mL DMF, 18 h. Yields
were determined by GC analysis using nꢀdodecane as an internal
standard.
To get further information about the reaction mechanism,
SternꢀVolmer quenching experiments were carried out
(Figure 3). The excited state of the photocatalyst was
quenched by 1ꢀbenzylpiperidine.[67] As shown in Figure
3, a clear decrease of light emission was observed with
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the increase of substrate concentration and no change
towards the syntheses of natural products, which will be
promising method for other pharmaceuticals. Additionalꢀ
ly, detailed mechanistic studies revealed the role of the
photocatalyst, base and oxygen and led to the proposed
mechanism of this reaction.
1
2
3
4
5
6
7
8
was observed in case of a solution saturated with oxyꢀ
gen. In conclusion, oxygen molecule did not react with
the excited state of the photocatalyst rather starting maꢀ
terial did. Furthermore, visibleꢀlightꢀmediated selective
oxidation of 1ꢀbenzyl piperidine under 18Oꢀlabelled oxyꢀ
gen atmosphere, afforded 2c as the main product with
an isolated yield of 88% which clearly revealed the amꢀ
ide oxygen atoms in our products came from the oxygen
atmosphere (Scheme 6). Finally, KH/KD value of 3.2 in
KIE experiment strongly suggested the C–H bond cleavꢀ
age in the rateꢀdetermining step (Scheme 6).
18O
18O2
rose bengal (3 mol%)
N
N
H2O
(a)
(b)
DBN (1.5 eq.), DMF
r.t., 18 h, blue LED
2c
1a
9
O
D D
O2 (balloon)
rose bengal (3 mol%)
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N
N
D2O
DBN (1.5 eq.), DMF
r.t., 18 h, blue LED
KH/KD = 3.2
H
H
N
N
I
SET
Rose Bengal
OH
1a
*
R
ꢀH
DBN
H
Blue
LED
R
N
II
1O2
O2
R
H
O2
O
O
H
N
N
Figure 3: SternꢀVolmer plot for the oxygenation of 1ꢀ
benzylpiperidine.
H2O
III
1b
Scheme 6: (a) Oxygenation of 1ꢀbenzylpiperidine in
presence of 18O2; (b) KIE experiment and plausible
mechanism of this reaction.
Combining all the mechanistic experiments, plausible
mechanism for the visibleꢀlightꢀmediated metalꢀfree cataꢀ
lytic oxygenation reaction is proposed in Scheme 6. We
rationalized that at first photocatalyst was excited by the
irradiation of visible light and underwent a single electron
transfer (SET) with 1ꢀbenzylpiperidine (1a). The role of
the base in our system was to deprotonate radical I to
form more stable radical II. The photocatalyst radical
anion then generated the actual oxidants superoxide
radical anion and peroxide anion from O2 (reported value
for the reductionꢀpotential of excited state of rose bengal
resides at –1.33 V vs SCE), which is sufficient for the
reduction of molecular oxygen to its superoxide radical
ASSOCIATED CONTENT
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: shoubhik.das@chemie.uniꢀgoettingen.de
Author Contributions
†Y. Z. and D. R. contributed equally.
Funding Sources
We thank Fonds der Chemischen Industrie (FCI, Liebigꢀ
Fellowship to S.D.) and Chinese Scholarship Council
(CSC funding to Y.Z.) for the financial support.
ꢀ
anion (•O2/O2 ) with the reduction potential residing at ꢀ
0.56 V vs SCE).[68] The radical II reacted with the superꢀ
oxide anion and peroxide anion to generate intermediate
III. Finally, it transformed into the product (1b). At the
same time the water will form as the only byꢀproduct.
Supporting Information
The Supporting Information is available free of charge on
the ACS publications website.
In summary, we have developed a visibleꢀlightꢀmediated
α-oxygenation of tertiary and secondary amines using a
cheap and commercially available metalꢀfree catalyst
which showed broad substrates scope and produced
water as sole byꢀproduct. We believe this protocol can
be applied to the oxygenation of drug molecules and
Experimental details, characterization data and spectra
for the compounds of the synthesized compounds
(PDF).
Acknowledgements
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We are thankful to Prof. Dr. Lutz Ackermann for his supꢀ
port.
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Table of contents:
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33 substrates
O
O2 (balloon)
Rose Bengal
R3
Metalꢀfree oxygenation
R1
R3
N
R1
N
O2 as the oxidant
R2
DBN, DMF, rt
blue LED
R2
Natural product syntheses
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