Photocatalytic N-formylation of amines via a reductive quenching cycle in the presence of air

Article abstract of DOI:10.1039/c7ob00250e

Photochemical N-formylation of amines was performed under simple and mild reaction conditions. Amines are common electron donors in reductive photocatalysis, which then typically decompose after donating an electron to the photocatalyst. We have found that these oxidized amines can be utilized to give N-formamides in the presence of air without additional formylating agents. The reaction proceeds via the in situ formation of enamines. Oxygen (air) is necessary for the reaction to occur as it regenerates the photocatalyst forming superoxide radical anions as crucial intermediates involved in the reaction.

Full text of DOI:10.1039/c7ob00250e

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
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DOI: 10.1039/C7OB00250E
Journal Name
ARTICLE
Photocatalytic N-Formylation of Amines via a Reductive
Quenching Cycle in the Presence of Air
Received 00th January 20xx,
Accepted 00th January 20xx
Tamal Ghosh, Amrita Das and Burkhard König*
DOI: 10.1039/x0xx00000x
The photochemical N-formylation of amines was performed under simple and mild reaction conditions. Amines are
common electron donors in reductive photocatalysis, which then typically decompose after donating an electron to the
photocatalyst. We have found that these oxidized amines can be utilized to give N-formamides in the presence of air
without additional formylating agents. The reaction proceeds via the in situ formation of enamines. Oxygen (air) is
necessary for the reaction to occur as it regenerates the photocatalyst forming superoxide radical anions as crucial
intermediates involved in the reaction.
www.rsc.org/
formamides, but they typically require high temperatures at
reflux conditions[24] or strong bases[25] in the presence of
different formylating reagent or C1 building blocks e.g. CO,[25-
Introduction
Photoredox catalysis proceeds via two possible catalytic cycles:
reductive or oxidative quenching pathways.[1] In the reductive
quenching cycle, the excited state photocatalyst takes up an
electron returning to the ground state in the reduced form.
The use of amines as electron donors is very common.[2-10] The
amine reductively quenches the photocatalyst forming the
radical cation of the amine, which decomposes via different
irreversible pathways (Fig. 1).[11-12] We thought it will be
beneficial if the oxidized amines can be used for further
organic transformations. We were particularly interested to
investigate the fate of the oxidized amines in a reductive
photocatalytic cycle in the presence of air. To our surprise, we
found out that amines are converted to N-formamides in
moderate yields without additional formylating agent or any C1
building block source. The formylation of amines is an
important transformation in organic, medicinal and biological
chemistry,[13-14] as N-formamides are useful intermediates for
the synthesis of biologically active molecules.[15-18] Formamides
are used as Lewis bases, which can catalyze reactions such as
the allylation[19-20] and hydrosilylation[21] of carbonyl com-
pounds. More importantly, formamides are utilized as
reagents in Vilsmeier formylation reactions[22] and they have
been employed in the synthesis of isocyanides and form-
amidines.[23]
26]
CO2,[27-28] DMF,[24]29] chloroform,[30] methanol,[31-32]
formaldehyde/paraformaldehyde,[33-36] formic acid[37-38] and its
derivatives. Most of these methods involve either moisture
sensitive, toxic or expensive reagents.
Fig. 1: Decomposition products observed in the oxidation of
tributylamine.[39]
Herein, we report the photochemical oxidation of amines
yielding N-formamides under mild reaction conditions without
additional formylation agents. In 1970, the electrochemical
oxidation of amines to amides was reported, which used
elemental oxygen.[39] In 1976, Mann et. al. showed[40] the
electrochemical oxidation of tropane and nortropane giving N-
formamide as one of the products. In 2014, Wang et. al.
reported[41] the photochemical transformation of enamines to
N-formamides by singlet oxygen. We suggest that under our
reaction conditions the reaction proceeds via an enamine
intermediate, but singlet oxygen is unlikely be involved. In the
presence of different singlet oxygen quenchers[42-44] (e.g., 1,4-
diazabicyclo[2.2.2]octane (DABCO), 1,3-diphenylisobenzofuran
or 9,10-diphenylanthracene) the reaction still occurs at the
A variety of methods are available for the formation of N-
Institute of Organic Chemistry, Faculty of Chemistry and Pharmacy, University of
Regensburg, D-93040 Regensburg, Germany.
* To whom correspondence should be addressed: Burkhard.Koenig@ur.de
Electronic Supplementary Information (ESI) available: [for experimental procedure,
GC calibration curves and NMR spectra]. See DOI: 10.1039/x0xx00000x
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same rate with similar yields excluding the singlet oxygen and was transformed to N,N-dibutylformamidVeiew(2Arbtic)le aOfntliener
DOI: 10.1039/C7OB00250E
participation. Tertiary amines are better electron donors than losing a butyl group. Reactions without any additives in
secondary amines, because of their less positive reduction ethanol gave 16% of the formylated product of piperidine, but
potentials.[45] They form radical cations easily, reducing the the addition of butyraldehyde doubled the reaction yield
catalyst to the corresponding radical anion. The radical anion (Table 1, entry 10-11). Using some selected aldehydes as
of the catalyst is oxidized by molecular oxygen, which acts as additives resulted in a higher reaction yield (Table 1, entry 12-
the sacrificial electron acceptor yielding a superoxide radical 13). The role of n-Bu3N or butyraldehyde or other selected
anion (Fig. 2). The superoxide radical anions can be utilized in aldehydes accelerating the formylation of secondary amines is
combination with other reagents to produce valuable discussed in detail in the mechanistic part.
compounds.[46] We have used photochemically generated
superoxide radical anions to form N-formamides from amines.
Table 1: Optimization of the reaction conditions.
N-formamides
D
D
Decomposition
D
D
*
*
PC
PC
PC
PC
O2
R-X
B
A
PC
PC
O
O2
R-X
C
O
R
salt
Eosin Y disodium
R
N
R
R
N
R
or
H
R
N
R
R
N
R
or
EtOH, air
nm
any
of amines without
additional
source
Formylation
agent
or
C1 building block
LED
formylating
535
Fig. 2: (A) A typical reductive quenching cycle where radical
cations of amines decompose after oxidation; (B) This work:
the radical cation of amines is used to form N-formamides; (C)
Photochemical N-formylation of amines without additional
formylating agent.
Results and discussion
Synthetic investigations
The reaction conditions were optimized using piperidine as a
substrate and the results are summarized in Table 1. The yields
were determined by GC/FID with an appropriate internal
standard after 8 hours of irradiation at 535 nm. Initially, the
reactions were performed in DMF, where 1-formylpiperidine
(
1a) was formed as a product (Table 1, entry 1), but the
addition of a tertiary amine (n-Bu3N) to the reaction mixture
increased the product yield (Table 1, entry 2). It was thought
that the formyl group of DMF is being transferred to the
amine, but solvents, which do not contain a formyl group give
the same product (Table 1, entry 3-5). Changing the tertiary
amine from n-Bu3N to DIPEA did not increase the yield (Table
1, entry 6). Increasing the amount of n-Bu3N from 1 to 2 equiv.
resulted in a higher reaction yield (Table 1, entry 7), but
increasing the catalyst loading (from 5 to 10 mol%) and more
n-Bu3N (3 equiv.) did not change the yield significantly (Table
1, entries 8 and 9). Different photocatalysts were screened
(Table 1, entry 14-22) for the reaction with Eosin Y disodium
salt providing the best results (Table 1, entry 7). The control
experiments (summarized in Table S1) show that light and
photocatalyst are both essential for the reaction to occur.
Oxygen is also necessary for the reaction to proceed (Table S1,
entry 6). Tributylamine was used to accelerate the reaction
Mainly secondary and tertiary amines were tested as
substrates in the catalytic system (Scheme 1).‡ For the
formylation of secondary amines, a tertiary amine (n-Bu3N)
was added, where both of the amines were transformed to the
respective formylated products. However, for the formylation
of tertiary amines no additives were required. Two equivalents
of n-Bu3N were used for the formylation of secondary amines
converting 32% of n-Bu3N into N,N-dibutylformamide (2b) with
a small amount of n-Bu3N left unreacted after 8 hours of
irradiation.
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of the iminium ion leads to the enamine. The formation of
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DOI: 10.1039/C7OB00250E
formamides from secondary amines follows a slightly different
pathway: the enamine is generated first, then it reductively
quenches the excited photocatalyst leading to the radical
cation of the enamine, which then reacts with the superoxide
radical anion in a stepwise mechanism similar to tertiary
amines. Secondary amines are not very efficient quenchers for
the photocatalyst and therefore form smaller amounts of
superoxide radical anion. The addition of a tertiary amine
accelerates the formylation of secondary amines, because it
produces more superoxide radical anion. The side product of
the oxidation of n-Bu3N is butyraldehyde, which reacts with
secondary amines to enamines. Table 1, entry 10 and 11, show
that the addition of butyraldehyde doubled the reaction yield,
indicating that butyraldehyde is essential to increase the
reaction yield. We suggest that butyraldehyde reacts with the
secondary amine to form an enamine, which gives rise to N-
formamide via a stepwise mechanism. In case of entry 1 and
10 (Table 1) the formyl group was derived from oxidative
amine decomposition. Use of phenylacetaldehyde or
isovaleraldehyde, known to form more stable enamines[49]
increases the reaction yields (Table 1, entry 12-13), which is a
further indication that the reaction is proceeding through an
enamine intermediate. Piperidine yields formamide more
easily than morpholine as piperidine (pKa = 11.22) is more
Scheme 1: Substrate scope for the formylation of amines (GC/FID
determined yields with internal standard).
Mechanistic investigations
Tertiary amines are easier oxidized than secondary amines,[45]
therefore they can reductively quench the excited state of the
photocatalyst better than secondary amines. After reductive
quenching, the radical anion of the catalyst is reoxidized by
molecular oxygen. The reported reaction does not work if we
use another electron acceptor (e.g. nitrobenzene) for the
regeneration of the catalyst (Table S1, entry 7), which indicates
the role of oxygen in the reaction to proceed. The solvent is
not acting as a formyl group source as we have screened
different solvents and the expected product is formed in
almost every solvent. We believe that the formylation of
tertiary amines proceeds through an imine intermediate,
which transforms into an enamine in situ. Previous reports
show[41] that enamines can be converted into N-formamides in
the presence of singlet oxygen. It has also been shown that the
basic than morpholine (pKa = 8.36)[50]
(Scheme 1, 1a vs 1c). The
lower yield for the formylation of DIPEA is due to the fact that
most of the DIPEA decomposes after oxidation to diisopropyl-
amine and acetaldehyde. Acetaldehyde, being a very volatile
compound evaporates from the open reaction vial very easily.
Therefore, diisopropylamine does not react, due to the
absence of any aldehyde to form an enamine. To prove the
mechanistic proposal further, we have used the intermediate,
1f as starting material, which converts into 1a after the
photoreaction. Aliphatic enamines are not very stable
compounds; they decompose quite fast if left in open
atmosphere. The moderate yields of the formylated products
can be the result of the decomposition of the in situ generated
enamines in the presence of air. Based on our mechanistic
experiments we propose the overall catalytic mechanism
depicted in the Fig. 3. An alternative mechanism has been
proposed in the supporting information (Fig. S10).
addition of DABCO (effective quencher of singlet oxygen) to
the reaction mixture stops the product formation. In our
reaction, we have deliberately added different singlet oxygen
quenchers (e.g. DABCO or 1,3-diphenylisobenzofuran or 9,10-
diphenylanthracene), but the reaction proceeds giving similar
product yields, which shows that singlet oxygen might not be
involved in the reaction mechanism. The lifetime of singlet
oxygen in deuterated solvents is substantially longer than in
non-deuterated solvents.[47] When we performed the reaction
in deuterated EtOH the reaction rate was unchanged, which
indicates that singlet oxygen is not involved in the reaction
(see SI, Scheme S2). No deuterium was incorporated into the
product showing that the hydrogen atom of the formyl group
is not coming from the solvent. After accepting an electron
from the radical anion of the catalyst, molecular oxygen
produces superoxide radical anions. The enamine can also act
as an electron donor and quench the excited state of the
photocatalyst forming an enamine radical cation.[48] This
radical cation of the enamine reacts with the superoxide
radical anion in a stepwise mechanism to give N-formamide.[46]
In the case of tertiary amines, it is reported[39] that after
oxidation and loss of a proton a radical is obtained (Fig. 1, (A)),
which may disproportionate to an enamine or deprotonation
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Table of Contents Entry
Photochemical N-formylation of amines was achieved without any additional formylating agents in the presence of air. Mechanistic
investigations suggest a reaction pathway proceeding via the addition of in situ formed radical cations of enamines with photochemically
generated superoxide radical anions.
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