Visible-Light-Mediated 1,2-Acyl Migration: The Reaction of Secondary Enamino Ketones with Singlet Oxygen

Article abstract of DOI:10.1002/anie.201407413

Secondary enaminones were oxidized by photochemically generated singlet oxygen, followed by nucleophilic addition of alcohol and an unexpected 1,2-acyl migration to afford quaternary amino acid derivatives. An ene-type reaction pathway is proposed. It is distinctively different from the typical [2+2] addition of singlet oxygen to a C=C bond pathway. Singled out: Secondary enaminones were oxidized by photochemically generated singlet oxygen, and subsequent nucleophilic addition of an alcohol and with an 1,2-acyl migration afforded quaternary amino acid derivatives. An ene-type reaction pathway is proposed. It is distinctively different from the typical [2+2] addition of singlet oxygen to a C=C bond.

Full text of DOI:10.1002/anie.201407413

Angewandte
Chemie
DOI: 10.1002/anie.201407413
Synthetic Methods
Visible-Light-Mediated 1,2-Acyl Migration: The Reaction of
Secondary Enamino Ketones with Singlet Oxygen**
Weigang Fan and Pixu Li*
Abstract: Secondary enaminones were oxidized by photo-
chemically generated singlet oxygen, followed by nucleophilic
addition of alcohol and an unexpected 1,2-acyl migration to
afford quaternary amino acid derivatives. An ene-type reaction
pathway is proposed. It is distinctively different from the
to give two carbonyl compounds. For the past several years,
addition of singlet oxygen to enecarbamates has been studied
extensively.[10] Other oxidants, such as potassium permanga-
nate[11] and H2O2,[12] were used to mediate the oxidation of
enaminones to amides as well. Recently, the groups of Xia[13]
and Wang[14] disclosed visible-light-promoted conversion of
enamines into amides and ketones. Not surprisingly, all of the
above-mentioned reactions afforded two carbonyl com-
pounds by carbon–carbon double-bond cleavage.
=
typical [2+2] addition of singlet oxygen to a C C bond
pathway.
S
inglet oxygen is an electronically excited state of molecular
oxygen and a reactive oxygen species. It has been applied in
organic synthesis as a powerful reagent[1] since the seminal
reports of Foote and Wexler[2] and Corey and Taylor[3] in the
1960s. There are several principal classes of reactions involv-
ing singlet oxygen, including oxidation of heteroatom com-
pounds,[1c,4] [2+2] cycloaddition,[1c,5] Diels–Alder [4+2] reac-
tion,[6] and Schenck ene reactions.[7] The reactions of singlet
oxygen with enamines and enaminones were firstly disclosed
by Ando et al.[8] and Wasserman and Ives[9] in the 1970s
Herein, we report a visible-light-promoted transformation
involving the ene-type reaction of secondary enamino
ketones with singlet oxygen, followed by a 1,2-acyl migration
to afford quaternary amino acid derivatives. The reaction
pathway is distinctively different from the previous reports of
=
C C bond cleavage by singlet oxygen (Scheme 1c).
With our continuing interest in developing novel visible-
light-mediated oxidation reactions using molecular oxygen as
the terminal oxidant,[15] we investigated the aerobic oxidation
of 4-(phenylamino)pent-3-en-2-one (1a) in the presence of
1 mol% [Ru(bpy)3]Cl2·6H2O under the irradiation of a 14 W
compact fluorescent lamp in MeOH. To our surprise, an
unexpected product, 2a, was obtained in 57% yield after
6 hours with a small amount of the compound 3a (Table 1,
entry 1). The structure of 2a was confirmed by the X-ray
analysis (see the Supporting Information).
=
(Schemes 1a and b). In both cases, the C C bonds of
enamines were cleaved through [2+2] cycloaddition reaction
Inspired by this result, we screened other reaction
parameters. The reaction carried out under an O2 balloon
afforded 2a in 62% yield, thus showing that a high concen-
tration of O2 promoted the reaction (Table 1, entry 2). Next,
two iridium-based photocatalysts were examined. It was
found that these sensitizers were not as effective for this
transformation (entries 3 and 4). The reaction with higher
loading of the photocatalyst did not provide better results and
the reaction was sluggish with 0.5 mol% [Ru(bpy)3]Cl2·6H2O
(entries 5 and 6). When other solvents, such as MeCN,
CH2Cl2, DMF, DMSO, and THF, were used with 10 equiv-
alents of MeOH, the yields fell significantly (entries 7–11). To
improve the yield of the reaction, additives, such as ZnF2,
KH2PO4, and LiBF4, were tested. Among them, KH2PO4 gave
a slightly better yield (entry 13). It is notable that the
photocatalyst, visible light, and dioxygen were all critical to
this reaction. In the absence of any of these components,
either none or only a trace amount of the product was
detected (entries 15–17).
Scheme 1. Selected examples involving oxidation of enamines or
enaminones.
[*] W. Fan, Dr. P. Li
Key Laboratory of Organic Synthesis of Jiangsu Province
College of Chemistry, Chemical Engineering, and Materials Science
Soochow University, 199 RenAi Road, Suzhou
Jiangsu 215123 (China)
We next surveyed various secondary enamino ketone
substrates to investigate the scope of the reaction. Enamino
ketones containing different functional groups underwent the
transformation smoothly. However, approximately 10% (by
HPLC area) of the fragmentation product 3 was observed in
most of the reactions. The results are summarized in Table 2.
E-mail: lipixu@suda.edu.cn
[**] Financial support is provided by NSFC (21102097) and the
Scientific Research Foundation for the Returned Overseas Chinese
Scholars, State Education Ministry.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201407413.
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Table 1: Optimization of reaction conditions.[a]
Table 2: Scope of enaminones.[a,b]
Entry
Catalyst
Solvent
Additive
2a
Yield [%][b]
1[c]
2
3
4
[Ru(bpy)3]Cl2·6H2O
[Ru(bpy)3]Cl2·6H2O
[Ir(ppy)3]
FIrpic
[Ru(bpy)3]Cl2·6H2O
(2 mol%)
MeOH
MeOH
MeOH
MeOH
MeOH
–
–
–
–
–
57
62
trace
n.r.
62
5
6
[Ru(bpy)3]Cl2·6H2O
(0.5 mol%)
MeOH
–
51
7[d]
[Ru(bpy)3]Cl2·6H2O
[Ru(bpy)3]Cl2·6H2O
[Ru(bpy)3]Cl2·6H2O
[Ru(bpy)3]Cl2·6H2O
[Ru(bpy)3]Cl2·6H2O
[Ru(bpy)3]Cl2·6H2O
[Ru(bpy)3]Cl2·6H2O
[Ru(bpy)3]Cl2·6H2O
–
MeCN
CH2Cl2
DMF
DMSO
THF
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
–
–
–
–
12
23
13
10
5
57
65
60
8[d]
9[d]
10[d]
11[d]
12
–
ZnF2
KH2PO4
LiBF4
KH2PO4
KH2PO4
KH2PO4
13
14
15
n.r.
n.r.
trace
16[e]
17[f]
[Ru(bpy)3]Cl2·6H2O
[Ru(bpy)3]Cl2·6H2O
[a] Reaction conditions: 1a (0.5 mmol, 0.1m in solvent), catalyst
(1 mol%), additive (1 equiv), irradiation with a 14 W CFL under a O2
balloon at room temperature for 6 h. [b] Determined by HPLC. [c] Open
to the air. [d] MeOH (10 equiv) was used as reagent. [e] In the dark.
[f] Under a N2 balloon. bpy=2,2’-bipyridine, DMF=N,N-dimethylform-
amide, FIrpic=iridium(III) bis(4,6-difluorophenylpyridinato)picolate,
ppy=2-phenylpyridine, n.r.=no reaction.
The para-methyl-, para-ethyl-, and para-isopropyl-substituted
4-(phenylamino)pent-3-en-2-ones afforded the corresponding
products in 60, 52, and 66% yields, respectively (2b–d).
Dimethyl-substituted enaminones gave the products in 50 and
44% yields (2e and 2 f). The electronics of the substitution
groups on the phenyl ring have some impact on the reaction.
An electron-donating methoxy group at the ortho-, meta-, or
para- positions provided the products in 61, 57, and 53%
yields, respectively (2g–i). The reaction of an enaminone
bearing two methoxy groups became sluggish, and only 25%
of the desired product was obtained after 48 h (2j). An
enaminone with a para-NHBoc substituent gave 37% of the
corresponding product 2k. Weak electron-withdrawing
groups, such as fluoro, chloro, bromo, at the para position of
the phenyl ring afforded products in 60, 64, and 68% yields,
respectively (2l–n). However, substrates with strong electron-
withdrawing groups were easily hydrolyzed to anilines. And
the desired products were formed in moderate yields (2o and
2p). The naphthyl-substituted enaminone afforded the cor-
responding product in 26% yield upon isolation (2q).
[a] Reaction conditions: 1 (0.5 mmol, 0.1m in MeOH), [Ru(bpy)3]-
Cl2·6H2O (1 mol%), KH2PO4 (1 equiv), irradiation with a 14 W CFL
under a O2 balloon at room temperature. [b] Yield is that of the isolated
product containing approximately 10% (HPLC area) of an inseparable
impurity (3).
benzoyl group migrated to the adjacent carbon atom. Next
several alcohols were used instead of methanol. It was found
that ethanol afforded the corresponding ethyl ester in 65%
yield (2s). Alcohols with longer chains, such as n-propanol
and n-butanol, gave lower yields (2t and 2u). These results
clearly showed that the alkoxy groups of the esters in the final
products were from the alcohols. The reaction carried out in
isopropanol resulted in a complex mixture presumably
because of the bulkiness of the secondary alcohol. And
trifluoroethanol leaded to a bad reaction too probably
because of its weak nucleophilicity.
Typically, dioxygen can be activated through a single-
electron transfer (SET) pathway to form O2CÀ or an energy-
transfer (ET) pathway to form singlet oxygen under visible-
light conditions. In recent visible-light-promoted reactions
sensitized by ruthenium- or iridium-based polypyridyl com-
To extend the scope of the reaction and gain insight into
the reaction mechanism, a series of experiments were carried
out. Firstly, the compound 1r bearing a benzoyl group instead
of an acyl group was studied (Scheme 2). The product 2r was
obtained in 48% yield upon isolation, together with 14%
yield of 3r. This result unambiguously indicated that the acyl/
2
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performed in mixed solvent systems with different ratios of
CH2Cl2 to MeOH (Scheme 3b). Clearly, the yields of the
reactions were improved progressively with the increasing
ratio of CH2Cl2 in the solvent mixture. It is another piece of
good evidence that the reaction goes through a singlet-oxygen
pathway. Moreover, addition of TEMPO or BHT as a radical
inhibitor did not suppress the reaction (73% or 61% yield
respectively, Scheme 3c), which indicated that the radical
process was unlikely in this reaction. The only experimental
result against the singlet-oxygen pathway is that the reaction
proceeded smoothly and comparable yield was obtained
when DABCO was added. However, it might be rationalized
that the reaction rate of enaminone with singlet oxygen is
faster than that of DABCO.
To investigate which reactant, either dioxygen or enam-
inone, interacts with the visible-light-excited photocatalyst,
a fluorescence emission quenching study was carried out. The
data showed that the emission intensity of excited catalyst was
remarkably affected by O2 (see the Supporting Information).
The fluorescence emission was hardly changed in a deaerated
solution of 1a in MeOH. However, when the solution was
bubbled with either air or oxygen gas, the emission intensity
was dramatically suppressed. Therefore, dioxygen rather than
1a reacted with the excited [Ru(bpy)3]Cl2·6H2O directly, and
triggered the reaction. Another result which could rule out
the probability of an SET process is the redox potential of the
substrate 1a measured by cyclic voltammetry (CV) experi-
Scheme 2. Investigation of reactant scope.
plexes, energy-transfer processes are rare.[16] Furthermore,
1O2 formed using photosensitizer under irradiation with an
underpowered compact fluorescent lamp is scarce.[17]
To distinguish between the singlet-oxygen pathway or the
radical pathway in our reaction, a serious of control experi-
ments and analytical studies were carried out (Scheme 3). It is
ments. E1aC
was measured at 1.24 V vs. SCE. It is higher
+/1a
than the potential of excited ruthenium(II) (ERu*2+
=
/Ru1+
0.77 V vs. SCE),[19] Rose Bengal (ERB*/RBCÀ = 0.99 V vs.
SCE),[20] and TPP (ETPP*/TPP·À = 0.81 V vs. SCE).[21] Although
the potential of 1a (E1aC+/1a) is lower than that of ruthenium-
(III) (ERu3+
= 1.29 V vs. SCE)[19], it was believed that the
/Ru2+
generation of singlet O2 by energy transfer is the dominant
reaction pathway because it is not possible to go through
oxidative quenching cycle with Rose Bengal (ERBC
=
+/RB
1.09 V vs. SCE)[20] and TPP (ETPP+/TPP = 0.95 V vs. SCE).[21]
On the basis of our observations and the literature
reports,[14,22] a plausible pathway for the reaction was pro-
posed in Scheme 4. After the absorption of a photon,
ruthenium(II) is converted into a high-energy excited singlet
1RuII*, which undergoes intersystem crossing (ISC) to triplet
3RuII*. Intermolecular energy transfer from 3RuII* to 3O2
regenerates the ground-state RuII and forms the reactive
1O2 species. Next, an ene-type reaction between 1a and O2
1
Scheme 3. Investigation of reaction mechanism. BHT=3,5-di-tert-
butyl-4-hydroxytoluene; TEMPO=2,2,6,6-tetramethylpiperidin-1-oxyl.
occurs to form the intermediate A, which dehydrates to afford
B. After that, a nucleophilic addition of alcohol to B followed
by 1,2-acyl migration and protonation leads to the product 2a.
During the study of the reaction mechanism, Rose Bengal
was found to be as effective as the transition-metal-based
[Ru(bpy)3]2+ catalyst. And the addition of 1 equivalent of
TEMPO to the standard reaction conditions gave slightly
better result (Schemes 3a and c). The two conditions were
applied to the syntheses of 2a, 2c, 2m, and 2n. In the case of
using Rose Bengal as the photocatalyst, the transition-metal-
free conditions gave comparable results. The desired products
were isolated in 64, 51, 62, and 63% yields, respectively. When
1 equivalent of TEMPO was added, the yields of the desired
products were 73, 64, 69, and 72%, respectively. They were
well known that Rose Bengal is a good photosensitizer for 1O2
generation under visible-light irradiation. Therefore, we
tested the reaction using Rose Bengal as the photocatalyst.
The product 2a was obtained in 69% yield after 6 hours
(Scheme 3a). On the contrary, fluorescein afforded 2a in only
4% yield under the otherwise same conditions. It is known
that fluorescein is not capable of generating singlet oxygen.[18]
These two reactions indicated that a singlet-oxygen pathway
is probably operative. Moreover, because dichloromethane is
a good solvent for tetraphenylporphine (TPP) to generate
singlet oxygen, a series of TPP-sensitized reactions were
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Scheme 4. Proposed mechanism.
slightly better than those obtained without TEMPO. The
yields of the reaction were not affected by the amount of the
TEMPO added, but the reaction rate was slowed down with
increasing addition of TEMPO.
In conclusion, we have discovered a visible-light-mediated
aerobic oxidation of secondary enaminones by singlet oxygen.
An unexpected 1,2-acyl migration afforded quaternary amino
acid derivatives. Unlike the typically reported singlet-oxygen-
promoted double-bond cleavage to form two carbonyl com-
pounds, this reaction is proposed to go through an ene-type
pathway. The investigation of developing an environmentally
benign, metal-free reaction with better yields and the study of
the role of TEMPO in the reaction are currently ongoing in
our laboratory. The results will be reported in due course.
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Experimental Section
Experimental details: [Ru(bpy)3]Cl2·6H2O (1 mol%) and KH2PO4
(1 equiv) were added to a solution of the enaminone 1 (0.5 mmol) in
alcohol (5 mL). The Schlenk tube was charged with O2 using
a balloon. The reaction mixture was stirred under a 14 W CFL
irradiation at room temperature for an appropriate time. After
reaction completion as monitored by TLC, the reaction mixture was
quenched with water (20 mL), followed by extraction with ethyl
acetate (3 ꢀ 20 mL). The combined organic layers were washed with
brine and dried over anhydrous MgSO4. The mixture was filtered to
remove drying agent. The filtrate was concentrated under reduced
pressure. The crude reaction mixture was purified by column
chromatography with petroleum ether/dichloromethane to give the
desired product.
Received: July 20, 2014
Revised: August 19, 2014
Published online: && &&, &&&&
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Keywords: ene reaction · photochemistry ·
reaction mechanisms · ruthenium · singlet oxygen
.
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4
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Synthetic Methods
W. Fan, P. Li*
&&&& — &&&&
Visible-Light-Mediated 1,2-Acyl
Migration: The Reaction of Secondary
Enamino Ketones with Singlet Oxygen
Singled out: Secondary enaminones were
oxidized by photochemically generated
singlet oxygen, and subsequent nucleo-
philic addition of an alcohol and with an
1,2-acyl migration afforded quaternary
amino acid derivatives. An ene-type
reaction pathway is proposed. It is dis-
tinctively different from the typical [2+2]
=
addition of singlet oxygen to a C C
bonds.
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5
These are not the final page numbers!