Aerobic oxidation of a tertiary aliphatic amine under visible-light photocatalysis: Facile synthesis of methylene-bridged bis-1,3-dicarbonyl compounds

Article abstract of DOI:10.1002/asia.201200807

Lights, camera, action! An efficient protocol for the formation of methylene-bridged bis-1,3-dicarbonyl compounds has been developed through an aerobic photocatalytic oxidative coupling reaction between 1,3-dicarbonyl compounds and a tertiary aliphatic amine. Copyright

Full text of DOI:10.1002/asia.201200807

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DOI: 10.1002/asia.201200807
Aerobic Oxidation of a Tertiary Aliphatic Amine Under Visible-Light
Photocatalysis: Facile Synthesis of Methylene-Bridged Bis-1,3-dicarbonyl
Compounds
Woo-Jin Yoo, Arata Tanoue, and Shu Kobayashi*[a]
¯
The development of new synthetic methodologies that uti-
The use of visible light as a means to initiate organic
transformations has attracted significant interest in the syn-
thetic organic community.[6] Following the initial sporadic re-
ports on photocatalytic oxidative activation of tertiary ali-
phatic amines,[7] the advent of metal polypyridine complexes
as efficient photocatalysts has renewed interest in this field,
and visible-light photocatalysis has been shown to be a re-
markably effective and versatile method for the a-function-
alization of tertiary aryl amines under mild aerobic oxida-
tive conditions.[8] However, the utility of a visible-light pho-
toredox catalyst to oxidize amines for their use as methylene
donors has not been reported. In this context, we wish to
report an efficient protocol for the synthesis of methylene-
bridged bis-1,3-dicarbonyl compounds through an aerobic
photocatalytic oxidative coupling reaction between 1,3-di-
carbonyl compounds and a tertiary aliphatic amine.
À
lize carbon–hydrogen (C H) bonds as substrates is of great
À
interest due to the challenges associated with selective C H
bond functionalization and the potential to streamline syn-
thesis by the elimination of pre-activated coupling part-
ners.[1] The cross-dehydrogenative coupling (CDC) reaction
À
of the C H bond adjacent to a nitrogen atom represents
a remarkably successful strategy towards the realization of
À
an efficient synthetic method for carbon–carbon (C C)
bond formation.[2] The mode of activation for the CDC reac-
tions with tertiary amines occurs through the oxidative for-
mation of a reactive iminium intermediate, which is then
subsequently trapped by a variety of nucleophiles to gener-
À
ate the desired C C bond.
An underappreciated but similar oxidative transformation
with tertiary amines is their use as a carbon source through
À
a sequential CDC reaction/carbon–nitrogen (C N) bond
We began our studies by examining various tertiary
amines as potential methylene donors by utilizing previously
reported reaction conditions for CDC reactions under visi-
ble-light irradiation (Table 1). The initial reaction of 1a with
N,N-dimethylarylamines under aerobic oxidative conditions
À
cleavage process to generate new C C bonds (Scheme 1).
Table 1. Evaluation of tertiary amines as methylene donors.[a]
Scheme 1. Tertiary amines as methylenation and acylation reagents.
Following the initial report of an iron-catalyzed protocol for
the synthesis of methylene-bridged bis-1,3-dicarbonyl com-
pounds[3] by Li et al. using tert-butyl hydroperoxide (TBHP)
as a sacrificial oxidant and N,N-dimethylaniline as the meth-
ylene donor,[4] a variety different synthetic procedures for
the use of tertiary amines as methylenation and acylation re-
agents have been reported.[5] However, despite these recent
advances in the use of amines as methylene and acyl donors,
new synthetic methodologies to perform these reactions
under mild aerobic conditions are highly desirable.
Entry
Amine
Yield [%][b]
1
2
3
4
8
13
>5
52
5
6
65
23
[a] Dr. W.-J. Yoo, A. Tanoue, Prof. Dr. S. Kobayashi
Department of Chemistry, School of Science
The University of Tokyo
[a] Reaction conditions: 1,3-diketone 1a (0.25 mmol), amine
(0.25 mmol), [Ru(tBu-bpy)3]2PF6 (0.0025 mmol, 1 mol%) in MeCN
(1 mL) at 308C for 18 h under open air and 7.1 W white LED illumina-
tion. [b] Yield based on 1a and determined by 1H NMR spectroscopic
analysis using 1,1,2,2-tetrachloroethane as an internal standard. tBu-
bpy=4,4’-di-tert-butyl-2,2’-dipyridyl.
7-3-1, Hongo, Bunkyo-ku, Tokyo, 113-0033 (Japan)
Fax : (+81)356840634
E-mail: shu_kobayashi@chem.s.u-tokyo.jp
AHCTUNGTRENNUNG
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201200807.
2764
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Chem. Asian J. 2012, 7, 2764 – 2767

Table 2. Optimization of reaction conditions.[a]
with [RuACHTUNGTRENNUNG(tBu-bpy)3]2PF6 as a visible-light photocatalyst led
to the desired product with very low yields (Table 1, en-
tries 1–3). Surprisingly, when we examined tertiary aliphatic
amines, the expected methylene-bridged 1,3-dicarbonyl com-
pound 2a was obtained with modest yields (Table 1, en-
tries 4 and 5). In order to improve the atom-economy of the
methylene donor, we examined N,N-dimethylethylamine as
a substrate. However, the yield of 2a was rather low
(Table 1, entry 6).
With these preliminary results in hand, we continued to
optimize the reaction conditions (Table 2). We began by
screening a variety of known ruthenium-based visible-light
photocatalysts (Table 2, entries 1–5) and found [Ru-
Entry
Catalyst
Yield [%][b]
1
2
3
4
5
6
7
[Ru
[Ru
[Ru
[Ru
[Ru
N
65
48
76
10
61
23
46
>95
>95
[Ir
N
N
ACHTUNGTRENNUNG(bpz)3]2PF6 provided 2a with a yield of 76%. Other visible-
8[c]
9[c,d]
[Ru
[Ru
U
light photocatalysts were examined (Table 2, entries 6 and
7), but the yield could not be improved. We found that addi-
tional screening of solvents and concentration did not im-
prove the aerobic oxidation reaction.[9] We hypothesized
that the open air conditions may be problematic, since the
ambient moisture may facilitate the nonproductive demethy-
lation of the amine. Thus, performing the oxidative coupling
reaction in a closed system with molecular sieves significant-
ly improved the yield (Table 2, entries 8 and 9).
[a] Reaction conditions: 1,3-diketone 1a (0.25 mmol), N,N-dimethylben-
zylamine (0.25 mmol), visible-light photocatalyst (0.0025 mmol, 1 mol%)
in MeCN (1 mL) at 308C for 18 h under open air and 7.1 W white LED
illumination. [b] Yield based on 1a and determined by 1H NMR spectro-
scopic analysis using 1,1,2,2-tetrachloroethane as an internal standard.
[c] Addition of 50 mg of 4 ꢁ MS under a balloon of dry air. [d] 12 h.
bpy=2,2’-bipyridyl, bpz=bipyrizyl, ppy=2-phenyl pyridyl.
With the optimized reaction conditions in hand, we exam-
ined the substrate generality of the aerobic oxidative cou-
pling reaction between various dicarbonyl nucleophiles 1a–
l and N,N-dimethylbenzylamine (Table 3). We began our
studies by examining various 1,3-diketones (1a–g) and
found that these nucleophiles were suitable substrates for
the aerobic oxidation reaction (Table 3, entries 1–7). We
found that the introduction of halogenated substituents on
the aromatic ring led to the formation of some side products
that diminished the yields of bis-carbonyls 3c–e (Table 3, en-
tries 3–5). When diketone 3g bearing an electron-rich sub-
stituent was utilized as a substrate, the reaction proceeded
much more slowly, and the reaction was incomplete after
12 h (Table 3, entry 7). However, when ScACTHNURTGNENG(U OTf)3 was intro-
duced as a Lewis acid co-catalyst,[10] the visible-light photo-
redox-catalyzed oxidative coupling reactions proceed
smoothly to afford 2g with an excellent yield (Table 3,
entry 8). It should be noted that the combination of a visi-
ble-light photoredox catalyst with ScACTHNUTRGENUG(N OTf)3 was very effec-
Table 3. Substrate scope.[a]
Entry
R1
R2
Yield [%][b]
1
2
3
4
5
6
7
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
92
90
75
57
75
94
70
92
91
88
83
91
34
4-Cl-C6H4
4-Br-C6H4
4-I-C6H4
4-Me-C6H4
4-MeO-C6H4
4-MeO-C6H4
OEt
OMe
OMe
OMe
OBn
8[c]
9[c]
10[c]
11[c]
12
13
Ph
4-Me-C6H4
4-MeO-C6H4
4-Br-C6H4
OBn
[a] Reaction conditions: 1,3-dicarbonyl 1a–l (0.25 mmol), N,N-dimethylbenzylamine (0.25 mmol), [Ru
ACHTUNGTRNE(NUNG bpz)3]2PF6 (0.0025 mmol, 1 mol%), 4 ꢁ MS
(50 mg) in MeCN (1 mL) at 308C for 12 h under a balloon of dry air and 7.1 W white LED illumination. [b] Yields of isolated product of 2a–l were
based on 1a–l. [c] Addition of Sc
Chem. Asian J. 2012, 7, 2764 – 2767
ACHTUNGRTEN(NUNG OTf)3 (0.0025 mmol, 1 mol%).
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
2765

Shu¯ Kobayashi et al.
COMMUNICATION
tive for this reaction and that Sc
G
cessively formed and then trapped by a second nucleophile.
the photocatalytic conditions. We also examined a variety of
b-ketoesters (2h–j) and found them to be excellent sub-
strates (Table 3, entries 9–12). With the exception of
a bromo-substituted b-ketoester 1j (Table 3, entry 12), Sc-
Although ScACTHGUNETRNNU(G OTf)3 is not strictly required in this proposed
mechanism, it is a beneficial co-catalyst that readily acti-
vates the 1,3-dicarbonyl compounds.
In conclusion, we have disclosed an efficient synthetic
procedure for the preparation of methylene-bridged 1,3-di-
carbonyl compounds through an aerobic photocatalytic oxi-
dative coupling reaction between 1,3-dicarbonyl compounds
and N,N-dimethylbenzyl amine. Unexpectedly, we discov-
ered that tertiary aliphatic amines were better methylene
donors than their aromatic counterparts under visible-light
photocatalysis. Further investigations into the use of metal
polypyridine complexes as effective catalysts for the CDC
coupling reactions with tertiary aliphatic amines under visi-
ble-light irradiation are now in progress.
ACHTUNGTRENNUNG(OTf)3 was required in order to smoothly convert these less
acidic nucleophiles to the desired methylene-bridged car-
bonyl compounds 2h–j. Finally, we examined dibenzyl malo-
nate (1l) as a potential substrate for the aerobic oxidative
reaction under visible-light irradiation (Table 3, entry 13).
We found that the reaction proceeded sluggishly to provide
the expected coupling product 2l with a modest yield. At-
tempts to improve the effectiveness of the reaction through
the use of ScACHTUNGTRENNUNG(OTf)3 led to some unknown decomposition
products, and prolonging the reaction time failed to improve
the conversion of the reaction.
A tentative mechanism for the aerobic coupling reaction
between N,N-dimethylbenzylamine and 1,3-dicarbonyl com-
pounds under visible-light irradiation is proposed in
Experimental Section
A typical experimental procedure is described for the synthesis of meth-
ylene-bridged 1,3-dicarbonyl compounds under visible-light irradiation:
Scheme 2. The initial excitation of [RuACHTUNGRTENUNG(bpz)3]2PF6 by visible
light and subsequent reductive quenching by N,N-dimethyl-
In a dried 10 mL two-necked test tube was added [RuACTHUNTGNRUE(GN bpz)3]2PF6
(0.0022 g, 0.0025 mmol, 1 mol%) and 4 ꢁ MS (0.05 g). The reaction
vessel was evacuated under high vacuum, and the atmosphere was re-
placed with a balloon of dry air. Then MeCN (1 mL) was introduced,
along with 1,3-dicarbonyl compound 1a (0.0561 g, 0.250 mmol) and N,N-
dimethylbenzylamine (38.0 mL, 0.253 mmol). The reaction mixture was al-
lowed to stir for 12 h at room temperature under a white LED lamp
(Toshiba E-CORE LDA7N/2). Then the reaction mixture was passed
through a plug of silica gel and concentrated under reduced pressure.
The resulting residue was purified by preparative TLC (EtOAc:hexane=
1:4) to afford the desired methylene-bridged bis-1,3-dicarbonyl com-
pound 2a (0.0532 g, 0.116 mmol, 92%) as a white solid.
Acknowledgements
This work was partially supported by a Grant-in-Aid for Science Re-
search from the Japan Society for the Promotion of Science (JSPS) and
Global COE Program (Chemistry Innovation through Cooperation of
Science and Engineering), The University of Tokyo, and MEXT, Japan.
À
Keywords: C H activation · oxidation · photochemistry ·
radicals
À
Scheme 2. Proposed reaction mechanism.
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Received: August 29, 2012
Published online: October 5, 2012
Chem. Asian J. 2012, 7, 2764 – 2767
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
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