Download PDF
Synlett 2015; 26(12): 1705-1709
DOI: 10.1055/s-0034-1379923
letter
© Georg Thieme Verlag Stuttgart · New York

Aerobic Photooxidative Synthesis of Secondary Aldimines from Benzylamines by Using Methylene Blue

Akifumi Okada
a   Gifu Pharmaceutical University, 1-25-4, Daigaku-nishi, Gifu 501-1196, Japan   Email: itoha@gifu-pu.ac.jp
,
Hiroki Yuasa
a   Gifu Pharmaceutical University, 1-25-4, Daigaku-nishi, Gifu 501-1196, Japan   Email: itoha@gifu-pu.ac.jp
,
Akitoshi Fujiya
a   Gifu Pharmaceutical University, 1-25-4, Daigaku-nishi, Gifu 501-1196, Japan   Email: itoha@gifu-pu.ac.jp
,
Norihiro Tada
a   Gifu Pharmaceutical University, 1-25-4, Daigaku-nishi, Gifu 501-1196, Japan   Email: itoha@gifu-pu.ac.jp
,
Tsuyoshi Miura
b   Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
,
Akichika Itoh*
a   Gifu Pharmaceutical University, 1-25-4, Daigaku-nishi, Gifu 501-1196, Japan   Email: itoha@gifu-pu.ac.jp
› Author Affiliations
Further Information

Publication History

Received: 12 March 2015

Accepted after revision: 30 April 2015

Publication Date:
18 June 2015 (online)

 
 PDF Download Permissions and Reprints All articles of this category


Abstract

We have developed a concise oxidative coupling of primary benzylamines to yield secondary aldimines catalyzed by methylene blue by using molecular oxygen as the oxidant in the presence of visible-light irradiation from fluorescent lamps.


#

Key words

aerobic - methylene blue - photooxidation - singlet oxygen - primary amine - imine

Oxidation is a significantly important and essential chemical reaction. However, numerous oxidation reactions are conducted using toxic heavy metals or stoichiometric amounts of organic reagents that generate large amounts of waste and are not environmentally friendly.[1] Recently, severe environmental problems have spurred an increased interest in use of benign molecular oxygen as an oxidant.[2] Molecular oxygen transfers between its triplet state and more reactive singlet state. Because the reaction rate of singlet oxygen is much greater than that of triplet oxygen owing to its high activity, the oxygenation of an organic substrate such as an alkene, diene, or an aromatic compound using singlet oxygen is one of the most common pathways in organic synthesis.[3] Light is an important factor in many reactions because it enables mild and selective reaction, thus the catalytic generation of singlet oxygen by irradiation with visible light in the presence of a photosensitizer is an important method in the development of environmentally benign processes.[4]

Imines are key intermediates in various organic transformations such as nucleophilic addition, aziridination, and cycloaddition.[5] Generally, imines have been synthesized by the condensation of carbonyl compounds with amines. They can also be prepared by the oxidation of secondary amines, including by visible-light-driven aerobic oxidation.[6] On the other hand, the methods of oxidative coupling of primary amines to imines are relatively less developed than the simple oxidation of secondary amines. These include aerobic oxidation using a transition-metal catalyst,[7] TBHBQ,[8] AIBN,[9] amine,[10] graphene oxide,[11] or high temperature.[12] Recently, aerobic photooxidation has also emerged for the oxidative coupling of primary amines using a transition-metal photocatalyst (e.g., Ti,[13] Au–Pd,[14] Ir,[15] and Nb[16]) or a nonmetal photocatalyst {e.g., carbon nitride,[17] phenothiazines,[18] methanocycloundeca[b]pyrimido[5,4-d]pyrrole-12,14-dione,[19] iodo-Bodipy,[20] or BDF-MON[21]}. However, there is still room for improvement because these reactions still require the use of heavy metals or synthesis of catalysts with complex structures.

Previously, we investigated mild oxidation using molecular oxygen and irradiation with fluorescent lamps using organophotocatalysts.[22] In the course of our study, we found that the use of methylene blue (MB), an inexpensive and readily available singlet oxygen generator, with potassium carbonate and molecular oxygen under visible-light irradiation from fluorescent lamps gave the corresponding N-benzylidenebenzylamine from benzylamine (Scheme [1]). To the best of our knowledge, this is the first example of the oxidative coupling of primary amines to imines using MB as an organophotocatalyst. Herein, we report the details of our study of this reaction.

Zoom Image
Scheme 1 Cross-dehydrogenative coupling reaction

Table [1] shows the optimization of the reaction conditions for aerobic photooxidative synthesis of imines conducted with 4-(tert-butyl)benzylamine (1a) as a test substrate irradiated by four fluorescent lamps for ten hours in oxygen atmosphere to prepare N-[4-(tert-butyl)benzyli­dene]-1-[4-(tert-butyl)phenyl]methanamine (2a). Among the solvents and additives examined, acetonitrile and ­potassium carbonate were found to afford the desired product 2a most efficiently (Table [1], entry 16). Variation of MB concentration showed that this reaction requires the concentration of more than 1.0 mol% (Table [1], entries 17–19).

Table 1 Summary of Reaction Conditionsa

Entry

MB (mol%)

Solvent

Additive

Yield (%)b

 1

1.0

hexane

–

19

 2

1.0

Et2O

–

25

 3

1.0

CH2Cl2

–

61

 4

1.0

EtOH

–

63

 5

1.0

MeOH

–

55

 6

1.0

H2O

–

15

 7

1.0

MeCN

–

72

 8

1.0

MeCN

TFA

 0

 9

1.0

MeCN

LiOH

54

10

1.0

MeCN

Et3N

15

11

1.0

MeCN

NaHCO3

77

12

1.0

MeCN

CaCO3

61

13

1.0

MeCN

Cs2CO3

73

14

1.0

MeCN

Li2CO3

65

15

1.0

MeCN

Na2CO

84

16

1.0

MeCN

K2CO3

98 (100)

17

1.0

MeCN

K2CO3

trace

18

0.5

MeCN

K2CO3

60

19

1.5

MeCN

K2CO3

99

a Reaction conditions: 1a (0.3 mmol), MB, and additive (3.7 equiv) in solvent were stirred and irradiated externally with four fluorescent lamps for 10 h.

b 1H NMR yields. Number in parentheses is isolated yield.

Table 2 Scope and Limitationa

Entry

Product

Yield (%)b

 1

100 (95)c

 2

 88

 3

 98

 4

 94

 5

 91

 6

100

 7

 97

 8

 92

 9

 85

10

100

11

 63

12

 99

a Reaction conditions: 1 (0.3 mmol), MB (1.0 mol%), and K2CO3 (3.7 equiv) in MeCN were stirred and irradiated externally with four fluorescent lamps for 10 h.

b Isolated yields.

c Reaction was performed on a 3 mmol scale for 45 h.

Table [2] shows the scope and limitations of photooxidative synthesis of imines produced from various benzylamines under previously described optimal reaction conditions.[23] Most of the substrates resulted in good to high yields, irrespective of whether an electron-withdrawing or electron-donating group was present (Table [2], entries 1–10). However, 4-trifluoromethylbenzylamine with a strong electron-withdrawing group afforded the product in moderate yield (Table [2], entry 11). 2-Thiophenmethylamine, a heterocyclic amine, showed 99% yield (Table [2], entry 12). The scale-up reaction was performed under optimized conditions, and the product was obtained in high yield (Table [2], entry 1). Unfortunately, aliphatic amines such as cyclohexylamine and dodecylamine were poor substrates. Although we employed N-tosylbenzylamine, a secondary amine, as a substrate, the corresponding product could not be obtained at all (not shown).

Result of the cross-coupling reaction is shown in Scheme [2]. When p-methoxybenzylamine (1c, 0.15 mmol, 0.5 equiv) and p-(trifluoromethyl)benzylamine (1b, 0.3 mmol) were reacted as substrates, the homocoupling products of p-methoxybenzylamine (2c, 1H NMR yield 24%) and that of p-(trifluoromethyl)benzylamine (2b, 1H NMR yield 50%) were produced with unidentified byproducts due to its lability through purification.

We performed several control experiments in an attempt to elucidate the reaction mechanism. Without MB, this reaction was almost suppressed, and 1a remained (Scheme [3], eq. 1). When butylated hydroxytoluene (BHT) was used as a radical inhibitor, 4-(tert-butyl)benzylamine (1a) was converted into 2a in high yield (Scheme [3], eq. 2). However, the reaction was supressed by the presence of 1,4-diazabicyclo[2.2.2]octane (DABCO, Scheme [3], eq. 3). These results indicate that this reaction proceeds via a singlet oxygen pathway. When 4-(tert-butyl)benzaldehyde, detected by 1H NMR analysis in the short reaction time, was used as substrate, a high yield of 2a was obtained (Scheme [3], eq. 4). Thus, it is suggested that arylaldehydes were produced as reaction intermediates.

Zoom Image
Scheme 2 Cross-coupling reaction. Yields were determined by 1H NMR spectroscopy.

Plausible mechanisms for this reaction are shown in Scheme [4]. Singlet oxygen is generated by photoirradiation in the presence of MB,[24] and then molecular oxygen abstracts a proton from benzylamine to form phenylmethanimine.[6] [20] On the first path, the successive addition of amine and the elimination of NH3, which results in the coupled imine, are shown.[25] In the other, the formation of benzaldehyde and successive condensation, which results in the coupled imine, are shown.

In conclusion, we have developed an oxidative coupling of primary benzylamine using molecular oxygen catalyzed by methylene blue in the presence of visible-light irradiation from fluorescent lamps. This reaction is interesting from the viewpoint of green chemistry because of the reduced waste products and the absence of heavy metals.

Zoom Image
Scheme 3 Study of reaction mechanisms. Yields were determined by 1H NMR spectroscopy.
Zoom Image
Scheme 4 Plausible pathways

#

   Permissions and Reprints All articles of this category
Zoom Image
Scheme 1 Cross-dehydrogenative coupling reaction
Zoom Image
Scheme 2 Cross-coupling reaction. Yields were determined by 1H NMR spectroscopy.
Zoom Image
Scheme 3 Study of reaction mechanisms. Yields were determined by 1H NMR spectroscopy.
Zoom Image
Scheme 4 Plausible pathways