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Synthesis 2012; 44(10): 1501-1506
DOI: 10.1055/s-0031-1290779
special topic
© Georg Thieme Verlag Stuttgart · New York

Copper-Catalyzed N–N Bond Formation by Homocoupling of Ketoximes via N–O Bond Cleavage: Facile, Mild, and Efficient Synthesis of Azines

Mi-Na Zhao
Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, Department of Chemistry & Materials Science, Northwest University, Xi’an 710069, P. R. of China, Email: guanzhh@nwu.edu.cn
,
Hao Liang
Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, Department of Chemistry & Materials Science, Northwest University, Xi’an 710069, P. R. of China, Email: guanzhh@nwu.edu.cn
,
Zhi-Hui Ren
Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, Department of Chemistry & Materials Science, Northwest University, Xi’an 710069, P. R. of China, Email: guanzhh@nwu.edu.cn
,
Zheng-Hui Guan*
Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, Department of Chemistry & Materials Science, Northwest University, Xi’an 710069, P. R. of China, Email: guanzhh@nwu.edu.cn
› Author Affiliations
Further Information

Publication History

Received: 03 February 2012

Accepted: 05 March 2012

Publication Date:
30 March 2012 (online)

 
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Abstract

A facile, mild, and efficient copper-catalyzed homocoupling of ketoximes involving N–O bond cleavage in the presence of sodium bisulfite (NaHSO3) has been developed. This reaction shows good functional group tolerance and affords a broad scope of azines in high yields.


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Key words

copper - homocoupling - ketoxime - azine - NaHSO3

Oximes and their derivatives are an important class of compounds with potential pharmaceutical properties[ 1 ] and they are also versatile functional groups.[ 2 ] Recently, considerable attention has been directed toward transition-metal-catalyzed coupling reactions using oximes and their derivatives as substrates in organic synthesis.[ 3 ] Palladium- or copper-catalyzed C–O cross-coupling of aryl halides or arylboronic acids with oximes were recently explored for the construction of a series of useful O-arylhydroxylamines.[ 4 ] Accordingly, an attractive, elegant strategy for the C–N cross-coupling of boronic acids with oxime O-carboxylates has also been used for the construction of highly substituted pyridines and N-substituted imines.[ 5 ] The development of new methodologies for the transition-metal-catalyzed coupling of oximes remains as a promising approach for the preparation of various nitrogen-containing­ compounds.[ 6 ]

Recently, our group reported a copper-catalyzed reductive acylation of ketoximes for preparation of enamides in the presence of sodium bisulfite (Scheme [1, equation] 1).[ 7 ] The success of this novel methodology encourage us to examine the formation of N-Boc enamines in the presence of di-tert-butyl dicarbonate under similar conditions. Unexpectedly, azines, which were generated from copper-catalyzed homocoupling of the oximes, were observed as the main product instead of N-Boc enamines (Scheme [1, equation] 2). Azines, N–N linked diimines, are extensively used as synthetic intermediates,[ 8 ] and they have received much attention recently due to their interesting optical,[ 9 ] biological,[ 10 ] and conductive properties,[ 11 ] and their potential application in liquid crystals, nonlinear optical materials.[ 12 ] Azines are generally prepared by the condensation of aldehydes or ketones with hydrazine hydrate in ethanol solution under reflux conditions;[ 13 ] hydrazine hydrate is hazardous and essential for this transformation. Versatile and efficient methods for the construction of azines using environmentally friendly and readily available starting materials remain highly desirable.[ 14 ] Herein, we report a facile and practical method for the copper-catalyzed homocoupling­ of oximes for the synthesis of azines.

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Scheme 1 Copper-catalyzed reductive coupling of oximes

Table 1 Optimization of the Reaction Conditionsa

Entry

Catalyst

Reductant

Solvent

Yieldb (%)

 1

CuI

NaHSO3

toluene

74

 2

CuI

NaHSO3

DMF

53

 3

CuI

NaHSO3

1,4-dioxane

 0

 4

CuI

NaHSO3

THF

 0

 5

CuI

NaHSO3

MeCN

17

 6

CuI

NaHSO3

DCE

90

 7

CuI

–

DCE

13

 8

CuI

Na2SO3

DCE

49

 9

CuI

Na2S2O4

DCE

71

10

CuBr

NaHSO3

DCE

64

11

CuCl

NaHSO3

DCE

60

12

Cu(OAc)2

NaHSO3

DCE

21

13

Pd(OAc)2

NaHSO3

DCE

 0

14

–

NaHSO3

DCE

 0

15c

CuI

NaHSO3

DCE

n.r.d

a Reaction conditions: 1a (0.2 mmol), (Boc)2O (0.4 mmol), catalyst (10 mol%), reductant (0.6 mmol), solvent (3 mL), under Ar, 140 °C, 12 h.

b Isolate yield.

c The reaction was performed in the absence of (Boc)2O.

d n.r. = no reaction.

Initially, acetophenone oxime (1a) was used as a model substrate to optimize the reaction conditions. The desired azine 2a was obtained in 74% yield when copper(I) iodide was used as a catalyst in the presence of sodium bisulfite in toluene (Table [1, entry] 1). Various catalysts, reducing agents, and solvents were then screened in this reaction. Examining the use of various solvents, 1,4-dioxane and tetrahydrofuran gave no product and N,N-dimethylform­amide or acetonitrile gave 2a in lower yield (entries 2–5). 1,2-Dichloroethane was the most suitable solvent for this reaction, giving azine 2a in an excellent 90% yield (entry 6). Sodium bisulfite is essential as the reducing agent in this copper-catalyzed homocoupling reaction, other reductants, such as sodium sulfite and sodium dithionite, were employed, but did not improve the yield of 2a (entries 7–9). Next catalyst was varied, and it was found that copper(I) iodide was a superior catalyst to other copper or palladium precursors, such as copper(I) bromide or chloride, copper(II) acetate, and palladium(II) acetate (entries 10–13). Furthermore, control experiments confirmed that the formation of 2a was not observed in the absence of either copper catalyst or di-tert-butyl dicarbonate (entries 14 and 15). Based on these studies, the optimal conditions are copper(I) iodide (10 mol%) and sodium bisulfite (3 equiv) in 1,2-dichloroethane under argon at 140 °C.

With these optimized reaction conditions in hand, we then examined the substrates scope of this novel copper(I) iodide catalyzed homocoupling reaction. The results are summarized in Table [2]. This transformation displayed good functional group tolerance and gave various azines in moderate to good yields. Ketoximes 1b–h with methyl, methoxy, fluoro, chloro, and bromo groups on aryl rings could easily be converted into the corresponding azines under the reaction conditions. Electron-donating ketoximes were more beneficial for this transformation, while the yields of electron-withdrawing ketoximes were decreased slightly (entries 2–8). Furthermore, the 2-acetylnaphthalene oxime (1i) also underwent the desired reaction to give the corresponding azine 2i in good yield (entry 9). Similarly, the homocoupling of aryl ethyl ketoximes 1j–m and cyclic ketoximes 1n,o also proceeded smoothly to give the corresponding azines 2j–o in good yields (entries 10–15).

To gain an insight into the reaction mechanism, the O-Boc-oxime 3a was first prepared by reacting acetophenone oxime (1a) with di-tert-butyl dicarbonate. Then 3a was refluxed in the presence of copper(I) iodide and sodium bisulfite in 1,2-dichloroethane at 140 °C for 12 hours, to give the corresponding azine 2a in 82% yield (Scheme [2]).

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Scheme 2 Investigation of the mechanism

On the basis of the results obtained above, a plausible mechanism for this reaction is depicted in Scheme [3]. The reaction is initiated by the formation of O-Boc-oxime intermediate 3 from the acylation of ketoxime 1 by di-tert-butyl dicarbonate. Next, cleavage of the N–O bond of the O-Boc-oxime 3 by Cu+ and expulsion of a Cu2+ gives the imine radical 4,[7] [15] which is assumed to undergo homocoupling rapidly to give azine product 2. The Cu2+ species is reduced by sodium bisulfite to regenerate the active Cu+ in the reaction.

In conclusion, we have developed a novel and efficient protocol for the copper-catalyzed homocoupling of ketoximes for the preparation of symmetrical azines. The procedure shows high functional group tolerance and allows rapid elaboration of readily available oximes into a variety of symmetrical substituted azines in good to excellent yields under mild reaction conditions. The reaction avoids the use of hazardous hydrazine hydrate and is also environmentally friendly. Investigations of an unsymmetrical version, the detailed mechanism, and synthetic applications of this reaction are under way in our laboratory.

Table 2 Copper(I) Iodide Catalyzed Reductive Homocoupling of Ketoximes To Give Azinesa

Entry

Oxime 1

Azine 2

Time (h)

Yieldb (%)

1

1a

2a

12

90

2

1b

2b

24

84

3

1c

2c

24

80

4

1d

2d

24

73

5

1e

2e

12

72

6

1f

2f

24

62

7

1g

2g

24

65

8

1h

2h

24

67

9

1i

2i

 9

60

10

1j

2j

24

72

11

1k

2k

24

73

12

1l

2l

24

75

13

1m

2m

12

63

14

1n

2n

12

82

15

1o

2o

 9

64

a Reaction conditions: 1 (0.4 mmol), (Boc)2O (0.8 mmol), CuI (10 mol%), NaHSO3 (1.2 mmol), DCE (5 mL), under Ar, 140 °C.

b Isolated yield.

Zoom Image
Scheme 3 Proposed mechanism for copper(I) iodide catalyzed homocoupling of ketoximes

Column chromatography was carried out on silica gel. 1H NMR spectra were recorded on 400 MHz in CDCl3 and 13C NMR spectra were recorded on 100 MHz in CDCl3. All new products were further characterized by HRMS. Unless otherwise stated, all reagents and solvents were purchased from commercial suppliers and used without further purification. The ketoximes were in all cases prepared from the corresponding ketones according to literature.[7] [16]


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Azines 2; General Procedure

A mixture of ketoximes 1 (0.4 mmol), (Boc)2O (0.8 mmol, 174.4 mg), NaHSO3 (1.2 mmol, 124.8 mg), and CuI (10 mol%, 7.6 mg) was stirred in DCE (5.0 mL) at 140 °C under argon. After completion of the reaction (TLC, hexane–EtOAc, 20:1), the mixture was cooled to r.t., diluted with EtOAc (25 mL), and washed with brine (20 mL). The organic layers were dried (anhyd Na2SO4), and evaporated in vacuo. The desired azines 2 were obtained after purification by flash chromatography (silica gel, hexane–EtOAc, 50:1).


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1,2-Bis(1-phenylethylidene)hydrazine (2a)

Yellow solid; yield: 42.4 mg (90%); mp 115–116 °C.

1H NMR (400 MHz, CDCl3): δ = 7.93–7.91 (m, 4 H), 7.43–7.41 (m, 6 H), 2.32 (s, 6 H).

13C NMR (100 MHz, CDCl3): δ = 157.6, 138.3, 129.6, 128.3, 126.6, 15.0.


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1,2-Bis(1-p-tolylethylidene)hydrazine (2b)

Yellow solid; yield: 44.5 mg (84%); mp 127–129 °C.

1H NMR (400 MHz, CDCl3): δ = 7.81 (d, J = 8.8 Hz, 4 H), 7.22 (d, J = 8.0 Hz, 4 H), 2.39 (s, 6 H), 2.30 (s, 6 H).

13C NMR (100 MHz, CDCl3): δ = 157.6, 139.6, 135.7, 129.0, 126.5, 21.3, 14.9.


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1,2-Bis[1-(3,4-dimethylphenyl)ethylidene]hydrazine (2c)

Yellow solid; yield: 47.4 mg (80%); mp 116–117 °C.

1H NMR (400 MHz, CDCl3): δ = 7.72 (s, 2 H), 7.61 (d, J = 8.0 Hz, 2 H), 7.18 (d, J = 8.0 Hz, 2 H), 2.32 (s, 6 H), 2.30 (s, 6 H), 2.28 (s, 6 H).

13C NMR (100 MHz, CDCl3): δ = 157.3, 138.3, 136.4, 136.1, 129.5, 127.6, 124.1, 19.9, 19.6, 15.0.


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1,2-Bis[1-(5,6,7,8-tetrahydronaphthalen-2-yl)ethylidene]hydrazine (2d)

Yellow solid; yield: 50.0 mg (73%); mp 84–86 °C.

1H NMR (400 MHz, CDCl3): δ = 7.61 (d, J = 8.8 Hz, 4 H), 7.10 (d, J = 8.0 Hz, 2 H), 2.81 (s, 8 H), 2.26 (s, 6 H), 1.81 (s, 8 H).

13C NMR (100 MHz, CDCl3): δ = 157.3, 138.9, 137.0, 135.7, 129.1, 127.2, 123.7, 29.5, 29.3, 23.1, 23.1, 15.0.


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1,2-Bis[1-(3-methoxyphenyl)ethylidene]hydrazine (2e)

Yellow solid; yield: 42.6 mg (72%); mp 90–92 °C.

1H NMR (400 MHz, CDCl3): δ = 7.50 (s, 2 H), 7.43 (d, J = 7.6 Hz, 2 H), 7.33–7.29 (t, J = 8.0 Hz, 2 H), 6.95 (d, J = 8.0 Hz, 2 H), 3.84 (s, 6 H), 2.27 (s, 6 H).

13C NMR (100 MHz, CDCl3): δ = 159.5, 157.1, 139.7, 129.2, 119.2, 115.6, 111.5, 55.3, 15.1.


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1,2-Bis[1-(4-fluorophenyl)ethylidene]hydrazine (2f)

Yellow solid; yield: 33.5 mg (62%); mp 125–127 °C.

1H NMR (400 MHz, CDCl3): δ = 7.90–7.86 (m, 4 H), 7.10–7.05 (t, J = 8.8 Hz, 4 H), 2.29 (s, 6 H).

13C NMR (100 MHz, CDCl3): δ = 163.7 (d, J C,F = 248.9 Hz), 157.4, 134.5, 128.5 (d, J C,F = 8.3 Hz), 115.3 (d, J C,F = 22.0 Hz), 14.9.


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1,2-Bis[1-(4-chlorophenyl)ethylidene]hydrazine (2g)

Pale yellow solid; yield: 39.3 mg (65%); mp 154–155 °C.

1H NMR (400 MHz, CDCl3): δ = 7.82 (d, J = 8.0 Hz, 4 H), 7.36 (d, J = 8.4 Hz, 4 H), 2.27 (s, 6 H).

13C NMR (100 MHz, CDCl3): δ = 157.2, 136.6, 135.7, 128.5, 127.9, 14.9.


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1,2-Bis[1-(4-bromophenyl)ethylidene]hydrazine (2h)

Yellow solid; yield: 52.5 mg (67%); mp 161–162 °C.

1H NMR (400 MHz, CDCl3): δ = 7.75 (d, J = 8.0 Hz, 4 H), 7.52 (d, J = 8.8 Hz, 4 H), 2.26 (s, 6 H).

13C NMR (100 MHz, CDCl3): δ = 157.3, 137.0, 131.5, 128.1, 124.1, 14.9.


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1,2-Bis[1-(naphthalen-2-yl)ethylidene]hydrazine (2i)

Brown solid; yield: 40.6 mg (60%); mp 198–200 °C.

1H NMR (400 MHz, CDCl3): δ = 8.24 (d, J = 10.4 Hz, 4 H), 7.90–7.84 (m, 6 H), 7.51–7.49 (m, 4 H), 2.47 (s, 6 H).

13C NMR (100 MHz, CDCl3): δ = 157.6, 135.8, 134.0, 133.0, 128.6, 127.9, 127.6, 126.8, 126.6, 126.3, 124.0, 15.0.


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1,2-Bis(1-phenylpropylidene)hydrazine (2j)

Yellow solid; yield: 38.7 mg (72%); mp 59–60 °C.

1H NMR (400 MHz, CDCl3): δ = 7.92–7.90 (m, 4 H), 7.43–7.41 (m, 6 H), 2.90–2.88 (m, 4 H), 1.14–1.11 (t, J = 7.2 Hz, 6 H).

13C NMR (100 MHz, CDCl3): δ = 162.8, 137.3, 129.5, 128.4, 126.8, 21.9, 11.4.


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1,2-Bis(1-p-tolylpropylidene)hydrazine (2k)

Yellow solid; yield: 42.7 mg (73%); mp 100–101 °C.

1H NMR (400 MHz, CDCl3): δ = 7.81 (d, J = 8.0 Hz, 4 H), 7.23 (d, J = 7.2 Hz, 4 H), 2.88–2.86 (m, 4 H), 2.39 (s, 6 H), 1.13–1.09 (m, 6 H).

13C NMR (100 MHz, CDCl3): δ = 163.0, 139.8, 134.9, 129.4, 127.0, 22.1, 21.6, 11.8.


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1,2-Bis[1-(3,4-dimethylphenyl)propylidene]hydrazine (2l)

Yellow solid; yield: 48.0 mg (75%); mp 61–62 °C.

1H NMR (400 MHz, CDCl3): δ = 7.71 (s, 2 H), 7.61 (d, J = 8.0 Hz, 2 H), 7.18 (d, J = 7.6 Hz, 2 H), 2.88–2.84 (m, 4 H), 2.32 (s, 6 H), 2.30 (s, 6 H), 1.12–1.08 (t, J = 7.6 Hz, 6 H).

13C NMR (100 MHz, CDCl3): δ = 162.4, 138.2, 136.5, 135.0, 129.6, 127.9, 124.3, 21.8, 19.9, 19.6, 11.5.

HRMS (ESI): m/z [M + H]+ calcd for C22H29N2: 321.2325; found: 321.2325.


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1,2-Bis[1-(5,6,7,8-tetrahydronaphthalen-2-yl)propylidene]hydrazine (2m)

Yellow solid; yield: 47.9 mg (63%); mp 90–91 °C.

1H NMR (400 MHz, CDCl3): δ = 7.61 (d, J = 10.4 Hz, 4 H), 7.11 (d, J = 8.0 Hz, 2 H), 2.86–2.81 (m, 12 H), 1.81 (s, 8 H), 1.11–1.07 (t, J = 7.6 Hz, 6 H).

13C NMR (100 MHz, CDCl3): δ = 162.4, 138.8, 137.1, 134.6, 129.1, 127.4, 123.9, 29.5, 29.3, 23.1, 23.1, 21.8, 11.5.


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1,2-Bis[3,4-dihydronaphthalen-1(2H)-ylidene]hydrazine (2n)

Yellow solid; yield: 47.2 mg (82%); mp 134–135 °C.

1H NMR (400 MHz, CDCl3): δ = 8.30–8.29 (m, 2 H), 7.29–7.25 (m, 4 H), 7.17–7.15 (m, 2 H), 2.82–2.81 (m, 4 H), 2.77–2.74 (m, 4 H), 1.93–1.90 (m, 4 H).

13C NMR (100 MHz, CDCl3): δ = 157.0, 140.4, 132.8, 129.4, 128.6, 126.2, 125.4, 29.9, 27.3, 22.1.


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1,2-Bis(2,3-dihydroinden-1-ylidene)hydrazine (2o)

Yellow solid; yield: 33.2 mg (64%); mp 164–166 °C.

1H NMR (400 MHz, CDCl3): δ = 7.90 (d, J = 7.6 Hz, 2 H), 7.38–7.29 (m, 6 H), 3.07–3.01 (m, 8 H).

13C NMR (100 MHz, CDCl3): δ = 169.9, 149.7, 138.3, 131.0, 126.9, 125.6, 122.5, 28.5, 28.2.


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Acknowledgment

This research was supported by National Natural Science Founda­tion of China (NSFC-21002077).



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Zoom Image
Scheme 1 Copper-catalyzed reductive coupling of oximes
Zoom Image
Scheme 2 Investigation of the mechanism
Zoom Image
Scheme 3 Proposed mechanism for copper(I) iodide catalyzed homocoupling of ketoximes