CuI-Catalyzed Aerobic Oxidative Î±-Aminaton Cyclization of Ketones to

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CuI-Catalyzed Aerobic Oxidative alpha-Aminaton Cyclization of Ketones to Access Aryl or Alkenyl-Substituted Imidazoheterocycles Yuanfei Zhang, Zhengkai Chen, Wenliang Wu, Yuhong Zhang, and Weiping Su J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 20 Nov 2013 Downloaded from http://pubs.acs.org on November 22, 2013

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The Journal of Organic Chemistry

CuI-Catalyzed Aerobic Oxidative α-Aminaton Cyclization of Ketones to Access Aryl or Alkenyl-Substituted Imidazoheterocycles Yuanfei Zhang,a Zhengkai Chen,b Wenliang Wu,a Yuhong Zhang*,b and Weiping Su*,a a

State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of

Matter, Chinese Academy of Sciences, Fuzhou, Fujian 350002, China E-mail: [email protected] b

Department of Chemistry, Zhejiang University, Hangzhou 310027, China

E-mail: [email protected]

ABSTRACT: CuI-catalyzed aerobic oxidative synthesis of imidazoheterocycles has been achieved. Four hydrogen atoms were removed in one step. This protocol was compatible with a broad range of functional groups, and has also successfully extended to unsaturated ketones bringing about the formation of alkenyl-substituted imidazoheterocycles which were difficult to be prepared by previous means. Preliminary mechanistic studies indicated that this reaction was most likely to proceed through a catalytic Ortoleva−King reaction. By using this method, marketed drug Zolimidine could be prepared on gram scale from commercially available materials with 90% yield obtained. 1. INTRODUCTION Imidazo[1,2-a]pyridines are prominent among N-fused heterocycles, and are extensively found in

ACS Paragon Plus Environment


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biologically

active

molecules.1

Several

compounds

bearing

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the

core

structure

of

imidazo[1,2-a]pyridine ring systems have been successfully developed into commercially available drugs including alpidem, zolpidem, zolimidine, and olprinone, etc (Scheme 1).2 They are also useful frameworks in material science,3 and abnormal N-heterocyclic carbenes in organometallic chemistry.4 Scheme 1. Biologically active compounds sharing imidazo[1,2-a]pyridine rings.

Progresses were made to gain access to substituted imidazo[1,2-a]pyridines.5 Among them, the reaction of 2-aminopyridines with mono α-halogenocarbonyl compounds remains the most commonly used means in both laboratory synthesis and industrial manufacture.3d,5e,6 However, this methodology is still imperfect. Mono halogenation of carbonyl compounds, particularly unsaturated ones, is still challenging.7 In addition to the difficulties in controlling mono substituted product, halogenations using cheap X2 (mainly bromide) as halogen source were ineffective for unsaturated ketones.8 Furthermore, the coupling efficiency were not good enough with respect to halogenated unsaturated ketones.2h Because of those intrinsic defects, a wide range of unsaturated ketones cannot be easily incorporated into imidazoheterocycles using this traditional method, severely limiting the structural diversity of imidazoheterocycles. Herein, we


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describe a CuI-catalyzed aerobic oxidative α-aminaton cyclization of ketones leading to substituted imidazoheterocycles. Starting from simple and readily available materials, this transformation is straightforward and of high efficiency, and is also applicable to unsaturated ketones. Towards waste free synthesis, transition-metals catalyzed oxidative functionalization of organic molecule involving dioxygen activation present one of most powerful means in organic synthesis.9 Special attentions have been paid to copper/O2 system which exhibits broad catalytic activities over a spectrum of substrates.9e,9h,10 Some biomimetic oxidation systems based on copper as co-catalysis have been developed as well.11 Using CuI as catalysis under aerobic conditions, the role of iodine anion has been ignored by most authors.10,11a In this work, iodine anion is crucial to the current transformation. 2. RESULTS AND DISCUSSION Initially, we examined the reaction of 2-aminopyridine (1a) and acetophenone (2a) in the presence of copper salts (5 mol%) in DMF at 100 oC under aerobic conditions. Interestingly, only CuI gave the desired product 2-phenylimidazo[1,2-a]pyridine in 66% yield (Table 1, entry 1). Other copper sources, CuCl, CuBr, CuCl2 and CuBr2, etc, though under the otherwise identical conditions, failed to produce the product in any detectable amount (Table 1 entries 2-12). Next, we checked the effect of solvents, the yield was not obviously increased in DMA and NMP (Table 1, entries 13

and

14).

Taking

into

account

previous

reports

concerning

the

synthesis

of

imidazo[1,2-a]pyridines,3d,5e,6 we reasoned that this reaction might proceed via an initial α-iodination of acetophenone and subsequent amination/cyclization sequence, which differs from the C-H bond functionalization mechanism or SET process.12 Thus, the efficiency of α-iodination



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of acetophenone was decisive for the overall yield. With this hypothesis in mind, we surveyed various Lewis acid to accelerate the α-iodination step (Table 1, entries 15-22). Gratifyingly, 81% yield was obtained accompanied with the addition of 1mol% In(CF3SO3)3 in NMP under 1atm O2 (Table 1, entry 17). Table 1. Optimization of the reaction conditionsa

Entry

catalyst

Additive (equiv)

Solvent

Yield (%)b

1

CuI

-

DMF

66

2

CuCl

-

DMF

NDc

3

CuBr

-

DMF

NDc

4

CuCl2

-

DMF

NDc

5

CuBr2

-

DMF

NDc

6

Cu(OAc)2

-

DMF

NDc

7

Cu(CF3SO3)2

-

DMF

NDc

8

CuO

-

DMF

NDc

9

Cu2O

-

DMF

NDc

10

CuF2

-

DMF

NDc

11

CuSO4

-

DMF

NDc

12

Cu(NO3)2.3H2O

-

DMF

NDc

13

CuI

-

DMA

68


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14

CuI

-

NMP

69

15

CuI

In(CF3SO3)3 (2.5%)

DMA

70d

16

CuI

In(CF3SO3)3 (2.5%)

NMP

82d

17

CuI

In(CF3SO3)3 (1%)

NMP

81d

18

CuI

BF3.Et2O (10%)

NMP

50d

19

CuI

TsOH (10%)

NMP

71d

20

CuI

TsOH (10%)

NMP

46e

21

CuI

CuBr2 (5%)

NMP

71d,e

22

CuI

CuBr2 (5%)

NMP

80d,e

a

Reaction Conditions: 1a (0.6 mmol), 2a (0.3 mmol), cat. (5 mol%), solvent (2 mL), O2 (1 atm),

100 oC, 24 h. b Isolated yield. c ND = Not Detected (by GC-MS). d The reaction was carried out for 30 h. e Under 1 atm air. DMF = N,N-dimethylformamide. DMA = N,N-dimethylacetamide. NMP = N-methyl-2-pyrrolidone. With the optimized reaction conditions in hand, we evaluated the scope of the reaction. As depicted in (Table 2), the nature of substituents on the benzene ring of (hetero)aryl methyl ketones did not affect the reaction much, good to excellent yields were obtained. Notably, cyano group was also compatible with the current reaction condition (Table 2, 3c).10f Propiophenone and butyrophenone were transformed into the corresponding products in synthetically useful yields with some variations from the standard conditions (Table 2, 3t and 3u). With regards to 2-aminopyridine counterparts, to those with electron-withdrawing group, higher temperature was required to achieve satisfying yields (Table 2, 3n-3q), and vice versa (Table 2, 3m). 2-aminopyrimidine and 2-aminothiazole which were ineffective in prior work could be applicable



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to our system as well (Table 2, 3q and 3r).5h Table 2. CuI-catalyzed aerobic oxidative reaction of 2-aminopyridines with Arylketonesa

a

Reaction Conditions: 1a (0.6 mmol), 2a (0.3 mmol), CuI (5 mol%), In(CF3SO3)3 (1 mol%) ,

NMP (2 mL), O2 (1 atm), 100 oC , 30 h. Isolated yields. b The reaction was carried out at 90 oC. c


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The reaction was carried out at 120 oC for 48 h. d Without In(CF3SO3)3. e 1a (0.9 mmol), 5 mol% CuBr2 was used instead of In(CF3SO3)3. Surprisingly, the reaction was also amenable to unsaturated ketones bringing about the formation of alkenyl-substituted imidazoheterocycles (Table 3). Those obtained compounds were rarely investigated due to the difficulties imposed in their preparations.13 Though α,β-unsaturated ketones are well recognized as Michael acceptors, the Michael addition cyclization products were not observed.5i Extending the conjugated system between carboxyl group and benzene ring had no distinct impact on the yields (Table 3, 4d, 4g, 4j, 4m and 4p). However, the absence of conjugated system was fatal to the reaction (Table 3, 4q). It is noteworthy that alkenyl group can be easily transformed making the structural diversity of imidazoheterocycles abundant. Table 3. CuI-catalyzed aerobic oxidative reaction of 2-aminopyridines with unsaturated ketonesa



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a

Reaction Conditions: 1a (0.6 mmol), 2b (0.3 mmol), CuI (5 mol%), In(CF3SO3)3 (1 mol%) ,

NMP (2 mL), O2 (1 atm), 100 oC , 30 h. Isolated yields. b The reaction was carried out at 120 oC for 48 h. c The reaction was carried out at 90 oC. Application of this method to the synthesis of zolimidine (3v) on gram scale from commercially available materials was successful with 90% isolated yield (Scheme 2). Interestingly, with the protection of 2', 3' hydroxyl groups, adenosine which is an important fragment in biochemistry could be converted to imidazo[1,2-i]purineheterocycle in 36% yield (Scheme 3). Although this process ran at 120 oC under oxygen atmosphere, the rest hydroxyl group was still intact.14 Scheme 2. Gram scale synthesis of zolimidine.


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Scheme 3. Reaction of 2', 3'-O-isopropylideneadenosine with acetophenone.a

a

Conditions: 2',3'-O-Isopropylideneadenosine (0.6 mmol), acetophenone (0.3 mmol), CuI (5

mol%), In(CF3SO3)3 (1 mol%) , NMP (2 mL), O2 (1 atm), 120 oC , 48 h. Isolated yield. To gain some insights into the reaction mechanism, an intramolecular reaction was carried out, 3a was produced in only 19% yield (Scheme 4, Eq. (1)), which indicates that both copper-catalyzed tandem condensation-oxidative C-N bond formation cyclization and SET process are in some degree impossible.9h,10b,12,15 When quantitative CuI was used, iodinated product 3x was introduced in good yield (Scheme 4, Eq. (3)), which shows that the release of iodine is possible in the reaction.16,17 The generation of dehydrogenative product 5a further confirmed the possibility (Scheme 4, Eq. (4)). 3a was not formed when AgOAc was used to quench the iodine anion (Scheme 4, Eq. (5)). Cu(CF3SO3)2, CuSO4, and Cu(NO3).3H2O, etc, which were unreactive could work well when TBAI or NaI was used as additive (Table 4). Recently, the boom of hypervalent iodine chemistry, especially issues concerning catalytic iodination cascade substitution reactions convince us to believe that this transformation proceeds through a similar passway.18



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Scheme 4. Mechanistic studies.

Table 4. Evaluating the effect of iodine aniona

Entry

catalyst

Additive (equiv)

Solvent

Yield (%)b

1

CuCl

TBAI (5%)

NMP

16

2

CuBr

TBAI (5%)

NMP

0

3

CuCl2

TBAI (5%)

NMP

0


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4

CuBr2

TBAI (5%)

NMP

0

5

Cu(OAc)2

TBAI (5%)

NMP

0

6

Cu(CF3SO3)2

TBAI (5%)

NMP

52 (55)

7

CuSO4

TBAI (5%)

NMP

33

8

Cu(NO3)2.3H2O

TBAI (5%)

NMP

40

9

CuCl

NaI (5%)

NMP

9

10

CuBr

NaI (5%)

NMP

CuI-Catalyzed Aerobic Oxidative Î±-Aminaton Cyclization of Ketones to

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