Mn(II)-Catalyzed C-H Alkylation of Imidazopyridines and N

Subscriber access provided by WEBSTER UNIV

Article

Mn(II)-Catalyzed C-H Alkylation of Imidazopyridines and NHeteroarenes via Decarbonylative and Cross-dehydrogenative coupling Sadhanendu Samanta, and Alakananda Hajra J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00366 • Publication Date (Web): 07 Mar 2019 Downloaded from http://pubs.acs.org on March 7, 2019

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 31 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The Journal of Organic Chemistry

Mn(II)-Catalyzed C-H Alkylation of Imidazopyridines and N-Heteroarenes via Decarbonylative and Cross-dehydrogenative coupling Sadhanendu Samanta and Alakananda Hajra * Department of Chemistry, Visva-Bharati (A Central University), Santiniketan 731235, India N N

Ar

N

decarbonylative

N

Mn(II), DTBP

R

R CHO

imidazopyridines other N-heteroarenes

N

CDC

Ar

N

Mn(II), DTBP

H

R H

alkyl source aldehyde/alkane/ether/alcohol

Ar

R 44 Examples up to 89% yield

ABSTRACT: A Mn(II)-catalyzed efficient C-H alkylation of imidazoheterocycles and N-heteroarenes with aliphatic aldehydes has been developed via oxidative decarbonylation. Other alkylating agents such as cyclic alkanes, ethers and alcohols also coupled with N-heteroarenes through cross-dehydrogenative coupling. Regioselectively C5-alkylated imidazoheterocycles have been synthesized in good yields. Experimental results show that radical pathway might be involved in this reaction.

INTRODUCTION: Direct C−H alkylation of N-heteroarenes1 remains a formidable challenge to the synthetic organic chemist due to their broad pharmacological activity and ability to tune physicochemical properties.2 Minisci reaction is a well-developed protocol for C-H functionalization of N-heteroarenes.3 The classical Minisci reaction is done by using carboxylic acids as an alkyl source.4 Recently, a number of methodologies have been

1 ACS Paragon Plus Environment

The Journal of Organic Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 2 of 31

developed by using different alkylating agents such as alkyl halides, alkyltrifluoroborates, boronic acids, acid chlorides etc.5 Ackermann et al. reported a directing group assisted CH alkylation of arenes using alkyl halide as alkylating agent in presence of Mn(II)catalyst.6 However, use of aliphatic aldehyde for alkylation remains a challenge. Aliphatic aldehydes have been utilized as a source of both acyl radicals and alkyl radicals but it is very difficult to control acylation and alkylation.7 Thus, efforts are continuing for the selective synthesis of alkyl radicals from aldehydes via oxidative decarbonylation.8 Moreover, C(sp2)-H functionalization of azaarenes with an array of moieties such as simple alkanes,9 amines,10 ethers11 and alcohols,12 via cross-dehydrogenative coupling (CDC) is an attractive area of research.

One of the important nitrogen containing fused heterocycles, Imidazo[1,2-a]pyridine has attracted significant interest over the past few years.13 Imidazopyridine moieties have shown many biological activities, for instance, antitumor, antiprotozoal, antiviral, antimicrobial, antiherpes, fungicidal, hypnotic activities, etc.14a This heterocyclic scaffold is also the core structure of several drugs such as alpidem, zolpidem, olprinone, zolimidine, necopidem, and saripidem.14b Figure 1. Selected Examples of Biologically Active Molecules Ph

OMe

N CO2Me MeO

N O

N N

Et

OMe MeO

O

Me

Ph kinase PDK 1 inhibitors CF3 F3C N

N

MeO

divaplon

papaverine O

Cl

N

NH HN

N

O O

HO HN

GSK-923295

mefloquine

N HO


Page 3 of 31 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Different functionalities present in imidazo[1,2-a]pyridines and N-heteroarenes regulate their pharmacological activities as shown in Figure 1. Thus a number of methodologies have been developed for the synthesis and functionalization of imidazoheterocycles.15 Most of these reported methods provide functionalization at the C-3 position of imidazoheterocycles.13,15-17 However, functionalization at C-5 position of imidazoheterocycles is only done by transitionmetal catalyzed cross-coupling reaction from pre-activated substrates.15 The literature reveals that there is no such method for the direct C-5 functionalization on imidazo[1,2-a]pyridines. In continuation of our research on the synthesis and functionalization of imidazoheterocycles,17 herein we wish to disclose a Mn(II)-catalyzed oxidative C-H alkylation of imidazopyridines with aldehydes, simple alkanes, ethers, and alcohols to provide 5-alkylated derivatives (Scheme 1). Scheme 1. Functionalization of imidazoheterocycles (a) Previous work on C-3 functionalization: N Ph

N

N

FG

Ph

N

N

FG

Ph

N

radical

ionic H H FG FG = -CF3, -SAr, -SeAr, -SCN, -CF2COOEt, amine, halogens, -OR, -NO, -SO2Ph, etc. (b) C-5 functionalization via cross-coupling: N Ph

N

N

Pd(II)

R1

Ph

N

R1-B(OH)2

N

Pd(II)

Ph

N

R2-SnBu3 R2

I/Br

(c) This work: N N R

Ph

N

CDC R H Mn(II)/ DTBP

Ph

N H

N

decarbonylation R CHO Mn(II)/ DTBP

N

Ph

R

RESULTS AND DISCUSSION:

We commenced our study by taking 8-methyl-2-phenylimidazo[1,2-a]pyridine 1a and isobutyraldehyde 2a as model substrates. Initially, we started our reaction using 5 equiv. of 3 ACS Paragon Plus Environment


aldehyde as an alkylating agent with 5 mol % Cu(OTf)2 and 3 equiv. of DTBP (di-tert-butyl peroxide) in 1,2-DCB under Ar atmosphere. To our delight, 5-alkylated imidazo[1,2-a]pyridine (3aa) was obtained in 51% yield at 130 oC after 6 h (Table 1, entry 1). It is worthy to mention that acylation did not occur under the present reaction conditions.6b Encouraged by this initial result, we carried out the reaction in different conditions and the results are shown in Table 1. The screening of other metal catalysts, such as Fe(acac)3, Co(OAc)2, Mn(OAc)3.2H2O, Mn(OAc)2 and MnO2 (Table 1, entries 2−6) revealed that efficient alkylation occurred in presence of Mn(OAc)2 as a catalyst in 1,2-DCB solvent (Table 1, entry 5). Next we checked the effect of other common solvents like chlorobenzene, 1,2-DCE, toluene, DMF, and CH3CN (Table 1, entries 7−11). Among them, 1,2-DCB was found to be the most effective solvent yielding 87% of the desired product (Table 1, entry 5). Further optimization was performed using different oxidants such as TBPB (tert-butyl peroxybenzoate), TBHP (tert-butyl hydroperoxide), and K2S2O8 (Table 1, entries 12−14). However, they were not so effective like DTBP. Lower yield of the desired product was obtained in absence of catalyst (Table 1, entry 15). However the reaction did not proceed in absence of oxidant (Table 1, entry 16). The yield of the reaction was not increased significantly with further increasing the catalyst loading even at high temperature. Only a trace amount of product was obtained at 80 oC (Table 1, entry 17). The reaction did not proceed at all under O2 atmosphere (Table 1, entry 18), which probably due to the formation of carboxylic acid by auto-oxidation of aldehyde.8b Moreover, the yield of the reaction decreased significantly in presence of 2 equiv. of 2a (Table 1, entry 19). Thus, the optimized yield was obtained using 5 mol % of Mn(OAc)2 and 3 equiv. of DTBP in 1,2-DCB at 130 °C for 6 h under Ar atmosphere (Table 1, entry 5).


Page 4 of 31

Page 5 of 31 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Table 1. Optimization of the Reaction Conditionsa Me

O C

N N 1a

Me N

Catalyst (5 mol %) H

N

Oxidant (3 equiv.) Solvent, 130 oC Ar

2a

oxidant (3 equiv.)

1

catalyst (5 mol %) Cu(OTf)2

2

3aa

yields (%)

DTBP

solvent (2 ml) 1,2-DCB

Fe(acac)3

DTBP

1,2-DCB

49

3

Co(OAc)2

DTBP

1,2-DCB

58

4

Mn(OAc)3.2H2O

DTBP

1,2-DCB

64

5

Mn(OAc)2

DTBP

1,2-DCB

87

6

MnO2

DTBP

1,2-DCB

71

7

Mn(OAc)2

DTBP

chlorobenzene

75

8

Mn(OAc)2

DTBP

1,2-DCE

11

9

Mn(OAc)2

DTBP

toluene

-

10

Mn(OAc)2

DTBP

DMF

-

11

Mn(OAc)2

DTBP

CH3CN

trace

12

Mn(OAc)2

TBPB

1,2-DCB

-

13

Mn(OAc)2

TBHP

1,2-DCB

21

14

Mn(OAc)2

K2S2O8

1,2-DCB

-

15

-

DTBP

1,2-DCB

42

16

Mn(OAc)2

-

1,2-DCB

-

17b

Mn(OAc)2

DTBP

1,2-DCB

86c, traced

18e

Mn(OAc)2

DTBP

1,2-DCB

-

19

Mn(OAc)2

DTBP

1,2-DCB

57f

entry

51

aReaction

conditions: Carried out with 0.2 mmol of 1a, 1 mmol of 2a in presence of 5 mol % catalyst and 3 equiv. oxidant in 2 mL of solvent under Ar atmosphere at 130 °C for 6 h. b10 mol % catalyst is used. cStirred at 150 oC. dStirred at 80 oC for 12 h. eO atmosphere. f2 equiv. of 2a is used. 2

After getting the optimized reaction conditions in hand, the substrate scope of the decarbonylative alkylation was examined with a number of aliphatic aldehydes (Scheme 5 ACS Paragon Plus Environment


Page 6 of 31

2). A series of C5-alkylated imidazo[1,2-a]pyridines were obtained under the present reaction conditions in good to excellent yields (3aa-3ng). Aliphatic secondary aldehydes, such

as

isobutyraldehyde

(2a),

2-methylbutanal

(2b),

2-ethylbutanal

(2c),

2-

methylpentanal (2d), cyclohexanecarbaldehyde (2e), and 2-ethylhexanal (2f) were successfully produced the desired decarbonylated products in moderate to good yields (3aa-3af). Similarly, pivaldehyde (2g) also formed a tertiary carbon radical after decarbonylation, offering the desired alkylated product 3ag in 89% yield. It is noteworthy to mention that the linear aliphatic aldehyde (2h) also produced the corresponding alkylsubstituted product (3ah) in good yield. Scheme 2. Substrate Scope of Imidazo[1,2-a]pyridinesa


Page 7 of 31 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


R

R2

N

1

N

R

1

O C

Mn(OAc)2 (5 mol %) H

2

Ph

3aa, 87%

Ph

N

Ph

N

R

3ah, 55%

1

N 3dg, R1 = Me, 79% 3eg, R1 = OMe, 78%

3cf, 67%

3ba, 66% N N

R2

N

3fg, R2 = 4-Me, 74% 3gg, R2 = 4- F, 79% 3hg, R2 = 4-Cl, 82% 3ig, R2 = 3-Br, 52% 3jg, R2 = 4-CN, 69% 3kg, R2 = 4-CF3, 71% N

OMe

N

N SO2Me

N 3lg, 54% O Ph

N 3me, 79%

Ph

N

N

Ph

N

3ag, 89% N

Ph

N

Ph

N

3af, 85%

N

Me

N

N

3ae, 76%

3ad, 84%

3ac, 87%

N

Ph

N

Me

Ph

N

Ph

N

Me

N

N

N

3ab, 75%

Me

3

R

Me

N

N N

N

Me

Me

Me

R

DTBP (3 equiv.) 1,2-DCB, 130 oC Ar

R2

N

1

3ng, 49%

CHO N

H 2j 2i unreactive aldehyde

aReaction

conditions: 0.2 mmol of 1, 1 mmol of 2 in presence of 5 mol % Mn(OAc)2 and 3 equiv. DTBP in 2 mL 1,2-DCB under Ar atmosphere at 130 °C for 6 h.

After investigating the scope of aliphatic aldehydes, we next turned our attention on the scope of imidazoheterocycles. Imidazo[1,2-a]pyridine with electron-donating substituent on the pyridine ring like –Me and –OMe provided the corresponding products (3dg and 3eg) in good yields. Imidazo[1,2-a]pyridine bearing various substituents like -Me and OMe on the pyridine ring reacted well with aldehyde and the desired C5-alkylated



products were obtained in excellent yields (3fg and 3me). Halogen (−F, −Cl, and −Br) containing imidazopyridines afforded the desired products in moderate to good yields (3gg-3ig). Strong electron-withdrawing groups like −CN and –CF3 containing imidazopyridines were well tolerated under the optimized reaction conditions (3jg and 3kg). It is notable that marketed drug, zolimidine also produced the alkylated product in good yield which might show better bioactivity (3lg). In addition, naphthyl substituted imidazo[1,2-a]pyridine also worked well under the optimized reaction conditions (3ng). However, the present decarbonylation reaction was not applicable for benzaldehyde (2i) and N,N-dimethylformamide (2j).


Page 8 of 31

Page 9 of 31 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Scheme 3. Substrate Scope of CDC reactiona R1

R1

Mn(OAc)2 (5 mol %)

N R H

N

4

1 Me

N

DTBP (3 equiv.) 1,2-DCB, 130 oC Ar

R

R= N

O

O

O

N 5aa, 83%

5 O

O

R

N

5ab, 78% 5ac, 76% 5ad, 88% 5ae, 63%

N

O

Ph

N

O

HO

OH 5ah, 58% 5ai, 77% 5af : 1a (4:1) 5ag, 56% 58%

O O

5aj, 44%

5bd, 82%, (79%)

b

N N

Ph

N

Cl

N

Me

N Ph

Ph

N O

S

O 5da, 64%

N

N

5od, 35%

5ak, 75%

N

N N

Ph

unreactive substrate

conditions: 0.2 mmol of 1, 8 equiv. of 4 in presence of 5 mol % Mn(OAc)2 and 3 equiv. DTBP in 2 mL 1,2-DCB under Ar atmosphere at 130 °C for 8 h. b5 mmol scale. aReaction

To further demonstrate the versatility of this reaction, we have developed a new protocol for the direct C-H alkylation of imidazo[1,2-a]pyridines with unactivated alkanes through the cross-dehydrogenative coupling (CDC) in presence of Mn(OAc)2 and DTBP as shown in Scheme 3. A variety of simple alkanes (4a and 4b), cyclic ethers (4c-4f) and acylic ether 4g could provide the corresponding ortho-alkylated products (5aa-5ag) in moderate to excellent yields. Notably, simple alcohols (4h and 4i) and mesitylene (4j) were also reacted smoothly to provide the corresponding 5-alkylated products in moderate to good yields (5ai-5aj). Chloro-substituted imidazopyridines (1o) afforded the desired product 5od in 35% yield. In addition, tetrahydrothiophene (4k) provided only 3-substituted 9 ACS Paragon Plus Environment


Page 10 of 31

product in 75% yield. It may be due to the presence of sulphur atom in tetrahydrothiophene, which makes the thiophenyl radical less nucleophilic in nature.15f However, unsubstituted imidazo[1,2-a]pyridine and 2-phenylimidazo[1,2-a]pyrimidine did not provide any product under the reaction conditions. Scheme 4. Substrate Scope of N-heteroarenes

S

O

N

N

6a, 78%a

a5

b

6f, 55%

b

N

N

6c, 68%b

6d, 73%b

CN

N

N 6e, 78%

Cl

6b, 72%b N N

N

N

6g, 81%

b

N

S

O

N

O 6h, 69%c

6i, 86%d

equiv. of 2a is used. b5 equiv. of 2g is used. c8 equiv. of 4d is used. d8 equiv. of 4a is used.

To explore the applicability of present decarbonylation reaction on heteroarenes we studied with simple 5- and 6-membered rings represented in Scheme 4. 5-Membered heterocycles like benzothiazole and benzoxazole provided the desired decarbonylative products 6a and 6b in 78% and 72% yields respectively. Substrates containing 6-member heterocycles also reacted well (6c-6d). Notably, quinoxaline and phthalazine provided the monoalkylated product (6e and 6f) in good yields under the optimized reaction conditions. The heteroarenes such as benzothiazole and isoquinoline also afforded alkylated products by the reaction with alkane and alkyl ethers via CDC (6h and 6i).


Page 11 of 31 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Scheme 5. Gram-Scale Synthesis

Me N N 1a, 5 mmol

+

O C

Me N


2g, 5 equiv.

DTBP (3 equiv.) 1,2-DCB, 130 °C Ar, 6h

N

3ag, (1.09 g, 83%)

The gram-scale synthesis was performed under the normal laboratory set-up by taking 8methyl-2-phenylimidazo[1,2-a]pyridine (1a) and pivaldehyde (2g) (Scheme 5). 5-(tertButyl)-8-methyl-2-phenylimidazo[1,2-a]pyridine

was

isolated

without

significant

decrease in yield (83%), that signifies the efficiency and practical applicability of this present methodology. In order to investigate the mechanistic pathway for the alkylation reaction of imidazopyridines with aldehydes, few control experiments were performed as shown in Scheme 6. In presence of radical scavengers like 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) and 2,6-di-tert-butyl-4-methylphenol (BHT), only a trace amount of product formed (Scheme 6, eq 1, (i) and (ii)). No formation of the desired product was obtained in presence of 1,1-diphenylethylene (DPE) (Scheme 6, eq 1, (iii)). However, (3-methylbut1-ene-1,1-diyl)dibenzene (8) was obtained in 64% yield under the optimized reaction conditions with 3 equiv. DPE (Scheme 6, eq 2). These results indicate that the reaction probably proceeds through a radical pathway. However, under the optimized reaction conditions aliphatic acid 9 did not response to this reaction (Scheme 6, eq 3). 2Phenylpropanal afforded the dehydrated product (10) in 65% yield (Scheme 6, eq 4). When the reaction was carried out with 5 mol % Mn(OAc)2 and 1 equiv. TFA, the dehydrated product (11) was formed (Scheme 6, eq 5) which indicates that nucleophilic 11 ACS Paragon Plus Environment


Page 12 of 31

character of imidazopyridine might be more facile rather than electron-deficient character of pyridine ring in acidic conditions. Scheme 6. Control Experiments

O

N Ph

N 1a


DTBP (3 equiv.) 2a 1,2-DCB, 130 oC Ar Radical scavengers 3 equiv. O

Ph Ph 7, DPE (3 equiv.)

(i) TEMPO: 3aa, trace (ii) BHT: 3aa, 11% (iii) DPE: 3aa, 0%

standard conditions

Ph

(2)

Ph 8, 64%

2a O

Ph

1a

standard conditions

9, 1 equiv. N

O H

Ph

N

standard conditions

Ph 2k

1a Ph


2a

Ph

N

Ph

(4)

10, 65%

O

N

1b

(3)

N.R

OH

N

N

(1)

Ph

N

H

N N

N

TFA (1 equiv.) 1,2-DCB, 130 oC Ar

N N

Ph

(5)

11, 51%

A plausible mechanism is proposed for this transformation based on the previous literature reports18 and experimental results (Scheme 7). Initially, Mn(II) facilitates the homolytic cleavage of the oxidant DTBP to produce the tert-butoxyl radical with the tertbutoxy Mn(III) species. Next tert-butoxyl radical abstracts the aldehyde hydrogen atom to provide the acyl radical A under heating conditions. Then, the acyl radical A undergoes 12 ACS Paragon Plus Environment

Page 13 of 31 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


decarbonylation to afford alkyl radical B. The alkyl radical (B) attacks at the C5-position of imidazo[1,2-a]pyridine providing intermediate (C). Finally, the product 3aa is obtained by the deprotonation of the intermediate D through the regeneration of Mn(II)catalyst. On the other hand, in case of CDC reaction, homolytic cleavage of DTBP forms a tert-butoxy radical which abstracts the C(sp3)-H proton adjacent to the oxygen atom of ether, alcohol or cycloalkane. Then, the alkyl radical (E) attacks at the ortho-position of imidazo[1,2-a]pyridine to produce the desired product 5. Selective C-5 functionalization occurs due to π-deficient nature of pyridine ring. Moreover, electron-donating ability of imidazolium nitrogen activates C-5 position for selective functionalization.5f Scheme 7. Probable mechanism CHO 2a

OtBu

DTBP

CO (A)

HOtBu t Mn(II) Mn(III)O Bu

(B)

decarbonylation 1a N

N

N Ph

N

N H

-H+

3aa

-CO

Ph [O]

Ph

N (C)

(D) and

OtBu

DTBP

X 4

H

HOtBu

X (E) CDC

t Mn(II) Mn(III)O Bu

N N

N Ph

N

N -H+

X

5

Ph [O]

X X

(G)


Ph

N (F)

1a


CONCLUSION: In summary, we have developed a Mn(II)-catalyzed C-H alkylation of imiazoheterocycles and other heteroarenes using aliphatic aldehydes as alkylating agents. This methodology provides a safe and efficient route for the synthesis of a wide range of alkylated heterocycles. To the best of our knowledge there is no earlier report for the direct synthesis of C-5 alkylated imidazoheterocycles. Unactivated alkanes, ethers, and alcohols also coupled with different heteroarenes in the optimized reaction conditions. We believe that the present methodology will show much importance in organic synthesis, medicinal chemistry, and material sciences. EXPERIMENTAL SECTION: General Information: All reagents were purchased from commercial sources and used without further purification. All solvents were dried and distilled before use. Commercially available solvents were freshly distilled before the reaction. All reactions involving moisture sensitive reactants were executed using oven dried glassware. 1H NMR spectra were determined on 400 MHz spectrometer as solutions in CDCl3. Chemical shifts are expressed in parts per million (δ) and the signals were reported as s (singlet), d (doublet), t (triplet), m (multiplet) and coupling constants (J) were given in Hz.

13C{1H}

NMR spectra were recorded at 100 MHz in CDCl3

solution. Chemical shifts as internal standard are referenced to CDCl3 (δ = 7.26 for 1H and δ = 77.16 for

13C{1H}

NMR) as internal standard. TLC was done on silica gel coated glass slide.

General safety precautions like wearing laboratory coat, use of hand gloves and goggles have been taken during experimental work. Starting Materials: All the imidazoheterocycles were prepared by our reported method.17a 2-Phenylimidazo[1,2-a]pyridine (1b):17a White solid (85%, 32 mg); Rf = 0.50 (PE : EA = 71 : 29); 1H NMR (400 MHz, CDCl3): δ 8.11-8.09 (m, 1H), 7.96-7.94 (m, 2H), 7.85 (s, 1H), 7.62 (d, J = 9.2 Hz, 1H), 7.44-7.41 (m, 2H), 7.34-7.30 (m, 1H), 7.17-7.13 (m, 1H), 6.77-6.74 (m, 1H); 13C{1H}

NMR (100 MHz, CDCl3): δ 145.8, 145.7, 133.8, 128.8, 128.0, 126.1, 125.7, 124.7,

117.6, 112.5, 108.2. 7-Methoxy-2-phenylimidazo[1,2-a]pyridine (1e):17a White solid (81%, 36 mg); Rf = 0.50 (PE : EA = 72 : 28); 1H NMR (400 MHz, CDCl3): δ 7.91-7.86 (m, 3H), 7.65 (s, 1H), 7.42-7.38 (m, 14 ACS Paragon Plus Environment

Page 14 of 31

Page 15 of 31 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


2H), 7.30-7.27 (m, 1H), 6.88 (d, J = 2.4 Hz, 1H), 6.47-6.45 (m, 1H), 3.83 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 157.9, 147.2, 145.4, 133.9, 128.7, 127.7, 126.0, 125.8, 107.5, 106.9, 94.7, 55.5. 2-(Naphthalen-2-yl)imidazo[1,2-a]pyridine (1n):17a Yellow solid (86%, 41 mg); Rf = 0.50 (PE : EA = 78 : 22); 1H NMR (400 MHz, CDCl3): δ 8.51 (s, 1H), 8.12 (d, J = 6.8 Hz, 1H), 8.01-7.82 (m, 5H), 7.67 (d, J = 8.8 Hz, 1H), 7.50-7.45 (m, 2H), 7.20-7.16 (m, 1H), 6.79-6.75 (m, 1H); 13C{1H}

NMR (100 MHz, CDCl3): δ 145.8, 145.7, 133.8, 133.3, 131.0, 128.48, 128.45, 127.8,

126.4, 126.1, 125.7, 125.0, 124.9, 124.2, 117.5, 112.6, 108.7. Typical Experimental Procedure for the Synthesized Compounds (3aa-3ng, 6a-6g): A

mixture

of

8-methyl-2-phenylimidazo[1,2-a]pyridine

(0.2

mmol,

21.6

mg)

(1a),

isobutyraldehyde (1.0 mmol, 72 mg) (2a), manganese(II) acetate (5 mol %, 1.7 mg), DTBP (3.0 equiv., 120 µL) and 1,2-dichlorobenzene (2 mL) was taken in a screw cap tube under argon atmosphere. Then the reaction mixture was vigorously stirred at 130 oC for 6 h. After completion of the reaction (TLC) the reaction was cooled to room temperature and extracted with dichloromethane. The organic phase was dried over anhydrous Na2SO4. The crude residue was obtained after evaporating the solvent in vacuum and was purified by column chromatography on silica gel using a mixture petroleum ether and ethyl acetate (94:6) as an eluting solvent to afford the pure product (3aa) (43 mg, 87%) as a yellow liquid. 5-Isopropyl-8-methyl-2-phenylimidazo[1,2-a]pyridine (3aa): Yellow liquid (87%, 43 mg); Rf = 0.50 (PE : EA = 94 : 6); 1H NMR (400 MHz, CDCl3): δ 8.02-8.00 (m, 2H), 7.84 (s, 1H), 7.44 (t, J = 7.6 Hz, 2H), 7.34-7.30 (m, 1H), 6.98 (d, J = 6.4 Hz, 1H), 6.55 (d, J = 7.2 Hz, 1H), 3.27-3.21 (m, 1H), 2.65 (s, 3H), 1.42 (d, J = 6.8 Hz, 6H);

13C{1H}

NMR (100 MHz, CDCl3): δ 146.9,

145.3, 141.8, 134.5, 128.7, 127.8, 126.3, 124.7, 123.8, 107.3, 105.8, 30.1, 20.4, 17.0; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C17H19N2: 251.1543; found: 251.1566. 5-(sec-Butyl)-8-methyl-2-phenylimidazo[1,2-a]pyridine (3ab): Yellow liquid (75%, 39 mg); Rf = 0.50 (PE : EA = 95 : 5); 1H NMR (400 MHz, CDCl3): δ 8.02-8.00 (m, 2H), 7.83 (s, 1H), 7.44 (d, J = 8.0 Hz, 2H), 7.34-7.30 (m, 1H), 6.97 (d, J = 7.6 Hz, 1H), 6.52 (d, J = 7.2 Hz, 1H), 3.063.01 (m, 1H), 2.65 (s, 3H), 1.92-1.87 (m, 1H), 1.73-1.65 (m, 1H), 1.37 (d, J = 6.8 Hz, 3H), 0.99 (t, J = 7.6 Hz, 3H);

13C{1H}

NMR (100 MHz, CDCl3): δ 147.0, 145.2, 140.8, 134.5, 128.7,

127.8, 126.3, 124.6, 123.7, 108.1, 105.7, 36.9, 27.1, 17.9, 17.0, 11.7; Anal. Calcd for C18H20N2: C, 81.78; H, 7.63; N, 10.60%; Found: C, 81.91; H, 7.58; N, 10.51%. 15 ACS Paragon Plus Environment


Page 16 of 31

8-Methyl-5-(pentan-3-yl)-2-phenylimidazo[1,2-a]pyridine (3ac): Yellow liquid (87%, 48 mg); Rf = 0.50 (PE : EA = 94 : 6); 1H NMR (400 MHz, CDCl3): δ 8.02-8.00 (m, 2H), 7.87 (s, 1H), 7.44 (t, J = 7.6 Hz, 2H), 7.34-7.30 (m, 1H), 6.99-6.97 (m, 1H), 6.49 (d, J = 6.8 Hz, 1H), 2.952.88 (m, 1H), 2.65 (s, 3H), 1.85-1.78 (m, 4H), 0.90 (t, J = 7.6 Hz, 6H);

13C{1H}

NMR (100

MHz, CDCl3): δ 147.2, 145.1, 139.1, 134.5, 128.7, 127.7, 126.3, 124.5, 123.6, 109.3, 105.9, 44.4, 25.1, 17.1, 11.6; Anal. Calcd for C19H22N2: C, 81.97; H, 7.97; N, 10.06%; Found: C, 82.19 H, 7.88; N, 9.93%. 8-Methyl-5-(pentan-2-yl)-2-phenylimidazo[1,2-a]pyridine (3ad): Yellow liquid (84%, 46 mg); Rf = 0.50 (PE : EA = 94 : 6); 1H NMR (400 MHz, CDCl3): δ 8.02-8.00 (m, 2H), 7.84 (s, 1H), 7.44 (t, J = 7.6 Hz, 2H), 7.34-7.30 (m, 1H), 6.97 (d, J = 7.2 Hz, 1H), 6.52 (d, J = 7.2 Hz, 1H), 3.14-3.09 (m, 1H), 2.65 (s, 3H), 1.86-1.81 (m, 1H), 1.66-1.60 (m, 1H), 1.39 (d, J = 6.8 Hz, 4H), 0.95 (t, J = 7.2 Hz, 4H); 13C{1H} NMR (100 MHz, CDCl3): δ 147.0, 145.2, 141.1, 134.5, 128.7, 127.8, 126.3, 124.6, 123.7, 108.1, 105.7, 36.7, 35.2, 20.5, 18.4, 17.0, 14.2; Anal. Calcd for C19H22N2: C, 81.97; H, 7.97; N, 10.06%; Found: C, 82.15; H, 7.89; N, 9.96%. 5-Cyclohexyl-8-methyl-2-phenylimidazo[1,2-a]pyridine (3ae): White solid (76%, 44 mg); Rf = 0.50 (PE : EA = 95 : 5); M.p. 117-118 °C; 1H NMR (400 MHz, CDCl3): δ 8.02-7.99 (m, 2H), 7.82 (s, 1H), 7.44 (t, J = 8.0 Hz, 2H), 7.34-7.29 (m, 1H), 6.97 (d, J = 6.8 Hz, 1H), 6.51 (d, J = 7.2 Hz, 1H), 2.89-2.83 (m, 1H), 2.64 (s, 3H), 2.17 (d, J = 10.8 Hz, 2H), 1.96-1.84 (m, 3H), 1.561.42 (m, 5H);

13C{1H}

NMR (100 MHz, CDCl3): δ 146.8, 145.2, 141.1, 134.5, 128.7, 127.8,

126.4, 124.7, 123.9, 107.7, 105.6, 40.3, 31.0, 26.6, 26.4, 17.1; Anal. Calcd for C20H22N2: C, 82.72; H, 7.64; N, 9.65%; Found: C, 82.59; H, 7.68; N, 9.73%. 5-(Heptan-3-yl)-8-methyl-2-phenylimidazo[1,2-a]pyridine (3af): Yellow liquid (85%, 52 mg); Rf = 0.50 (PE : EA = 93 : 7); 1H NMR (400 MHz, CDCl3): δ 8.02-7.99 (m, 2H), 7.87 (s, 1H), 7.44 (t, J = 8.0 Hz, 2H), 7.34-7.30 (m, 1H), 6.98-6.96 (m, 1H), 6.50 (t, J = 7.2 Hz, 1H), 3.002.93 (m, 1H), 2.65 (s, 3H), 1.83-1.76 (m, 4H), 1.31-1.25 (m, 4H), 0.91-0.84 (m, 6H);

13C{1H}

NMR (100 MHz, CDCl3): δ 147.2, 145.1, 139.5, 134.5, 128.7, 127.8, 126.3, 124.5, 123.7, 109.3, 105.9, 43.0, 32.2, 29.4, 25.7, 22.9, 17.1, 14.0, 11.6; Anal. Calcd for C21H26N2: C, 82.31; H, 8.55; N, 9.14%; Found: C, 82.11; H, 8.61; N, 9.28%. 5-(tert-Butyl)-8-methyl-2-phenylimidazo[1,2-a]pyridine (3ag): Yellow liquid (89%, 46 mg); Rf = 0.50 (PE : EA = 94 : 6); 1H NMR (400 MHz, CDCl3): δ 8.11 (s, 1H), 8.03-8.01 (m, 2H), 7.45 (t, J = 8.0 Hz, 2H), 7.35-7.31 (m, 1H), 6.96-6.94 (m, 1H), 6.62 (d, J = 7.2 Hz, 1H), 2.66 (s, 3H), 1.56 (s, 9H);

13C{1H}

NMR (100 MHz, CDCl3): δ 147.8, 144.4, 143.6, 134.5, 128.7, 127.7, 16 ACS Paragon Plus Environment

Page 17 of 31 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


126.4, 125.2, 123.7, 109.3, 108.7, 35.2, 27.9, 17.1; Anal. Calcd for C18H20N2: C, 81.78; H, 7.63; N, 10.60%; Found: C, 81.99; H, 7.56; N, 10.45%. 5-Butyl-8-methyl-2-phenylimidazo[1,2-a] pyridine (3ah): Yellow gummy mass (55%, 29 mg); Rf = 0.50 (PE : EA = 94 : 6); 1H NMR (400 MHz, CDCl3): δ 8.02-7.99 (m, 2H), 7.79 (s, 1H), 7.44 (t, J = 8.0 Hz, 2H), 7.34-7.30 (m, 1H), 6.95-6.93 (m, 1H), 6.51 (d, J = 7.2 Hz, 1H), 2.88 (t, J = 7.6 Hz, 2H), 2.65 (s, 3H), 1.84-1.76 (m, 2H), 1.52-1.46 (m, 2H), 1.00 (t, J = 7.2 Hz, 3H); 13C{1H}

NMR (100 MHz, CDCl3): δ 146.8, 145.3, 136.1, 134.4, 128.7, 127.8, 126.3, 124.7,

123.7, 110.2, 105.7, 31.9, 28.0, 22.6, 17.1, 14.0; Anal. Calcd for C18H20N2: C, 81.78; H, 7.63; N, 10.60%; Found: C, 81.58; H, 7.68; N, 10.74%. 5-Isopropyl-2-phenylimidazo[1,2-a]pyridine (3ba): Yellow gummy mass (66%, 31 mg); Rf = 0.45 (PE : EA = 81 : 19); 1H NMR (400 MHz, CDCl3): δ 8.00-7.98 (m, 2H), 7.86 (s, 1H), 7.56 (d, J = 9.2 Hz, 1H), 7.44 (t, J = 7.6 Hz, 2H), 7.35-7.31 (m, 1H), 7.22-7.18 (m, 1H),6.65 (d, J = 7.2 Hz, 1H), 3.31-3.24 (m, 1H), 1.44 (d, J = 6.8 Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3): δ 146.5, 145.7, 144.2, 134.0, 128.8, 128.0, 126.2, 125.2, 115.1, 107.5, 105.3, 30.3, 20.3; Anal. Calcd for C16H16N2: C, 81.32; H, 6.82; N, 11.85%; Found: C, 81.46; H, 6.75; N, 11.78%. 5-(Heptan-3-yl)-8-methyl-2-(p-tolyl)imidazo[1,2-a]pyridine (3cf): Yellow liquid (67%, 42 mg); Rf = 0.45 (PE : EA = 88 : 12); 1H NMR (400 MHz, CDCl3): δ 7.89 (d, J = 8.0 Hz, 2H), 7.83 (s, 1H), 7.24 (d, J = 8.0Hz, 2H), 6.97-6.95 (m, 1H), 6.48 (d, J = 7.2 Hz, 1H), 3.00-2.92 (m, 1H), 2.65 (s, 3H), 2.39 (s, 3H), 1.84-1.74 (m, 4H), 1.29-1.27 (m, 4H), 0.90-0.84 (m, 6H);

13C{1H}

NMR (100 MHz, CDCl3): δ 147.1, 145.2, 139.4, 137.5, 131.7, 129.4, 126.2, 124.4, 123.6, 109.1, 105.5, 42.9, 32.2, 29.4, 25.7, 22.9, 21.4, 17.1, 14.0, 11.6; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C22H29N2: 321.2325; found: 321.2307. 5-(tert-Butyl)-7-methyl-2-phenylimidazo[1,2-a]pyridine (3dg): Yellow gummy mass (79%, 41 mg); Rf = 0.50 (PE : EA = 78 : 22); 1H NMR (400 MHz, CDCl3): δ 8.02 (s, 1H), 7.98-7.96 (m, 2H), 7.43 (t, J = 8.0 Hz, 2H), 7.34-7.29 (m, 2H), 6.54 (d, J = 1.6 Hz, 1H), 2.39 (s, 3H), 1.56 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3): δ 148.0, 145.1, 144.6, 135.7, 134.2, 128.7, 127.8, 126.2, 114.1, 111.7, 108.3, 35.3, 27.8, 21.6; Anal. Calcd for C18H20N2: C, 81.78; H, 7.63; N, 10.60%; Found: C, 81.59; H, 7.71; N, 10.70%. 5-(tert-Butyl)-7-methoxy-2-phenylimidazo[1,2-a]pyridine (3eg): Brown gummy mass (78%, 43 mg); Rf = 0.45 (PE : EA = 79 : 21); 1H NMR (400 MHz, CDCl3): δ 7.96-7.94 (m, 3H), 7.43 (t, J = 8.0 Hz, 2H), 7.33-7.29 (m, 1H), 6.89 (d, J = 1.2 Hz, 1H), 6.45 (d, J = 1.2 Hz, 1H), 3.86 (s, 3H), 1.55 (s, 9H);

13C{1H}

NMR (100 MHz, CDCl3): δ 158.2, 149.0, 146.7, 144.5, 134.2, 128.8, 17 ACS Paragon Plus Environment


127.7, 126.0, 107.7, 104.2, 93.0, 55.5, 35.4, 27.9; Anal. Calcd for C18H20N2O: C, 77.11; H, 7.19; N, 9.99%; Found: C, 77.35; H, 7.09; N, 10.12%. 5-(tert-Butyl)-2-(p-tolyl)imidazo[1,2-a]pyridine (3fg): Yellow gummy mass (74%, 39 mg); Rf = 0.50 (PE : EA = 82 : 18); 1H NMR (400 MHz, CDCl3): δ 8.08 (s, 1H), 7.88 (d, J = 8.0 Hz, 2H), 7.56 (d, J = 8.8 Hz, 1H), 7.27-7.25 (m, 2H), 7.18-7.14 (m, 1H), 6.73-6.71 (m, 1H), 2.39 (s, 3H), 1.57 (s, 9H);

13C{1H}

NMR (100 MHz, CDCl3): δ 147.5, 145.9, 145.0, 137.8, 131.2, 129.5,

126.1, 124.9, 115.6, 108.8, 108.6, 35.5, 27.7, 21.4; Anal. Calcd for C18H20N2: C, 81.78; H, 7.63; N, 10.60%; Found: C, 81.93; H, 7.59; N, 10.48%. 5-(tert-Butyl)-2-(4-fluorophenyl)imidazo[1,2-a]pyridine (3gg): Yellow gummy mass (79%, 42 mg); Rf = 0.50 (PE : EA = 81 : 19); 1H NMR (400 MHz, CDCl3): δ 8.05 (s, 1H), 7.97-7.94 (m, 2H), 7.56 (d, J = 9.6 Hz, 1H), 7.19-7.11 (m, 3H), 6.73 (d, J = 7.6 Hz, 1H), 1.57 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3): δ 162.8 (JC-F = 245 Hz), 147.6, 146.0, 144.1, 130.4 (JC-F = 3 Hz), 127.9 (JC-F = 9 Hz), 125.1, 115.7 (JC-F = 18 Hz), 115.6, 109.0, 108.6, 35.5, 27.8; Anal. Calcd for C17H17FN2: C, 76.09; H, 6.39; N, 10.44%; Found: C, 75.91; H, 6.50; N, 10.57%. 5-(tert-Butyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine (3hg): Brown gummy mass (82%, 46 mg); Rf = 0.50 (PE : EA = 80 : 20); 1H NMR (400 MHz, CDCl3): δ 8.09 (s, 1H), 7.93-7.91 (m, 2H), 7.56 (d, J = 9.2 Hz, 1H), 7.42-7.40 (m, 2H), 7.20-7.16 (m, 1H), 6.75-6.73 (m, 1H), 1.57 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3): δ 147.6, 146.0, 143.8, 133.7, 132.7, 129.0, 127.5, 125.3, 115.7, 109.1, 108.9, 35.5, 27.7; Anal. Calcd for C17H17ClN2: C, 71.70; H, 6.02; N, 9.84%; Found: C, 71.92; H, 5.95; N, 9.91%. 2-(3-Bromophenyl)-5-(tert-butyl)imidazo[1,2-a]pyridine (3ig): Yellow gummy mass (52%, 34 mg); Rf = 0.50 (PE : EA = 82 : 18); 1H NMR (400 MHz, CDCl3): δ 8.13 (t, J = 2.0 Hz, 1H), 8.11 (s, 1H), 7.93-7.91 (m, 1H), 7.56 (d, J = 8.8 Hz, 1H), 7.47-7.44 (m, 1H), 7.31 (t, J = 8.0 Hz, 1H), 7.21-7.17 (m, 1H), 6.76-6.73 (m, 1H), 1.58 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3): δ 147.7, 146.1, 143.4, 136.3, 130.8, 130.4, 129.1, 125.4, 124.8, 123.0, 115.8, 109.29, 109.21, 35.5, 27.8; Anal. Calcd for C17H17BrN2: C, 62.02; H, 5.20; N, 8.51%; Found: C, 61.86; H, 5.14; N, 8.60%. 4-(5-(tert-Butyl)imidazo[1,2-a]pyridin-2-yl)benzonitrile (3jg): Brown gummy mass (69%, 37 mg); Rf = 0.50 (PE : EA = 86 : 14); 1H NMR (400 MHz, CDCl3): δ 8.19 (s, 1H), 8.09 (d, J = 8.0 Hz, 2H), 7.72 (d, J = 8.2 Hz, 2H), 7.58 (d, J = 9.2 Hz, 1H), 7.24-7.20 (m, 1H), 6.78-6.76 (m, 1H), 1.58 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3): δ 147.9, 146.3, 142.8, 138.6, 132.7, 126.6, 125.9, 119.2, 116.0, 111.1, 110.2, 109.5, 35.5, 27.8; Anal. Calcd for C18H17N3: C, 78.52; H, 6.22; N, 15.26%; Found: C, 78.31; H, 6.31; N, 15.38%. 18 ACS Paragon Plus Environment

Page 18 of 31

Page 19 of 31 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


5-(tert-Butyl)-2-(4-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridine (3kg): Yellow gummy mass (71%, 45 mg); Rf = 0.50 (PE : EA = 83 : 17); 1H NMR (400 MHz, CDCl3): δ 8.18 (s, 1H), 8.10 (d, J = 8.4 Hz, 2H), 7.69 (d, J = 8.4 Hz, 2H), 7.58 (d, J = 9.2 Hz, 1H), 7.22-7.18 (m, 1H), 6.776.75 (m, 1H), 1.59 (s, 9H);

13C{1H}

NMR (100 MHz, CDCl3): δ 147.8, 146.2, 143.4, 137.6,

129.7 (JC-F = 31 Hz), 126.3, 125.8 (JC-F = 4 Hz), 125.6, 124.6 (JC-F = 16 Hz), 115.9, 109.7, 109.3, 35.5, 27.8; Anal. Calcd for C18H17F3N2: C, 67.91; H, 5.38; N, 8.80%; Found: C, 68.06; H, 5.33; N, 8.89%. 5-(tert-Butyl)-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (3lg): White gummy mass (54%, 35 mg); Rf = 0.45 (PE : EA = 61 : 39); 1H NMR (400 MHz, CDCl3): δ 8.22 (s, 1H), 8.208.18 (m, 2H), 8.02-8.00 (m, 2H), 7.60 (d, J = 9.2 Hz, 1H), 7.22 (d, J = 8.8 Hz, 1H), 6.80-6.78 (m, 1H), 3.09 (s, 3H), 1.59 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3): δ 147.8, 146.4, 142.6, 139.4, 128.0, 126.8, 126.1, 115.9, 110.3, 109.7, 44.7, 35.6, 27.8; Anal. Calcd for C18H20N2O2S: C, 65.83; H, 6.14; N, 8.53%; Found: C, 65.60; H, 6.19; N, 8.45%. 5-Cyclohexyl-2-(4-methoxyphenyl)imidazo[1,2-a]pyridine (3me): Yellow gummy mass (79%, 48 mg); Rf = 0.50 (PE : EA = 80 : 20); 1H NMR (400 MHz, CDCl3): δ 7.93-7.90 (m, 2H), 7.75 (s, 1H), 7.52 (d, J = 9.2 Hz, 1H), 7.19-7.15 (m, 1H), 6.98 (d, J = 8.8 Hz, 2H), 6.60 (d, J = 6.8 Hz, 1H), 3.85 (s, 3H), 2.92-2.85 (m, 1H), 2.18 (d, J = 10.4 Hz, 2H), 1.97-1.85 (m, 3H), 1.55-1.43 (m, 5H); 13C{1H} NMR (100 MHz, CDCl3): δ 159.6, 146.4, 145.5, 143.3, 127.5, 126.8, 125.0, 114.7, 114.2, 107.7, 104.2, 55.4, 40.5, 30.8, 26.6, 26.3; Anal. Calcd for C20H22N2O: C, 78.40; H, 7.24; N, 9.14%; Found: C, 78.22; H, 7.29; N, 9.26%. 5-(tert-Butyl)-2-(naphthalen-2-yl)imidazo[1,2-a]pyridine (3ng): Brown gummy mass (49%, 29 mg); Rf = 0.50 (PE : EA = 86 : 14); 1H NMR (400 MHz, CDCl3): δ 8.53 (s, 1H), 8.24 (s, 1H), 8.08-8.06 (m, 1H), 7.93-7.90 (m, 2H), 7.85 (d, J = 6.8 Hz, 1H), 7.62 (d, J = 8.8 Hz, 1H), 7.507.46 (m, 2H), 7.21-7.17 (m, 1H), 6.76-6.74 (m, 1H), 1.61 (s, 9H);

13C{1H}

NMR (100 MHz,

CDCl3): δ 147.8, 146.0, 144.8, 133.9, 133.3, 131.4, 128.47, 128.42, 127.8, 126.4, 126.0, 125.2, 124.9, 124.4, 115.7, 109.3, 109.0, 35.5, 27.8; Anal. Calcd for C21H20N2: C, 83.96; H, 6.71; N, 9.33%; Found: C, 84.16; H, 6.66; N, 9.18%. 2-Isopropylbenzo[d]thiazole (6a):4b Yellow liquid (78%, 27 mg); Rf = 0.45 (PE : EA = 98 : 2); 1H

NMR (400 MHz, CDCl3): δ 7.97 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.46-7.42 (m,

1H), 7.35-7.31 (m, 1H), 3.46-3.39 (m, 1H), 1.48 (d, J = 7.2 Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3): δ 178.7, 153.2, 134.8, 125.9, 124.6, 122.7, 121.6, 34.2, 23.0.



2-(tert-Butyl)benzo[d]oxazole (6b):4b Yellow liquid (72%, 25 mg); Rf = 0.50 (PE : EA = 97 : 3); 1H

NMR (400 MHz, CDCl3): δ 7.70-7.68 (m, 1H), 7.49-7.47 (m, 1H), 7.31-7.26 (m, 2H), 1.49 (s,

9H); 13C{1H} NMR (100 MHz, CDCl3): δ 173.6, 150.9, 141.4, 124.5, 124.1, 119.8, 110.4, 34.3, 28.6. 4-tert-Butyl-2-chloro-pyrimidine (6c):4c Brown gummy mass (68%, 23 mg); Rf = 0.55 (PE : EA = 98 : 2); 1H NMR (400 MHz, CDCl3): δ 8.52 (d, J = 5.2 Hz, 1H), 7.27-7.26 (m, 1H), 1.36 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3): δ 181.9, 161.2, 159.5, 115.3, 38.0, 29.3. 2-(tert-Butyl)-8-methylquinoline (6d): Colorless oil (73%, 29 mg); Rf = 0.50 (PE : EA = 96 : 4); 1H

NMR (400 MHz, CDCl3): δ 8.05 (d, J = 8.4 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.53 (t, J = 8.4

Hz, 2H), 7.38 (t, J = 7.6 Hz, 1H), 2.85 (s, 3H), 1.51 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3): δ 167.9, 146.3, 137.5, 136.0, 129.1, 126.3, 125.4, 125.2, 117.8, 38.5, 30.3, 17.8; Anal. Calcd for C14H17N: C, 84.37; H, 8.60; N, 7.03%; Found: C, 84.53; H, 8.52; N, 6.95%. 2-(tert-Butyl)-quinoxaline (6e):5e Light yellow liquid (78%, 29 mg); Rf = 0.40 (PE : EA = 97 : 3); 1H NMR (400 MHz, CDCl3): δ 8.97 (s, 1H), 8.06-8.03 (m, 2H), 7.73-7.65 (m, 2H), 1.50 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3): δ 163.7, 143.5, 141.7, 140.8, 129.7, 129.3, 129.0, 128.9, 37.3, 29.8. 1-(tert-Butyl)phthalazine (6f): Brown liquid (75%, 27 mg); Rf = 0.40 (PE : EA = 97 : 3); 1H NMR (400 MHz, CDCl3): δ 9.38 (s, 1H), 8.47 (d, J = 8.0 Hz, 1H), 7.97-7.94 (m, 1H), 7.89-7.84 (m, 2H), 1.70 (s, 9H);

13C{1H}

NMR (100 MHz, CDCl3): δ 165.1, 151.0, 139.2, 131.4, 131.1,

128.0, 126.1, 124.9, 39.4, 30.9; Anal. Calcd for C12H14N2: C, 77.38; H, 7.58; N, 15.04%; Found: C, 77.21; H, 7.67; N, 15.12%. 2-(tert-Butyl)isonicotinonitrile (6g): Yellow liquid (81%, 25 mg); Rf = 0.40 (PE : EA = 98 : 2); 1H

NMR (400 MHz, CDCl3): δ 8.72 (d, J = 5.2 Hz, 1H), 7.54 (t, J = 1.2 Hz, 1H), 7.32-7.30 (m,

1H), 1.37 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3): δ 171.2, 149.7, 122.2, 121.1, 120.6, 117.2, 38.0, 29.9; Anal. Calcd for C10H12N2: C, 74.97; H, 7.55; N, 17.48%; Found: C, 75.14; H, 7.49; N, 17.37%. Typical Experimental Procedure for the Synthesized Compounds (5aa-5ak, 6h and 6i): A mixture of 8-methyl-2-phenylimidazo[1,2-a]pyridine (0.2 mmol, 21.6 mg) (1a), cyclopentane (1.6 mmol, 112 mg) (4a), manganese(II) acetate (5 mol %, 1.7 mg), DTBP (3.0 equiv., 120 µL) and 1,2-dichlorobenzene (2 mL) was taken in a screw cap tube under argon atmosphere. Then the reaction mixture was vigorously stirred at 130 oC for 8 h. After completion of the reaction 20 ACS Paragon Plus Environment

Page 20 of 31

Page 21 of 31 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(TLC) the reaction was cooled to room temperature and extracted with dichloromethane. The organic phase was dried over anhydrous Na2SO4. The crude residue was obtained after evaporating the solvent in vacuum and was purified by column chromatography on silica gel using a mixture petroleum ether and ethyl acetate (92:8) as an eluting solvent to afford the pure product (5aa) (45 mg, 83%) as a yellow gummy mass. 5-Cyclopentyl-8-methyl-2-phenylimidazo[1,2-a]pyridine (5aa): Yellow gummy mass (83%, 45 mg); Rf = 0.40 (PE : EA = 92 : 8); 1H NMR (400 MHz, CDCl3): δ 8.02-7.99 (m, 2H), 7.85 (s, 1H), 7.44 (t, J = 8.0 Hz, 2H), 7.34-7.30 (m, 1H), 6.95 (d, J = 7.2 Hz, 1H), 6.56 (d, J = 6.8 Hz, 1H), 3.39-3.32 (m, 1H), 2.65 (s, 3H), 2.25-2.21 (m, 2H), 1.82-1.79 (m, 6H); 13C{1H} NMR (100 MHz, CDCl3): δ 146.9, 145.1, 139.8, 134.5, 128.7, 127.7, 126.3, 124.6, 123.6, 107.6, 106.4, 41.4, 30.5, 25.1, 17.1; Anal. Calcd for C19H20N2: C, 82.57; H, 7.29; N, 10.14%; Found: C, 82.42; H, 7.32; N, 10.26%. 8-Methyl-2-phenyl-5-(tetrahydrofuran-2-yl)imidazo[1,2-a]pyridine (5ac): Yellow liquid (76%, 42 mg); Rf = 0.40 (PE : EA = 90 : 10); 1H NMR (400 MHz, CDCl3): δ 8.01-7.99 (m, 2H), 7.82 (s, 1H), 7.43 (t, J = 8.0 Hz, 2H), 7.34-7.30 (m, 1H), 7.00-6.98 (m, 1H), 6.75 (d, J = 6.8 Hz, 1H), 5.14 (d, J = 6.4 Hz, 1H), 4.18-4.13 (m, 1H), 4.04-3.99 (m, 1H), 2.66 (s, 3H), 2.47-2.42 (m, 1H), 2.15-2.03 (m, 3H);

13C{1H}

NMR (100 MHz, CDCl3): δ 146.9, 145.5, 136.1, 134.3, 128.7,

127.8, 126.3, 126.1, 123.4, 108.5, 106.3, 76.3, 69.0, 29.8, 25.6, 17.1; Anal. Calcd for C18H18N2O: C, 77.67; H, 6.52; N, 10.06%; Found: C, 77.88; H, 6.48; N, 9.94%. 5-(1,4-Dioxan-2-yl)-8-methyl-2-phenylimidazo[1,2-a]pyridine (5ad): Brown gummy mass (88%, 51 mg); Rf = 0.40 (PE : EA = 89 : 11); 1H NMR (400 MHz, CDCl3): δ 8.01-7.98 (m, 3H), 7.44 (t, J = 8.0 Hz, 2H), 7.34-7.30 (m, 1H), 6.98-6.96 (m, 1H), 6.76 (d, J = 6.8Hz, 1H), 4.94-4.91 (m, 1H), 4.17-4.13 (m, 1H), 3.96-3.79 (m, 5H), 2.66 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 146.7, 145.6, 134.1, 131.8, 128.7, 127.9, 127.4, 126.3, 123.0, 110.7, 106.7, 73.4, 68.5, 66.8, 66.5, 17.2; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C18H18N2O2Na: 317.1260; found: 317.1249. 5-(Benzo[d][1,3]dioxol-2-yl)-8-methyl-2-phenylimidazo[1,2-a]pyridine (5ae): Yellow solid (63%, 41 mg); M.p. 138-139 °C; Rf = 0.40 (PE : EA = 92 : 8); 1H NMR (400 MHz, CDCl3): δ 7.96-7.94 (m, 2H), 7.92 (s, 1H), 7.42 (t, J = 7.6 Hz, 2H), 7.34-7.30 (m, 1H), 7.14 (s, 1H), 7.00 (s, 2H), 6.95 (t, J = 3.6 Hz, 4H), 2.69 (s, 3H);

13C{1H}

NMR (100 MHz, CDCl3): δ 146.8, 146.7,

146.0, 133.8, 129.7, 128.9, 128.8, 128.1, 126.4, 122.6, 122.5, 112.4, 109.3, 107.4, 106.0, 17.4; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C21H16N2O2Na: 351.1104; found: 351.1097. 21 ACS Paragon Plus Environment


8-Methyl-5-(2-methyltetrahydrofuran-2-yl)-2-phenylimidazo[1,2-a]pyridine

Page 22 of 31

+

8-methyl-2-

phenylimidazo[1,2-a]pyridine (5af : 1a) Yellow liquid (58%, 58 mg); Rf = 0.40 (PE : EA = 93 : 7); 1H NMR (400 MHz, CDCl3): δ 8.13 (s, 1H), 8.02-8.0 (m, 2H), 7.45-7.41 (m, 2H), 7.34-7.30 (m, 1H), 6.98-6.96 (m, 1H), 6.79 (d, J = 7.2 Hz, 1H), 4.12-4.09 (m, 1H), 3.87-3.82 (m, 1H), 2.66 (s, 3H), 2.59-2.56 (m, 1H), 2.17-2.09 (m, 1H), 1.97-1.96 (m, 1H), 1.71 (s, 3H);

13C{1H}

NMR

(100 MHz, CDCl3): δ 147.6, 144.9, 139.5, 134.4, 128.7, 127.8, 126.4, 126.3, 125.9, 123.5, 123.4, 112.5, 108.9, 108.5, 82.7, 67.7, 36.2, 25.9, 24.9, 17.2; Anal. Calcd for C33H32N4O: C, 79.17; H, 6.44; N, 11.19 %; Found: C, 79.31; H, 6.40; N, 11. 25%. 5-(1-Ethoxyethyl)-8-methyl-2-phenylimidazo[1,2-a]pyridine (5ag): Yellow liquid (56%, 31 mg); Rf = 0.40 (PE : EA = 91 : 9); 1H NMR (400 MHz, CDCl3): δ 8.17 (s, 1H), 8.03-8.00 (m, 2H), 7.44 (t, J = 7.6 Hz, 2H), 7.34-7.30 (m, 1H), 6.96-6.94 (m, 1H), 6.65 (d, J = 6.8 Hz, 1H), 4.75-4.70 (m, 1H), 3.47-3.37 (m, 2H), 2.67 (s, 3H), 1.64 (d, J = 6.4 Hz, 3H), 1.21 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 147.1, 145.4, 136.2, 134.4, 128.7, 127.8, 126.6, 126.3, 123.1, 110.3, 107.3, 75.2, 64.2, 18.9, 17.2, 15.5; Anal. Calcd for C18H20N2O: C, 77.11; H, 7.19; N, 9.99%; Found: C, 76.85; H, 7.28; N, 9.86%. 1-(8-Methyl-2-phenylimidazo[1,2-a]pyridin-5-yl)ethan-1-ol (5ah): Yellow liquid (58%, 29 mg); Rf = 0.40 (PE : EA = 89 : 11); 1H NMR (400 MHz, CDCl3): δ 7.92-7.90 (m, 2H), 7.86 (s, 1H), 7.42 (t, J = 8.0 Hz, 2H), 7.33-7.29 (m, 1H), 6.81-6.79 (m, 1H), 6.43 (d, J = 7.2 Hz, 1H), 5.004.95 (m, 1H), 2.62 (s, 3H), 1.60 (d, J = 6.4 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 146.7, 144.7, 137.9, 134.1, 128.7, 127.8, 126.16, 126.10, 123.6, 108.9, 107.1, 66.5, 20.7, 17.1; Anal. Calcd for C16H16N2O: C, 76.16; H, 6.39; N, 11.10%; Found: C, 76.39; H, 6.46; N, 10.96%. 2-(8-Methyl-2-phenylimidazo[1,2-a]pyridin-5-yl)propan-2-ol (5ai): White solid (77%, 40 mg); Rf = 0.40 (PE : EA = 88 : 12); M.p. 153-154 °C; 1H NMR (400 MHz, CDCl3): δ 8.27 (s, 1H), 7.91-7.88 (m, 2H), 7.41 (t, J = 8.0 Hz, 2H), 7.32-7.28 (m, 1H), 6.76-6.74 (m, 1H), 6.27 (d, J = 7.2 Hz, 1H), 2.64 (s, 3H), 1.65 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3): δ 147.3, 143.5, 140.0, 134.2, 128.5, 127.6, 126.1, 126.0, 123.5, 110.7, 108.9, 71.3, 28.1, 17.1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C17H19N2O: 267.1492; found: 267.1468. 5-(3,5-Dimethylbenzyl)-8-methyl-2-phenylimidazo[1,2-a]pyridine (5aj): Brown gummy mass (44%, 28 mg); Rf = 0.40 (PE : EA = 93 : 7); 1H NMR (400 MHz, CDCl3): δ 7.96-7.94 (m, 2H), 7.71 (s, 1H), 7.41 (t, J = 8.0 Hz, 2H), 7.32-7.28 (m, 1H), 6.97-6.95 (m, 1H), 6.91 (s, 1H), 6.84 (s, 2H), 6.44 (d, J = 7.2 Hz, 1H), 4.15 (s, 2H), 2.68 (s, 3H), 2.28 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3): δ 146.7, 145.3, 138.6, 135.4, 134.6, 134.4, 128.9, 128.7, 127.8, 126.6, 126.3, 125.3, 22 ACS Paragon Plus Environment

Page 23 of 31 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


123.5, 112.3, 106.2, 38.5, 21.4, 17.1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C23H23N2: 327.1856; found: 327.1854. 5-(1,4-Dioxan-2-yl)-2-phenylimidazo[1,2-a]pyridine (5bd): Yellow gummy mass (82%, 45 mg); Rf = 0.50 (PE : EA = 72 : 28); 1H NMR (400 MHz, CDCl3): δ 7.98-7.97 (m, 3H), 7.62 (d, J = 8.8 Hz, 1H), 7.44 (t, J = 8.0 Hz, 2H), 7.35-7.31 (m, 1H), 7.20-7.16 (m, 1H), 6.87 (d, J = 6.8 Hz, 1H), 4.96-4.93 (m, 1H), 4.19-4.15 (m, 1H), 3.98-3.95 (m, 2H), 3.92-3.80 (m, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 146.3, 146.2, 134.2, 133.7, 128.8, 128.2, 126.2, 124.3, 117.2, 110.6, 106.2, 73.3, 68.5, 66.8, 66.6; Anal. Calcd for C17H16N2O2: C, 72.84; H, 5.75; N, 9.99%; Found: C, 72.64; H, 5.69; N, 10.12%. 5-Cyclopentyl-7-methyl-2-phenylimidazo[1,2-a]pyridine (5da): Yellow liquid (64%, 35 mg); Rf = 0.40 (PE : EA = 76 : 24); 1H NMR (400 MHz, CDCl3): δ 7.98-7.96 (m, 2H), 7.78 (s, 1H), 7.43 (t, J = 8.0 Hz, 2H), 7.33-7.29 (m, 2H), 6.49 (s, 1H), 3.39-3.31 (m, 1H), 2.39 (s, 3H), 2.27-2.22 (m, 2H), 1.87-1.79 (m, 6H);

13C{1H}

NMR (100 MHz, CDCl3): δ 147.1, 145.3, 141.4, 135.6,

134.4, 128.7, 127.8, 126.1, 113.5, 110.3, 105.4, 41.4, 30.6, 25.2, 21.7; Anal. Calcd for C19H20N2: C, 82.57; H, 7.29; N, 10.14%; Found: C, 82.74; H, 7.21; N, 10.05%. 6-Chloro-5-(1,4-dioxan-2-yl)-2-phenylimidazo[1,2-a]pyridine (5od): Brown gummy mass (35%, 21 mg); Rf = 0.40 (PE : EA = 82 : 18); 1H NMR (400 MHz, CDCl3): δ 8.08 (d, J = 2.0 Hz, 1H), 7.96-7.93 (m, 2H), 7.81 (s, 1H), 7.43 (t, J = 8.0 Hz, 2H), 7.35-7.30 (m, 2H), 5.42-5.39 (m, 1H), 4.59-4.56 (m, 1H), 4.05-4.02 (m, 2H), 3.89-3.85 (m, 1H), 3.79-3.73 (m, 1H), 3.44-3.38 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 146.4, 142.0, 133.5, 128.8, 128.6, 128.3, 126.2, 122.4, 122.3, 120.8, 108.6, 73.1, 71.4, 67.4, 66.6; Anal. Calcd for C17H15ClN2O2: C, 64.87; H, 4.80; N, 8.90%; Found: C, 65.02; H, 4.73; N, 8.81%. 8-Methyl-2-phenyl-3-(tetrahydrothiophen-2-yl)imidazo[1,2-a]pyridine (5ak): Brown gummy mass (75%, 44 mg); Rf = 0.40 (PE : EA = 91 : 9); 1H NMR (400 MHz, CDCl3): δ 8.33 (d, J = 7.52 Hz, 1H), 7.68-7.65 (m, 2H), 7.46 (t, J = 7.6 Hz, 2H), 7.39-7.35 (m, 1H), 7.02-7.00 (m, 1H), 6.74 (t, J = 6.8 Hz, 1H), 5.33-5.29 (m, 1H), 3.26-3.19 (m, 1H), 3.16-3.11 (m, 1H), 2.65 (s, 3H), 2.44-2.37 (m, 1H), 2.34-2.20 (m, 2H), 2.04-1.94 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 146.1, 144.4, 134.9, 129.4, 128.6, 127.9, 127.8, 123.7, 123.1, 117.5, 111.6, 43.6, 33.7, 31.6, 17.4; Anal. Calcd for C18H18N2S: C, 73.43; H, 6.16; N, 9.52%; Found: C, 73.24; H, 6.22; N, 9.45%. 1-(1,4-Dioxan-2-yl)isoquinoline (6h):11a Brown gummy mass (69%, 29 mg); Rf = 0.40 (PE : EA = 96 : 4); 1H NMR (400 MHz, CDCl3): δ 8.52 (d, J = 5.6 Hz, 1H), 8.31 (d, J = 8.4 Hz, 1H), 7.83 23 ACS Paragon Plus Environment


Page 24 of 31

(d, J = 8.0 Hz, 1H), 7.70-7.60 (m, 3H), 5.48-5.45 (m, 1H), 4.16-4.06 (m, 4H), 3.90-3.87 (m, 2H); 13C{1H}

NMR (100 MHz, CDCl3): δ 156.1, 141.9, 136.6, 130.1, 127.6, 126.6, 124.8, 121.1,

75.9, 70.4, 67.7, 66.6. 2-Cyclopentylbenzo[d]thiazole (6i): Yellow oil (86%, 34 mg); Rf = 0.40 (PE : EA = 98 : 2); 1H NMR (400 MHz, CDCl3): δ 7.96 (d, J = 8.4 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.45-7.41 (m, 1H), 7.34-7.31 (m, 1H), 3.59-3.50 (m, 1H), 2.29-2.21 (m, 2H), 1.98-1.85 (m, 4H), 1.76-1.72 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ 177.2, 153.3, 134.9, 125.9, 124.6, 122.6, 121.6, 44.9, 34.1, 25.7; Anal. Calcd for C12H13NS: C, 70.90; H, 6.45; N, 6.89%; Found: C, 70.75; H, 6.50; N, 6.99%. (3-Methylbut-1-ene-1,1-diyl)dibenzene (8): Colorless oil (64%, 79 mg); Rf = 0.55 (PE : EA = 100 : 0); 1H NMR (400 MHz, CDCl3): δ 7.45-7.41 (m, 2H), 7.38-7.34 (m, 1H), 7.31-7.24 (m, 7H), 5.96 (d, J = 10.4 Hz, 1H), 2.54-2.48 (m, 1H), 1.08 (d, J = 6.4 Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3): δ 142.8, 140.6, 139.3, 137.4, 129.9, 128.29, 128.20, 127.2, 126.9, 126.8, 28.8, 23.3; Anal. Calcd for C17H18: C, 91.84; H, 8.16%; Found: C, 91.95; H, 8.05%. (Z)-8-Methyl-2-phenyl-3-(2-phenylprop-1-en-1-yl)imidazo[1,2-a]pyridine (10): Yellow gummy mass (65%, 42 mg); Rf = 0.40 (PE : EA = 92 : 8); 1H NMR (400 MHz, CDCl3): δ 8.00-7.98 (m, 2H), 7.43 (t, J = 7.6 Hz, 2H), 7.38-7.30 (m, 2H), 7.09-7.04 (m, 4H), 6.83-6.81 (m, 1H), 6.63 (s, 1H), 6.36 (t, J = 7.2 Hz, 1H), 2.62 (s, 3H), 2.42 (d, J = 1.6 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 145.1, 142.7, 142.3, 140.7, 135.2, 128.5, 128.4, 128.1, 127.6, 127.4, 126.9, 126.6, 123.0, 121.9, 118.7, 114.6, 111.3, 25.0, 17.1; Anal. Calcd for C23H20N2: C, 85.15; H, 6.21; N, 8.63%; Found: C, 84.99; H, 6.27; N, 8.74%. 3-(2-Methylprop-1-en-1-yl)-2-phenylimidazo[1,2-a]pyridine (11): Yellow gummy mass (51%, 25 mg); Rf = 0.40 (PE : EA = 78 : 22); 1H NMR (400 MHz, CDCl3): δ 7.98-7.96 (m, 2H), 7.857.83 (m, 1H), 7.64-7.61 (m, 1H), 7.42-7.39 (m, 2H), 7.31-7.27 (m, 1H), 7.19-7.15 (m, 1H), 6.806.76 (m, 1H), 6.26 (s, 1H), 2.04 (d, J = 1.2 Hz, 3H), 1.47 (d, J = 0.8 Hz, 3H);

13C{1H}

NMR

(100 MHz, CDCl3): δ 144.7, 144.0, 142.2, 135.2, 128.5, 127.5, 127.4, 124.2, 123.8, 118.3, 117.5, 112.3, 112.0, 25.7, 20.5; Anal. Calcd for C17H16N2: C, 82.22; H, 6.49; N, 11.28%; Found: C, 82.39; H, 6.40; N, 11.21%. Experimental Procedure for the Gram Scale Synthesis of 3ag: A mixture of 8-methyl-2-phenylimidazo[1,2-a]pyridine (5 mmol, 1.04 g) (1a), isobutyraldehyde (5 equiv., 2.15 g) (2a), manganese(II) acetate (5 mol %, 43 mg), DTBP (3.0 equiv., 2.19 g) and 24 ACS Paragon Plus Environment

Page 25 of 31 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


1,2-dichlorobenzene (30 mL) was taken in a 100 mL ace round-bottom pressure flask under argon atmosphere. Then the reaction mixture was vigorously stirred at 130 oC for 6 h. After completion of the reaction (TLC) the reaction was cooled to room temperature and extracted with dichloromethane. The organic phase was dried over anhydrous Na2SO4. The crude residue was obtained after evaporating the solvent in vacuum and was purified by column chromatography on silica gel using a mixture petroleum ether and ethyl acetate (94:6) as an eluting solvent to afford the pure product (3ag) (1.09 g, 83%) as a yellow liquid. Experimental Procedure for the Gram Scale Synthesis of 5bd: A mixture of 2-phenylimidazo[1,2-a]pyridine (5 mmol, 0.97 g) (1b), 1,4-dioxane (8 equiv., 3.52 g) (4d), manganese(II) acetate (5 mol %, 43 mg), DTBP (3.0 equiv., 2.19 g) and 1,2dichlorobenzene (30 mL) was taken in a 100 mL ace round-bottom pressure flask under argon atmosphere. Then the reaction mixture was vigorously stirred at 130 oC for 8 h. After completion of the reaction (TLC) the reaction was cooled to room temperature and extracted with dichloromethane. The organic phase was dried over anhydrous Na2SO4. The crude residue was obtained after evaporating the solvent in vacuum and was purified by column chromatography on silica gel using a mixture petroleum ether and ethyl acetate (72:28) as an eluting solvent to afford the pure product (5bd) (1.10 g, 79%) as a yellow gummy mass. ASSOCIATED CONTENT: Supporting information: The Supporting Information is available free of charge on the ACS Publications website at DOI: Scanned copies of 1H and 13C{1H} NMR spectra of the synthesized compounds (PDF). Author Information Corresponding Author *Email: [email protected] ACKNOWLEDGMENT: A.H. acknowledges the financial support from SERB-DST, (Grant no. EMR/2016/001643). S.S. thanks UGC-New Delhi (UGC-SRF) for his fellowship. REFERENCES: 1. (a) Joseph, J.; Antonchick, A. P. Free Radicals in Heterocycle Functionalization, Top. Heterocycl. Chem. 2018, 54, 93–150. (b) Dong, Z.; Ren, Z.; Thompson, S. J.; Xu, Y.; 25 ACS Paragon Plus Environment


Dong, G. Transition-Metal-Catalyzed C-H Alkylation Using Alkenes. Chem. Rev. 2017, 117, 9333–9403. (c) Seregin, I. V.; Gevorgyan, V. Direct Transition Metal-Catalyzed Functionalization of Heteroaromatic Compounds. Chem. Soc. Rev. 2007, 36, 1173–1193. (d) Zhang, J. R.; Xu, L.; Liao, Y. Y.; Deng, J. C.; Tang, R. Y. Advances in Radical Oxidative C-H Alkylation of N-Heteroarenes. Chinese J. Chem. 2017, 35, 271–279. 2. (a) Cernak, T.; Dykstra, K. D.; Tyagarajan, S.; Vachal, P.; Krska, S. W. The Medicinal Chemist’s Toolbox for Late Stage Functionalization of Drug-like Molecules. Chem. Soc. Rev. 2016, 45, 546–576. (b) Vitaku, E.; Smith, D. T.; Njardarson, J. T. Analysis of the Structural Diversity, Substitution Patterns, and Frequency of Nitrogen Heterocycles among U.S. FDA Approved Pharmaceuticals. J. Med. Chem. 2014, 57, 10257–10274. 3. (a) Seiple, I. B.; Su, S.; Rodriguez, R. A.; Gianatassio, R.; Fujiwara, Y.; Sobel, A. L.; Baran, P. S. Direct C – H Arylation of Electron-Deficient Heterocycles with Arylboronic Acids. J. Am. Chem. Soc. 2010, 132, 13194–13196. (b) Galloway, J. D.; Mai, D. N.; Baxter, R. D. Silver-Catalyzed Minisci Reactions Using Selectfluor as a Mild Oxidant. Org. Lett. 2017, 19, 5772–5775. 4. (a) Minisci, F.; Vismara, E.; Fontana, F. Recent Developments of Free-Radical Substitutions of Heteroaromatic Bases. Heterocycles 1989, 28, 489–519. (b) Zhao, W. M.; Chen, X. L.; Yuan, J. W.; Qu, L. B.; Duan, L. K.; Zhao, Y. F. Silver Catalyzed Decarboxylative Direct C2-Alkylation of Benzothiazoles with Carboxylic Acids. Chem. Commun. 2014, 50, 2018–2020. (c) Mai, W. P.; Sun, B.; You, L. Q.; Yang, L. R.; Mao, P.; Yuan, J. W.; Xiao, Y. M.; Qu, L. B. Silver Catalysed Decarboxylative Alkylation and Acylation of Pyrimidines in Aqueous Media. Org. Biomol. Chem. 2015, 13, 2750–2755. 5. (a) Garza-Sanchez, R. A.; Tlahuext-Aca, A.; Tavakoli, G.; Glorius, F. Visible LightMediated Direct Decarboxylative C-H Functionalization of Heteroarenes. ACS Catal.


Page 26 of 31

Page 27 of 31 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


2017, 7, 4057–4061. (b) McCallum, T.; Barriault, L. Direct Alkylation of Heteroarenes with Unactivated Bromoalkanes Using Photoredox Gold Catalysis. Chem. Sci. 2016, 7, 4754–4758. (c) Matsui, J. K.; Primer, D. N.; Molander, G. A. Metal-Free C-H Alkylation of Heteroarenes with Alkyltrifluoroborates: A General Protocol for 1°, 2° and 3° Alkylation. Chem. Sci. 2017, 8, 3512–3522. (d) Zhang, L.; Liu, Z. Q. Molecular OxygenMediated Minisci-Type Radical Alkylation of Heteroarenes with Boronic Acids. Org. Lett. 2017, 19, 6594–6597. (e) Sun, A. C.; McClain, E. J.; Beatty, J. W.; Stephenson, C. R. J. Visible Light-Mediated Decarboxylative Alkylation of Pharmaceutically Relevant Heterocycles. Org. Lett. 2018, 20, 3487–3490. (f) Hara, F. O.; Blackmond, D. G.; Baran, P. S. Radical-Based Regioselective C-H Functionalization of Electron-Deficient Heteroarenes: Scope, Tunability, and Predictability. J. Am. Chem. Soc. 2013, 135, 12122–12134. 6. (a) Shen, Z.; Huang, H.; Zhu, C.; Warratz, S.; Ackermann, L. MnCl2-Catalyzed C-H Alkylation on Azine Heterocycles. Org. Lett. 2019, 21, 571-574. (b) Liu, W.; Cera, G.; Oliveira, J. C. A.; Shen, Z.; Ackermann, L. MnCl2-Catalyzed C-H Alkylations with Alkyl Halides. Chem. - A Eur. J. 2017, 23, 11524-11528. 7. (a) Matcha, K.; Antonchick, A. P. Metal-Free Cross-Dehydrogenative Coupling of Heterocycles with Aldehydes. Angew. Chem., Int. Ed. 2013, 52, 2082–2086. (b) Tang, R. J.; Kang, L.; Yang, L. Metal-Free Oxidative Decarbonylative Coupling of Aliphatic Aldehydes with Azaarenes: Successful Minisci-Type Alkylation of Various Heterocycles. Adv. Synth. Catal. 2015, 357, 2055–2060. (c) Siddaraju, Y.; Lamani, M.; Prabhu, K. R. A Transition Metal-Free Minisci Reaction: Acylation of Isoquinolines, Quinolines, and Quinoxaline. J. Org. Chem. 2014, 79, 3856–3865. (d) Zhang, L.; Zhang, G.; Li, Y.; Wang, S.; Lei, A. The Synergistic Effect of Self-Assembly and Visible-Light Induced the



Oxidative C-H Acylation of N-Heterocyclic Aromatic Compounds with Aldehydes. Chem. Commun. 2018, 54, 5744–5747. 8. (a) Biswas, P.; Paul, S.; Guin, J. Aerobic Radical-Cascade Alkylation/Cyclization of α,βUnsaturated Amides: An Efficient Approach to Quaternary Oxindoles. Angew. Chem., Int. Ed. 2016, 55, 7756–7760. (b) Paul, S.; Guin, J. Dioxygen-Mediated Decarbonylative C-H Alkylation of Heteroaromatic Bases with Aldehydes. Chem. - A Eur. J. 2015, 21, 17618–17622. (c) Luo, Z.; Han, X.; Fang, Y.; Liu, P.; Feng, C.; Li, Z.; Xu, X. CopperCatalyzed Decarboxylative and Oxidative Decarbonylative Cross-Coupling between Cinnamic Acids and Aliphatic Aldehydes. Org. Chem. Front. 2018, 5, 3299–3305. 9. (a) Antonchick, A. P.; Burgmann, L. Direct Selective Oxidative Cross-Coupling of Simple Alkanes with Heteroarenes. Angew. Chem., Int. Ed. 2013, 52, 3267-3271. (b) Banerjee, A.; Sarkar, S.; Patel, B. K. C-H Functionalisation of Cycloalkanes. Org. Biomol. Chem. 2017, 15, 505–530. (c) Yi, H.; Zhang, G.; Wang, H.; Huang, Z.; Wang, J.; Singh, A. K.; Lei, A. Recent Advances in Radical C-H Activation/Radical CrossCoupling. Chem. Rev. 2017, 117, 9016–9085. 10. Bosset, C.; Beucher, H.; Bretel, G.; Pasquier, E.; Queguiner, L.; Henry, C.; Vos, A.; Edwards, J. P.; Meerpoel, L.; Berthelot, D. Minisci-Photoredox-Mediated αHeteroarylation of N-Protected Secondary Amines: Remarkable Selectivity of Azetidines. Org. Lett. 2018, 20, 6003–6006. 11. (a) Jin, J.; MacMillan, D. W. C. Direct α-Arylation of Ethers through the Combination of Photoredox-Mediated C-H Functionalization and the Minisci Reaction. Angew. Chem., Int. Ed. 2015, 54, 1565–1569. (b) Liu, S.; Liu, A.; Zhang, Y.; Wang, W. Direct CαHeteroarylation of Structurally Diverse Ethers: Via a Mild N-Hydroxysuccinimide Mediated Cross-Dehydrogenative Coupling Reaction. Chem. Sci. 2017, 8, 4044–4050.


Page 28 of 31

Page 29 of 31 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


12. (a) Correia, C. A.; Yang, L.; Li, C. Palladium-Catalyzed Minisci Reaction with Simple Alcohols. Org. Lett. 2011, 13, 4581-4583. (b) Cui, Z.; Shang, X.; Shao, X. F.; Liu, Z. Q. Copper-Catalyzed Decarboxylative Alkenylation of Sp3 C-H Bonds with Cinnamic Acids via a Radical Process. Chem. Sci. 2012, 3, 2853–2858. 13. (a) Bagdi, A. K.; Santra, S.; Monir, K.; Hajra, A. Synthesis of Imidazo[1,2-a]Pyridines: a Decade Update. Chem. Commun. 2015, 51, 1555-1575. (b) Pericherla, K.; Kaswan, P.; Pandey, K.; Kumar, A. Recent Developments in the Synthesis of Imidazo[1,2a]pyridines. Synthesis 2015, 47, 887-912. (c) Bagdi, A. K.; Hajra, A. Design, Synthesis, and Functionalization of Imidazoheterocycles. Chem. Rec. 2016, 16, 1868-1885. (d) Ravi, C.; Adimurthy, S. Synthesis of Imidazo[1,2-a]Pyridines: C-H Functionalization in the Direction of C-S Bond Formation. Chem. Rec. 2017, 17, 1019–1038. (e) Yu, Y.; Su, Z.; Cao, H. Strategies for Synthesis of Imidazo[1,2- a]Pyridine Derivatives: Carbene Transformations or C−H Functionalizations. Chem. Rec. 2019, 19, 1–15. 14. (a) Baviskar, A. T.; Amrutkar, S. M.; Trivedi, N.; Chaudhary, V.; Nayak, A.; Guchhait, S. K.; Banerjee, U. C.; Bharatam, P. V.; Kundu, C. N. Switch in Site of Inhibition: A Strategy for Structure-Based Discovery of Human Topoisomerase IIα Catalytic Inhibitors. ACS Med. Chem. Lett. 2015, 6, 481–485. (b) Enguehard-Gueiffier, C.; Gueiffier, A. Recent Progress in the Pharmacology of Imidazo[1,2-a]Pyridines. Mini-Rev. Med. Chem. 2007, 7, 888-899. 15. (a) Cao, H.; Lei, S.; Li, N.; Chen, L.; Liu, J.; Cai, H.; Qiu, S.; Tan, J. Cu-Catalyzed Selective C3-Formylation of Imidazo[1,2-a]Pyridine C-H Bonds with DMSO Using Molecular Oxygen. Chem. Commun. 2015, 51, 1823–1825. (b) Yan, K.; Yang, D.; Wei, W.; Lu, S.; Li, G.; Zhao, C.; Zhang, Q.; Wang, H. Copper-Catalyzed Domino Synthesis of Benzo[b]Thiophene/Imidazo[1,2-a]Pyridines by Sequential Ullmann-Type Coupling



and Intramolecular C(Sp2)-H Thiolation. Org. Chem. Front. 2016, 3, 66–70. (c) Liu, P.; Gao, Y.; Gu, W.; Shen, Z.; Sun, P. Regioselective Fluorination of Imidazo[1,2a]Pyridines with Selectfluor in Aqueous Condition. J. Org. Chem. 2015, 80, 11559– 11565. (d) Yang, Q.; Li, S.; Wang, J. (Joelle). Cobalt-Catalyzed Cross-Dehydrogenative Coupling of Imidazo[1,2- a]Pyridines with Isochroman Using Molecular Oxygen as the Oxidant. Org. Chem. Front. 2018, 5, 577–581. (e) Guo, Y. J.; Lu, S.; Tian, L. L.; Huang, E. L.; Hao, X. Q.; Zhu, X.; Shao, T.; Song, M. P. Iodine-Mediated Difunctionalization of Imidazopyridines with Sodium Sulfinates: Synthesis of Sulfones and Sulfides. J. Org. Chem. 2018, 83, 338–349. (f) Zhang, J. R.; Liao, Y. Y.; Deng, J. C.; Feng, K. Y.; Zhang, M.; Ning, Y. Y.; Lin, Z. W.; Tang, R. Y. Oxidative Dual C-H Thiolation of Imidazopyridines with Ethers or Alkanes Using Elemental Sulphur. Chem. Commun. 2017, 53, 7784–7787. (g) Nitha, P. R.; Joseph, M. M.; Gopalan, G.; Maiti, K. K.; Radhakrishnan, K. V.; Das, P. Chloroform as a Carbon Monoxide Source in PalladiumCatalyzed Synthesis of 2-Amidoimidazo[1,2-a] Pyridines. Org. Biomol. Chem. 2018, 16, 6430–6437. (h) Rafique, J.; Saba, S.; Rosário, A. R.; Braga, A. L. Regioselective, Solvent- and Metal-Free Chalcogenation of Imidazo[1,2-a]Pyridines by Employing I2/DMSO as the Catalytic Oxidation System. Chem. - A Eur. J. 2016, 22, 11854–11862. 16. Koubachi, J.; Kazzouli, S. E.; Bousmina, M.; Guillaumet, G. Functionalization of Imidazo[1,2‐a]pyridines by Means of Metal‐Catalyzed Cross‐Coupling Reactions. Eur. J. Org. Chem. 2014, 2014, 5119-5138. 17. (a) Bagdi, A. K.; Rahman, M.; Santra, S.; Majee, A.; Hajra, A. Copper‐Catalyzed Synthesis of Imidazo[1,2‐a]pyridines through Tandem Imine Formation‐Oxidative Cyclization under Ambient Air: One‐Step Synthesis of Zolimidine on a Gram‐Scale. Adv. Synth. Catal. 2013, 355, 1741-1747. (b) Samanta, S.; Mondal, S.; Santra, S.; Kibriya, G.; 30 ACS Paragon Plus Environment

Page 30 of 31

Page 31 of 31 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Hajra,

A.

FeCl3-Catalyzed

Cross-Dehydrogenative

Coupling

between

Imidazoheterocycles and Oxoaldehydes. J. Org. Chem. 2016, 81, 10088–10093. (c) Mondal,

S.;

Samanta,

S.;

Singsardar,

M.;

Hajra,

A.

Aminomethylation

of

Imidazoheterocycles with Morpholine. Org. Lett. 2017, 19, 3751–3754. (d) Samanta, S.; Hajra, A. Regioselective Synthesis of Unsymmetrical Biheteroaryls: via Copper(II)Catalyzed Cascade Annulation. Chem. Commun. 2018, 54, 3379–3382. (e) Kibriya, G.; Bagdi, A. K.; Hajra, A. Visible-Light-Promoted C(Sp3)-C(Sp2) Cross-Dehydrogenative Coupling of Tertiary Amine with Imidazopyridine. J. Org. Chem. 2018, 83, 10619– 10626. 18. (a) Patra, T.; Maiti, D. Decarboxylation as the Key Step in C−C Bond-Forming Reactions. Chem. - A Eur. J. 2017, 23, 7382–7401. (b) Zhang, B.; Studer, A. Recent Advances in the Synthesis of Nitrogen Heterocycles via Radical Cascade Reactions Using Isonitriles as Radical Acceptors. Chem. Soc. Rev. 2015, 44, 3505–3521. (c) Tang, S.; Wang, P.; Li, H.; Lei, A. Multimetallic Catalysed Radical Oxidative C(Sp3)-H/C(Sp)H Cross-Coupling between Unactivated Alkanes and Terminal Alkynes. Nat. Commun. 2016, 7, 1–8.


Mn(II)-Catalyzed C-H Alkylation of Imidazopyridines and N

Recommend Documents