Three Sequential C-N Bond Formation: tert-Butyl Nitrite as a N1

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Three Sequential C-N Bond Formation: tert-Butyl Nitrite as a N1 Synthon in a Three Component Reaction Leading to Imidazo[1,2-a]quinolines/ Imidazo[2,1-a]isoquinolines Prasenjit Sau, Amitava Rakshit, Anju Modi, Ahalya Behera, and Bhisma K. Patel J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02815 • Publication Date (Web): 20 Dec 2017 Downloaded from http://pubs.acs.org on December 22, 2017

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The Journal of Organic Chemistry

Three Sequential C− −N Bond Formation: tert-Butyl Nitrite as a N1 Synthon in a Three Component Reaction Leading to Imidazo[1,2-a]quinolines / Imidazo[2,1-a]isoquinolines Prasenjit Sau, Amitava Rakshit, Anju Modi, Ahalya Behera and Bhisma K. Patel* Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati-781039, India Fax: (+91)361-26909762. E-mail: [email protected] RECEIVED DATE (will be automatically inserted after manuscript is accepted). ABSTRACT: tert-Butyl nitrite serves the dual role of an oxidant as well as a N1 synthon in a multi-component reaction involving quinolines/isoquinolines and styrenes. Herein two sp2 C−H’s functionalization of styrenes and one of quinolines/isoquinolines leads to the formation of fused quinolines/isoquinolines via three sequential C−N bond formation.

Further functionalization and late stage functionalization of biologically important organic frameworks amplifies its activity towards pharmaceutical and medicinal chemistry. Quinolines and isoquinolines are integral part in many natural products and building blocks of several pharmaceuticals.1 The functionalized derivatives of those viz. imidazo[1,2-a]quinoline (I, II and IV) and imidazo[2,1-a]isoquinoline (III) exhibit effective biological activities such as inhibitors of Shiga Toxin, hypertensive, antiallergic, contraceptive and antiasthmatic anxiolytic (Figure 1).2

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Figure 1. Representative Biologically Active Imidazo[1,2-a]quinolines and Imidazo[2,1a]isoquinolines Various functionalizations of quinolines and isoquinolines has been documented in the literature viz. alkylation,3a,b halogenation,3c sulfonation,3d trifluoromethylation etc.3e-g Of late, CH functionalization is an alternative strategy to create complex structural frameworks from small organic molecules. Consequently, the CH functionalization protocols have been applied to quinoline and isoquinoline moieties. In this regard, Liu et.al. demonstrated a novel route for the synthesis of C1-benzyl and benzoyl substituted isoquinolines through a direct oxidative CH functionalization of isoquinolines using alkyl benzene as the coupling partner.4a Our group has also developed a Lewis acid catalyzed C1 or C2 arylation of isoquinolines and quinolines (Scheme 1a)4b using methylarenes as the aroyl surrogates.4b On the other hand direct 1,2-difunctionalization of alkenes with or without the involvement of sp2 C–H bonds have played a vital role in building complex molecules. Bisfunctionalization of olefins such as dihydroxylation,5 hydroalkylation,6 oxyamination,7 carbohalogenation,8

oxyarylation,9

aminofluorination,10

aminocyanation,11

nitration,12

carboboration,13 and others14 are well documented in the literature. Our group has recently reported an efficient synthesis of isoxazolines via 1,2-difunctionalization of styrene in the


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presence of quinoline (as a base), tert-butyl nitrite as the N−O source in the presence of catalyst Sc(OTf)3 (Scheme 1b).15 Taking cues from these radical mediated reactions, especially, nitration of alkenes12 using tert-buty nitrite and C1 or C2 aroylation of N-heterocycles,4 we envisaged a double functionalization of styrene and a concomitant C2 functionalization of quinoline or a C1 functionalization of isoquinoline leading to the synthesis of fused heterocycles. Scheme 1. Strategies for C− −H Functionalization of N-Heterocycles with Alkyl benzene and Styrenes

By judiciously choosing the catalyst and other reaction parameters it was possible to fuse styrene onto both quinoline and isoquinoline moieties in the presence of tert-butyl nitrite (TBN) (Scheme 1c). Our initial investigation started using quinoline (0.25 mmol), styrene (0.625 mmol), Cu(OTf)3 (10 mol %), Cs2CO3 (2 equiv) and tert-butylnitrite (2 equiv) in 1,2dichloroethane (DCE) at 80 οC. Interestingly, the reaction resulted in the formation of a new product (1a, 41%), spectroscopic analysis confirmed its structure to be 2-phenylimidazo[1,2a]quinoline (1a).16 In this structure the incorporation of a new N atom is associated with the formation of three C−N bonds. We believe that TBN to be the possible source of additional nitrogen atom in this product. So far TBN has been exploited mainly as a source of NO and NO2 radicals.12,20 Besides this it has been employed as a nitrogenating agent in the formation of



nitriles from alkylbenzene17a and terminal aryl alkenes.17b Prior to this report there is only one illustration where TBN has been used as a N1 synthon in the synthesis of cinnolines from 2-vinyl aniline.17c In spite of the recent surge in the use of TBN, we feel it is an underutilized reagent, thus exploring alternative pattern of reactivity would open novel avenues for synthetic chemists. Herein, we disclose a copper catalyzed three-component synthesis of N-fused heterocycles involving quinoline/isoquinoline, styrene and TBN as the N1 synthon via three sequential C−N bond formations.

Encouraged by the above unprecedented three component reaction, further optimization were carried out by varying various reaction parameters using styrene (a) and quinoline (1) as the coupling partners in the presence of tBuONO. Initially, a variety of non-polar solvents such as p-xylene (31%), toluene (29%) and chlorobenzene (36%) and polar aprotic solvents such as DMF (21%) and DMSO (0%) were tested (Table 1, entries 2−6). However, all the solvents tested were found to be less effective compared to DCE (41%) (Table 1, entry 1). Other Cu(I) and Cu(II) salts such as Cu(OAc)2 (33%), CuCl2 (35%) and CuCl (39%) (Table 1, entries 7−9) gave poor yields compared to Cu(OTf)2 (43%) whereas, CuBr and CuI provided improved yields of 45% and 49% respectively (Table 1, entries 10 and 11). With CuI as the suitable catalyst, other inorganic (K2CO3 and KOtBu) and organic (DMAP and DBU) bases were screened. Inorganic bases K2CO3 (43%) (Table 1, entry 12) gave lower yield compared to Cs2CO3 whereas, KOtBu furnished an improved yield of 53% (Table 1, entry 13). However, no encouraging results could be obtained using organic bases such as DMAP (31%) and DBU (29%) (Table 1, entries 14 and 15). When the reaction was carried out in the absence of Cu-catalyst no product formation was detected (Table 1, entry 16), suggesting the involvement of copper salt in facilitating the reaction, possible via the formation of an iminium carbocation.18 When the reaction was


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performed in the absence of base under otherwise identical condition resulted in a suppressed yield (27%) of (1a) (Table 1, entry 17). These results suggest the involvement of both catalyst and base in this multi-component reaction. In a pursuit to improve the yield, further reactions were carried out in the presence of oxidants. Interestingly, the use of various oxidants such as ditert-butyl peroxide (61%), DDQ (56%), K2S2O8 (55%), tert-butyl peroxybenzoate (53%) significantly improved the product yield, with DTBP being the most effective (Table 1, entries 18−21). Increasing the catalyst loading to 15 mol % improved the yield up to 66% (Table 1, entry 22). No noticeable enhancement in the yield (68%) was observed when the catalyst loading was increased up to 20 mol % (Table 1, entry 23). There was no enhancement in the yield (66%) when the additive (DTBP) loading was increased to 4 equiv (Table 1, entry 24) however the yield of the product decreased to 62% when the quantity of additive (DTBP) was reduced to 2 equiv (Table 1, entry 25). Reaction carried out both at higher 100 οC (53%) or lower 60 οC (40%) temperature were detrimental to the product formation. (Table 1, entries 26 and 27). After screening of various reaction parameters, the optimized condition for this transformation is the use of quinoline (0.25 mmol), styrene (0.625 mmol), CuI (15 mol %), tBuOK (0.5 mmol), tertbutylnitrite (0.5 mmol) and DTBP (0.75 mmol) at 80 οC in DCE solvent (Table 1, Entry 22).



Table 1. Optimization of the Reaction Conditionsa

entry 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

catalyst (mol %) Cu(OTf)2 (10.0) Cu(OTf)2 (10.0) Cu(OTf)2 (10.0) Cu(OTf)2 (10.0) Cu(OTf)2 (10.0) Cu(OTf)2 (10.0) Cu(OAc)2 (10.0) CuCl2 (10.0) CuCl (10.0) CuBr (10.0) CuI (10.0) CuI (10.0) CuI (10.0) CuI (10.0) CuI (10.0) CuI(10.0) CuI (10.0) CuI (10.0) CuI (10.0) CuI (10.0) CuI (15.0) CuI (20.0) CuI (15.0) CuI (15.0) CuI (15.0) CuI (15.0)

base Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 K2CO3 KOtBu DMAP DBU KOtBu t BuOK t BuOK t BuOK t BuOK t BuOK t BuOK t BuOK t BuOK t BuOK t BuOK

solvent DCE p-xylene toluene PhCl DMF DMSO DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE

additive DTBP DDQ K2S2O8 TBPB DTBP DTBP DTBP DTBP DTBP DTBP

yield %b 43 31 29 36 21 0 33 35 39 45 49 43 53 31 29 0 27 61 56 55 53 66 68 66c 62d 53e 40f

a

Reaction conditions: Quinoline (1) (0.25 mmol), styrene (a) (0.625 mmol), catalyst (mol %), base (0.5 mmol), tert-butylnitrite (0.5 mmol) and additive (0.75 mmol) at 80 οC. bYield after 8 h. cDTBP 4 equiv dDTBP 2 equiv e Temperature 100 οC. fTemperature 60 οC.

This multi-component synthesis of imidazo[1,2-a]quinolines was then explored with various quinolines and aromatic terminal alkenes (Scheme 2) under the optimized reaction condition. Styrenes having electron-donating substituents such as p-Me (b), p-tBu (c) and p-OMe (d) successfully coupled with quinoline (1), yielding their corresponding imidazo[1,2a]quinolines (1b, 49%), (1c, 53%) and (1d, 45%) in moderate yields (Scheme 2).


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Scheme 2. Substrate Scope for Synthesis of Imidazo[1,2-a]quinolinesa,b CuI (15 mol %) t BuONO (2 equiv) N

R1 (1-3)

N

R2 (a-g)

N

R1

DTBP (3 equiv) tBuOK (2 equiv) DCE, 80 oC, 8 h.

N

(1a-3g) R2 Me

R2

N

N 2

R = H (1a, 66%) R2 = H (1a, 62%)c R2 = p-Me (1b, 49%) R2 = p-tert-butyl (1c, 53%) R2 = p-OMe (1d, 45%) N R2 = p-Br (1e, 64%) N Me R2 = p-Cl (1f, 67%) R2 = p-F (1g 69%) R2 = p-Cl (3f, 70%)

R2

N R2 = H (2a, 62%) R2 = p-Br (2e, 63%) R2 = p-Cl (2f, 67%) R2 = p-F (2g, 70%) R2 = m-Cl (2h, 69%) R2

2

R = p-F (3g, 71%)

a

Reaction conditions: quinoline (1) (0.25 mmol), styrene (a) (0.625 mmol), CuI (0.038 mmol), tBuOK (0.5 mmol), tert-butylnitrite (0.5 mmol) and DTBP (0.75 mmol) at 80 οC in DCE (1.5 mL). bYield after 8 h. cYield reported for 1 mmol scale

Styrenes bearing electron-withdrawing substituents such as p-Br (e), p-Cl (f) and p-F (g), all provided their respective imidazo[1,2-a]quinolines (1e, 64%), (1f, 67%) and (1g, 69%) in moderate yields. In order to expand the scope of this methodology, substituted quinolines such as 3-methylquinoline (2) and 6-methylquinoline (3) were tested with various substituted styrenes (a), (e), (f), (g) and (h) and all afforded their respective fused products (2a, 62%), (2e, 63%), (2f, 67%), (2g, 70%), (2h, 69%), (3f, 70%) and (3g, 71%) in good yields (Scheme 2).



Scheme 3. Substrate Scope for Synthesis of Imidazo[2,1-a]isoquinolines a,b t

N R1

(4-6)

R2

CuI (15 mol %) BuONO (2 equiv) DTBP (3 equiv) BuOK (2 equiv) DCE, 80 oC, 8 h.

N

R1

N

t

(a-j)

Me N N

(4a-6b)

R2

NO2

N N

N N

R2 R2 = H (4a, 64%) R2 = p-Me (4b, 53%) R2 = p-tert-butyl (4c, 55%) R2 = p-Br (4e, 65%) R2 = p-Cl (4f, 68%) R2 = p-F (4g, 71%)

R2 R2 = H (5a, 61%) R2 R2 = p-Cl (5f, 66%) R2 = H (6a, 60%) R2 = p-F (5g, 72%) R2 = p-Me (6b, 51%) R2 = m-Cl (5h, 68%) R2 = m-F (5i, 74%) R2 = m-Me (5j, 60%)

a

Reaction conditions: isoquinoline (1) (0.25 mmol), styrene (a) (0.625 mmol), CuI (0.038 mmol), tBuOK (0.5 mmol), tert-butylnitrite (0.5 mmol) and DTBP (0.75 mmol) at 80 οC in DCE (1.5 mL). bYield after 8 h.

Owing to the importance of isoquinoline framework in many biological systems and with the positive outcome of the present coupling strategy with quinoline, we sought to test the similar fusion of isoquinoline with styrene. To our delight, the reaction of isoquinoline (4) with styrene (a) under the identical condition lead to the synthesis of analogues coupled product 2phenylimidazo[2,1-a]isoquinoline (4a, 64%) (Scheme 3). Encouraged by this positive result we further executed this strategy to other styrenes and isoquinolines. Styrenes having electrondonating such as p-Me (b), p-tBu (c) or electron-withdrawing such as p-Br (e), p-Cl (f) and p-F (g) substituents, all underwent effective coupling with isoquinoline (4) to produce their desired products [(4b, 53%), (4c, 55%), (4e, 65), (4f, 68%) and (4g, 71%)] as shown in Scheme 3. The structure of the product (4f) has been further confirmed by single crystal X-ray diffraction study (Figure 2).


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Figure 2. Ortep diagram of compound (4f) Furthermore, substituted isoquinolines such as 3-methylisoquinoline (5) and 5nitroisoquinoline (6) both reacted smoothly with various substituted styrenes (a), (b), (f), (g), (h), (i) and (j) affording their corresponding imidazo[2,1-a]isoquinolines (5a, 61%), (5f, 66%), (5g, 72%), (5h, 68%), (5i, 74%), (5j, 60%), (6a, 60%) and (6b, 51%) in modest yields (Scheme 3). In this protocol, both electron-donating and electron-withdrawing substituents on either of the substrate provided almost identical yields of their product. This may be due to the higher reactivity of reaction intermediates, in this multi-step strategy. However, in this process aliphatic alkenes failed to react completely which may be due to the instability of the radical generated during the reaction. Scheme 4. Synthesis of 4-((2-Phenylimidazo[2,1-a]isoquinolin-3-yl)methyl)morpholine (4ak).

4-((2-Phenylimidazo[2,1-a]isoquinolin-3-yl)methyl)morph-oline hydrochloride (4ak) is a very important compound possessing significant range of biological activities.2d It has been successfully applied in determining the functional activity of several living organisms.2d Compound (4ak) was successfully synthesized from (4a) by coupling it with morpholine (k).



The later serve the dual role of a one-carbon synthon as well as the morpholine unit following the protocol of Hajra et.al (Scheme 4).19 In order to elucidate a plausible mechanism, an experiment was performed in the presence of a radical scavenger 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO, 3 equiv) under otherwise identical condition. Retardation in the desired product (1a,

Three Sequential C-N Bond Formation: tert-Butyl Nitrite as a N1

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