Revisiting the reaction of β-chloroacroleins with 2-aminophenol: a new observation

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Revisiting the reaction of β-chloroacroleins with 2-aminophenol: a new observation
  Revisiting the reaction of   b -chloroacroleins with 2-aminophenol:a new observation Rabin Bera  a,c , G. Dhananjaya  a , Shambu Nath Singh  a , B. Ramu  a , Sai Uday Kiran  b ,P. Rajender Kumar  a , K. Mukkanti  c , Manojit Pal  b, * , y a Custom Pharmaceutical Services, Dr. Reddy’s Laboratories Limited, Bollaram Road, Miyapur, Hyderabad-500049, Andhra Pradesh, India b Chemistry, Discovery Research, Dr. Reddy’s Laboratories Limited, Bollaram Road, Miyapur, Hyderabad-500049, Andhra Pradesh, India c Chemistry Division, Institute of Science and Technology, JNT University, Kukutpally, Hyderabad-500072, Andhra Pradesh, India Received 27 July 2007; received in revised form 16 October 2007; accepted 26 October 2007Available online 1 November 2007 Abstract The reaction of   b -chloroacrolein with 1 equiv of 2-aminophenol in DMF proceeds smoothly to afford 11-hydroxy derivative of chromeno-quinoline in good yield. This single pot method allows for a rapid access to a variety of chromenoquinolines or oxepinoquinolines depending onthe nature of   b -chloroacrolein used. The structures were established by spectroscopic data and further confirmed by X-ray diffraction analysis. Aplausible mechanism for this reaction has been proposed. The reaction seemed to proceed via a chloroimine species, whose intermediacy hasbeen established, followed by the construction of the fused quinoline ring.   2007 Elsevier Ltd. All rights reserved.  Keywords:  b -Chloroacroleins; 2-Aminophenol; Chromenoquinoline; Oxepinoquinoline 1. Introduction Drugs that modulate the transcriptional activity of humanprogesterone receptor (hPR) play important role in medicine,and over the years hPR agonists have been used therapeuti-cally. 1 Due to the undesirable side effects caused by all the ste-roidal hRP modulators, a polynuclear heterocyclic framework such as chromenoquinoline ( I , Fig. 1) has been designed andidentified as an effective pharmacophore for the developmentof better nonsteroidal hPR agonists. 2 Additionally, this class of compounds has shown glucocorticoid receptor agonist and an-tagonist activity and androgen receptor antagonist activity. 3 Based on these reports that this framework can be utilizedfor the development of potential drugs, we became interestedin the synthesis of substituted 6  H  -chromeno[4,3- b ]quinolines( II ) and 6,7-dihydrobenzo[2,3]oxepino[4,5- b ]quinolines ( III )derived from  I  (Fig. 1). The new chromenoquinolines  II were initially designed via changing the connectivity betweenchromene and quinoline moiety. However, since the earlierwork on  I  was limited to the effect of substituents on D andC ring, 2a hence we focused on modifying the A and B ringalso followed by the expansion of C ring as shown in Figure 1.We presumed that these compounds containing 8-hydroxyqui-noline 2b moiety might be useful for conducting structure e ac-tivity relationship (SAR) studies related to the compound  I  andthat some of them might show the similar pharmacologicalproperties to  I . Additionally, the substituent, e.g., hydroxylgroup present on the quinoline ring might help in further func-tionalization of   II  and  III .Whilst a large number of methods are known for the con-struction of quinoline rings, only a few have been reportedfor chromenoquinolines. These include (i) condensation of 2-aminobenzaldehyde with chroman-4-one, 4a e c (ii) heating(200   C) 4d or irradiation 4e of phenyl-[3-(phenylimino-methyl)-2  H  -chromen-4-yl]-amine hydrochloride, and (iii) treatmentof   N  -phenyl-2-prop-2-ynyloxy-benzamide with POCl 3 . 4f  Onthe other hand, 6,7-dihydro-benzo[2,3]oxepino[4,5- b ]quinolines * Corresponding author. Tel.:  þ 91 40 23045439; fax:  þ 91 40 23045438.  E-mail address: (M. Pal). y Present address: New Drug Discovery, R&D Center, Matrix LaboratoriesLimited, Bollaram, Andhra Pradesh 502 325, India.0040-4020/$ - see front matter    2007 Elsevier Ltd. All rights reserved.doi:10.1016/j.tet.2007.10.101  Available online at Tetrahedron 64 (2008) 582 e  can be obtained via condensation of 1-(2-amino-phenyl)-eth-anone hydrochloride with 3,4-dihydro-2  H  -benzo[ b ]oxepin-5-one at high temperature (140   C). 4g Many of these processes,however, suffer from disadvantages, such as the use of excessreagents, longer reaction time, and the low yields of products.More importantly, none of these processes appeared to be suit-able for the synthesis of both  II  and  III . Thus, development of an appropriate and general, but cost effective process, for thepreparation of   II  and  III  was highly desirable. Due to our con-tinued interest in the design and synthesis of polynuclear het-erocyclic compounds of potential biological interest, 5 we haverecently reported the Pd-mediated synthesis of furoquinolinesvia construction of the fused furan ring. 5d Herein, we reporta very simple and single pot synthesis of hydroxy derivativesof various 6  H  -chromeno[4,3- b ]quinolines and 6,7-dihydroben-zo[2,3]oxepino[4,5- b ]quinolines via construction of the fusedquinoline moiety using  b -chloroacroleins and 2-aminophenolas synthetic precursors (Scheme 1). 2. Results and discussion Recently, condensation followed by cyclization of hetero-cyclic  b -chloroaldehydes with 2-aminophenol has been stud-ied, which led to the formation of 1,5-benzoxazepines ingood yields. 6 Accordingly, we reacted 4-chloro-2  H  -chro-mene-3-carboxaldehyde ( 1a ) with 1.1 equiv of 2-aminophenol( 2a ) in DMF (5 mL) at 25   C for 1.0 h followed by heating thereaction mixture at 120   C for 4 h. To our surprise, the corre-sponding 1,5-benzoxazepine ( 3aa ) was not isolated from thereaction mixture (Scheme 2). Based on analytical data [ 1 H(Fig. 2) and  13 C NMR, Mass { m  /  z  250.3 (M þ 1, 100%)},and a broad peak at 3364 cm  1 in IR spectra due to the phe-nolic OH], the product isolated after usual work up and puri-fication was identified as 6  H  -chromeno[4,3- b ]quinoline-11-ol( 3a , C 16 H 11 NO 2 ). This was supported by the molecular struc-ture of 2-bromo-6  H  -chromeno[4,3- b ]quinolin-11-ol ( 3e ) beingconfirmed by X-ray analysis (Fig. 3). 7 We were delighted to isolate the chromenoquinoline deriva-tive where the fused quinoline ring seemed to have formed viaan unprecedented pathway under the reaction condition stud-ied (see later for mechanistic discussion). Thus, encouragedby these results we then decided to assess the generality andscope of this one-pot process. A variety of 2-aminophenols( 2 ) were employed in this reaction and a range of 6  H  -chro-meno[4,3- b ]quinoline derivatives ( 3a e f  ) were synthesized ONHOONHOZZONH Ar  ABCD Change of connectivity between chromene and quinoline moiety I II IIIchromenequinoline Expansion of ether ring Figure 1. Design of new chromenoquinolines and oxepinoquinolines. (CH 2 ) n OClHOZH 2 NHO X+(CH 2 ) n OZNHO X1. DMF, 25 °C, 1h 1 2 2. 120 °C, 2-4 h 3 Scheme 1. Reaction of   b -chloroacroleins with 2-aminophenol. OClHOH 2 NHOONHO1. DMF, 25 °C, 1h 1a + 2a 2. 120 °C, 2-4 h 3a OON X 3aa Scheme 2. Reaction of 4-chloro-2  H  -chromene-3-carboxaldehyde ( 1a ) with 1.1 equiv of 2-aminophenol ( 2a ).Figure 2.  1 H NMR (in DMSO- d  6 ) spectra of 6  H  -chromeno[4,3- b ]quinoline-11-ol ( 3a ).583  R. Bera et al. / Tetrahedron 64 (2008) 582 e  589  (Table 1) in good yields. As evident from Table 1, all the 2-aminophenols participated in this reaction smoothly andthe yields of the products were remarkably similar irrespectiveof the presence of electron donating/withdrawing groups onthe aniline ring (entry 1 vs entries 3 e 5, Table 1). No other sig-nificant side products including 1,5-benzoxazepine were iso-lated. Generally, all the reactions were carried out in DMFat 120   C instead of refluxing DMF. 6 However, the use of other solvents, e.g., ethanol was investigated and found to beless effective in terms of yield of the product (entry 2, Table1). The methodology was extended successfully to preparethe hydroxy derivatives of 6,7-dihydrobenzo[2,3]oxe-pino[4,5- b ]quinoline ( 3g e i ) in good yields (entry 8 e 10, Table1). Thus  b -chloroacroleins appeared to be useful synthetic pre-cursors for the preparation of 6  H  -chromenoquinolines ( 3a e f  )and 6,7-dihydrobenzo[2,3]oxepino[4,5- b ]quinolines ( 3g e i ).All the  b -chloroacroleins ( 1 ) were readily prepared from thecorresponding ketones by a Vilsmeier e Haack  e Arnold reac-tion 8 according to Scheme 3. All the 2-aminophenols usedare commercially available.Mechanistically, the present two-step reaction in a singlepot seems to proceed via (a) generation of a 4-chloroiminein situ at low temperature in the initial step, (b) followed bythe construction of fused quinoline ring at elevated tempera-ture in the next step to afford the observed product  3 . A plau-sible mechanism showing the formation of compound  3  froma 4-chloroimine is depicted in Scheme 4. To prove the inter-mediacy of 4-chloroimine, the reaction of   1a  with  2a  wascarried out in DMF at 25   C for 1.0 h where the corresponding4-chloroimine ( 4 ) was isolated in 75% yield (Scheme 5). Thespectral data of the solid product (mp 156 e 157   C) obtainedwas found to be identical in all respects as reported earlier(lit. mp 156 e 158   C). 6 It is interesting to note that the reactionof   1a  with 2 equiv of aniline in chloroform at room tempera-ture afforded the corresponding enaminoimine in 80% yield,which on pyrolysis (200   C) furnished 6  H  -chromeno[4,3- b ]-quinoline. 4a Since the formation of enaminoimine was not ob-served in the present case perhaps due to the use of lesserquantity (1.0 equiv) of   2a , the intermediacy of enaminoiminecan be ruled out. Moreover, isolation of 6  H  -chromeno[4,3- b ]-quinoline-11-ol ( 3a ) in 80% yield from compound  4  whenheated at 120   C for 4 h (Scheme 4) clearly suggests that thereaction proceeds via a chloroimine intermediate. Thus, oncegenerated in situ the chloroimine undergoes intermolecular cy-cloaddition at elevated temperature as shown in Scheme 3. Thefused tetrahydro pyrimidine intermediate ( X-1 ) formed thencollapsed to chroman-4-ylideneamine species ( X-2 ), whichas a result of intra-molecular rearrangement followed by aro-matization furnish  3  with the regeneration of chloraminethereby completing the reaction cycle. 9,10 3. Conclusions In conclusion, the reaction of   b -chloroacroleins with 2-ami-nophenols in DMF was investigated, which yielded chromeno-quinolines and oxepinoquinolines thereby providing an easymethod for the synthesis of these compounds. Contrary tothe earlier report 6 no 1,5-benzoxazepine derivative was iso-lated under the present reaction conditions. The single stepprocedure described here could be attractive as it is simple,easy to handle, and does not involve the use of expensive re-agents or catalysts. The process is also free from the use of ex-cess 2-aminophenol or photochemical conditions and found tobe general for the synthesis of quinoline based polynuclearheterocycles. Therefore, the process may prove to be a power-ful tool in the direct synthesis of chromenoquinoline/oxepino-quinolines based agents of potential pharmacological interest,preparation of which via other route may require lengthy syn-thetic procedure. Moreover, this design may be applicable togenerate diversity-based library of polynuclear heterocycliccompounds. 4. Experimental  4.1. General  Unless stated otherwise, reactions were monitored by thinlayer chromatography (TLC) on silica gel plates (60 F 254 ),visualizing with ultraviolet light or iodine spray. Flash Figure 3. X-ray crystal structure of   3e  (ORTEP diagram). Displacement ellip-soids are drawn at 50% probability level for non-hydrogen atoms.584  R. Bera et al. / Tetrahedron 64 (2008) 582 e  589
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