This article was downloaded by: [Massachusetts Institute of Technology] On: 28 February 2013, At: 04:34 Publisher: Taylor & Francis Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/lsyc20 Reaction of Diphenacylanilines with 2-Aminobenzophenone: An Abnormal Friedlander Reaction Yielding Indoles Nidhin Paul a & Shanmugam Muthusubramanian a a Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai, India Accepted author version posted online: 10 May 2012.Version of record first published: 21 Feb 2013. To cite this article: Nidhin Paul & Shanmugam Muthusubramanian (2013): Reaction of Diphenacylanilines with 2-Aminobenzophenone: An Abnormal Friedlander Reaction Yielding Indoles, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 43:8, 1200-1209 To link to this article: http://dx.doi.org/10.1080/00397911.2011.627524 PLEASE SCROLL DOWN FOR ARTICLE Full terms and conditions of use: http://www.tandfonline.com/page/terms-and-conditions This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. The publisher does not give any warranty express or implied or make any representation that the contents will be complete or accurate or up to date. The accuracy of any instructions, formulae, and drug doses should be independently verified with primary sources. The publisher shall not be liable for any loss, actions, claims, proceedings, demand, or costs or damages whatsoever or howsoever caused arising directly or indirectly in connection with or arising out of the use of this material.
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This article was downloaded by: [Massachusetts Institute of Technology]On: 28 February 2013, At: 04:34Publisher: Taylor & FrancisInforma Ltd Registered in England and Wales Registered Number: 1072954 Registeredoffice: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: AnInternational Journal for RapidCommunication of Synthetic OrganicChemistryPublication details, including instructions for authors andsubscription information:http://www.tandfonline.com/loi/lsyc20
Reaction of Diphenacylanilines with2-Aminobenzophenone: An AbnormalFriedlander Reaction Yielding IndolesNidhin Paul a & Shanmugam Muthusubramanian aa Department of Organic Chemistry, School of Chemistry, MaduraiKamaraj University, Madurai, IndiaAccepted author version posted online: 10 May 2012.Version ofrecord first published: 21 Feb 2013.
To cite this article: Nidhin Paul & Shanmugam Muthusubramanian (2013): Reaction ofDiphenacylanilines with 2-Aminobenzophenone: An Abnormal Friedlander Reaction Yielding Indoles,Synthetic Communications: An International Journal for Rapid Communication of Synthetic OrganicChemistry, 43:8, 1200-1209
To link to this article: http://dx.doi.org/10.1080/00397911.2011.627524
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-and-conditions
This article may be used for research, teaching, and private study purposes. Anysubstantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,systematic supply, or distribution in any form to anyone is expressly forbidden.
The publisher does not give any warranty express or implied or make any representationthat the contents will be complete or accurate or up to date. The accuracy of anyinstructions, formulae, and drug doses should be independently verified with primarysources. The publisher shall not be liable for any loss, actions, claims, proceedings,demand, or costs or damages whatsoever or howsoever caused arising directly orindirectly in connection with or arising out of the use of this material.
Many of the bioactive alkaloids from the plants of marine or terrestrial domainare based on the indole moiety.[1] The indole framework has vast application inmaterial sciences,[2] agrochemicals,[3] and pharmaceuticals. Indoles and their deriva-tives are known to exhibit antibacterial,[4] antifungal,[4b] antiviral,[5] antitubercular,[6]
anticancer,[7] anti–Alzheimer’s disease,[8] anti-HIV,[9] gonadotropine-releasinghormone antagonist,[10] and h5-HT2A receptor antagonist[11] properties. Melatonin1 (Fig. 1), an important hormone that regulates biological rhythms and acts as areceptor-independent free-radical scavenger,[12,7b] and the natural product martefra-gin A 2, which is an inhibitor of lipid peroxidation,[13] have indole in their molecularmakeup. 3-(1H-Indol-3-yl)propanoic acid 3, which is extracted from the rootnodules of the pea plant (Pisum sativum), is a potent neuroprotective agent.[14]
Received July 1, 2011.
Address correspondence to Shanmugam Muthusubramanian, Department of Organic Chemistry,
School of Chemistry, Madurai Kamaraj University, Madurai 625021, India. E-mail: muthumanian2001@
yahoo.com
Synthetic Communications1, 43: 1200–1209, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.627524
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Fluvastatin 4[15] is a synthetic member of the statin class containing the indolemoiety. Indolodioxane (U86192A) 5 is active in antihypertension[16] and MDL103371 6 is a kind of glycine receptor antagonist[17] for the treatment of strokes.Tryptophan derivatives possess inhibitory activity against the IDO enzyme.[18]
Well-documented strategies for the synthesis of indoles include the Fisher indole syn-thesis,[19] the Bischler indole synthesis,[20] and the Madlung cyclization.[21] Despitemany creative approaches,[22] general and efficient syntheses that control the intro-duction of substituents at C-2 and C-3[23] of the indole are still lacking.
In continuation of our interest in the construction of novel organic mole-cules,[24] herein we report the abnormal Friedlander reaction of 2-aminobenzophe-none with diphenacylaniline, resulting in indole derivatives.
RESULTS AND DISCUSSION
Different diphenacylanilines were prepared by a reported procedure[25] fromsubstituted phenacyl bromide and aniline. With the expectation of generating bisqui-nolines 9 through a double-Friedlander reaction, diphenacylaniline 8 is allowed toreact with 2mol of 2-aminobenzophenone 7 (Scheme 1) with different acid catalysts.
Figure 1. Structures of indole drugs and alkaloids. (Figure is provided in color online.)
Scheme 1. Synthesis of 2-aroyl-3-arylindole 11. (Figure is provided in color online.)
ABNORMAL FRIEDLANDER REACTION 1201
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A product has been isolated and, in order to optimize the reaction conditions, wecarried out the reaction under different time intervals and varied the solvents andcatalysts (Table 1). The course of the reaction was monitored by thin-layer chro-matography (TLC) in each case and it was observed that the reaction yielded the bestresult when refluxed in ethanol for 2 h with 15mol% of (�)-camphorsulfonic acid(CSA). Further increase in the catalyst concentration does not improve the yield.Among the different solvents tried, ethanol gave maximum yield (Table 1). Thereaction has been generalized by carrying it out on a set of substrates, and the crudeproduct separated in each case was recrystallized from an ethanol–ethyl acetatemixture (3:2) to provide the pure product in 76–88% yield (Table 2).
CSA (15mol %) in 7ml of ethanol was added to a mixture of 2-aminobenzo-phenone 7 (2mmol) and diphenacylaniline 8 (1mmol). The mixture was allowedto reflux for 2 h, and after the completion of the reaction (TLC), the reaction mixturewas poured into ice-cold water. The solid that separated was recrystallized from3:2 alcohol–ethyl acetate mixture to give 11.
The reaction was expected to yield nitrogen-linked bisquinolines 9 by adouble-Friedlander pathway or quinolones 10 by an intermolecular phenyl ringtransfer, but the product obtained has been shown to be indoles 11 (Scheme 1).The presence of a broad singlet at 9.72 ppm (1H, NH) in the proton NMR spectrumof 11j and the appearance of a carbonyl peak at 188.2 ppm in its 13C NMR spectrum
Table 1. Solvent and catalyst screening for the synthesis of 11a from diphenacyl aniline
Entry Solvent Catalyst (mol%) Time (h) Yield of 11a (%)
1 MeOH (�)-CSA (20) 2.5 70a
2 CH3CN (�)-CSA (20) 3.5 74a
3 THF (�)-CSA (30) 3.0 —b
4 Ethylene glycol (�)-CSA (15) 3.5 55c
5 DMF (�)-CSA (30) 3.0 36c
6 Water (�)-CSA (15) 2.0 32c
7 CH3Cl (�)-CSA (15) 2.0 —b
8 EtOH p-TSA (25) 2.5 68c
9 EtOH p-TSA (15) 3.5 60c
10 EtOH (�)-CSA (15) 2.0 82a
11 EtOH (�)-CSA (35) 3.5 80a
12 EtOH Citric acid (20) 4.0 54c
13 EtOH Citric acid (45) 4.5 71a
14 EtOH HCl (20) 3.5 63c
15 EtOH SnCl4 � 6H2O (15) 3.0 72a
16 EtOH AlCl3 (20) 4.5 57c
17 EtOH YbCl3 (15) 3.0 73a
18 EtOH Yb(Otf)3 (15) 3.0 70a
19 EtOH BiCl3 (25) 4.5 71a
20 EtOH InCl3 (15) 4.5 68a
21 EtOH KOH (20) 5.0 —d
aRecrystallized from ethyl acetate.bNo characteristic product.cSeparated through column.dReactants recovered.
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prompted us to eliminate bisquinoline as the possible product.[(4-Chlorophenyl)(5-chloro-3-phenyl-1H-2-indolyl)methanone (11j) was isolated ascolorless solid; mp 206–207 �C; 1H NMR (300MHz, CDCl3) dH: 7.03 (d, 2H,J¼ 8.7Hz, Ar-H), 7.11–7.20 (m, 5H, Ar-H), 7.35 (dd, 1H, J¼ 8.7, 1.8Hz, Ar-H),7.45 (d, 3H, J¼ 8.7Hz, Ar-H), 7.68 (d, 1H, J¼ 1.8Hz, Ar-H), 9.72 (s, 1H, NH);13C NMR (75MHz, CDCl3) dC: 113.3, 121.2, 124.8, 126.9, 127.2, 127.3, 127.9,128.2, 128.4, 130.7, 130.8, 131.5, 132.8, 134.8, 135.4, 138.2, 188.2. Anal. calcd. forC21H13Cl2NO: C, 68.87; H, 3.58; N, 3.82%. Found: C, 68.82; H, 3.54; N, 3.86%].The doublet at 7.03 ppm (J¼ 8.7Hz, 2H, H-30) is ascribed to meta hydrogens ofpara-chloroaryl ring, which has (i) H, H-COSY (correlation spectroscopy) withanother doublet at 7.45 ppm (J¼ 8.7Hz, H-20), (ii) C, H-COSY with C-30 at128.2 ppm, and (iii) HMBCs (heteronuclear multiple bond correlation) with C-10
at 135.4 ppm and C-40 at 138.2 ppm. The doublet at 7.45 ppm has C, H-COSY withC-20 at 130.8 ppm and a decisive HMBC with the carbonyl signal at 188.2 ppm,which is impractical in the expected quinolone system (10) and feasible only withthe indole moiety, 11. In the indole ring, the doublet at 7.68 ppm (J¼ 1.8Hz) isascribed to H-4 which has C, H-COSY relation with C-4 at 121.2 ppm and HMBCswith C-6 at 127.3 and C-7a at 134.8 ppm. The proton signal at 7.35 ppm (dd, 1H,J¼ 8.7, 1.8Hz) is due to H-6 and has a C, H-COSY connection with C-6 andHMBCs with C-4 and C-7a. The expected doublet for H-7 hydrogen has mergedwith H-20 but was identified from the H, H-COSY contour with H-6 (Fig. 2). Even
Table 2. Synthesis of indole from diphenacyl aniline
Entry X Ph Ar Ar0 Compound obtained Time (h) Yield of 11 (%)a
1 H C6H5 C6H5 C6H5 11a 2.0 82
2 H C6H5 C6H5 4-MeC6H4 11a 2.3 80
3 H C6H5 C6H5 4-ClC6H4 11a 1.6 88
4 H C6H5 C6H5 4-FC6H4 11a 2.0 87
5 H C6H5 4-MeC6H4 C6H5 11b 2.0 79
6 H C6H5 4-MeC6H4 4-MeC6H4 11b 2.1 80
7 H C6H5 4-MeC6H4 4-ClC6H4 11b 1.7 83
8 H C6H5 4-ClC6H4 4-ClC6H4 11c 2.5 85
9 H C6H5 4-ClC6H4 4-MeC6H4 11c 2.6 78
10 H C6H5 4-BrC6H4 C6H5 11d 2.0 84
11 H C6H5 4-OMeC6H4 C6H5 11e 2.1 79
12 H C6H5 4-OMeC6H4 4-ClC6H4 11e 1.5 82
13 H C6H5 2-Naphthyl C6H5 11f 1.5 78
14 H C6H5 3-ClC6H4 C6H5 11g 2.3 82
15 Cl C6H5 C6H5 C6H5 11 h 2.5 83
16 Cl C6H5 C6H5 4-ClC6H4 11 h 2.5 85
17 Cl C6H5 4-MeC6H4 C6H5 11i 1.8 82
18 Cl C6H5 4-ClC6H4 4-ClC6H4 11j 2.3 81
19 Cl C6H5 4-BrC6H4 C6H5 11k 2.0 76
20 Cl C6H5 4-OMeC6H4 C6H5 11 l 1.5 80
21 Cl C6H5 4-OMeC6H4 4-ClC6H4 11 l 2.0 87
22 Cl 2-FC6H4 C6H5 C6H5 11m 2.0 82
23 Cl 2-FC6H4 4-ClC6H4 C6H5 11n 2.1 81
24 Cl 2-FC6H4 4-ClC6H4 4-ClC6H4 11n 1.6 84
aAfter purification by recrystallization.
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though the mass value (for 11i, m=e 344.0848 [M� 1]; calcd. 344.0920 [M� 1]) is notable to distinguish between quinolone 10 and indole 11, the structure of product isunambiguously confirmed from single-crystal X-ray analysis of 11b (Fig. 3).
Crystallographic data (excluding structure factors) for compound 11b in thisarticle have been deposited with the Cambridge Crystallographic Data Centre assupplementary publication number CCDC 824612. Copies of the data can beobtained, free of charge, on application to CCDC, 12 Union Road, CambridgeCB2 1EZ, UK [fax: þ44 (0)1223-336033 or e-mail: [email protected]].
It is pertinent to note that the indole moiety obtained by the abnormalFriedlander reaction was reported earlier from the reaction of phenacyl bromideand 2-aminobenzophenone,[26] but the details regarding the reaction and the spectraldata were not well documented.
As phenacyl bromide has been shown to react with 2-aminobenzophenone,[26]
providing 2-aroyl-3-arylindoles, it is suspected that in the present investigationdiphenacyl aniline would have cleaved under acidic conditions, providing the
Figure 2. Selected HMBCs and 1H and 13C chemical shifts in compound 11j. (Figure is provided in color
online.)
Figure 3. ORTEP diagram for 11b. (Figure is provided in color online.)
1204 N. PAUL AND S. MUTHUSUBRAMANIAN
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reactive PhCOCH2þ species and aniline, and the phenacyl cation would have then
reacted with 2-aminobenzophenone, giving the indole. The isolation of aniline asa by-product from the reaction medium has added weight to this suspicion.However, a blank reaction in which a mixture of diphenacylaniline and camphor-sulfonic acid was subjected to identical reaction conditions failed to give anyaniline, and the starting material was left unchanged. This prompted us to proposea suitable mechanism for the formation of indole (Scheme 2) in which the active meth-ylene attacks the carbonyl carbon to form intermediate 12. The amino group thendisplaces the -NArCH2COAr, whose leaving group ability could be increased byprotonation by the acid catalyst. The monophenacylaniline generated in this reactioncan undergo a similar reaction, yielding another mole of indole leaving aniline.The feasibility of monophenacylaniline 16 undergoing this reaction was provedindependently by taking 16 as the starting material instead of 8 (Scheme 3).
It is interesting that under Friedlander conditions diphenacylaniline and mono-phenacylaniline prefer to undergo a different reaction, yielding indole. An attemptedbase-catalyzed Friedlander reaction between 7 and 8 was also not successful as theexpected products were not obtained.
Please see the Supporting Information, available online, for complete experi-mental details.
Scheme 2. Proposed mechanism for the formation of indole. (Figure is provided in color online.)
Scheme 3. Synthesis of 2-aroyl-3-arylindole from monophenacyl aniline. (Figure is provided in color
online.)
ABNORMAL FRIEDLANDER REACTION 1205
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CONCLUSION
This article describes the reaction of diphenacylanilines with 2-aminobenzo-phenone in the presence of (�)-CSA to give 2-aroyl-3-arylindoles by an abnormalFriedlander reaction.
ACKNOWLEDGMENTS
The authors thank the Department of Science and Technology, New Delhi, forfunds under IRHPA program for the high-resolution NMR spectrometer and theUniversity Grants Commission, New Delhi, for the financial support to one of theauthors, N. P. N. Srinivasan of Thiagarajar College, Madurai, Tamil Nadu, India,and J. C. Menendez of Departamento de Quimica Organica y Farmaceutica, Univer-sidad Complutense, Madrid, Spain, are acknowledged for the X-ray diffraction andmass analyses respectively.
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