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DOI: 10.1055/s-0030-1258536
tert-Amino Effect in peri-Substituted Naphthalenes: Syntheses of Naphthazepine and Naphthazonine Ring Systems
Dedicated to Professor Tamás Roska on the occasion of his 70th birthday
Publication History
Publication Date:
30 July 2010 (online)
Abstract
Novel straightforward syntheses of naphtho-fused azepines and benzazonine via tert-amino effect are described. Starting from 1-naphthylamine, 8-N,N-dialkylaminonaphthalene-1-carbaldehydes could be obtained in two steps. The aldehyde was prepared by a Suzuki reaction of 8-bromonaphthalene-1-carbaldehyde with ortho-pyrrolidinophenylboronic acid. Treatment of aldehydes with active methylene compounds afforded naphthazepines and novel benzazonine ring system, respectively, through rearrangement of isolable vinyl intermediates or benzo[de]quinolinium derivatives or without isolation of any intermediates. A mechanistic investigation supports an intramolecular hydride transfer for the ring closure to azepine or azonine. Our results indicate that the tert-amino effect may provide a valuable approach to the synthesis of ortho- and peri-fused aza-ring systems.
Key words
tert-amino effect - naphthazepine - naphthazonine - benzo[d,e]quinolinium - peri-interaction
The term ‘tert-amino effect’ was introduced by Meth-Cohn and Suschitzky nearly forty years ago, to describe thermal rearrangement reactions of ortho-substituted tert-anilines via cyclization to benzofused aza-ring systems. [¹] Seven types of the tert-amino effect have been distinguished so far, according to the size of the ring formed and its mode of formation. [²] One version of type 2 reactions, the isomerization reaction of tert-anilines with an ortho-vinyl group and their heterocyclic analogues has received much attention, due to its high synthetic value to obtain biologically useful tetrahydroquinolines and related fused ring systems with predictable regio- and stereochemistry. [³a-³f] This type of tert-amino effect can occur in two steps: the rate-limiting first step involves a hydrogen migration from the N-methylene carbon to the α-vinyl carbon affording a 1,5-dipolar intermediate that cyclizes in the second step to a tetrahydropyrido-fused system with the formation of a new carbon-carbon σ-bond (Figure [¹] ). An additional feature of such reactions is the requirement of strongly electron-withdrawing substituents in the vinyl group to stabilize the negative end of the dipolar intermediate. In context of the hydrogen migration, a sigmatropic [1,5]-hydrogen shift and an ionic mechanism with hydride transfer have been proposed.
Figure 1 Isomerization via type 2 tert-amino effect
In our studies, kinetics, thermodynamics, steric features, the synthetic scope, and methodological limitations of this type of tert-amino effect have been investigated and various types of pyrido-fused diazines have been prepared. [4a-f] An impressive number and diversity of very recent examples, [5a-e] illustrate further the synthetic potential of type 2 tert-amino effect.
Interestingly, only very few isomerization reactions have been reported, which led to the formation of a seven-membered or larger ring. [6] In our approaches, vinyl-substituted bi- or triaryl-tert-amines A and B could be cyclized to diarene-fused azocines [7a] and triarene-fused azecines, [7b] respectively, via type 2 tert-amino effect (Figure [²] ). Following this line, we also decided to study ortho-fused aromatic ring systems, the prototype of which is naphthalene, possessing key functionalities in peri-positions.
Figure 2 Some recent and new extensions of type 2 tert-amino effect: syntheses of diarene-fused azocines, triarene-fused azecines, and naphthalene-fused azepine or azonine ring systems
Herein we report on novel extensions of the tert-amino effect to 1-dialkylamino- and 1-(2-dialkylaminophenyl)-8-vinylnaphthalenes, C and D, respectively, to open new routes to ortho- and peri-fused naphthazepine and naphthazonine ring systems (Figure [²] ); these compounds show, in turn, some structural resemblances to naphthalenes I and II (Figure [³] ) and related compounds exhibiting anti-HIV activity. [8]
Figure 3 Synthetic lignan analogues I and II evaluated as anti-HIV agents
In our study, acyclic and cyclic amino and vinyl substitutents were employed. Synthesis of vinyl derivatives was accomplished in three steps, starting from commercially available 1-naphthylamine (1). Its dimethylation according to the published protocol led to dimethylaminonaphthalene (2a). [9a] Pyrrolidino derivative 2b [9b] was obtained by alkylation with 1,4-dibromobutane. The peri-selective formylation afforded aldehydes 3a [¹0] and 3b (Scheme [¹] ).
Scheme 1 Reagents and conditions: for 2a (a): Me2SO4, H2O, NaOH, r.t., 4 h; for 2a-d 6 (a): (CD3)2SO4, H2O, NaOH, r.t., 4 h; for 2b (a): Br(CH2)4Br, (i-Pr)2EtN, toluene, 110 ˚C, 15 h; for 3a,b (b): i) n-BuLi, Et2O, r.t., 48 h; ii) DMF, -60 ˚C, 1 h; iii) MeOH, -20 ˚C, 3 h.
We first carried out Knoevenagel condensation of 8-dimethylaminonaphthalene-1-carbaldehyde (3a) with active methylene compounds at room temperature in ethanol. With acyclic malononitrile (MN), the expected vinyl compound 4 could be smoothly obtained. However, treatment of 3a with cyclic active methylene compounds, such as 1,3-dimethylbarbituric acid (DMBA) or 1H-indene-1,3(2H)-dione (ID) led, not fully unexpectedly, [7a] to zwitterionic benzo[d,e]quinolinium derivatives 5 and 6 as only isolable products in excellent yields (Scheme [²] ). Compounds 5 and 6 could be formed from intermediate vinyl compounds by cyclization via a tert-amino effect. The cyclic vinyl substituent might facilitate the ring formation by efficient delocalization of the developing negative charge and forcing the nucleophilic and electrophilic centers closer to each other by steric buttressing.
Scheme 2 Reagents and conditions: for 4: MN, EtOH, piperidine, r.t., 7 h; for 5: DMBA, EtOH, piperidine, r.t., 5 h; for 6: ID, EtOH, piperidine, r.t., 6 h.
Compounds 5 and 6 could be easily distinguished from the vinyl compounds, based on upfield NMR shifts of the α-CH group (Figure [4] ). The X-ray analysis of 5 unambiguously revealed that C¹-N bond formation (bond distance of 1.630 Å, see Figure [5] ) did occur. The Wallis group, in their excellent comprehensive study, provided X-ray evidences for through-space attractive peri-interactions between nucleophilic donor and electron-deficient acceptor atoms in naphthalenes. [¹¹] Moreover, they also reported on the formation of a naphthazepine from β-benzoyl-β-nitrovinyl analogue of 4 by heating a sample in an NMR tube, although the product was not isolated; [¹¹a] interestingly, the synthetic value of the isomerization has not been explored.
| Reaction | Solvent | Yield (%) | Time (h) | Temp (˚C) | |||||||||||||||
| 4 → 7 | DMSO | 85 | 23.5 | 60 | |||||||||||||||
| 4 → 7 | DMSO | 81 | 2.5 | 100 | |||||||||||||||
| 4 → 7 | DMSO | 81 | 0.2 | 100b | |||||||||||||||
| 4 → 7 | neat | 61 | 3 | 160 | |||||||||||||||
| 4 → 7 | neat | 80 | 0.3 | 162b | |||||||||||||||
| 5 → 8 | DMSO | 0 | 24 | 60 | |||||||||||||||
| 5 → 8 | DMSO | 81 | 5 | 100 | |||||||||||||||
| 5 → 8 | DMSO | 80 | 0.7 | 100b | |||||||||||||||
| 5 → 8 | neat | 67 | 2 | 180 | |||||||||||||||
| 5 → 8 | neat | 60 | 0.7 | 180b | |||||||||||||||
| 6 → 9 | DMSO | 85 | 15 | 80 | |||||||||||||||
|
| |||||||||||||||||||
|
a Conditions:
2 mmol/10 mL DMSO.b Microwave assisted
reactions at 105 W max. power. | |||||||||||||||||||
Figure 4 Some characteristic NMR data [¹H NMR, ¹³C NMR in CDCl3, δ (ppm)] of compounds 4-14
Figure 5 Characteristic atomic distances (Å) measured by X-ray diffraction
We particularly focused on the possible transformations of compounds 4-6 to obtain novel series of 1,2-dihydronaphtho[1,8-b,c]azepines. Reactions were carried out in DMSO, neat, at different temperatures with traditional and microwave heating. From vinyl derivative 4, azepine 7 could only be isolated in a fairly good yield (Table [¹] ). To investigate whether the rearrangement reaction takes place intramolecularly, compound 4-d 6, the hexadeuterated dimethyl analogue of 4 was prepared from amine 1 following the methods described above, except using (CD3)2SO4 for dimethylation of the amino group. The isomerization reactions of 4 and 4-d 6 (Scheme [³] ) were monitored by ¹H NMR spectroscopy at 100 ˚C in DMSO-d 6 and the rate constants of reactions were calculated. The value of kinetic isotope effect (k H /k D = 2.5420/0.8920 = 2.85) supports that a hydrogen (or deuterium, respectively) located in the dimethyl group migrates in the rate limiting step. NMR and MS analyses of the product obtained from 4-d 6 indicated that no deuterium loss occurred in the reaction (accordingly, it could be assigned to 7-d 6), moreover, there could be detected no incorporation of deuterium when rearrangement of 4 to 7 was carried out in D2O. On the basis of these findings, we propose that the isomerization of 4 affording azepine 7 proceeds in an intramolecular pathway. It could also be suggested that isomerization takes place in two steps, starting with a hydride transfer from the N-methyl group to the electron-deficient vinyl carbon affording a dipolar intermediate, following cyclization to azepine with the formation of a new C-C bond between the oppositely polarized carbon atoms in the second step. The short distances between atoms involved in the hydride transfer also support this mechanism (Figure [5] ).
Scheme 3 Reagents and conditions: for 7-d 6: DMSO-d 6, 100 ˚C, 4 h.
Transformation of zwitterionic compounds 5 and 6 to azepines 8 and 9, respectively, could also be rationalized. It could occur through intermediate vinyl compounds formed with opening of the five-membered ring. When we monitored the rearrangement of 5 with ¹H NMR spectroscopy at temperatures 50-80 ˚C in DMSO-d 6 , a broad signal was indeed identified that was assigned to a vinyl proton; upon elevating the temperature to 80 ˚C, there also appeared the signal set of naphthazepine 8.
In the second series of reactions, 8-pyrrolidinonaphthalene-1-carbaldehyde (3b) was treated with active methylene compounds MN, DMBA, ID. Under mild conditions at room temperature, naphthazepines 10-12 could be isolated, that is, cyclization via type 2 tert-amino effect occurred. To achieve higher rates for formation of azepines 10-12, reactions were carried out at 80 ˚C (Scheme [4] ). The increased reactivity of pyrrolidino vs. dimethylamino derivatives might be explained by more efficient overlap of nonbonding electron pair of pyrrolidine nitrogen with the aromatic π-system and a more favorable geometric position of the hydrogen for migration.
Scheme 4 Reagents and conditions: for 10: malononitrile, piperidine, EtOH, 80 ˚C, 7 h; for 11: 1,3-dimethylbarbituric acid, piperidine, EtOH, 80 ˚C, 4.5 h; for 12: 1H-indene-1,3(2H)-dione, piperidine, EtOH, 80 ˚C, 3 h.
The scope of rearrangements was further investigated in system D (Figure [²] ) possessing a phenylnaphthyl skeleton with key groups positioned at the phenyl and naphthalene rings. Preparation of 8-(2-pyrrolidinophenyl)-1-vinylnaphthalene (15) was easily accomplished from 8-bromonaphthalene-1-carbaldehyde (13) [¹²] in three steps (Scheme [5] ). Suzuki cross-coupling reaction of 13 with ortho-pyrrolidinophenylboronic acid afforded 14. The Knoevenagel condensation of 14 with MN led to vinyl derivative 15 in excellent yield. Interestingly, but not surprisingly, the X-ray analysis [¹³-¹6] of vinyl compound 15 showed that the distance between donor nitrogen and acceptor vinyl carbon was significantly longer than that in 4, as a consequence of unfavorable steric effects (Figure [5] ). Upon heating of 15 in DMSO even at higher temperatures (microwave irradiation, 190 ˚C for 5 h), no cyclization was detected.
Scheme 5 Reagents and conditions: for 14: 2-(pyrrolidin-1-yl)phenylboronic acid, Pd[PPh3]4, 0.2 M Na2CO3, DME, reflux, 1 h; for 15 malononitrile, piperidine, EtOH, r.t., 4 h; for 16: [bmim]BF4, 190 ˚C, 3 h.
Next, we thought to apply an ionic liquid as a particularly suitable solvent for high temperature polar reactions. The solution of 15 was heated in [bmim]BF4 at 190 ˚C. Under these conditions the isomerization could indeed be achieved and pyrrolonaphtho[1,8-e,f]azonine 16, representing a novel polycyclic ring system, was isolated in good yield (Scheme [5] ). [¹7]
In conclusion, novel 1,2-dihydrobenzo[c,d]indolium, naphtho[1,8-b,c]azepine and naphtho[1,8-e,f]azonine ring systems could be prepared from easily available peri-substituted naphthylamines by new extensions of tert-amino effect. Our results further demonstrate the high synthetic potential of tert-amino effect in the syntheses of otherwise hardly accessible medium-sized or larger fused aza-ring systems.
Supporting Information for this article is available online at http://www.thieme-connect.com.accesdistant.sorbonne-universite.fr/ejournals/toc/synlett.
- Supporting Information for this article is available online:
- Supporting Information
Acknowledgment
The authors thank the Hungarian Scientific Research Fund (K73389), Ministry of Health (ETT 099-03/2009) for financial supports, Dr. Tamás Gáti for his contribution to the assignments of NMR spectra, Dr. Péter Tétényi for recording IR spectra, and Dr. Petra Dunkel for helpful discussion. The X-ray analyses were supported by the EU and co-financed by the European Social Fund through the Social Renewal Operational Programme under the project CHEMIKUT (TÁMOP-4.2.2-08/1-2008-0012). The financial support of TEVA Hungary Ltd. is also highly appreciated.
- 1
Meth-Cohn O.Suschitzky H. Adv. Heterocycl. Chem. 1972, 14: 211 - 2a
Meth-Cohn O. Adv. Heterocycl. Chem. 1996, 65: 1 - 2b
Quintela JM. Recent Res. Dev. Org. Chem. 2003, 7: 259 - 2c
Mátyus P.Éliás O.Tapolcsányi P.Polonka-Bálint .Halász-Dajka B. Synthesis 2006, 2625 - 3a
Nijhuis WHN.Verboom W.Reinhoudt DN.Harkema S. J. Am. Chem. Soc. 1987, 109: 3136 - 3b
Groenen LC.Verboom W.Nijhuis WHN.Reinhoudt DN.Van Hummel GJ.Feil D. Tetrahedron 1988, 44: 4637 - 3c
Nijhuis WHN.Verboom W.El-Fadl AA.Harkema S.Reinhoudt DN. J. Org. Chem. 1989, 54: 199 - 3d
Nijhuis WHN.Verboom W.El-Fadl AA.Van Hummel GJ.Reinhoudt DN. J. Org. Chem. 1989, 54: 209 - 3e
Ojea V.Muinelo I.Figueroa MC.Ruiz M.Quintela JM. Synlett 1995, 622 - 3f
Tverdokhlebov AV.Gorulya AP.Tolmachev AA.Kostyuk AN.Chernega AN.Rusanov EB. Tetrahedron 2006, 62: 9146 - 4a
Mátyus P.Fuji K.Tanaka K. Heterocycles 1994, 37: 171 - 4b
Schwartz A.Beke G.Kővári Z.Böcskey Z.Farkas .Mátyus P. J. Mol. Struct. 2000, 528: 49 - 4c
Károlyházy L.Regdon G.Éliás O.Beke G.Tábi T.Hódi K.Erős I.Mátyus P. J. Mol. Struct. 2003, 666-667: 667 - 4d
Kaval N.Dehaen W.Mátyus P.Van Der Eycken E. Green Chem. 2004, 6: 125 - 4e
Kaval N.Halasz-Dajka B.Vo-Thanh G.Dehaen W.Van Der Eycken J.Mátyus P.Loupy A.Van Der Eycken E. Tetrahedron 2005, 61: 9052 - 4f
Dajka-Halász B.Földi A.Ludányi K.Mátyus P. ARKIVOC 2008, (iii): 102 - 5a
Devi I.Baruah B.Bhuyan PJ. Synlett 2006, 2593 - 5b
Paramonov IV.Belyaev NA.Glukhareva TV.Volkov AS.Deeva EV.Morzherin YY. Chem. Heterocycl. Compd. 2006, 42: 127 - 5c
Ivanov IC.Glasnov TN.Belaj F. J. Heterocycl. Chem. 2008, 45: 177 - 5d
Ryabtsova OY.Pozharskii AF.Degtyarev AV.Ozeryanskii VA. Mendeleev Commun. 2006, 313 - 5e
Povalyakhina MA.Pozharskii AF.Dyablo OV.Ozeryanskii VA.Ryabtsova OV. Mendeleev Commun. 2010, 20: 36 - 6a
Meth-Cohn O.Taylor DL. J. Chem. Soc., Chem. Commun. 1995, 1463 - 6b
Cheng Y.Meth-Cohn O.Taylor D. J. Chem. Soc., Perkin Trans. 1 1998, 1257 - 7a
Polonka-Bálint .Saraceno C.Ludányi K.Bényei A.Mátyus P. Synlett 2008, 2846 - 7b
Dunkel P.Túrós G.Bényei A.Ludányi K.Mátyus P. Tetrahedron 2010, 66: 2331 - 8
Sancho R.Medarde M.Sánchez-Palomino S.Madrigal BM.AlcamI J.Muñoz E.San Feliciano A. Bioorg. Med. Chem. Lett. 2004, 14: 4483 - 9a
Germuth FG. J. Am. Chem. Soc. 1929, 51: 1555 - 9b
Alder RW.Bryce MR.Goode NC. J. Chem. Soc., Perkin Trans. 2 1982, 477 - 10
Kirby AJ.Percy JM. Tetrahedron 1988, 44: 6903 - 11a
O’Leary J.Formosa X.Skranc W.Wallis JD. Org. Biomol. Chem. 2005, 3: 3273 - 11b
Bell PC.Wallis JD. Chem. Commun. 1999, 257 - 12
Bailey RJ.Card PJ.Shechter H. J. Am. Chem. Soc. 1983, 105: 6096 - 13
Altomare A.Cascarano G.Giacovazzo C.Guagliardi A. J. Appl. Crystallogr. 1993, 26: 343 - 14
Sheldrick GM. Programs for Crystal Structure Analysis (Release 97-2) Göttingen; Germany: 1998. - 15
Farrugia LJ. J. Appl. Crystallogr. 1999, 32: 837
References and Notes
The X-ray data are available from the Cambridge Crystallographic Data Centre CCDC under the numbers 5: 7770044, 7: 777045, 10: 777046, 11: 777047, 15: 777048, respectively. Copies of the data can be obtained free of charge on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 (1223)336033 or e-mail: deposit@ccdc.cam.ac.uk. The details of the X-ray structures will be published elsewhere.
17Experimental data are available in Supporting Information.
- 1
Meth-Cohn O.Suschitzky H. Adv. Heterocycl. Chem. 1972, 14: 211 - 2a
Meth-Cohn O. Adv. Heterocycl. Chem. 1996, 65: 1 - 2b
Quintela JM. Recent Res. Dev. Org. Chem. 2003, 7: 259 - 2c
Mátyus P.Éliás O.Tapolcsányi P.Polonka-Bálint .Halász-Dajka B. Synthesis 2006, 2625 - 3a
Nijhuis WHN.Verboom W.Reinhoudt DN.Harkema S. J. Am. Chem. Soc. 1987, 109: 3136 - 3b
Groenen LC.Verboom W.Nijhuis WHN.Reinhoudt DN.Van Hummel GJ.Feil D. Tetrahedron 1988, 44: 4637 - 3c
Nijhuis WHN.Verboom W.El-Fadl AA.Harkema S.Reinhoudt DN. J. Org. Chem. 1989, 54: 199 - 3d
Nijhuis WHN.Verboom W.El-Fadl AA.Van Hummel GJ.Reinhoudt DN. J. Org. Chem. 1989, 54: 209 - 3e
Ojea V.Muinelo I.Figueroa MC.Ruiz M.Quintela JM. Synlett 1995, 622 - 3f
Tverdokhlebov AV.Gorulya AP.Tolmachev AA.Kostyuk AN.Chernega AN.Rusanov EB. Tetrahedron 2006, 62: 9146 - 4a
Mátyus P.Fuji K.Tanaka K. Heterocycles 1994, 37: 171 - 4b
Schwartz A.Beke G.Kővári Z.Böcskey Z.Farkas .Mátyus P. J. Mol. Struct. 2000, 528: 49 - 4c
Károlyházy L.Regdon G.Éliás O.Beke G.Tábi T.Hódi K.Erős I.Mátyus P. J. Mol. Struct. 2003, 666-667: 667 - 4d
Kaval N.Dehaen W.Mátyus P.Van Der Eycken E. Green Chem. 2004, 6: 125 - 4e
Kaval N.Halasz-Dajka B.Vo-Thanh G.Dehaen W.Van Der Eycken J.Mátyus P.Loupy A.Van Der Eycken E. Tetrahedron 2005, 61: 9052 - 4f
Dajka-Halász B.Földi A.Ludányi K.Mátyus P. ARKIVOC 2008, (iii): 102 - 5a
Devi I.Baruah B.Bhuyan PJ. Synlett 2006, 2593 - 5b
Paramonov IV.Belyaev NA.Glukhareva TV.Volkov AS.Deeva EV.Morzherin YY. Chem. Heterocycl. Compd. 2006, 42: 127 - 5c
Ivanov IC.Glasnov TN.Belaj F. J. Heterocycl. Chem. 2008, 45: 177 - 5d
Ryabtsova OY.Pozharskii AF.Degtyarev AV.Ozeryanskii VA. Mendeleev Commun. 2006, 313 - 5e
Povalyakhina MA.Pozharskii AF.Dyablo OV.Ozeryanskii VA.Ryabtsova OV. Mendeleev Commun. 2010, 20: 36 - 6a
Meth-Cohn O.Taylor DL. J. Chem. Soc., Chem. Commun. 1995, 1463 - 6b
Cheng Y.Meth-Cohn O.Taylor D. J. Chem. Soc., Perkin Trans. 1 1998, 1257 - 7a
Polonka-Bálint .Saraceno C.Ludányi K.Bényei A.Mátyus P. Synlett 2008, 2846 - 7b
Dunkel P.Túrós G.Bényei A.Ludányi K.Mátyus P. Tetrahedron 2010, 66: 2331 - 8
Sancho R.Medarde M.Sánchez-Palomino S.Madrigal BM.AlcamI J.Muñoz E.San Feliciano A. Bioorg. Med. Chem. Lett. 2004, 14: 4483 - 9a
Germuth FG. J. Am. Chem. Soc. 1929, 51: 1555 - 9b
Alder RW.Bryce MR.Goode NC. J. Chem. Soc., Perkin Trans. 2 1982, 477 - 10
Kirby AJ.Percy JM. Tetrahedron 1988, 44: 6903 - 11a
O’Leary J.Formosa X.Skranc W.Wallis JD. Org. Biomol. Chem. 2005, 3: 3273 - 11b
Bell PC.Wallis JD. Chem. Commun. 1999, 257 - 12
Bailey RJ.Card PJ.Shechter H. J. Am. Chem. Soc. 1983, 105: 6096 - 13
Altomare A.Cascarano G.Giacovazzo C.Guagliardi A. J. Appl. Crystallogr. 1993, 26: 343 - 14
Sheldrick GM. Programs for Crystal Structure Analysis (Release 97-2) Göttingen; Germany: 1998. - 15
Farrugia LJ. J. Appl. Crystallogr. 1999, 32: 837
References and Notes
The X-ray data are available from the Cambridge Crystallographic Data Centre CCDC under the numbers 5: 7770044, 7: 777045, 10: 777046, 11: 777047, 15: 777048, respectively. Copies of the data can be obtained free of charge on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 (1223)336033 or e-mail: deposit@ccdc.cam.ac.uk. The details of the X-ray structures will be published elsewhere.
17Experimental data are available in Supporting Information.
Figure 1 Isomerization via type 2 tert-amino effect
Figure 2 Some recent and new extensions of type 2 tert-amino effect: syntheses of diarene-fused azocines, triarene-fused azecines, and naphthalene-fused azepine or azonine ring systems
Figure 3 Synthetic lignan analogues I and II evaluated as anti-HIV agents
Scheme 1 Reagents and conditions: for 2a (a): Me2SO4, H2O, NaOH, r.t., 4 h; for 2a-d 6 (a): (CD3)2SO4, H2O, NaOH, r.t., 4 h; for 2b (a): Br(CH2)4Br, (i-Pr)2EtN, toluene, 110 ˚C, 15 h; for 3a,b (b): i) n-BuLi, Et2O, r.t., 48 h; ii) DMF, -60 ˚C, 1 h; iii) MeOH, -20 ˚C, 3 h.
Scheme 2 Reagents and conditions: for 4: MN, EtOH, piperidine, r.t., 7 h; for 5: DMBA, EtOH, piperidine, r.t., 5 h; for 6: ID, EtOH, piperidine, r.t., 6 h.
Figure 4 Some characteristic NMR data [¹H NMR, ¹³C NMR in CDCl3, δ (ppm)] of compounds 4-14
Figure 5 Characteristic atomic distances (Å) measured by X-ray diffraction
Scheme 3 Reagents and conditions: for 7-d 6: DMSO-d 6, 100 ˚C, 4 h.
Scheme 4 Reagents and conditions: for 10: malononitrile, piperidine, EtOH, 80 ˚C, 7 h; for 11: 1,3-dimethylbarbituric acid, piperidine, EtOH, 80 ˚C, 4.5 h; for 12: 1H-indene-1,3(2H)-dione, piperidine, EtOH, 80 ˚C, 3 h.
Scheme 5 Reagents and conditions: for 14: 2-(pyrrolidin-1-yl)phenylboronic acid, Pd[PPh3]4, 0.2 M Na2CO3, DME, reflux, 1 h; for 15 malononitrile, piperidine, EtOH, r.t., 4 h; for 16: [bmim]BF4, 190 ˚C, 3 h.