New Ugi-Smiles-Metathesis Strategy toward the Synthesis of Pyrimido Azepines Laurent El Kaı¨m,* Laurence Grimaud,* and Julie Oble Laboratoire Chimie et proce´ de´ s, UMR 7652, Ecole Nationale Supe´ rieure de Techniques AVance´ es, 32 Bd Victor, Paris 75015, France
[email protected];
[email protected] ReceiVed April 11, 2007
A new strategy involving Ugi-Smiles coupling followed by ring-closure metathesis is described herein for the preparation of pyrimidine-fused heterocyclic scaffolds. The scope of this sequence is presented in relation with the heteroatom effect observed in the Ugi-Smiles coupling. Multicomponent reactions (MCR) in which three or more reactants are coupled together in a one-pot procedure are suitable for the preparation of a large collection of molecules. The combination of multicomponent reactions with post-condensation transformations offers the ability to introduce even more complexity in the generated scaffolds. In this area, the sequence Ugi four-component coupling/post-condensation reactions have emerged as one of the most classical and powerful tools toward high molecular diversity.1 Among all the post-Ugi modifications, olefin ring-closure metathesis (RCM) provides a very convergent pathway to macrocyclic lactams.2 Recently, our research group disclosed a new four-component coupling (4-CC) for the synthesis of N-aryl amines based on an Ugi-Smiles process.3 On the basis of these results, we envisioned the use of N-allyl amines and allyl-substituted phenols to synthesize benzo-fused azepines according to a MCRRCM strategy. The first results were disappointing, as 2-allyl-4-nitrophenol did not give any adduct in the Ugi-Smiles step (Scheme 1). Previous observations concerning the effect of heteroatoms close to the reaction center gave us, however, the clue to the successful formation of Ugi-Smiles adducts possessing an allyl residue on the phenol moiety. When the O-allyl phenol 1 was submitted to Ugi-Smiles coupling conditions with allylamine 2, the (1) For a recent review, see: Do¨mling, A. Chem. ReV. 2006, 106, 1789. (2) For recent examples, see: Piscopio, A. D.; Miller, J. F.; Koch, K. Tetrahedron 1999, 55, 8189-8198. Banfi, L.; Basso, A.; Guanti, G.; Riva, R. Tetrahedron Lett. 2003, 44, 7655-7658. Beck, B.; Larbig, G.; Mejat, B.; Magnin-Lachaux, M.; Picard, A; Herdtweck, E.; Do¨mling, A. Org. Lett. 2003, 5, 1047-1050. Krelaus, R.; Westermann, B. Tetrahedron Lett. 2004, 45, 5987-5990. Basso, A.; Banfi, L.; Riva, R.; Guanti, G. Tetrahedron 2006, 62, 8830-8837. Gracias, V.; Gasiecki, A. F.; Djuric, S. W. Org. Lett. 2005, 7, 3183-3186. (3) El Kaı¨m, L.; Grimaud, L.; Oble, J. Angew. Chem., Int. Ed. 2005, 117, 7961-7964.
expected aniline 3 was indeed formed in good yield (Scheme 1). As noted before,4 this effect can be best explained by an intramolecular hydrogen bond activating the Smiles rearrangement. The RCM reaction was performed using HoveydaGrubbs second generation catalyst5 either in dichloromethane and toluene, at room temperature and at reflux of the solvent. Unfortunately, no bicyclic product could be isolated from the resulting complex mixture probably because of isomerizations. To further test the feasibility of the MCR-RCM strategy, we prepared various 4-hydroxy pyrimidine olefin-substituted 5a-c from the corresponding β-keto ester 4a-c as shown in Scheme 2. Functionalization of β-keto esters were performed in ethanol at reflux using 1 equiv of EtONa and 1 equiv. of the corresponding alkenyl bromide. As such, various 5-allyl and 5-homoallyl 4-hydroxy pyrimidines 5a-c were readily prepared (Scheme 2). The 4-hydroxy pyrimidine 5d was obtained after isomerization of the allyl moiety according to the procedure described by Gross.6 We have already demonstrated that 4-hydroxy pyrimidine provide an efficient 4-CC in methanol (1 M solution) at 60 °C.7 Though these substituted pyrimidines did not react with allyl or methyl allyl amine under these conditions, the use of 3 M toluene solutions at higher temperature (110 °C) proved to be efficient. After heating several days, the desired Ugi-Smiles adducts 6a-g were obtained in good yields from 5 (Table 1). These compounds were then subjected to RCM conditions using second-generation ruthenium-based catalysts in toluene. The metathesis reaction was first performed on the homoallyl substrate 6a with 10 mol % of Hoveyda-Grubbs second generation catalyst in toluene in order to evaluate the feasibility of a one-pot procedure. No eight-membered ring cyclized product could be detected at room-temperature while the RCM proceeds smoothly at 110 °C within 12 h to give the bicyclic compound 7a in 67% yield (Table 1, entry 1).8 When stirred for 2 more days, 7a isomerized to give the conjugated isomer in 73% isolated yield. The bis-allyl-substituted MCR adducts 6b-f were then subjected to these metathesis conditions to provide the corresponding pyrimido azepine derivatives 7b-f via a tandem RCM-isomerization sequence (Table 1, entries 2-6). At this temperature (110 °C), the isomerization of the created double bond is very fast on the seven-membered ring probably because of the conjugation of the olefin with the pyrimidine core. When the RCM was performed at room temperature, the desired seven-membered fused pyrimidine 8b was now formed within 6 h without any isomerization (Scheme 3). Nevertheless, the vinyl-substituted pyrimidine 6g did not cyclize under these conditions or at a higher temperature (Table 1, entry 7). Attempts to perform the Ugi-Smiles/RCM process in a onepot procedure failed to give the desired pyrimido azepine (4) El Kaı¨m, L.; Gizolme, M.; Grimaud, L.; Oble, J. J. Org. Chem. 2007, ASAP. (5) (a) Kingbury, J. S.; Harrity, J. P. A.; Bonitatebus, P. J.; Hoveyda, A. H., Jr. J. Am. Chem. Soc. 1999, 121, 791; (b) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2000, 122, 8168. (6) Gross, J. L. Tetrahedron Lett. 2003, 44, 8563-8566. (7) El Kaı¨m, L.; Gizolme, M.; Grimaud, L.; Oble, J. Org. Lett. 2006, 8, 4019-4021. (8) The Grubbs II catalyst gives the same results.
10.1021/jo070706c CCC: $37.00 © 2007 American Chemical Society
Published on Web 06/22/2007
J. Org. Chem. 2007, 72, 5835-5838
5835
SCHEME 1.
Ugi-Smiles Couplings with Substituted Nitro Phenol
SCHEME 2.
Synthesis of Olefin-Substituted Pyrimidines
probably because of the degradation of the ruthenium carbene by the residual isocyanide.9 Pyrimidine derivatives and its fused heterocycles such as purines, pyrrolopyrimidines, pyrazolopyrimidines, etc., constitute the backbone of several biologically active compounds. For example, 4H-pyrido[1,2-a]pyrimidin-4-ones have been used as anticancer agents,10 HIV-integrase inhibitors;11 pteridines are potent antitumor agents.12 Therefore, novel methodologies for the synthesis of pyrimidine scaffolds are of particular interest in medicinal chemistry. To the best of our knowledge, this is the first report of the synthesis of 8,9-dihydro-5H-pyrimido[4,5-b]azepine. This sequence affords a very short synthesis of those derivatives and provides an easy access to libraries for medicinal and pharmaceutical applications. In conclusion, this study gives further evidence on the beneficial effect of heteroatoms on the scope of Ugi-Smiles couplings. Pyrimidines are valuable partners for this reaction, giving access to biologically relevant scaffolds with a high structural tolerance toward the Ugi-Smiles couplings. We are currently further exploring the use of uracil and purine derivatives in these 4-CC. (9) For a recent report, see: Galan, B. R.; Kalbarczyk, K. P.; Szczepankiewicz, S.; Keister, J. B.; Diver, S. T. Org. Lett. 2007, 9, 1203-1206. (10) Wang, W.; Constantine, R. N.; Lagniton, L. M.; Pecchi, S.; Burger, M. T.; Desai, M. C. WO2004113335, 2004. Chem. Abstr. 2005, 142, 93843. Hu, J.-F.; Wunderlich, D.; Thiericke, R.; Dahse, H.-M.; Grabley, S.; Feng, X.-Z.; Sattler, I. J. Antibiot. 2003, 56, 747-754. (11) Crescenzi, B.; Kinzel, O.; Muraglia, E.; Orvieto, F.; Pescatore, G.; Rowley, M.; Summa, V. WO 2004058757, 2004. Chem. Abstr. 2004, 141, 123648. (12) Bertino, J. R. J. Clin. Oncol. 1993, 11, 5-14.
5836 J. Org. Chem., Vol. 72, No. 15, 2007
Experimental Section General Procedure for Pyrimidine-Induced Ugi-4CR. To a 3 M solution of the aldehyde in toluene were added successively 1.0 equiv. of allylamine 2a-b, 1.0 equiv. of isocyanide, and 1.0 equiv. of pyrimidine 5a-d under inert atmosphere. The resulting mixture was stirred at 110 °C until completion (TLC). It was then concentrated in vacuo, and the crude product was purified by flash chromatography on silica gel. 2-[Allyl-(5-but-3-enyl-6-methyl-2-phenyl-pyrimidin-4-yl)amino]-4-methyl-pentanoic Acid Benzylamide 6a. The typical procedure was followed employing the allyl-substituted pyrimidine 5a (70 mg, 0.3 mmol) to afford compound 6a (100 mg, 71%, 4 days) as a yellow oil by flash chromatography on silica gel (petroleum ether/diethyl ether: 95/5). 1H NMR (CDCl3, 400 MHz) δ 8.64 (t, 1H, J ) 5.6 Hz), 8.22 (dd, 2H, J ) 7.8, 2.6 Hz), 7.497.34 (m, 4H), 7.21-7.08 (m, 4H), 5.80 (ddt, 1H, J ) 17.1, 10.2, 6.6 Hz), 5.65 (ddt, 1H, J ) 17.3, 10.3, 5.9 Hz), 5.13 (dd, 1H, J ) 17.1, 1.2 Hz), 5.04 (dd, 1H, J ) 17.3, 1.2 Hz), 5.05 (dd, 1H, J ) 10.3, 1.2 Hz), 5.01 (dd, 1H, J ) 10.2, 1.2 Hz), 4.73 (dd, 1H, J ) 9.1, 6.1 Hz), 4.47 (dd, 1H, J ) 14.6, 6.0 Hz), 4.33 (dd, 1H, J ) 14.6, 5.4 Hz), 4.10 (dd, 1H, J ) 16.4, 5.9 Hz), 3.87 (dd, 1H, J ) 16.4, 5.9 Hz), 2.82-2.62 (m, 2H), 2.57 (s, 3H), 2.26-2.20 (m, 1H), 2.01-1.84 (m, 2H), 1.66 (d, 2H, J ) 5.6 Hz), 0.92 (d, 3H, J ) 6.6 Hz), 0.81 (d, 3H, J ) 6.8 Hz). 13C NMR (CDCl3, 100.6 MHz) δ 173.0, 167.3, 164.7, 160.2, 138.7, 138.0, 137.5, 134.4, 130.5, 129.0, 128.3, 128.0, 127.7, 119.8, 118.3, 116.1, 62.0, 51.4, 43.9, 38.6, 32.8, 27.6, 25.3, 23.7, 23.4, 22.1. IR (thin film) 3401, 2942, 1666, 1542, 1454, 1161 cm-1. MS (DI, CI NH3) m/z 483. HRMS Calcd for C31H38N4O482.3046, Found 482.3055. General Procedure for Metathesis Reaction. To a 0.3 M solution of diene 6a-g in toluene were added 10% mol of Hoveyda-Grubbs second generation catalyst under inert atmosphere. The resulting mixture was stirred at the given temperature until completion (TLC). It was then concentrated in vacuo, and the crude product was purified with preparative chromatography. 4-Methyl-2-(4-methyl-2-phenyl-7,8-dihydro-pyrimido[4,5-b]azepin-9-yl)-pentanoic Acid Cyclohexylamide 7b. The typical procedure employing the diene 6b (92 mg, 0.20 mmol) under heating at 110 °C to afford compound 7b (58 mg, 67%, 1 day) as a white solid was followed with preparative chromatography (petroleum ether/diethyl ether: 50/50). 1H NMR (CDCl3, 400 MHz) δ 8.43-8.38 (m, 2H), 7.55-7.47 (m, 4H), 6.58 (dt, 1H, J ) 12.1, 1.9 Hz), 6.14 (dt, 1H, J ) 12.1, 3.6 Hz), 5.46 (br s, 1H), 3.793.68 (m, 2H), 3.00-2.91 (m, 1H), 2.66 (s, 3H), 2.56-2.51 (m, 2H), 1.87-1.71 (m, 3H), 1.68-1.59 (m, 2H), 1.54-1.15 (m, 8H), 0.98 (d, 3H, J ) 6.8 Hz), 0.89 (d, 3H, J ) 6.8 Hz). 13C NMR (CDCl3, 100.6 MHz) δ 171.6, 166.6, 163.6, 159.2, 137.9, 132.5, 130.7, 128.9, 128.1, 122.6, 113.3, 58.2, 47.8, 45.3, 36.5, 33.5, 33.1, 33.0, 25.8, 25.1, 24.7, 24.6, 24.2, 23.7, 22.6. IR (thin film) 3319,
TABLE 1. Ugi-Smiles/RCM Couplings
a
The compound 7b was obtained in 62% yield with the Grubbs II catalyst. b The Ugi-Smiles reaction was performed using a more diluted solution (1 M).
J. Org. Chem, Vol. 72, No. 15, 2007 5837
SCHEME 3.
Influence of the Temperature on the RCM
2931, 2857, 1670, 1534, 1427, 1386 cm-1. MS (DI, CI NH3) m/z 433. HRMS Calcd for C27H36N4O432.2889, Found 432.2882. mp 122.8 °C. 4-Methyl-2-(4-methyl-2-phenyl-5,8-dihydro-pyrimido[4,5-b]azepin-9-yl)-pentanoic Acid Cyclohexylamide 8b. The typical procedure was followed employing the diene 6b (50 mg, 0.11 mmol) at room temperature to afford compound 8b (70 mg, 84%, 6 h) as a yellow oil with preparative chromatography (petroleum ether/diethyl ether: 50/50). 1H NMR (CDCl3, 400 MHz) δ 8.368.30 (m, 2H), 7.50-7.44 (m, 3H), 7.07 (br s, 1H), 6.21-6.13 (m, 1H), 5.98-5.89 (m, 1H), 5.64 (br s, 1H), 4.05 (dd, 1H, J ) 15.5, 6.2 Hz), 3.88 (dd, 1H, J ) 15.5, 6.8 Hz), 3.81-3.71 (m, 1H), 3.56 (dd, 1H, J ) 16.6, 6.3 Hz), 3.46 (dd, 1H, J ) 16.6, 6.4 Hz), 2.53 (s, 3H), 1.62-1.87 (m, 6H), 1.59-1.43 (m, 3H), 1.36-1.19 (m, 4H), 0.98 (d, 3H, J ) 6.6 Hz), 0.88 (d, 3H, J ) 6.4 Hz). 13C NMR
5838 J. Org. Chem., Vol. 72, No. 15, 2007
(CDCl3, 100.6 MHz) δ 171.7, 163.7, 163.2, 160.5, 138.3, 131.5, 130.4, 128.3, 127.9, 127.8, 114.6, 57.4, 48.1, 42.9, 37.3, 33.3, 33.2, 26.4, 25.8, 25.3, 24.9, 24.8, 23.9, 23.6, 22.4. IR (thin film) 3329, 2920, 1668, 1533, 1336, 1162 cm-1. MS (DI, CI NH3) m/z 433. HRMS Calcd For C27H36N4O432.2889, Found 432.2893.
Acknowledgment. J.O. thanks the MENR for a fellowship. Financial support was provided by the ENSTA. Supporting Information Available: Experimental procedures and characterization data for all other new compounds. This material is available free of charge via the Internet at http://pubs.acs.org. JO070706C
