jo702342r[1]

One-Step Synthesis of Substituted Dihydro- and Tetrahydroisoquinolines by FeCl3â6H2O Catalyzed Intramolecular Friedel-Crafts Reaction of Benzylamino-Substituted Propargylic Alcohols Wen Huang,† Quansheng Shen,† Jialiang Wang,† and Xigeng Zhou*,†,‡ Department of Chemistry, Shanghai Key Laboratory of Molecular Catalysis and InnoVatiVe Materials, Fudan UniVersity, Shanghai 200433, People’s Republic of China, and State Key Laboratory of Organometallic Chemistry, Shanghai 200032, People’s Republic of China xgzhou@fudan.edu.cn ReceiVed October 30, 2007 A mild, versatile, and efficient method for the one-step synthesis of substituted dihydro- and tetrahydroisoquinolines has been developed by the FeCl3â6H2O catalyzed intramo- lecular allenylation/cyclization reaction of benzylamino- substituted propargylic alcohols, representing the first ex- ample of the intramolecular Friedel-Crafts reaction of propargylic alcohols. Dihydro- and tetrahydroisoquinoline moieties are present in a wide range of natural and unnatural compounds that exhibit important biological activities and in an array of substances used as intermediates in organic synthesis.1 Thus, a growing effort has been directed toward the efficient and selective preparation of various dihydro- and tetrahydroisoquinolines. Traditionally, the 1,2-dihydroisoquinolines can be indirectly prepared by nucleophilic addition to isoquinolinium salts, which are derived from the corresponding isoquinolines by acylation or alkyla- tion.2,3 Recently, it was found that Lewis acid-catalyzed tandem intramolecular cyclization/nucleophilic addition or nucleophilic addition then cyclization of 2-alkynylarylimines can provide a concise and efficient method for the direct synthesis of 1,3- and 1,3,4-substituted 1,2-dihydroisoquinolines.4 However, this strategy is not suitable to the selective construction of 4-sub- stituted and 1,4-disubstituted 1,2-dihydroisoquinolines. There- fore, the search for a new strategy for the direct synthesis of 1,2-dihydro- and tetrahydroisoquinolines from readily available starting materials would be a highly valuable but challenging subject. Catalytic substitution of the hydroxy group in alcohols with nucleophiles is an atom efficient and environmentally sound transformation that is currently receiving increased attention.5-7 Recent works showed that propargylic alcohols can serve as novel electrophilic alkyl equivalents for the intermolecular Friedel-Crafts reactions.5h-k,6e,7 However, the related intramo- lecular Friedel-Crafts reaction remains unexplored, possibly due to the difficulty of the cycloalkyne formation. Previously, we found that treatment of 1,3-dicarbonyl compounds with tertiary propargylic alcohols in the presence of Lewis acids could give the isomerized allenylation products.8 In this case it would be expected that an intramolecular allenylation/cyclization would be operating due to avoidance of the large ring strain. As a part of our continuing research on making use of propargylic alcohols † Fudan University. ‡ Shanghai Institute of Organic Chemistry. (1) (a) Chen, J.; Chen, X.; Bois-Choussy, M.; Zhu, J. J. Am. Chem. Soc. 2006, 128, 87. (b) Kwon, S.; Myers, A. G. J. Am. Chem. Soc. 2005, 127, 16796. (c) Magnus, P.; Matthews, K. S.; Lynch, V. Org. Lett. 2003, 5, 2181. (d) Magnus, P.; Matthews, K. S. J. Am. Chem. Soc. 2005, 127, 12476. (e) Scott, J. D.; Williams, R. M. Angew. Chem., Int. Ed. 2001, 40, 1463. (f) Scott, J. D.; Williams, R. M. J. Am. Chem. Soc. 2002, 124, 2951. For recent reviews, see: (g) Scott, J. D.; Williams, R. M. Chem. ReV. 2002, 102, 1669. (h) Chrzanowska, M.; Rozwadowska, M. D. Chem. ReV. 2004, 104, 3341. (2) For selected examples, see: (a) Diaba, F.; Houerou, C. L.; Grignon- Dubois, M.; Rezzonico, B.; Gerval, P. Eur. J. Org. Chem. 2000, 2915. (b) Diaz, J. L.; Miguel, M.; Lavilla, R. J. Org. Chem. 2004, 69, 3550. (c) Hewavitharanage, P.; Danilov, E. O.; Neckers, D. C. J. Org. Chem. 2005, 70, 10653. (3) The asymmetric version, see: (a) Funabashi, K.; Ratni, H.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2001, 123, 10784. (b) Taylor, M. S.; Tokunaga, N.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2005, 44, 6700. (c) Lu, S.; Wang, Y.; Han, X.; Zhou, Y. Angew. Chem., Int. Ed. 2006, 45, 2260. (4) (a) Ohtaka, M.; Nakamura, H.; Yamamoto, Y. Tetrahedron Lett. 2004, 45, 7339. (b) Asao, N.; Yudha S, S.; Nogami. T.; Yamamoto, Y. Angew. Chem., Int. Ed. 2005, 44, 5526. (c) Asao, N.; Iso, K.; Yudha S, S. Org. Lett. 2006, 8, 4149. (d) Yanada, R.; Obika, S.; Kono, H.; Takemoto, Y. Angew. Chem., Int. Ed. 2006, 45, 3822. (e) Obika, S.; Kono, H.; Yasui, Y.; Yanada, R.; Takemoto, Y. J. Org. Chem. 2007, 72, 4462. (5) For selected examples of Lewis acid catalyzed substitution of alcohols, see: (a) Yasuda, M.; Saito, T.; Ueba, M.; Baba, A. Angew. Chem., Int. Ed. 2004, 43, 1414. (b) Yasuda, M.; Somyo, T.; Baba, A. Angew. Chem., Int. Ed. 2006, 45, 793. (c) Saito, T.; Nishimoto, Y.; Yasuda, M.; Baba, A. J. Org. Chem. 2006, 71, 8516. (d) De, S. K.; Gibbs, R. A. Tetrahedron Lett. 2005, 46, 8345. (e) Rueping, M.; Nachtsheim, B. J.; Ieawsuwan, W. AdV. Synth. Catal. 2006, 348, 1033. (f) Rueping, M.; Nachtsheim, B. J.; Kuenkel, A. Org. Lett. 2007, 9, 825. (g) Terrasson, V.; Marque, S.; Georgy, M.; Campagne, J. M.; Prima, D. AdV. Synth. Catal. 2006, 348, 2063. (h) Georgy, M.; Boucard, V.; Campagne, J. M. J. Am. Chem. Soc. 2005, 127, 14180. (i). Zhan, Z. P.; Yang, W. Z.; Yang, R. F.; Yu, J. L.; Li, J. P.; Liu, H. J. Chem. Commun. 2006, 3352. (j) Zhan, Z. P.; Yu, J. L.; Liu, H. J.; Cui, Y. Y.; Yang, R. F.; Yang, W. Z.; Li, J. P. J. Org. Chem. 2006, 71, 8298. (k) Liu, J.; Muth, E.; Flo¨rke, U.; Henkel, G.; Merz, K.; Sauvageau, J.; Schwake, E.; Dyker, G. AdV. Synth. Catal. 2006, 348, 456. (l) Qin, H. B.; Yamagiwa, N.; Matsunaga, S.; Shibasaki, M. Angew. Chem., Int. Ed. 2007, 46, 409. (m) Kischel, J.; Mertins, K.; Michalik, D.; Zapf, A.; Beller, M. AdV. Synth. Catal. 2007, 349, 865. (n) Noji, M.; Konno, Y.; Ishii, K. J. Org. Chem. 2007, 72, 5161. (o) Huang, W.; Wang, J.; Shen, Q.; Zhou, X. Tetrahedron Lett. 2007, 48, 3969. (6) For selected examples of related Brønsted acid catalyzed transforma- tions, see: (a) Motokura, K.; Fujita, N.; Mori, K.; Mizugaki, T.; Ebitani, K.; Kaneda, K. Angew. Chem., Int. Ed. 2006, 45, 2605. (b) Shirakawa, S.; Kobayashi, S. Org. Lett. 2007, 9, 311. (c) Sanz, R.; Miguel, D.; Martı´nez, A.; AÄ lvarez-Gutie´rrez, J. M.; Rodrı´guez, F. Org. Lett. 2007, 9, 2027. (d) Sanz, R.; Martı´nez, A.; Miguel, D.; AÄ lvarez-Gutie´rrez, J. M.; Rodrı´guez, F. AdV. Synth. Catal. 2006, 348, 1841. (e) Sanz, R.; Martı´nez, A.; AÄ lvarez- Gutie´rrez, J. M.; Rodrı´guez, F. Eur. J. Org. Chem. 2006, 1383. (7) For selected examples of related metal catalyzed transformations, see: (a) Bustelo, E.; Dixneuf, P. H. AdV. Synth. Catal. 2005, 347, 393. (b) Nishibayashi, Y.; Inada, Y.; Yoshikawa, M.; Hidai, M.; Uemura, S. Angew. Chem., Int. Ed. 2003, 42, 1495. (c) Kennedy-Smith, J. J.; Young, L. A.; Toste, F. D. Org. Lett. 2004, 6, 1325. (8) Huang, W.; Wang, J.; Shen, Q.; Zhou, X. Tetrahedron 2007, 63, 11636. 1586 J. Org. Chem. 2008, 73, 1586-1589 10.1021/jo702342r CCC: $40.75 © 2008 American Chemical Society Published on Web 01/16/2008 as a practical and versatile alkylation reagent, we were interested in revealing the possibility of the intramolecular Friedel-Crafts reaction of benzylamino-substituted propargylic alcohols and thus developing a concise and versatile strategy for constructing dihydro- and tetrahydroisoquinoline ring frameworks.9 On the basis of this idea, a one-step synthetic route to tetrahydroiso- quinolines and their derivatives is sketched out in Scheme 1. Herein, we report the details of the scope and limitations of this process. After considering this possible reaction pathway, we first synthesized intermediates 7 by the following three routes:5g,l,10 (a) reacting the corresponding aldehyde (4) with TsNH2 and then reduction with NaBH4 in MeOH; (b) direct N-sulfonylation of the corresponding benzylamine (5); and (c) the direct hydroxy substitution of the corresponding alcohols (6) with sulfonamide promoted by FeCl3â6H2O. Route (a) requires two steps, but the aldehydes employed are cheap. Treatment of 7 with propargyl bromide in the presence of K2CO3 in acetone at reflux temperature gave N-tosyl, N-propargylic benzylamines (8) in good to excellent yields. Then, benzylamino-substituted prop- argylic alcohols 1a-j were synthesized in good yields by reaction of 8 with BuLi followed by treating with ketones (Scheme 2). Initial cyclization of 1a was studied in the presence of various Lewis acid catalysts in nitromethane to obtain the optimum reaction conditions. Table 1 shows the major results. All Lewis acid catalysts employed exhibit good catalytic activity for the reaction (Table 1, entries 1-6). However, when the Brønsted acid such as p-toluenesulfonic acid monohydrate (PTS) was used as a catalyst instead of Lewis acids, the ene-ketone was isolated as a major product due to the Meyer-Schuster rearrangement (Table 1 entry 7).11 The structure of product 2a was confirmed by 1H NMR, 13C NMR, HRMS, and X-ray diffraction analysis. The results clearly demonstrate the isomerization of the prop- argyl cation to allenyl cation (Figure 1). Considering that FeCl3â 6H2O is readily available and inexpensive, we then consistently used it to explore the scope of this reaction. A selection of various benzylamino-substituted propargylic alcohols 1b-j was investigated using FeCl3â6H2O as a catalyst in CH3NO2. Table 2 summarizes the results. With substitution of one phenyl by methyl at the propargylic position, the reaction continued to proceed smoothly to the corresponding allenylation/ cyclization product 2b in a good yield (Table 2, entry 1), despite the need to elevate the reaction temperature to 60 °C. However, when both the phenyl groups at the propargylic position were replaced by methyl groups, the desired product 2c could be obtained only in a low yield even by increasing reaction temperature and with a higher catalyst loading (Table 2, entry 2). In addition, aryl-substituted propargylic alcohol 1d, which (9) (a) Ishikawa, T.; Okano, M.; Aikawa, T.; Saito, S. J. Org. Chem. 2001, 66, 4635. (b) Ishikawa, T.; Manabe, S.; Aikawa, T.; Kudo, T.; Saito, S. Org. Lett. 2004, 6, 2361. (10) (a) Noji, M.; Ohno, T.; Fuji, K.; Futaba, N.; Tajima, H.; Ishii, K. J. Org. Chem. 2003, 68, 9340. (b) Carrettin, S.; Blanco, M. C.; Corma, A.; Hashmi, A. S. K. AdV. Synth. Catal. 2006, 348, 1283. (11) (a) Swaninathan, S.; Narayanan, K. V. Chem. ReV. 1971, 71, 429. (b) Lorber, C. Y.; Osborn, J. A. Tetrahedron Lett. 1996, 37, 853. SCHEME 1. Plausible Reaction Pathway SCHEME 2. Routes for the Synthesis of Propargylic Alcohols TABLE 1. Cyclization Reaction of 1a under Various Conditionsa entry catalyst T/°C time/h yieldb/% 1 Yb(OTf)3 rt 24 65 2 Yb(OTf)3 60 2 85 3 FeCl3 rt 1 86 4 FeCl3â6H2O rt 1 83 5 InCl3 rt 1 88 6 ZnCl2 rt 12 72 7c PTS rt 12 8 8 no rt 12 a Reaction conditions: 0.3 mmol 1a, 5 mol % of catalyst in 2 mL of nitromethane. b Isolated yield. c The main product was PhCH2N(Ts)CH2- COCHdCPh2. FIGURE 1. ORTEP diagram of the single-crystal X-ray Structure of 2a. J. Org. Chem, Vol. 73, No. 4, 2008 1587 has an electron-withdrawing chloride group at the para-position, was reactive enough to afford the tetrahydroisoquinoline product 2d in 75% yield (Table 2, entry 3). All the results indicate that an aryl substituent is likely to assist the isomerization of propargyl to allenyl by the conjugative effect. Next, we set out to study the scope and limitation of the nucleophilic coupling moiety in more detail. As shown in Table 2, various substituted benzene rings have been examined. The methyl substituent in the para-position of the benzylamine 1e had only a slight influence on the reactivity as compared to 1a (Table 2, entry 4), whereas 1f, bearing an electron-withdrawing chloride group in the same position, resulted in the isolation of the Meyer-Schuster rearranged ene-ketone 9 as the main product (Table 2, entry 5). This difference might be explained by the fact that the electron-withdrawing substituent on the benzene ring decreases the electron density of the ring, which is unfavorable to the Friedel-Crafts reaction. Interestingly, treatment of p-methoxybenzylamino-substituted propargylic alcohol 1g with FeCl3â6H2O under the same conditions led to the transformation of allene product to 1,3- diene one, affording dihydroisoquinoline 3g in 90% yield (Table 2, entry 6). This indicates that the methoxy group not only activates the benzene ring but also induces isomerization of 1,2- diene to 1,3-diene. A similar isomerization has been observed previously in the synthesis of quinolines.9b The formation of novel isomerization product 3h was unexpected when methoxy- activated propargylic alcohol 1h was used as a substrate (Table 2, entry 7).12 However, during the synthesis of 2a no similar 1,3-diene isomer was isolated even after a prolonged reaction time or at elevated temperature. These successful results encouraged us to extend this method to the synthesis of 1,4-disubstituted dihydroisoquinolines. Treat- ment of propargylic alcohol 1i with 5 mol % of FeCl3â6H2O afforded the corresponding 1,4-disubstituted tetrahydroisoquino- line 2i in 87% yield (Table 2, entry 8). The structure of compound 2i has been determined by the X-ray diffraction analysis. To our delight, for sterically hindered phenyl- substituted propargylic alcohol 1j the 1,4-disubstituted dihy- droisoquinoline product 3j was obtained in 76% yield (Table 2, entry 9). In addition, we found that the allene skeleton in other tetrahydroisoquinolines could also be transformed to the 1,3- diene isomers. For example, treatment of 2a and 2i with a catalytic amount of p-toluenesulfonic acid monohydrate in acetonitrile/dichloroethane at 60 °C for 6 h gave the corre- sponding dihydroisoquinoline derivatives 3a and 3i, respectively (Scheme 3). The X-ray crystal structure of 3i (Figure 2) definitively proves that the original tetrahydroisoquinoline ring has isomerized to the dihydroisoquinoline ring. Ishikawa and co-workers recently reported an efficient method for synthesis of quinolines and their analogues from arylamino- substituted propargylic silyl ethers.9b However, when the strategy was extended to the construction of tetrahydroisoquinoline rings, it required a stoichiometric amount of Lewis acid catalysts, and the substrates were limited to N-methoxybenzylamino-substi- (12) For isomerization of 1-amino-3-arylallene, see: Reinhard, R.; Glaser, M.; Neumann, R.; Maas, G. J. Org. Chem. 1997, 62, 7744. TABLE 2. Synthesis of Various Dihydro- and Tetrahydroisoquinolinesa a General reaction conditions: 0.3 mmol substrate 1, 5 mol % of FeCl3â6H2O in 2 mL of CH3NO2 at room temperature. b Isolated yield. c The reaction was carried out at 60 °C. d Using 30 mol % of catalyst. FIGURE 2. ORTEP diagram of the single-crystal X-ray structure of 3i. 1588 J. Org. Chem., Vol. 73, No. 4, 2008 tuted propargylic silyl ethers bearing an electron-donating group in the meta-position. Thus, this new approach would comple- ment the powerful techniques already available for the formation of dihydro- and tetrahydroisoquinoline rings. At the same time, the results presented here and in the previous paper9b demon- strate the synthetic potential and versatility of the intramolecular Friedel-Crafts reaction for dihydro- and tetrahydroisoquino- lines. In conclusion, we have developed an efficient method for direct synthesis of dihydro- and tetrahydroisoquinolines, which can be further functionalized, from benzylamino-substituted pro- pargylic alcohols. Advantages of the present method are easily accessible starting materials, mild conditions, and a wide range of inexpensive catalysts, all of which allow the method to be applied on an industrial scale. Furthermore, the results represent a good example that can map out the versatility of the propargylic alcohols as alkylation precursors and demonstrate that their reactivity modes from propargylation, through alle- nylation, to alkenylation can be finely tuned simply by changing the substituents. Further investigations on the mechanistic details and synthetic applications of this reaction are underway in our laboratory. Experimental Section General Procedure. To a solution of 1 (0.3 mmol) in CH3NO2 (2.0 mL) was added FeCl3â6H2O (0.015 mmol). The reaction mixture was stirred at room temperature or the corresponding conditions noted in the text (monitored by TLC). Then, the solvent was removed under reduced pressure and the crude product was purified by silica gel column chromatography to provide the desired product. Selected example, 4-(2,2-diphenylvinylidene)-2-(p-tolu- enesulfonyl)-1,2,3,4-tetrahydroisoquinoline (2a): 1H NMR (CDCl3, 400 MHz, 25 °C) ä 2.29 (s, 3H), 4.32 (s, 2H), 4.43 (s, 2H), 7.02- 7.12 (m, 5H), 7.26-7.41 (m, 11H), 7.58 (d, J ) 8.2 Hz, 2H); 13C NMR (CDCl3, 100 MHz, 25 °C) ä 203.5, 143.7, 136.1, 134.0, 131.0, 129.6, 128.7, 128.7, 128.6, 128.1, 127.9, 127.8, 127.5, 126.9, 126.6, 116.0, 100.1, 48.6, 47.2, 21.6. Anal. Calcd for C30H25NO2S: C, 77.72; H, 5.44; N, 3.02. Found: C, 77.52; H, 5.47; N, 2.96; EI- MS m/z (rel intensity) 463 (M+, 5%), 308 (M+ - Ts, 100%); HRMS (EI) calcd for C30H25NO2S 463.1606, found 463.1612. Acknowledgment. We thank the NNSF of China, NSF of Shanghai, and Shanghai Leading Academic Discipline Project for financial support (B108). Supporting Information Available: Experimental details, spectroscopic characterization data, copies of 1H and 13C NMR of new compounds, and CIF files giving crystallographic data of 2a, 2i, and 3i. This material is available free of charge via the Internet at http://pubs.acs.org. JO702342R SCHEME 3. Isomerization of Tetrahydroisoquinolines to Dihydroisoquinolines J. Org. Chem, Vol. 73, No. 4, 2008 1589