HETEROCYCLES

Communication | Special issue | Vol. 90, No. 2, 2015, pp. 847-856
Received, 30th June, 2014, Accepted, 13th August, 2014, Published online, 15th August, 2014.
DOI: 10.3987/COM-14-S(K)72

■ Facile Preparation of 1,2-Dihydroisoquinolines from N-Benzylsulfonamides and Bromoacetylenes

Masahito Yamagishi, Azusa Ishii, Takeshi Hata, and Hirokazu Urabe*

Department of Biomolecular Engineering, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama 226-8501, Japan

Abstract

Nucleophilic addition of N-benzylsulfonamides to 1-bromo-1-alkynes proceeded in a highly regio- and stereoselective manner to give (Z)-N-benzyl-N-(1-bromo-1-alken-2-yl)sulfonamides. These adducts cyclized via Pd-catalyzed aromatic C-H bond activation to afford 1,2-dihydroisoquinolines in good yields.

Nucleophilic addition to acetylenes having an electron-withdrawing group is a useful way to prepare functionalized olefins.1 Nonetheless, haloacetylenes (halo = Cl, Br, or I) have not been amply investigated in these reactions, because halogens are generally considered as quite weak electron-withdrawing groups.2-7 We have recently reported that 1-halo-1-alkynes underwent the nucleophilic addition with a few nitrogen nucleophiles such as imidazoles, imidazolines, or sulfonamides8 to give stereo-defined haloolefines.5f-h We also demonstrated that these olefinic adducts are quite useful starting materials for the synthesis of nitrogen heterocycles.5f,g Considering the convenience in the preparation of these heterocyclic compounds, we report herein that an alternative nucleophile, N-benzylsulfonamide, is amenable to the nucleophilic addition to haloacetylenes and their adducts to a subsequent palladium-catalyzed cyclization,9 as shown in Scheme 1. This overall reaction allows a novel

synthesis of 1,2-dihydroisoquinolines, which are frequently-found constituents in naturally occurring products and artificial pharmaceuticals.10,11
The first nucleophilic addition was examined with various 1-halo-1-alkynes 1-3 and representative N-benzylsulfonamides 4-7 (Table 1). Among the three haloacetylenes 1-3, bromoacetylene 2 showed the best result under the similar reaction conditions reported previously by us,5f giving 9 in good yield (Table 1, entry 2). Chloroacetylene 1 could be also used albeit giving a somewhat lower yield, but iodoacetylene 3 could not (entries 1 and 4). The addition products 8 and 9 were obtained virtually as a single olefinic isomer as depicted in Table 1, and other isomers were not detected in the crude reaction mixture. The amount of 4 may be reduced from 3 to 2 equiv, if the slight decrease in the product yield is acceptable (entries 2 and 3). Alternatively, an excess portion of 4 was recovered in good yield and could be recycled (entry 2). As far as sulfonamides 4-7 are concerned, these gave almost similar yields

(entries 2 and 5-7), irrespective of the size of their alkyl groups (R). The final choice of the ethyl group as the standard substituent was made based on the efficiency of the next cyclization step, which is discussed below.
Having obtained the adducts from haloacetylenes and N-benzylsulfonamides as shown in Table 1, we then examined their intramolecular cyclization (the second transformation in Scheme 1). When mesyl derivative 11 was treated with Pd(OAc)2 under the same reaction conditions as reported previously,5g the desired ring closure via aromatic C-H bond activation was sluggish to give dihydroisoquinoline 14 only

in 8% yield (entry 1, Table 2). After searching for better combinations of phosphine ligand and base (entries 2-9), we found the conditions of entry 10 best to give dihydroisoquinoline 14 in 60% yield. Under these conditions, the product yields of various sulfonyl derivatives fall in the following order: 15 (R = Et, entry 11) > 16 (R = n-Bu, entry 12) > 14 (R = Me, entry 10) > 17 (R = i-Pr, entry 13). Thus, alkyl substituent (R) of sulfonyl group had certain influence on the product yields, and among bromoolefins 9, 11, 12, and 13, ethanesulfonyl derivative 9 showed the highest yield (73%, entry 11). The size of sulfonyl groups may control the proximity of the phenyl and bromoolefin moieties suitable for the cyclization. Finally, further improvement of the yield could be achieved with ethanesulfonamide derivative 9 by increasing the amount of KOAc from 2 to 3 equiv, giving desired 15 in 80% yield (entry 14). Decreasing the amount of Pd(OAc)2 from 10 to 8 or 5 mol% retarded the reaction so that starting bromolefin 9 remained even after prolonged reaction periods (2 or 8 h in entries 15 or 16, respectively).
The dihydroisoquinoline structure assigned to 15 was confirmed by its derivatization to known isoquinoline 1812 via elimination of the sulfonyl group with t-BuOK as shown in eq 1.

Table 3 shows other 1,2-dihydroisoquinolines prepared from various 1-bromo-1-alkynes and N-benzylsulfonamides. Entries 1-6 show the variation of aryl groups in N-benzylsulfonamides, where the sulfonamides having an electron-rich (27 and 28 in entries 2 and 3) or electron-deficient (29 in entry 4) aryl group gave cis-olefinic adducts 32-34 in good yields. These products, in turn, underwent the cyclization via C-H bond activation under Pd catalysis to furnish dihydroisoquinolines 41-43 again in good yields. Even when the starting sulfonamides have a sterically demanding benzyl group (30 and 31 in entries 5 and 6), both nucleophilic addition and cyclization proceeded without any difficulty to afford the desired products 44 and 45 in comparable yields via the intermediate cis-bromoolefins 35 and 36. This preparation shows reasonable generality also for 1-bromo-1-alkynes. For example, they can carry an ω-benzyloxy or propargylic methoxy group in their alkyl side chains (23 and 24, entries 7 and 8) to give adducts 37 or 38 and then the corresponding 1,2-dihydroisoquinolines 46 or 47 in satisfactory yields. It should be noted that a free terminal or propargylic hydroxy group in the side chain of bromoacetylenes 25 and 26 (entries 9 and 10) does not need protection and it survived whole reaction conditions to give 1,2-dihydroisoquinolines 48 and 49 in good overall yields.

In order to show synthetic utility of the products, we performed several transformations starting from representative dihydroisoquinoline 15 (Scheme 2). First, 15 was readily hydrogenated to tetrahydroisoquinoline 50 in 92% yield under 1 atm of H2. While the chlorination of 15 with N-chlorosuccinimide proceeded at its enamine moiety to give 4-chloro-1,2-dihydroisoquinoline 51,13 its bromination with Br2 unexpectedly took place at the allylic position to furnish 52 having a bromoalkyl side chain.14,15 On the other hand, the TiCl4-promoted Friedel-Crafts reaction of 15 with alkanoyl chlorides gave 4-alkanoyl-1,2-dihydroisoquinolines 5316 and 54 in good yields. When 15 was treated with n-BuLi-t-BuOK,17 the intermediary formation of 18 (see eq 1) was followed by the addition of butylmetal species at its 1-position to give metalloenamine, which was then oxidized with air to give 1-butyl-4-hydroxyisoquinoline 55, consistent with a precedent in the literature.18

In conclusion, N-benzylsulfonamides underwent the nucleophilic addition to 1-bromo-1-alkynes in a highly regio- and stereoselective manner to give cis-bromoolefins in good yields. Their subsequent Pd-catalyzed cyclization via aromatic C-H bond activation gave 1,2-dihydroisoquinolines in good yields. Some synthetic applications of these 1,2-dihydroisoquinolines are also illustrated.

ACKNOWLEDGEMENTS
This work was supported by a Grant-in-Aid for Challenging Exploratory Research (22655014) from JSPS, Japan. M.Y. thanks the Japan Society for the Promotion of Science for a Research Fellowship for Young Scientist (25-7902).

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13. In a crude reaction mixture, the chloro derivative of 52 was also detected as a minor component (51/Cl-52 = 90:10). For details, see Supporting Information.
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