Direct and Efficient C(sp3)–H Functionalization of N-Acyl/Sulfonyl Tetrahydroisoquinolines (THIQs) With Electron-Rich Nucleophiles via 2,3-Dichloro-5,6-Dicyano-1,4-Benzoquinone (DDQ) Oxidation

A highly efficient metal-free oxidative direct C(sp3)–H functionalization of N-acyl/sulfonyl 1,2,3,4-tetrahydroisoquinolines (THIQs) with a wide range of electron-rich nucleophiles was accomplished under mild conditions through oxidation with DDQ and subsequent trapping of the resulting reactive and stable N-acyl/sulfonyl iminium ions. The synthetic utility of this method was illustrated by a concise and efficient total synthesis of (±)-benzo[a]quinolizidine (10) in 3 steps from the known N-Cbz 1,2,3,4-THIQ 4b.

The majority of oxidative functionalization reactions widely employed an aryl group as the activating and protecting group for 1,2,3,4-THIQs (Li, 2009;Scheuermann, 2010;Yoo and Li, 2010;Klussmann and Sureshkumar, 2011;Yeung and Dong, 2011;Rohlmann and Mancheño, 2013), since the aryl group on the nitrogen atom activates the C(sp 3 )-H bond at the C(1)-position of 1,2,3,4-THIQs and stabilizes the resulting iminium ion intermediate. Although Todd and co-workers recently identified that 4-methoxyphenyl (PMP) group is a removable protecting group in the oxidative direct C(sp 3 )-H functionalization (Tsang et al., 2013), it still proves to be problematic to remove the aryl protecting group from the nitrogen atom in the presence of other functional groups, SCHEME 1 | Proposed strategy for oxidative C(sp 3 )-H functionalization of N-acyl/sulfonyl 1,2,3,4-THIQs with electron-rich nucleophiles. which significantly limits the synthetic utility of oxidative functionalization of N-aryl 1,2,3,4-tetrahydroisoquinolines. For instance, the phenyl protecting group from amines was removed under harsh reaction conditions where only a small set of organic compounds could be tolerated (Girard et al., 2004(Girard et al., , 2005Girard and Hurvois, 2007). Therefore, use of easily removable N-acyl or N-sulfonyl groups on the nitrogen atom of 1,2,3,4-THIQs in place of the aryl ones would provide an attractive solution for enhancing the scope and synthetic utility of the direct C(sp 3 )-H functionalization of 1,2,3,4-THIQs through generating a more reactive N-acyl/sulfonyl iminium ion intermediate that can react with a broader range of nucleophiles.
Considering that 1,2,3,4-THIQ motifs are core units found in a multitude of pharmacologically active natural products and medicines, the development of an operationally convenient and practical method to introduce a wide range of nucleophiles is still a worthwhile project to pursue. Herein we wish to report a new direct metal-free direct C(sp 3 )-H functionalization of N-acyl/sulfonyl 1,2,3,4-THIQs with a variety of electron-rich nucleophiles via 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) oxidation under ambient conditions.

Initial Attempt and Optimization of the Reaction Conditions
At the outset of our studies, we examined the C(1)-allylation of N-Boc 1,2,3,4-THIQ 4a (Hickin et al., 2014), which is ubiquitous structural frameworks in numerous pharmacologically active THIQ natural products, as a model substrate to test the viability of the envisioned direct metal-free C(sp 3 )-H functionalization. The allyl moiety is exceptionally versatile and synthetically useful in that this functional group offers a wealth of opportunities to further functionalization (Denmark and Fu, 2003). Although Wang and co-workers (Yan et al., 2015) recently reported the use of allyltrimethylsilane (Me 3 SiCH 2 CH=CH 2 ) as the nucleophile in direct oxidative C(1)-allylation of N-acyl/N-sulfonyl 1,2,3,4-THIQs employing 2,2,6,6-tetramethylpiperidine-1oxoammonium tetrafluoroborate (T + BF − 4 ), success of such a direct oxidative transformation with an electron-rich allyltrialkylstannane was not yet to be proven, presumably, due to their high propensity of oxidation in the presence of oxidizing agents. It is difficult to generate N-acyl or N-sulfonyl iminium ion intermediates with commonly used transition FIGURE 1 | Selected biologically active natural products embodying C(1)-substituted 1,2,3,4-tetrahydroisoquinoline (THIQ) subunit. SCHEME 2 | DDQ-promoted C(1)-allylation of N-Boc 1,2,3,4-THIQ 4a with an electron-rich allyltributylstannane. metal catalysts or non-metal organic oxidants (Luo et al., 2020). Therefore, a judicious selection of oxidant is critical. We selected 1,2-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (Walker and Hiebert, 1967;Fu and Harvey, 1978;Wendlandt and Stahl, 2015) since it is inexpensive and stable organic solid that is conveniently handled under ambient conditions, and permits mild and more practical reaction conditions. To test the compatibility of allyltributylstannane ((n-Bu) 3 SnCH 2 CH=CH 2 ) in the presence of DDQ, DDQ (1.1 equiv) was added to a mixture of 4a (1.0 equiv) and (n-Bu) 3 SnCH 2 CH=CH 2 (2.5 equiv) in the presence of 4Å MS in DCM, and the reaction mixture was stirred for 1 h at ambient temperature (Scheme 2). However, the desired C(1)-allylated N-Boc 1,2,3,4-THIQ (±)-5a was not obtained, but most of 4a was recovered, presumably due to faster oxidation of electron-rich nucleophile (n-Bu) 3 SnCH 2 CH=CH 2 than 4a. Pleasingly, treatment of 4a with DDQ (1.1 equiv) as an oxidant in the presence of 4Å MS in DCM at room temperature for 30 min, thereby leading in situ high yield of the reactive N-Boc iminium ion along with consumption of the oxidant. The subsequent addition of (n-Bu) 3 SnCH 2 CH=CH 2 (2.5 equiv) afforded the desired (±)-5a in excellent yield (98%). Molecular sieves (4Å) was added to eliminate moisture that might be present in the reaction mixture and the reactivity of the N-Boc iminium ion lasted for several hours at room temperature under argon atmosphere. To the best of our knowledge, such a DDQ-mediated direct functionalization of C(sp 3 )-H functionalization of N-Boc 1,2,3,4-THIQ with electron-rich (n-Bu) 3 SnCH 2 CH=CH 2 as a nucleophile has not been reported yet.
Frontiers in Chemistry | www.frontiersin.org SCHEME 3 | Reaction scope of N-Boc 1,2,3,4-THIQ 4a and electron-rich nucleophiles. All reactions were conducted at 0.1 M concentration with 0.3 mmol of N-Boc 1,2,3,4-THIQ 4a (1.0 equiv), 0.33 mmol of DDQ (1.1 equiv) in the presence of 120 mg of 4Å MS at ambient temperature under argon atmosphere. After 30 min, 0.75 mmol of nucleophiles were added to the reaction mixture, and the reaction mixture was stirred for 1 h. Yield was based on isolated product after purification by chromatography.

A Concise and Efficient 3-Step Total Synthesis of (±)-Benzo[a]quinolizidine
We next turned on our attention to a short and efficient total synthesis of (±)-benzo[a]quinolizidine (10) to prove the synthetic utility of this method (Scheme 7). The oxidative direct C(sp 3 )-H functionalization of the readily available N-Cbz 1,2,3,4-THIQ 4b (Dunetz et al., 2005;Kim et al., 2018) with CH 2 =C(OTMS)H afforded aldehyde, which underwent Wittig olefination with a two carbon stabilized ylide Ph 3 P=CHCO 2 Me to furnish α,β-unsaturated ester (±)-8 in 79% yield in a onepot fashion, exhibiting high stereoselectivity (E/Z = 95:5), that is none the less to be rendered in consequential at this stage because the planned hydrogenation/deprotection/ring-closure reaction sequence was envisaged to provide a single product regardless of the olefin geometry. The hydrogenation of the olefin moiety, simultaneous deprotection of the Cbz group on the nitrogen atom of the THIQ framework and ring closure was achieved smoothly by hydrogenation (1 atm) over 10% Pd/C in EtOAc to provide the desired lactam (±)-9 in 85%. Reduction of lactam (±)-9 with LiAlH 4 in THF according to Reddy and co-workers (Reddy et al., 2013) afforded (±)-benzo[a]quinolizidine (10) in 77%, whose spectral data were in good agreement with those reported in the literature (Williams et al., 2005;Szawkalo et al., 2007;Reddy et al., 2013;Talk et al., 2016).

CONCLUSIONS
In conclusion, N-acyl/sulfonyl 1,2,3,4-THIQ iminium complexes in situ generated by DDQ were found to be very effective and compatible with a wide range of electron-rich nucleophiles. New and useful nucleophiles such as silyl enol ethers and silyl ketene acetals are employed to afford Mannich-type products and use of phenols, heteroaromatics furnished Friedel-Crafts-type products. Further studies are ongoing to expand the synthetic utility of this products to natural product or synthetically useful compounds.

General Methods
Except as otherwise indicated, reactions were carried out under argon atmosphere in flame-or oven-dried glassware. In aqueous work-up, all organic solutions were dried over sodium sulfate (Na 2 SO 4 ) or magnesium sulfate (MgSO 4 ), and filtered prior to rotary evaporation at water aspirator pressure. Reactions were monitored by thin layer chromatography (TLC) with 0.25-mm E. Merck pre-coated silica gel plates (Kieselgel 60F 254 , Merck). Spots were detected by viewing under a UV light, colorizing with charring after dipping in p-anisaldehyde solution with SCHEME 6 | Proposed reaction mechanism for DDQ-promoted C(1)-allylation of N-acyl/sulfonyl 1,2,3,4-THIQs.
acetic acid and sulfuric acid and ethanol, or ceric ammonium molybdate solution with sulfuric acid and ethanol. Silica gel for flash chromatography (particle size 0.040-0.063 mm) was supplied by E. Merck. Yields refer to chromatographically and spectroscopically pure compounds unless otherwise noted.

Materials
All commercial reagents and solvents were purchased from Sigma Aldrich Co. or Tokyo Chemical Industry (TCI) and used as received with the following exceptions. All solvents were freshly purified and dried by standard techniques just before use. Tetrahydrofuran (THF) was distilled from sodium/benzophenone. Dichloromethane (CH 2 Cl 2 ), acetonitrile (MeCN), N, N-dimethylformamide (Me 2 NC(=O)H), benzene (C 6 H 6 ) and toluene (C 7 H 8 ) were distilled from calcium hydride (CaH 2 ). Methanol (MeOH) was distilled from magnesium sulfate (MgSO 4 ).
Instrumentation 1 H and 13 C spectra were recorded on Varian Mercury-400BB (400 MHz). Chemical shifts are reported as δ value relative to internal chloroform (δ 7.26 for 1 H and δ 77.0 for 13 C). Data are represented as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad), coupling constant in Hz, and integration. High resolution mass spectra (HRMS) were recorded on JEOL JMS-700 (FAB or EI) mass spectrometer. High resolution values are calculated to four decimal places from the molecular formula, all found values being within a tolerance of 5 ppm.
To a stirred solution of (±)-6c (87.4 mg, 0.30 mmol) in ethylene glycol/H 2 O [3.0 mL, 1:1 (v/v)] was added KOH (168.3 mg, 3.0 mmol) at room temperature. The reaction mixture was heated at reflux for 12 h under argon atmosphere and cooled to room temperature and then quenched with saturated NH 4 Cl (5 mL) and the layers were separated and the aqueous layer was extracted with EtOAc (2 × 20 mL). The combined organic layer was washed with brine (5 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, EtOAc/MeOH/Et 3 N = 15:1:0.1) to afford (±)-8 (49.0 mg, 0.21 mmol) as a colorless oil.

DATA AVAILABILITY STATEMENT
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

AUTHOR CONTRIBUTIONS
DL contributed conception and design of the study. HY and DL have been involved in the synthesis of all compounds with the help of HK. S-HB and DL analyzed the results and wrote the paper. All authors contributed to manuscript revision, read, and approved the submitted version. Yu, J., Li, Z., Jia, K., Jiang, Z., Liu, M., and Su, W. (2013). Fast, solvent-free asymmetric alkynylation of prochiral sp 3 C-H bonds in a ball mill for the preparation of optically active tetrahydroisoquinoline derivatives. Tetrahedron Lett. 54, 2006Lett. 54, -2009Lett. 54, . doi: 10.1016Lett. 54, /j.tetlet.2013.007 Zhang, G., Ma, Y., Wang, S., Zhang, Y., and Wang, R. (2012).
Enantioselective metal/organo-catalyzed aerobic oxidative sp 3 C-H olefination of tertiary amines using molecular oxygen as the sole oxidant. J. Am. Chem. Soc. 134, 12334-12337. doi: 10.1021/ ja303333k Conflict of Interest: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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