Intramolecular dehydrogenative coupling of biaryl tertiary amines promoted with t -BuOK/DMF: A convenient synthesis of 6-aryl-5,6-dihydrophenanthridines

A number of 6-aryl-5,6-dihydrophenanthridines were prepared in good yields via an intramolecular dehydrogenative coupling of biaryl tertiary amines promoted by t -BuOK/DMF. A reaction mechanism involving  -aminoalkyl radical intermediates is suggested.


Introduction
][3][4][5][6][7][8][9][10] This strategy, introduced by Li and other researchers, is demonstrated to be a superior alternative to classic coupling procedures using prefunctionalized starting materials.CDC reactions are generally achieved in the presence of transition-metal catalysts and sacrificial oxidants or Hacceptors.2][13][14][15][16] In 2015, Wu and co-workers developed a t-BuOLi-promoted CDC reaction of quinolone N-oxides and 1,3-azoles without external oxidants. 17A t-BuOK/DMSO mediated intermolecular CDC reaction of nitroarenes and indoles in an open flask was also reported. 18These transformations usually proceed via oxidative SET (single electron transfer) C−H activation and the subsequent generation of radical intermediates.

Results and Discussion
Initially, we examined the reaction of 1a in DMF with 3.0 equiv. of t-BuOK at 120 °C.To our delight, 2a was obtained in a moderate yield.Furthermore, a number of bases and reaction solvents were examined and the results are summarized in Table 1.t-BuONa, t-BuOLi, and K2CO3 were tested, however, no 2a was obtained (Table 1, entries 2-4).The reaction in DMSO was also applicable, but a lower yield was observed (Table 1, entry 5).THF was found to be incompatible with the reaction and no product 2a was obtained.The effect of t-BuOK loading was also examined and the best yield was obtained with 3.0 equiv. of t-BuOK (Table With the optimal reaction conditions in hand, the reaction was extended to a variety of biaryl tertiary amines, and the results are summarized in Scheme 2. Substrates with electron-donating groups such as methoxyl and methyl groups on the aryl amine motif were well tolerated.Substrates with single and double methoxyl substitutions gave the products 2b-2e in good yields.The substrates with a methyl substitution gave the products 2f-2h in lower yields.Radical delocalization between the methyl group and amino alkyl group accounts for the poor yield of products.The ortho-methyl substituted substrate 1h gave a poor yield which implies that this transformation is sensitive to steric hindrance.Substitution with an electron-withdrawing CF3 group showed a detrimental effect.Although complete consumption of 1i was observed, no expected product 2i could be isolated.A substrate with a naphthyl group was also examined and the product 2j was obtained in a moderate yield.The 2-thienyl substituted substrate 1k was found to be unreactive. The effect of the substitutions on the biaryl motif was also examined.The replacement of biaryl group with a naphthyl group (1l) led to the loss of the reactivity.The substrates with a methyl substitution gave the products 2m-2n in poor yields.However, the substrate with a pyridyl group (1o) gave a 68% yield.When the methyl group on the nitrogen was changed to ethyl, the product 2p was obtained in a 68% yield.However, the benzyl replacement (1q) proved to inhibit the reaction.
To have a better understanding of the mechanism, radical trapping experiments were performed (Scheme 3).The reaction was totally inhibited in the presence of oxygen and butylated hydroxytoluene (BHT).The results implicate a radical reaction pathway.

Scheme 3. Radical trapping experiments.
Based on our previous studies and the present results, a tentative reaction mechanism is proposed (Scheme 3).DMF is deprotonated by t-BuOK to give the carbamoyl radical A. After a single-electron transfer (SET) step, the α-amino alkyl radical B is generated.B then undergoes an intramolecular radical addition to the phenyl ring.The resulting aryl radical C transfers an electron to DMF and is subsequently deprotonated by t-BuOK to give 2a.© ARKAT USA, Inc

Conclusions
In summary, we have developed an intramolecular dehydrogenative coupling of biaryl tertiary amines promoted by t-BuOK/DMF.A number of 6-aryl-5,6-dihydrophenanthridines were prepared in good yields.A radical reaction pathway is proposed.The finding provides a new synthetic approach to dihydrophenanthridine derivatives.

Experimental Section
General. 1 H NMR and 13 C NMR spectra were recorded on Bruker AVANCE 400 spectrometer.Chemical shifts of protons are reported in parts per million downfield from tetramethylsilane and are referenced to residual protium in the NMR solvent (CDCl3: δ 7.26).Chemical shifts of carbon are referenced to the carbon resonances of the solvent (CDCl3: δ 77.0) unless otherwise stated.Peaks are labeled as singlet (s), broad singlet (br), doublet (d), triplet (t), double doublet (dd), multiplet (m).Melting points were measured on a WRS-2A melting point apparatus and are uncorrected.GC spectra were taken on an Agilent-6890A instrument.All products were further characterized by HRMS (high resolution mass spectra).The t-BuOK was purchased from Alfa Aesar chemical company and used without further purification.THF, DMF were dried and redistilled according to standard methods.DMSO was dried over 4Å molecular sieves.

Table 1 .
Optimization of reaction conditions a b Yields were obtained by GC with n-dodecane as the internal standard.The value in the parentheses is the isolated yield after column chromatography.cNot detected.Reaction conditions: 1a-1q (0.2 mmol), t-BuOK (0.6 mmol), DMF (2.0 mL), nitrogen atmosphere, 150 °C, 3 h.Isolated yields.