HETEROCYCLES

Short Paper | Special issue | Vol. 84, No. 2, 2012, pp. 1345-1353
Received, 3rd July, 2011, Accepted, 22nd August, 2011, Published online, 24th August, 2011.
DOI: 10.3987/COM-11-S(P)76

■ Synthesis of Substituted Phenazines via Palladium-Catalyzed Aryl Ligation

Jeffrey D. Winkler,* Barry M. Twenter, and Thomas Gendrineau

Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia
PA 19104-6323, U.S.A.

Abstract

A method for the “ligation” of two aromatic rings has been achieved via synthesis of functionalized phenazines by double Buchwald-Hartwig amination of a variety of substituted bromoanilines, followed by in situ oxidation.

The ligation of aromatic rings represents an important tool for the synthesis of molecules of increasing complexity,2 with important applications in the synthesis of natural and unnatural products. We describe here the implementation of such a strategy for the preparation of substituted phenazines,3 leading to the synthesis of disubstituted heterocycles that cannot be otherwise prepared with comparable levels of efficiency (Figure 1).

Previous efforts by Beifuss4 and Senanayake5 have suggested that such a process should be possible, although with only single examples in unoptimized yields, both of which employ the highly pyrophoric ligand tri-t-butyl phosphine.6 We report herein the optimization of this process and its implementation as a method of choice for the synthesis of unsymmetrically disubstituted phenazines. We further describe the application of this reaction sequence to the aryl ligation of two molecules of tryptophan to generate the previously unreported heterocyclic ring system 1,7-dihydrodipyrrolo-[2,3-b:2’,3’-i]phenazine, a highly fluorescent pentacyclic ring system.

We report herein that a series of bromoanilines that are substituted with either electron-donating or electron-withdrawing groups can be regioselectively converted to the corresponding disubstitutedphenazines in good yields using BINAP or other crystalline phosphine ligands in lieu of tri-t-butyl phosphine (Table 1).
Using the Buchwald C-N Ligand Kit available from Strem Chemicals, a series of phosphines were surveyed, and the two ligands that afforded the highest yields are presented in the Table for each substrate, illustrating the absence of a single optimal phosphine ligand in this reaction. Similar results were observed with the 2-chloroaniline (64% yield) although the corresponding triflates resulted only in oxygen to nitrogen triflate migration in lieu of the desired coupling reaction. The last entry in Table 1 is particularly notable as, even though the observed yield is moderate, none of the desired phenazine product was observed with BINAP.7
We next examined the reaction of more complex aminoaromatics derived from amino acid precursors, as outlined in Figure 2. Aryl ligation of tryptophan using this strategy could lead to the previously undescribed dihydrodipyrrolophenazine ring system shown in 13. Toward that end, dimerization of 10,8 leads to the formation of the corresponding phenazine in 51% yield. However, all attempts to convert 11 to the ring-opened product under the reaction conditions described by Hino and coworkers7 led to none of the desired product 13. Direct dimerization of the N-Boc tryptophan 12 produced the desired ring system 15 in 49% yield. The UV spectrum of 13 was notable for a λmax of 406 nm, and the fluorescence spectrum of 13 featured a λem of 538 nm, with a Stokes’ shift of 132 nm.

The analogous reaction of the phenylalanine-derived substrate 14 afforded the corresponding phenazine 15 in 63% yield. A further example of the regiochemical control that is possible with this phenazine construction strategy is the formation of 17, albeit in 40% yield, from 16, without formation of the corresponding dibenzo[a,j]phenazine, a result that would not be possible using the more classical approaches to the synthesis of substituted phenazines.9
Finally, we demonstrate that this strategy is not limited to dimerization. By judicious choice of substituents on the aniline ring, i.e., by exploiting the decreased reactivity of anilines substituted with electron-withdrawing groups, we have demonstrated that the reaction of 18 with 2-bromoaniline leads to the formation of 19 in 65% yield. The application of this methodology to the synthesis of diverse substituted phenazines is currently underway in our laboratory and our results will be reported in due course.

EXPERIMENTAL
General Methods: Solvents used for extraction and purification were certified ACS grade from Fisher. Unless otherwise indicated, all reactions were run under an inert atmosphere of Argon. Anhydrous toluene was obtained via distillation from sodium metal. Fisher HPLC grade dichloromethane, chloroform, and methanol were used without further purification as reaction solvents. Commercial reagents were used as received. Deuterated solvents were obtained from Cambridge Isotope labs. Merck pre-coated silica gel plates (250 µm, 60 F254) were used for analytical TLC. Spots were visualized using 254 nm ultraviolet light, with either ceric ammonium molybdate or phosphomolybdic acid stains as visualizing agents. Chromatographic purifications were performed on Sorbent Technologies silica gel (particle size 32-63 microns). 1H and 13C NMR spectra were recorded at 500 MHz, 360 MHz and 125 MHz, 90 MHz respectively, in CDCl3 or (CD3)2SO on a Bruker AM-500, DRX-500, or DRX-360 spectrometer. Chemical shifts are reported relative to internal chloroform (δ 7.27 for 1H, δ 77.23 for 13C) or dimethyl sulfoxide (δ 2.50 for 1H, δ 39.53 for 13C). Infrared spectra were recorded on a NaCl plate using a Perkin-Elmer 1600 series Fourier transform spectrometer. Optical rotation measurements were recorded using a Jasco P2000 polarimeter. High resolution mass spectra were obtained on an Autospec high resolution double-focusing electrospray ionization/chemical ionization spectrometer with either DEC 11/73 or OPUS software data system.

General Procedure for Phenazines in Table 1
To a solution of bromide (1 equiv) in toluene (0.1 M) was added Cs2CO3 (2.0 equiv), phosphine ligand (0.08 equiv), and Pd(OAc)2 (0.05 equiv) at room temperature. The reaction mixture was allowed to stir and warm to 120 °C for 4-24 h. Once the reaction appeared to be complete by consumption of the bromide by TLC analysis, the mixture was allowed to cool to room temperature, diluted with CHCl3, and filtered through celite. The solution was concentrated, loaded on silica gel, and purified by silica gel chromatography.

Phenazine (entry 3)
Reaction of 2-bromoaniline according to the general procedure with purification by flash chromatography (10:1 hexanes:EtOAc to 1:1 hexanes:EtOAc) provided phenazine 3 as a yellow solid (95% yield): mp 170 °C. Rf 0.25 (10:1 hexanes:EtOAc). 1H NMR (CDCl3, 500 MHz): δ = 8.27 (dd, J = 6.7, 3.4 Hz, 4H), 7.86 (dd, J = 6.7, 3.4 Hz, 4H). 13C NMR (CDCl3, 125 MHz): δ = 143.8, 130.7, 129.9. FTIR (thin film) 3739, 3053, 2928, 2857, 1625, 1513, 1462, 1358, 1249, 1181, 1146, 1110, 1007, 953, 895, 819, 752, 743, 600 cm-1. HRMS (ES) Calcd for C12H8N2: 181.0766 (M+H+), found 181.0735 (M+H+).

1,6-Dimethylphenazine (entries 4 and 5)
Reaction of 2-bromo-3-methylaniline or 2-bromo-6-methylaniline according to the general procedure with purification by flash chromatography (100:1 hexanes:EtOAc to 10:1 hexanes:EtOAc) provided phenazine 4/5 as a yellow solid (92% yield): mp 220 °C. Rf 0.37 (10:1 hexanes:EtOAc). 1H NMR (CDCl3, 500 MHz): δ = 8.15 (d, J = 8.7 Hz, 2H), 7.72 (dd, J = 8.7, 6.7 Hz, 2H), 7.66 (d, J = 6.7 Hz, 2H), 2.95 (s, 6H). 13C NMR (CDCl3, 125 MHz): δ = 143.0, 142.9, 137.8, 130.2, 129.7, 128.1, 18.0. FTIR (thin film) 2921, 1725, 1455, 1370, 1270, 1121, 850, 791, 743 cm-1. HRMS (ES) Calcd for C14H12N2: 209.1079 (M+H+), found 209.1070 (M+H+).

2,7-Di-tert-butylphenazine (entry 6)
Reaction of 2-bromo-4-tert-butylaniline according to the general procedure with purification by flash chromatography (20:1 hexanes:EtOAc to 10:1 hexanes:EtOAc) provided phenazine 6 as a yellow solid (55% yield): mp 210 °C. Rf 0.35 (10:1 hexanes:EtOAc). 1H NMR (CDCl3, 500 MHz): δ = 8.14-8.18 (m, 4H), 7.94 (dd, J = 9.1, 2.1 Hz, 2H), 1.50 (s, 18H). 13C NMR (CDCl3, 125 MHz): δ = 153.5, 143.5, 142.5, 130.3, 128.9, 124.2, 35.7, 31.0. FTIR (thin film) 2957, 2870, 1627, 1467, 1418, 1363, 1259, 1135, 935, 876, 821, 737, 626 cm-1. HRMS (ES) Calcd for C20H24N2: 293.2018 (M+H+), found 293.2011 (M+H+).

2,7-Bis(trifluoromethyl)phenazine (7)
Reaction of 2-bromo-4-(trifluoromethyl)aniline according to the general procedure with purification by flash chromatography (20:1 hexanes:EtOAc to 10:1 hexanes:EtOAc) provided phenazine 7 as a yellow solid (80% yield): mp 115 °C. Rf 0.50 (10:1 hexanes:EtOAc). 1H NMR (CDCl3, 500 MHz): δ = 8.63 (s, 2H), 8.41 (d, J = 9.1 Hz, 2H), 8.04 (dd, J = 9.1, 2.0 Hz, 2H). 13C NMR (CDCl3, 125 MHz): δ = 144.7, 143.3, 131.8, 128.4, 126.7, 124.7, 122.5. FTIR (thin film) 2925, 1426, 1334, 1266, 1205, 1165, 1135, 1053, 896, 836 cm-1. HRMS (ES) Calcd for C14H6F6N2: 316.0435 (M-), found 316.0444 (M-).

2,7-Dimethoxyphenazine (8)
Reaction of 2-bromo-5-methoxyaniline according to the general procedure with purification by flash chromatography (5:1 hexanes:EtOAc to 1:1 hexanes:EtOAc) provided phenazine 8 as a yellow solid (72% yield): mp 242 °C. Rf 0.25 (3:1 hexanes:EtOAc). 1H NMR (CDCl3, 500 MHz): δ = 8.03 (d, J = 9.4 Hz, 2H), 7.50 (dd, J = 9.4, 2.7 Hz, 2H), 7.40 (d, J = 2.7 Hz, 2H), 4.01 (s, 6H). 13C NMR (CDCl3, 125 MHz): δ = 160.4, 143.6, 140.6, 130.1, 126.2, 105.1, 56.0. FTIR (thin film) 2920, 1624, 1481, 1428, 1294, 1218, 1112, 1009, 839, 808 cm-1. HRMS (ES) Calcd for C14H12N2O2: 241.0977 (M+H+), found 241.0973 (M+H+).

N,N'-(Phenazine-2,7-diyl)bis(N-methylacetamide) (entry 9)
To a solution of N-(4-aminophenyl)-N-methylacetamide (136 mg, 0.83 mmol) in CHCl3 (8.3 mL) was added NBS (147 mg, 0.83 mmol) portion wise over 15 min. The reaction was allowed to stir and warm to room temperature over 30 min and then quenched with water (10 mL). The mixture was diluted and extracted with CH2Cl2 (3 x 10mL), the combined organic extracts were washed with sat aq Na2S2O3 (10 mL), brine (10 mL), and dried over sodium sulfate. The mixture was dried in vacuo, loaded onto silica gel, and purified by flash chromatography (3:1 hexanes:acetone to 1:1 hexanes:acetone) to provide bromoaniline 22 as a brown solid (77% yield): mp 120 °C. Rf 0.45 (1:1 hexanes:acetone). 1H NMR (CDCl3, 500 MHz): δ = 7.26 (d, J = 2.3 Hz, 1H), 6.93 (dd, J = 8.4, 2.3 Hz, 1H), 6.77 (d, J = 8.4 Hz, 1H), 4.24 (s, 2H), 3.19 (s, 3H), 1.87 (s, 3H). 13C NMR (CDCl3, 125 MHz): δ = 171.2, 144.0, 135.9, 131.3, 127.4, 116.0, 108.9, 37.5, 22.5. FTIR (thin film) 3455, 3336, 1636, 1505, 1423, 1382, 1310, 1144, 1034, 977, 934, 822 cm-1. HRMS (ES) Calcd for C9H11BrN2O: 240.09976 (M-H-), found 240.9962 (M-H-).
Reaction of N-(4-amino-3-bromophenyl)-N-methylacetamide according to the general procedure with purification by flash chromatography (20:1 CH2Cl2:MeOH to 10:1 CH2Cl2:MeOH) provided phenazine 9 as an orange solid (43% yield): mp 240 °C. Rf 0.15 (1:1 hexanes:acetone). 1H NMR (CDCl3, 500 MHz, 50 °C): δ = 8.27 (d, J = 9.2 Hz, 1H), 8.05 (d, J = 1.9 Hz, 1H), 7.75 (dd, J = 9.2, 1.9 Hz, 1H), 3.48 (s, 3H), 2.11 (s, 3H). 13C NMR (CDCl3, 125 MHz, 50 °C): δ = 170.4, 146.5, 143.9, 142.8, 131.2, 131.1, 125.9, 37.5, 22.9. FTIR (thin film) 2922, 1667, 1479, 1424, 1376, 1340, 1120, 1072, 984, 830 cm-1. HRMS (ES) Calcd for C18H18N4O2: 323.1508 (M+H+), found 323.1497 (M+H+).

(2S,3aR,7aR,9S,10aR,14aR)-Tetramethyl 7,14-diacetyl-3,3a,7,7a,10,10a,14,14a-octahydropyrrolo-
[3',2':4,5]pyrrolo[2,3-b]pyrrolo[3',2':4,5]pyrrolo[2,3-i]phenazine-1,2,8,9(2H,9H)-tetracarboxylate (11)
Reaction of bromoaniline 10 according to the general procedure with purification by flash chromatography (20:1 CH2Cl2:MeOH to 10:1 CH2Cl2:MeOH) provided phenazine 11 as an orange film (51% yield): Rf 0.16 (1:1 hexanes:acetone). 1H NMR (CDCl3, 500 MHz, 50 °C): δ = 8.58 (s, 2H), 7.87 (d, J = 1.5 Hz, 2H), 6.46 (d, J = 6.4 Hz, 2H), 4.70 (d, J = 8.1 Hz, 2H), 4.25 (t, J = 6.9 Hz, 2H), 3.76 (s, 6H), 2.96 (s, 6H), 2.70-2.85 (m, 4H), 2.67 (s, 6H). 13C NMR (CDCl3, 125 MHz, 50 °C): δ = 171.1, 170.7, 155.2, 143.8, 143.6, 141.6, 139.7, 124.1, 114.6, 79.1, 60.0, 53.3, 52.0, 45.3, 34.4, 24.1. FTIR (thin film) 3730, 3394, 2292, 1714, 1443, 1391, 1178, 1121. [α]D25 = 191.00 (c = 0.30, CHCl3). HRMS (ES) Calcd for C32H32N6O10: 661.2258 (M+H+), found 661.2272 (M+H+).

Di-tert-butyl 3,9-bis((S)-3-methoxy-2-((methoxycarbonyl)amino)-3-oxopropyl)dipyrrolo[2,3-b:2',3'-i]-phenazine-1,7-dicarboxylate (13)
To a solution of 12 (51 mg, 0.11 mmol) in toluene (1.1 mL) was added Cs2CO3 (72 mg, 0.22 mmol), and RuPhos palladacycle (4 mg, 0.005 mmol) at room temperature. The reaction mixture was heated to 120 °C for 18 h at which point an additional equiv of RuPhos palladacycle (4 mg, 0.005 mmol) was added and reaction continued to stir at 120 °C four more hours. The reaction mixture was cooled to room temperature, diluted with CH2Cl2 (20 mL), filtered through celite, dried in vacuo, loaded onto silica gel, and purified by flash chromatography (3:1 benzene:EtOAc to 1:1 benzene:EtOAc) to provide phenazine (13) as an orange solid (49% yield): mp 180 °C. Rf 0.26 (1:1 hexanes:acetone). 1H NMR (CDCl3, 500 MHz): δ = 8.91 (bs, 2H), 8.36 (s, 2H), 7.71 (s, 2H), 5.48 (d, J = 7.3 Hz, 2H), 4.81-4.88 (m, 2H), 3.77 (s, 6H), 3.71 (s, 6H), 3.30-3.48 (m, 4H), 1.78 (s, 18H). 13C NMR (CDCl3, 125 MHz): δ = 171.9, 156.3, 149.2, 141.2, 139.7, 137.7, 136.3, 130.4, 116.9, 114.8, 112.7, 84.4, 53.6, 52.6, 52.4, 28.2, 27.9. FTIR (thin film) 3310, 2954, 1726, 1536, 1425, 1374, 1329, 1254, 1153, 1067, 855 cm-1. [α]D25 = 20.7 (c = 0.33, CDCl3). HRMS (ES) Calcd for C38H44N6O12: 799.2915 (M+Na+), found 799.2934 (M+Na+).

(2S,2'S)-Dimethyl 3,3'-(phenazine-2,7-diyl)bis(2-((tert-butoxycarbonyl)amino)propanoate) (15)
Reaction of bromoaniline 14 according to the general procedure with purification by flash chromatography (3:1 hexanes:acetone to 2:1 hexanes:acetone) provided phenazine 15 as a brown film (63% yield): Rf 0.28 (2:1 hexanes:acetone). 1H NMR (CDCl3, 500 MHz): δ = 8.16 (d, J = 8.9 Hz, 2H), 7.99 (s, 2H), 7.65 (d, J = 8.9 Hz, 2H), 5.14 (d, J = 7.9 Hz, 2H), 4.71-4.83 (m, 2H), 3.75 (s, 6H), 3.25-3.48 (m, 4H), 1.39 (s, 18H). 13C NMR (CDCl3, 125 MHz): δ = 171.9, 155.0, 143.1, 142.7, 139.1, 132.4, 129.5, 129.2, 80.1, 54.0, 52.4, 38.8, 28.1. FTIR (thin film) 2927, 1712, 1510, 1364, 1165, 1057 cm-1. [α]D25 = 11.6 (c = 1.25, CHCl3). HRMS (ES) Calcd for C30H38N4O8: 605.2587 (M+Na+), found 605.2595 (M+Na+).

Dibenzo[a,h]phenazine (17)
Reaction of bromoaniline 16 according to the general procedure with purification by flash chromatography (25:1 hexanes:EtOAc to 10:1 hexanes:EtOAc) provided phenazine 17 as a yellow solid (40% yield): mp 280 °C. Rf 0.43 (10:1 hexanes:EtOAc). 1H NMR (CDCl3, 500 MHz): δ = 9.49 (d, J = 7.8 Hz, 1H), 8.19 (d, J = 9.2 Hz, 1H), 8.11 (d, J = 9.2 Hz, 1H), 8.00 (d, J = 6.9 Hz, 1H), 7.79-7.89 (m, 2H). 13C NMR (CDCl3, 125 MHz): δ = 142.1, 141.9, 133.5, 132.4, 131.4, 129.5, 128.4, 127.9, 127.7, 125.3. . FTIR (thin film) 2919, 2851, 1727, 1458, 1382, 1341, 1258, 1115, 827, 741. HRMS (ES) Calcd for C20H12N2: 281.1079 (M+H+), found 281.1080 (M+H+).

Dimethyl phenazine-1,3-dicarboxylate (19)
Reaction of ortho bromo aniline 18 according to the general procedure with purification by flash chromatography (10:1 hexanes:EtOAc to 1:1 hexanes:EtOAc) provided phenazine 19 as a yellow solid (65% yield): mp 144 °C. Rf 0.17 (5:1 hexanes:EtOAc). 1H NMR (CDCl3, 500 MHz): δ = 9.11 (d, J = 1.9 Hz, 1H), 8.77 (d, J = 1.9 Hz, 1H), 8.34 (m, 1H), 8.27 (m, 1H), 7.87-7.95 (m, 2H), 4.13 (s, 3H), 4.06 (s, 3H). 13C NMR (CDCl3, 125 MHz): δ = 166.7, 165.6, 144.7, 144.2, 142.4, 142.3, 136.4, 132.4, 132.2, 131.9, 131.0, 130.7, 130.6, 130.1, 53.1, 53.0. FTIR (thin film) 1725, 1600, 1520, 1435, 1329, 1244, 1099, 1030, 755. HRMS (ES) Calcd for C16H12N2O4: 297.0875 (M+H+), found 297.0873 (M+H+).

ACKNOWLEDGEMENTS
We grateful acknowledge the invaluable assistance of Professor E. James Petersson (University of Pennsylvania) in obtaining and interpreting the fluorescence data. We also thank Professor Ivan Dmochowski (University of Pennsylvania) for helpful discussions regarding the fluorescence properties of the phenazines, and the donors of the Petroleum Research Fund, administered by the American Chemical Society (ND-48955) for the generous support of this research.

References

1. We warmly dedicate this manuscript to our friend and colleague Professor Albert Padwa, in grateful acknowledgement of his lifetime of creative accomplishments in organic chemistry.
2. For an excellent discussion of increasing molecular complexity, see E. J. Corey and X.-M. Cheng, ‘The Logic of Chemical Synthesis,’ Wiley, New York, 1995.
3. For an excellent recent review, see U. Beifuss and M. Tietze, Top. Curr. Chem., 2005, 244, 77.
4. Reference 3, p. 109.
5. M. Shen, G. Li, B. Lu, A. Hossain, F. Roschangar, V. Farina, and C. Senanayake, Org. Lett., 2004, 6, 4129. CrossRef
6. For conceptually related examples, see a) M. Tietze, A. Iglesias, E. Merisor, J. Conrad, I. Klaiber, and U. Beifuss, Org. Lett., 2005, 7, 1549; CrossRef b) T. Emoto, N. Kubosaki, Y. Yamagiwa, and T. Kamikawa, Tetrahedron Lett., 2000, 41, 355. CrossRef
7. All compounds were characterized by full spectroscopic (NMR, IR, high resolution MS) data. Yields refer to spectroscopically and chromatographically homogeneous (>95%) materials.
8. Prepared from the known amino compound (M. Taniguchi, A. Gonsho, M. Nakagawa, and T. Hino, Chem. Pharm. Bull., 1983, 31, 1856) by 1) Boc protection; 2) bromination; and 3) Boc deprotection; For an excellent review on the chemistry of hexahydropyrroloindoles, see D. Crich and A. Banerjee, Acc. Chem. Res., 2007, 40, 151. CrossRef
9. For a discussion of the regiochemistry of phenazine formation, see Y. Kosugi, K. Itoho, H. Okazaki, and T. Yanai, J. Org. Chem., 1995, 60, 5690. CrossRef