A General and Efficient Synthesis of Azaindoles and Diazaindoles

Christian Harcken; Yancey Ward; David Thomson; Doris Riether

doi:10.1055/s-2005-922753

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Synlett 2005(20): 3121-3125
DOI: 10.1055/s-2005-922753

LETTER

A General and Efficient Synthesis of Azaindoles and Diazaindoles

Christian Harcken, Yancey Ward, David Thomson, Doris Riether*
Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road/P.O. Box 368, Ridgefield, Connecticut 06877, USA
Fax: +1(203)7916072; e-Mail: driether@rdg.boehringer-ingelheim.com;

Further Information

Publication History

Received 30 August 2005
Publication Date:
28 November 2005 (online)

Abstract
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Abstract

The DBU-mediated cyclization of ortho-(Boc-amino)alkynyl pyridines, -pyridazines, -pyrimidines and -pyrazines efficiently generates azaindoles and diazaindoles, respectively. The reaction proceeds under mild conditions and in high yields. A variety of functional groups are tolerated.

Key words

azaindole - diazaindoles - cyclization - heterocycles - alkynes

References

1 Hands D. Sishop B. Cameron M. Edwards JS. Cottrell IF. Wright SHB. Synthesis 1996, 877

Article in Thieme Connect Google Scholar
2 Modnikova GA. Titkova RM. Glushkov RG. Sokolova AS. Silin VA. Chernov VA. Pharm. Chem. J. 1988, 22: 135

Crossref Google Scholar
3 Kuzmich D. Mulrooney C. Synthesis 2003, 1671

Article in Thieme Connect Google Scholar
4 Ujjainwalla F. Warner D. Tetrahedron Lett. 1998, 39: 5355

Crossref Google Scholar
5 Song JJ. Tan Z. Gallou F. Xu J. Yee NK. Senanayake CH. J. Org. Chem. 2005, 70: 6512

Crossref Google Scholar
6 Castro CE. Stevens RD. J. Org. Chem. 1963, 28: 2163

Google Scholar
7 Xu L. Lewis IR. Davidsen SK. Summers JB. Tetrahedron Lett. 1998, 39: 5159

Crossref Google Scholar
8 Mazéas D. Guillaumet G. Viaud M.-C. Heterocycles 1999, 50: 1065

Crossref Google Scholar
9 Kumar V. Dority JA. Bacon ER. Singh B. Lesher GY. J. Org. Chem. 1992, 57: 6995

Crossref Google Scholar
10 Ames DE. Bull D. Tetrahedron 1982, 38: 383

Crossref Google Scholar
11 Norman MH. Chen N. Chen Z. Fotsch C. Hale C. Han N. Hurt R. Jenkins T. Kincaid J. Liu L. Lu Y. Moreno O. Santora VJ. Sonnenberg JD. Karbon W. J. Med. Chem. 2000, 43: 4288

Google Scholar
12 Sakamoto T. Kondo Y. Iwashita S. Yamanaka H. Chem. Pharm. Bull. 1987, 35: 1823

Crossref Google Scholar
13 Brière J.-F. Dupas G. Quéguiner G. Bourguignon J. Heterocycles 2000, 52: 1371

Crossref Google Scholar
14 Ames DE. Brohi MI. J. Chem. Soc., Perkin Trans. 1 1980, 1384

Crossref Google Scholar
15 Koradin C. Dohle W. Rodriguez AL. Schmid B. Knochel P. Tetrahedron 2003, 59: 1571

Crossref Google Scholar
16 Rodriguez AL. Koradin C. Dohle W. Knochel P. Angew. Chem. Int. Ed. 2000, 39: 2488

Crossref PubMed Google Scholar
17 Choi-Sledeski YM. Kearney R. Poli G. Pauls H. Gardner C. Gong D. Becker M. Davis R. Spada A. Liang G. Chu V. Brown K. Collussi D. Leadley R. Rebello S. Moxey P. Morgan S. Bentley R. Kasiewski C. Maignan S. Guilloteau J.-P. Mikol V. J. Med. Chem. 2003, 46: 681

Crossref Google Scholar
18 Kelly TA. Patel UR. J. Org. Chem. 1995, 60: 1875

Crossref Google Scholar
22 Venuti MC. Stephenson RA. Alvarez R. Bruno JJ. Strosberg AM. J. Med. Chem. 1988, 31: 2136

Crossref Google Scholar
23 Crous R. Dywer C. Holzapfel CW. Heterocycles 1999, 51: 721

Google Scholar
24 Park SS. Choi J.-K. Yum EK. Ha D.-C. Tetrahedron Lett. 1998, 39: 627

Crossref Google Scholar
25 Estel L. Marsais F. Queguiner G. J. Org. Chem. 1988, 53: 2740

Crossref Google Scholar

19

General Procedure for the Sonogashira Coupling.
To a solution of ortho-(Boc-amino)halogeno pyridine or diazine (1 mmol) in anhyd DMF (1 mL) and Et₃N (3 mL) was added copper iodide (0.10 mmol), Pd(PPh₃)₂Cl₂ (0.05 mmol) and the alkyne (1 mmol) under argon and the reaction stirred at r.t. for 15 h. The reaction was diluted with EtOAc (10 mL), washed with sat. aq NH₄Cl solution (2 × 5 mL) and the combined aqueous layers were extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (5 mL), dried over MgSO₄ and concentrated. Column chromatography (hexane-EtOAc) yielded ortho-(Boc-amino)alkynyl pyridines or diazines in 37-99% yield.
Data for Alkynes. Compound 7: prepared from (4-iodopyridin-3-yl)carbamic acid tert-butyl ester. [23] ¹H NMR (400 MHz, CDCl₃): δ = 9.35 (s, 1 H), 8.20 (d, J = 5.06 Hz, 1 H), 7.19 (d, J = 5.06 Hz, 1 H), 7.06 (s, 1 H), 2.51 (t, J = 7.07 Hz, 2 H), 1.72 (qt, J = 7.07 Hz, J = 7.33 Hz, 2 H), 1.55 (s, 9 H), 1.09 (t, J = 7.33 Hz, 3 H).
Compound 9: ¹H NMR data are in accordance with data reported in the literature. [7]
Compound 11: prepared from (2-bromopyridin-3-yl)carbamic acid tert-butyl ester. [22] ¹H NMR (400 MHz, CDCl₃): δ = 8.42 (d, J = 9.08 Hz, 1 H), 8.19 (dd J = 1.39 Hz, J = 4.67 Hz, 1 H), 7.18 (dd, J = 4.67 Hz, J = 8.57 Hz, 1 H), 2.53 (t, J = 7.08 Hz, 2 H), 1.74 (qt, J = 7.33 Hz, J = 7.08 Hz, 2 H), 1.54 (s, 9 H), 1.10 (t, J = 7.33 Hz, 3 H).
Compound 13: prepared from (3-iodopyridin-2-yl)carbamic acid tert-butyl ester. [24] ¹H NMR (400 MHz, CDCl₃): δ = 8.36 (dd, J = 5.05 Hz, J = 1.77 Hz, 1 H), 7.60 (dd, J = 7.58 Hz, 1.77 Hz, 1 H), 7.57 (s, 1 H), 6.90 (dd, J = 7.58 Hz, J = 5.05 Hz, 1 H), 2.49 (t, J = 7.07 Hz, 2 H), 1.69 (qt, J = 7.33 Hz, J = 7.07 Hz, 2 H), 1.54 (s, 9 H), 1.09 (t, J = 7.33 Hz, 3 H).
Compound 15: ¹H NMR (400 MHz, CDCl₃): δ = 9.74 (br s, 1 H), 9.29 (br s, 1 H), 6.90 (s, 1 H), 2.99 (t, J = 7.58 Hz, 2 H), 1.69 (m, 11 H), 0.99 (t, J = 7.33 Hz, 3 H).
Compound 17: ¹H NMR (400 MHz, CDCl₃): δ = 8.97 (br s, 1 H), 7.92 (br s, 1 H), 6.74 (s, 1 H), 2.99 (t, J = 7.58 Hz, 2 H), 1.69 (qt, J = 7.58 Hz, J = 7.58 Hz, 2 H), 1.63 (s, 9 H), 1.01 (t, J = 7.58 Hz, 3 H).
Compound 19: ¹H NMR (400 MHz, CDCl₃): δ = 9.41 (s, 1 H), 8.73 (s, 1 H), 6.96 (br s, 1 H), 2.49 (t, J = 7.08 Hz, 2 H), 1.66 (qt, J = 7.33 Hz, J = 7.08 Hz, 2 H), 1.48 (s, 9 H), 1.03 (t, J = 7.33 Hz, 3 H).
Compound 21: ¹H NMR (400 MHz, CDCl₃): δ = 8.34 (br s, 1 H), 8.24 (br s, 1 H), 6.46 (br s, 1 H), 2.96 (t, J = 7.58 Hz, 2 H), 1.69 (qt, J = 7.58 Hz, J = 7.34 Hz, 2 H), 1.62 (s, 9 H), 0.99 (t, J = 7.34 Hz, 3 H).
Compound 23: ¹H NMR (400 MHz, CDCl₃): δ = 9.32 (s, 1 H), 8.14 (d, J = 5.03 Hz, 1 H), 7.16 (d, J = 4.80 Hz, 1 H), 6.97 (s, 1 H), 4.53 (s, 2 H), 1.46 (s, 9 H).
Compound 25: ¹H NMR (400 MHz, CDCl₃): δ = 9.26 (br s, 1 H), 8.12 (d, J = 5.05 Hz, 1 H), 7.25 (s, 1 H), 7.11 (d, J = 5.05 Hz, 1 H), 3.79 (t, J = 5.71 Hz, 2 H), 2.60 (t, J = 6.95 Hz, 2 H), 1.85 (tt, J = 6.95 Hz, J = 5.71 Hz, 2 H), 1.48 (s, 9 H).
Compound 27: ¹H NMR (400 MHz, CDCl₃): δ = 9.28 (s, 1 H), 8.14 (d, J = 5.05 Hz, 1 H), 7.13 (d, J = 5.05 Hz, 1 H), 6.98 (s, 1 H), 3.41 (s, 1 H), 1.60 (s, 6 H), 1.46 (s, 9 H).
Compound 29: ¹H NMR (400 MHz, CDCl₃): δ = 9.35 (s, 1 H), 8.21 (d, J = 5.05 Hz, 1 H), 7.25-7.52 (m, 6 H), 7.04 (br s, 1 H), 1.49 (s, 9 H).
Compound 31: ¹H NMR (400 MHz, CDCl₃): δ = 8.85 (s, 1 H), 8.10 (d, J = 5.05 Hz, 1 H), 7.32 (d, J = 5.05 Hz, 1 H), 7.23 (d, J = 8.85 Hz, 2 H), 6.57 (s, J = 8.85 Hz, 2 H), 1.45 (s, 9 H).
Compound 33: ¹H NMR (400 MHz, CDCl₃): δ = 9.41 (s, 1 H), 8.22 (d, J = 5.06 Hz, 1 H), 7.20 (d, J = 5.06 Hz, 1 H), 7.04 (s, 1 H), 4.86 (s, 1 H), 4.22 (d, J = 5.56 Hz, 2 H), 1.56 (s, 9 H), 1.48 (s, 9 H).

20

Typical Procedure for the Cyclization.
To a solution of ortho-(Boc-amino)alkynyl pyridine or diazine (1 mmol) in MeOH-H₂O (5 mL, 3:1) was added DBU (5 mmol) and the reaction heated to 65-85 °C for 1-14 h. Then, MeOH was removed under vacuum and the solution cooled in an ice-water bath; H₂O was added dropwise to precipitate the azaindole or diazaindole. Compounds 16, 18, 28, and 30 did not solidify from aqueous solution. In these cases the H₂O-DBU mixture was decanted from the oil. The oil is then dissolved in MeOH and the precipitation procedure repeated. Compound 28 was purified by chromatography. The precipitate was collected by filtration, washed with H₂O and dried to give the desired products (>95% purity). Yields 62%-97%.
Data for Azaindoles and Diazaindoles. Compound 8: mp (MeOH-H₂O) 158 °C. ¹H NMR (400 MHz CDCl₃): δ = 8.71 (s, 1 H), 8.20 (d, J = 5.31 Hz, 1 H), 7.43 (d, J = 5.31 Hz, 1 H), 6.28 (s, 1 H), 2.80 (t, J = 7.58 Hz, 2 H), 1.81 (qt, J = 7.58 Hz, J = 7.33 Hz, 2 H), 1.03 (t, J = 7.33 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 145.22, 137.99, 134.03, 133.50, 132.73, 99.02, 30.45, 22.36, 13.90. HRMS (APCI): m/z calcd for C₁₀H₁₃N₂ [M + 1]: 161.1073; found: 161.1075.
Compound 10: ¹H NMR data are in accordance with data reported in the literature. [25]
Compound 12: mp (MeOH-H₂O) 123 °C. ¹H NMR (400 MHz, CDCl₃): δ = 10.43 (s, 1 H), 8.40 (dd, J = 1.26 Hz, 4.80 Hz, 1 H), 7.59 (d J = 8.08 Hz, 1 H), 7.02 (dd, J = 4.80 Hz, 8.08 Hz, 1 H), 6.44 (s, 1 H), 2.80 (t, J = 7.58 Hz, 2 H), 1.76 (qt, J = 7.33 Hz, J = 7.58 Hz, 2 H), 0.98 (t, J = 7.33 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 147.27, 145.08, 141.98, 129.39, 117.72, 115.63, 99.68, 30.70, 22.37, 13.85. HRMS (APCI): m/z calcd for C₁₀H₁₃N₂ [M + 1]: 161.1073; found: 161.1076.
Compound 14: mp (MeOH-H₂O) 65 °C. ¹H NMR (400 MHz, CDCl₃): δ = 12.37 (s, 1 H), 8.21 (d, J = 4.55 Hz, 1 H), 7.83 (dd, J = 7.83 Hz, J = 1.26 Hz, 1 H), 7.03 (dd, J = 7.83 Hz, J = 4.80 Hz, 1 H), 6.20 (s, 1 H), 2.86 (t, J = 7.58 Hz, 2 H), 1.86 (qt, J = 7.58 Hz, J = 7.33 Hz, 2 H), 1.04 (t, J = 7.33 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 149.33, 141.78, 140.18, 127.63, 122.00, 115.38, 97.17, 30.84, 22.46, 13.99. HRMS (APCI): m/z calcd for C₁₀H₁₃N₂ [M + 1]: 161.1073; found: 161.1073.
Compound 16: mp (MeOH-H₂O) 154 °C. ¹H NMR (400 MHz, CDCl₃): δ = 9.46 (br s, 1 H), 9.28 (br s, 1 H), 6.35 (s, 1 H), 2.89 (t, J = 7.46 Hz, 2 H), 1.81 (qt, J = 7.45 Hz, J = 7.33 Hz, 2 H), 0.95 (t, J = 7.33 Hz, 3 H). ¹³C NMR (100 MHz, MeOH-d ₄): δ = 148.43, 145.51, 137.86, 133.96, 126.91, 99.78, 30.95, 23.37, 14.09. HRMS (APCI): m/z calcd for C₉H₁₂N₃ [M + 1]: 162.1025; found: 162.1032.
Compound 18: mp (MeOH-H₂O) 177 °C. ¹H NMR (400 MHz, CDCl₃): δ = 10.02 (br s, 1 H), 8.83 (br s, 1 H), 7.44 (br s, 1 H), 6.64 (s, 1 H), 2.81 (t, J = 7.46 Hz, 2 H), 1.79 (qt, J = 7.46 Hz, J = 7.34 Hz, 2 H), 0.97 (t, J = 7.34 Hz, 3 H). ¹³C NMR (100 MHz, MeOH-d ₄): δ = 151.68, 149.60, 130.76, 107.23, 97.11, 29.69, 21.40, 12.47. HRMS (APCI): m/z calcd for C₉H₁₂N₃ [M + 1]: 162.1025; found: 162.1032.
Compound 20: mp (MeOH-H₂O) 176 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.87 (s, 1 H), 8.63 (s, 1 H), 6.39 (s, 1 H), 2.79 (t, J = 7.46 Hz, 2 H), 1.75 (qt, J = 7.46 Hz, J = 7.46 Hz, 2 H), 0.95 (t, J = 7.46 Hz, 3 H). ¹³C NMR (100 MHz, MeOH-d ₄): δ = 151.10, 150.11, 148.43, 137.04, 127.43, 98.08, 29.75, 21.46, 12.33. HRMS (APCI): m/z calcd for C₉H₁₂N₃ [M + 1]: 162.1025; found: 162.1031.
Compound 22: mp (MeOH-H₂O) 156 °C. ¹H NMR (400 MHz, CDCl₃): δ = 10.26 (br s, 1 H), 8.36 (br s, 1 H), 8.08 (br s, 1 H), 6.40 (s, 1 H), 2.81 (t, J = 7.58 Hz, 2 H), 1.79 (qt, J = 7.58 Hz, J = 7.34 Hz, 2 H), 0.99 (t, J = 7.34 Hz, 3 H). ¹³C NMR (100 MHz, MeOH-d ₄): δ = 149.67, 143.79, 141.70, 137.77, 136.53, 98.67, 31.67, 23.26, 14.09. HRMS (APCI): m/z calcd for C₉H₁₂N₃ [M + 1]: 162.1025; found: 162.1031.
Compound 24: mp (MeOH-H₂O) 185 °C. ¹H NMR (400 MHz, MeOH-d ₄): δ = 8.60 (s, 1 H), 8.00 (d, J = 5.56 Hz, 1 H), 7.43 (d, J = 5.81 Hz, 1 H), 6.44 (s, 1 H), 4.79 (s, 2 H). HRMS (APCI): m/z calcd for C₈H₉N₂O [M + 1]: 149.0709; found: 149.0711.
Compound 26: mp (MeOH-H₂O) 161 °C. ¹H NMR (400 MHz, MeOH-d ₄): δ = 8.52 (s, 1 H), 7.96 (d, J = 5.56 Hz, 1 H), 7.44 (d, J = 5.56 Hz, 1 H), 6.29 (s, 1 H), 3.62 (t, J = 6.32 Hz, 2 H), 2.90 (t, J = 7.71 Hz, 2 H), 1.98 (tt, J = 6.32 Hz, J = 7.71 Hz, 2 H). HRMS (APCI): m/z calcd for C₁₀H₁₃N₂O [M + 1]: 177.1022; found: 177.1026.
Compound 28: oil. ¹H NMR (400 MHz, MeOH-d ₄): δ = 8.60 (s, 1 H), 8.01 (d, J = 5.56 Hz, 1 H), 7.50 (d, J = 5.65 Hz, 1 H), 6.43 (s, 1 H), 1.57 (s, 6 H). HRMS (APCI): m/z calcd for C₁₀H₁₁N₂ [M - H₂O + 1]: 159.0916; found: 159.0917.
Compound 30: mp (MeOH-H₂O) 205 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.92 (s, 1 H), 8.14 (d, J = 5.56 Hz, 1 H), 7.80 (d, J = 7.96 Hz, 2 H), 7.50 (d, J = 5.31 Hz, 1 H), 7.41 (dd, J = 7.58 Hz, J = 7.58 Hz, 2 H), 7.33 (dd, J = 6.81 Hz, J = 6.81 Hz, 2 H), 6.79 (s, 1 H). HRMS (APCI): m/z calcd for C₁₃H₁₁N₂ [M + 1]: 195.0916; found: 195.0921.
Compound 32: mp (MeOH-H₂O) 188 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.76 (s, 1 H), 8.22 (d, J = 5.56 Hz, 1 H), 7.53 (d, J = 8.59 Hz, 2 H), 7.46 (d, J = 5.30 Hz, 1 H), 6.77 (d, J = 8.33 Hz, 2 H), 6.65 (s, 1 H), 3.49 (br s, 2 H). HRMS (APCI): m/z calcd for C₁₃H₁₂N₃ [M + 1]: 210.1031; found: 210.1034.
Compound 34: mp (MeOH-H₂O) 64 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.75 (s, 1 H), 8.22 (d, J = 5.56 Hz, 1 H), 7.45 (dd, J = 5.56 Hz, J = 1.01 Hz, 1 H), 6.33 (s, 1 H), 5.15 (s, 1 H), 4.41 (d, J = 6.06 Hz, 2 H), 1.49 (s, 9 H). HRMS (APCI): m/z calcd for C₁₃H₁₈N₃O₂ [M + 1]: 248.1393; found: 248.1384.

21

Unpublished results: pyridines and diazines with substituents such as NMe₂, OMe, or CN are well tolerated in this reaction.