Increasing the N-H Acidity: Introduction of Highly Electronegative Groups into the Hydrazine Molecule

Abstract

Various hydrazine derivatives containing combinations of trifluoroacetyl, trifluoromethanesulfonyl, and 2,4-dinitrophenyl groups were prepared. Synthetic strategy is studied in terms of using protecting groups and direct acylation.

acylations - hydrazines - neighboring-group effects - protecting groups - sulfonamides

References

1 For a review see: Ragnarsson U. Chem. Soc. Rev.  2001,  30:  205 ; and references therein

2a Mäeorg U. Grehn L. Ragnarsson U. Angew. Chem., Int. Ed. Engl.  1996,  35:  2626 

2b Brosse N. Jamart-Gregoire B. Tetrahedron Lett.  2002,  43:  249 

2c Tubrik O. Mäeorg U. Org. Lett.  2001,  3:  2297 

2d Tubrik O. Mäeorg U. Sillard R. Ragnarsson U. Tetrahedron  2004,  60:  8363 

3a Brosse N. Pinto M.-F. Jamart-Gregoire B. J. Org. Chem.  2000,  65:  4370 

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5c Mcmahon EG, Olins GM, and Schuh JR. inventors; PCT Int. Appl. WO  9640256. 

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10 Braun MW, Rudolph WH, Palsherm SB, and Eichholz KL. inventors; US Patent  5532411. 

11

An oven-dried flask was charged with 224 mg of the compound 1 (1 mmol), then evacuated and backfilled with argon. Then, 8 mL of Et₂O was added to dissolve the solid and the solution was cooled down to -80 °C. A 1.6 M solution of n-BuLi in hexane (2 equiv, 1.26 mL) was added dropwise and the obtained mixture stirred for 30 min. In the other flask, 6 mL of trifluoroacetylanhydride was added to the solution of pyridinium chloride (10 equiv) in minimum quantity of TFA. The emerging gaseous CF₃COCl was passed into the solution of metallated compound 1. The mixture was stirred for 30 min at -80 °C and then let to warm up to r.t. LiCl was filtered off and solvents were evaporated in vacuo, yielding 271 mg of 2 (mp 148-150 °C). The ESI molecular ion does not exist due to the rapid decomposition to 1. ¹³C NMR (DMSO-d ₆): δ = 116.1 (q, J _CF = 286 Hz, CF₃CONH), 117.1 [q, J _CF = 294 Hz, (CF₃CO)₂N], 155.8 (q, J _CF = 37 Hz, CF₃CONH), 159.2 [q, J _CF = 33, (CF₃CO)₂N]. Compound 3 was obtained in the same way in THF using 1 equiv n-BuLi for the first deprotonation of 1. After the reaction with CF₃COCl the addition of 1 equiv n-BuLi and CF₃COCl was repeated. THF was removed using rectifi-cation, furnishing 3 as a colorless oil. ESI-HRMS: m/z calcd for C₈HF₁₂N₂O₄: 416.9739; found: 416.9745 [MH]⁺. ¹³C NMR (DMSO-d ₆): δ = 116.9 [q, J _CF = 293 Hz, (CF₃CO)₂N], 160.2 [q, J _CF = 34, (CF₃CO)₂N].

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13 Fritz H. Kristinsson H. Mollenkopf M. Winkler T. Magn. Res. Chem.  1990,  28:  331 

14

Compound 4a: mp 130-132 °C. ¹H NMR (DMSO-d ₆): δ = 1.42 (s, 9 H, Boc), 9.31 (s, 1 H, NH), 11.27 (s, 1 H, NH). ¹³C NMR (DMSO-d ₆): δ = 27.9 (Me, Boc), 80.1 (C_q, Boc), 115.9 (q, CF₃, J _CF = 287 Hz), 154.4 (CO, Boc), 156.2 (q, CF₃CO, J _CF = 36 Hz). IR: 3294, 3192 (NH), 1740, 1696 (C = O) cm^-1. Anal. Calcd for C₇H₁₁F₃N₂O₃: C, 36.85; H, 4.86; N, 12.28. Found: C, 37.14; H, 4.77; N, 12.03.
Compound 4b: mp 106-108 °C. ¹H NMR (CDCl₃): δ = 5.150 (s, 2 H, PhCH₂), 4.341 (s, 5 H, CH_arom), 9.096 (s, 1 H, NH-Z), 10.926 (s, 1 H, NHCOCF₃). ¹³C NMR (CDCl₃): δ = 67.4 (PhCH₂), 116.0 (q, J _CF = 286 Hz, CF₃), 128.1, 128.3, 128.5, 136.0 (C_arom), 155.8 (CO, Z), 157.1 (q, J _CF = 38 Hz, CF₃CO). ESI-MS: m/z calcd for C₁₀H₈F₃N₂O₃: 261.049; found: 261.096 [M^-].

15 Schreiber SL. Tetrahedron Lett.  1980,  21:  1027 

16

Compound 4d: mp 140-141 °C. ¹H NMR (DMSO-d ₆): δ = 5.15 (s, 2 H, PhCH₂), 7.38 (s, 5 H, Ph), 10.12 (s, 1 H, NH-Z), 11.66 (s, 1 H, NHSO₂CF₃). ¹³C NMR (DMSO-d ₆): δ = 66.9 (s, PhCH₂), 119.2 (q, J _CF = 321 Hz, CF₃SO₂), 127.9, 128.2, 128.4, 136.0 (C_arom), 156.1 (CO). ESI-MS: m/z calcd for C₉H₈F₃N₂O₄S: 297.016; found: 297.083 [M^-].
Compound 4e: mp 161-163 °C. ¹H NMR (DMSO-d ₆): δ = 7.29 (d, J _CH = 9.6 Hz, 1 H, Ar), 8.39 (m, 1 H, Ar), 8.90 (d, J _CH = 2.6 Hz, 1 H, Ar), 10.41 (s, 1 H, NH). ¹³C NMR (DMSO-d ₆): δ = 115.1 (C_arom), 115.9 (J _CF = 286 Hz, COCF₃), 123.1, 130.5, 137.6, 147.1 (C_arom), 156.4 (J _CF = 36 Hz, CO). ESI-MS: m/z calcd for C₈H₄F₃N₄O₅: 293.013; found: 293.071 [M^-].

17 Hendrickson JB. Sternbach DD. J. Org. Chem.  1975,  40:  3450