tert-Butyl
Isocyanide as a Convertible Reagent in Ugi Reaction: Microwave-Assisted
Preparation of 5,6-Dihydropyrazolo[1,5-a]pyrazine-4,7-diones

Mikhail Nikulnikov; Sergey Tsirulnikov; Volodymyr Kysil; Alexandre Ivachtchenko; Mikhail Krasavin

doi:10.1055/s-0028-108766

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Synlett 2009(2): 260-262
DOI: 10.1055/s-0028-108766

LETTER

tert-Butyl Isocyanide as a Convertible Reagent in Ugi Reaction: Microwave-Assisted Preparation of 5,6-Dihydropyrazolo[1,5-a]pyrazine-4,7-diones

Mikhail Nikulnikov^a,b, Sergey Tsirulnikov^a, Volodymyr Kysil^c, Alexandre Ivachtchenko^c, Mikhail Krasavin*^a,b
^a Chemical Diversity Research Institute, 2a Rabochaya St., Khimki, Moscow Region 114401, Russian Federation
Fax: +7(495)6269780; e-Mail: myk@chemdiv.com;
^b Department of Organic and Biological Chemistry, L. N. Tolstoy State Pedagogical University, 125 Lenin Avenue, Tula 300026, Russian Federation
^c ChemDiv, Inc., 6605 Nancy Ridge Drive, San Diego, CA 92121, USA

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Publication History

Received 29 August 2008
Publication Date:
15 January 2009 (online)

Abstract
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Abstract

tert-Butyl amides resulting from Ugi MCR of t-BuNC and 5-substituted-1H-pyrazole-3-carboxylic acids with various aldehydes and amines undergo cyclization into 5,6-dihydropyrazolo[1,5-a]pyrazine-4,7-diones in glacial acetic acid under microwave irradiation. This reaction is a remarkable case of neighboring-group-assisted cleavage of tert-butyl amides and demonstrates utility of t-BuNC as a new convertible isocyanide.

Key words

Ugi multicomponent reaction - convertible isocyanides - microwave-assisted cyclization - post-Ugi MCR cyclization

References and Notes

1a Dömling A. Ugi I. Angew. Chem. Int. Ed. 2000, 39: 3168

Search in Google Scholar
1b Dömling A. Chem. Rev. 2006, 106: 17

Search in Google Scholar
2 Hulme C. Morrissette MM. Volz FA. Burns CJ. Tetrahedron Lett. 1998, 39: 1113

Crossref Search in Google Scholar
3 Keating TA. Armstrong RW. J. Am. Chem. Soc. 1995, 117: 7842

Crossref Search in Google Scholar
4 Rikimaru K. Yanagisawa A. Kan T. Fukuyama T. Synlett 2004, 41

Thieme Connect
5a Isaacson J. Gilley CB. Kobayashi Y. J. Org. Chem. 2007, 72: 3913

Search in Google Scholar
5b Vamos M. Ozboya K. Kobayashi Y. Synlett 2007, 1595
6 Walborsky HM. Niznik GE. J. Org. Chem. 1972, 37: 187

Crossref Search in Google Scholar
7a Blackburn C. Guan B. Tetrahedron Lett. 2000, 41: 1495

Search in Google Scholar
7b Veljkovic I. Zimmer R. Reissig H.-U. Bruedgam I. Hartl H. Synthesis 2006, 2677
8 Baraldi PG. Cacciari B. Leoni A. Recanatini M. Roberti M. Rossi M. Manfredini S. Periotto V. Simoni D. Farmaco 1991, 46: 1337

Search in Google Scholar
9 Baraldi PG. Cacciari B. Romagnoli R. Spalluto G. Arzneim.-Forsch. 1999, 49: 997

Search in Google Scholar
10a Baraldi PG. Leoni A. Cacciari B. Manfredini S. Simoni D. Bergomi M. Menta E. Spinelli S. J. Med. Chem. 1994, 37: 4329

Search in Google Scholar
10b Baraldi PG. Leoni A. Cacciari B. Manfredini S. Simoni D. Bioorg. Med. Chem. Lett. 1993, 3: 2511

Search in Google Scholar
11 Baraldi PG. Casolari A. Manfredini S. Periotto V. Zanirato V. Florio C. Traversa V. Bertelli GM. Borea PA. Arzneim.-Forsch. 1988, 38: 1262

Search in Google Scholar
12 Pirrung MC. Ghorai S. J. Am. Chem. Soc. 2006, 128: 11771

Search in Google Scholar

13

Other reaction conditions that were screened and proved inefficient for post-MCR cyclization of 3 included conventional heating in AcOH, conventional and microwave heating in TFA, as well as using base promoters (KOt-Bu, NaH) in various solvents (e.g., THF, DMF, dioxane). tert-Butyl isonitrile was chosen on the basis of its commercial availability in large quantities. However, we are also finding it superior to other isocyanides in the present post-MCR cyclization. These finding will be disclosed in a separate communication.

14

Parallel evaporation of volatiles from the microwave reactor tube was carried out using GeneVac^® equipment.

15

No further purification and characterization (except LC-MS analysis) of the crude Ugi reaction products 3 were performed.

16

Characterization Data for Selected Compounds
Compound 2f: white solid, mp 122-123 ˚C. ^¹H NMR (300 MHz, CDCl₃): δ = 7.58 (s, 1 H), 7.50-7.55 (t, J = 8.1 Hz, 1 H), 7.27-7.31 (m, 2 H), 7.19-7.24 (m, 1 H), 7.08-7.13 (m, 3 H), 7.00 (ddd, J = 8.4, 2.5, 1.0 Hz, 1 H), 6.89 (d, J = 8.4 Hz, 2 H), 5.63 (d, J = 14.5 Hz, 1 H), 5.58 (s, 1 H), 3.87 (s, 3 H), 3.82 (s, 3 H), 3.45 (d, J = 14.5 Hz, 1 H), 2.38 (s, 3 H). ^¹³C NMR (75Hz, CDCl₃): δ = 160.2, 159.7, 159.3, 158.1, 154.3, 138.0, 137.3, 132.1, 131.5, 131.1, 129.8, 129.5, 129.1, 126.6, 126.3, 125.7, 119.1, 116.4, 114.1, 111.1, 110.4, 60.6, 55.0, 54.9, 45.6, 19.2. LC-MS: m/z = 433 [M + H]. Anal. Calcd for C₂₈H₂₅N₃O₄: C, 71.93; H, 5.39; N, 8.99. Found: C, 72.04; H, 5.43; N, 9.02.
Compound 2i: beige solid, mp 152-153 ˚C (decomp.). ^¹H NMR (300 MHz, CDCl₃): δ = 7.25 (dd, J = 7.4, 5.3 Hz, 2 H), 7.07-7.12 (m, 4 H), 6.83-6.90 (m, 3 H), 5.57 (d, J = 14.5 Hz, 1 H), 5.17 (s, 1 H), 3.79 (s, 3 H), 3.48 (d, J = 14.5 Hz, 1 H), 2.03-2.12 (m, 1 H), 1.05-1.15 (m, 2 H), 0.90-0.96 (m, 2 H). ^¹³C NMR (75Hz, CDCl₃): δ = 164.0, 162.9 (d, J _C-F = 248.5 Hz), 159.5, 159.3, 153.9, 137.2, 129.7, 129.5 (d, J _C-F = 2.9 Hz), 128.7 (d, J _C-F = 8.6 Hz), 126.1, 116.3 (d, J _C-F = 21.7), 114.1, 110.4, 63.3, 54.4, 45.5, 9.2, 9.1, 8.9. LC-MS: m/z = 406 [M + H]. Anal. Calcd for C₂₃H₂₀FN₃O₃: C, 68.14; H, 4.97; N, 10.36. Found: C, 68.19; H, 5.03; N, 10.39.
Compound 2j: white solid, mp 147-149 ˚C (decomp.). ^¹H NMR (300 MHz, CDCl₃): δ = 7.61 (d, J = 3.5 Hz, 1 H), 7.48 (s, 1 H), 7.46 (d, J = 5.0 Hz, 1 H), 7.25-7.37 (m, 5 H), 7.12-7.18 (m, 3 H), 7.02 (t, J = 8.4 Hz, 2 H), 5.76 (s, 1 H). ^¹³C NMR (75Hz, CDCl₃): δ = 162.9 (d, J _C-F = 248.5 Hz), 159.6, 153.7, 153.4, 138.1, 137.5, 132.4, 130.2 (d, J _C-F = 2.8 Hz), 129.1, 128.7 (d, J _C-F = 8.6 Hz), 129.3, 128.0, 127.9, 127.6, 126.7, 116.1 (d, J _C-F = 22.1), 111.0, 68.7. LC-MS: m/z = 404 [M + H]. Anal. Calcd for C₂₂H₁₄FN₃O₂S: C, 65.50; H, 3.50; N, 10.47. Found: C, 65.54; H, 3.60; N, 10.51.