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TCI Practical Example: Introduction of Cyano Group with Homologation Using TosMIC

We are proud to present the synthesis of 2-cynoadamantane with homologation using TosMIC. TosMIC is an easy-to-handle and almost odorless solid.

Used Chemicals

• p-Toluenesulfonylmethyl Isocyanide (=TosMIC) [T1046]
• 2-Adamantanone [A0719]
• Potassium tert-Butoxide (= tBuOK) [P1008]
• 2,2-Dimethoxyethane (= DME)
• Ethanol (= EtOH)

Procedure

tBuOK (934 mg, 8.32 mmol, 2.5 eq.) was added to a solution of 2-adamantanone (500 mg, 3.33 mmol) and TosMIC (845 mg, 4.33 mmol, 1.3 eq.) in DME/EtOH (10.4 mL/0.8 mL), cooling with a water bath. The mixture was stirred for 30 minutes at room temperature and for 4 hours at 40 °C. The reaction mixture was filtered and the insoluble was washed with DME. The filtrate was concentrated under reduced pressure to a volume of 2-3 mL, and the residue was charged with neutral alumina (10 g), eluted with a mixture of hexane:dichloromethane = 5:1 (60 mL) and concentrated under reduce pressure to give 2-cyanoadamantane (441 mg, 82% yield) as a white solid.

Experimenter’s Comments

The reaction mixture was monitored by TLC (ethyl acetate:hexane = 1:10, Rf = 0.6).

Analytical Data

2-Cyanoadamantane

¹H NMR (270 MHz, CDCl₃); δ 2.90 (brs, 1H), 2.18-2.13 (m, 4H), 1.94-1.87 (m, 4H), 1.77-1.72 (m, 6H).

Lead Reference

• A Simple One-Step Synthesis of 2-Cyanoadamantane, a Precursor to Adamantane-2-Carboxylic Acid
  • O. H. Oldenziel, A. M. van Leusen, Synth. Commun. 1972, 2, 281.

Other References

• Discovery and Metabolic Stabilization of Potent and Selective 2-Amino-N-(adamant-2-yl) Acetamide 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitors
  • J. J. Rohde, M. A. Pliushchev, B. K. Sorensen, D. Wodka, Q. Shuai, J. Wang, S. Fung, K. M. Monzon, W. J. Chiou, L. Pan, X. Deng, L. E. Chovan, A. Ramaiya, M. Mullally, R. F. Henry, D. F. Stolarik, H. M. Imade, K. C. Marsh, D. W. A. Beno, T. A. Fey, B. A. Droz, M. E. Brune, H. S. Camp, H. L. Sham, E. U. Frevert, P. B. Jacobson, J. T. Link, J. Med. Chem. 2007, 50, 149.