A Publication
of Reliable Methods
for the Preparation
of Organic Compounds
Annual Volume
Org. Synth. 1997, 74, 101
DOI: 10.15227/orgsyn.074.0101
Submitted by Derek H. R. Barton, Mi Chen, Joseph Cs. Jászberényi, and Dennis K. Taylor1.
Checked by Richard A. Hartz and Amos B. Smith, III.
1. Procedure
CAUTION! These reactions, which involve toxic reagents, must be carried out (including workup) in an efficient fume hood.
A. 2-tert-Butyl-1,1,3,3-tetramethylguanidine (1). To an oven-dried, 500-mL, three-necked, round-bottomed flask, equipped with a nitrogen inlet with gas bubbler, magnetic stirring bar, thermometer, condenser, and a 250-mL dropping funnel, are added triphosgene (14.8 g, 0.05 mol) (Note 1), and anhydrous toluene (120 mL) (Note 2). The mixture is kept under argon and cooled to ≈10°C with the aid of an external ice bath. A solution of N,N,N',N'-tetramethylurea (18.0 mL, 0.15 mol) (Note 3) in dry toluene (50 mL) is slowly added to the mixture over 30 min (Note 4). After the addition is complete, the mixture is allowed to warm to ambient temperature, and stirring of the mixture is continued for an additional hour. During this time a white precipitate forms (Note 5). tert-Butylamine (47.3 mL, 0.45 mol) (Note 6) is slowly added to the mixture over 30 min (Note 7). After the addition is complete, the mixture is heated under reflux for 5 hr and then cooled to room temperature. Anhydrous ether (200 mL) (Note 8) is added and the white precipitate is quickly removed by filtration (Note 9). The precipitate is washed with a further quantity of anhydrous ether (300 mL) (Note 10) and immediately dissolved in aqueous 25% sodium hydroxide solution (100 mL). The mixture is then extracted with three portions of ether (300 mL). The combined organic layers are dried (potassium carbonate), filtered, and the solvent is removed under reduced pressure. The resulting colorless liquid is purified by distillation (bp 88–89°C/36 mm) to afford 18.7 g (73%) of 2-tert-butyl-1,1,3,3-tetramethylguanidine 1 (Note 11).
B. 2,2,6-Trimethylcyclohexen-1-yl iodide (2). To an oven-dried, 500-mL, three-necked, round-bottomed flask, equipped with a nitrogen inlet with gas bubbler, magnetic stirring bar, and a 250-mL dropping funnel, are added 2,2,6-trimethylcyclohexanone hydrazone (4.6 g, 0.03 mol) (Note 12), anhydrous ether (100 mL) (Note 8), and 2-tert-butyl-1,1,3,3-tetramethylguanidine (1) (46.25 g, 0.27 mol). The mixture is kept under argon at ambient temperature and an ethereal solution (100 mL) of iodine (15.25 g, 0.06 mol) is added to the mixture over 40 min with vigorous stirring. (Note 13). After the addition is complete, stirring is continued for an additional 30 min. The ether is removed under reduced pressure (Note 14) and the residue is heated at 90°C for 30 min (Note 15) under an inert atmosphere. The reaction mixture is allowed to attain ambient temperature. Ether (100 mL) is added and the organic phase is washed twice with 2 N hydrochloric acid (30 mL), aqueous sodium thiosulfate solution (30 mL), aqueous sodium bicarbonate solution (30 mL) and saturated sodium chloride solution (30 mL). The organic phase is dried (sodium sulfate) and the solvent is removed under reduced pressure to afford crude iodide (2). Purification of 2 can be achieved by flash chromatography (Note 16) affording pure iodide (2) (6.34 g, 85%) as a colorless oil. (Note 17).
2. Notes
1. Triphosgene was purchased from the Aldrich Chemical Company, Inc., and used as received.
2. Toluene is distilled from calcium hydride (CaH2) under argon just prior to use.
3. N,N,N',N'-Tetramethylurea was purchased from the Aldrich Chemical Company, Inc., and purified by distillation prior to use.
4. Although no major temperature increase is observed, the reaction proceeds best with slow addition.
5. This salt is the corresponding Vilsmeier salt. See reference 2.
6. tert-Butylamine was purchased from the Aldrich Chemical Company, Inc., and dried prior to use by distillation from CaH2 under argon.
7. No major temperature increase is observed.
8. Diethyl ether is distilled from sodium under argon just prior to use.
9. The white precipitate should be collected as quickly as possible to avoid hydrolysis to the starting urea. The precipitate turns pale yellow if hydrolysis is occurring. Additional ether (300 mL) may be needed to ensure complete transfer of the solids to the filtration apparatus.
10. The filtrate must be colorless, indicating that all impurities have been removed.
11. Distillation is not neccessary if the solids are washed correctly. Spectral data for 1 are as follows: IR (neat) cm−1: 1620; 1H NMR (CDCl3) δ: 1.22 (s, 9 H), 2.67 (s, 12 H). 1 should be stored under argon in the refrigerator to prevent hydrolysis. The purity is estimated to be ≈95% by NMR and TLC analysis. The impurity is the starting urea and could not be avoided.
12. The hydrazone of 2,2,6-trimethylcyclohexanone is prepared according to a procedure outlined in reference 3. To a solution of absolute ethanol (37 mL), hydrazine (26.0 g, 25.40 mL), and triethylamine (6.8 g, 9.43 mL) is added 2,2,6-trimethylcyclohexanone (6.3 g, 7.0 mL). The mixture is heated to 100°C for 2–3 days, cooled to ambient temperature, and the solvent removed under reduced pressure. Recrystallization of the residue from hexanes affords the hydrazone as white needles (4.85 g, 70%, mp 48–49°C). The spectra are as follows: 1H NMR (CDCl3) δ: 1.0–1.2 (m, 9 H), 1.40–1.92 (m, 6 H), 2.95 (m, 1 H), 4.51 (s, 2 H); 13C NMR (CDCl3) δ: 17.18, 17.39, 26.51, 28.92, 29.48, 31.68, 37.61, 40.43, 162.47.
13. Vigorous stirring is required as large quantities of precipitate form during the addition.
14. The nitrogen inlet is removed and replaced with a line to a water pump.
15. Heating causes most of the solids to liquify. The temperature refers to the outside oil bath temperature.
16. Flash chromatography was performed on standard Silica Gel 60Å, (230–400 mesh) with hexane, Rf = 0.75.
17. Spectral data for 2 are as follows: 1H NMR (CDCl3) δ: 1.09 (s, 6 H), 1.53–1.72 (m, 4 H), 1.87 (s, 3 H), 2.12 (t, 2 H); 13C NMR (CDCl3) d: 19.40, 31.08, 31.56, 33.69, 37.86, 39.51, 117.36, 137.70. Compound 2 deteriorates rapidly at ambient temperature, but is stable for several weeks if stored under argon in the refrigerator. The purity is estimated to be >98% by NMR and TLC analysis. No microanalytical data was obtained because of the instability of 2.
Handling and Disposal of Hazardous Chemicals
The procedures in this article are intended for use only by persons with prior training in experimental organic chemistry. All hazardous materials should be handled using the standard procedures for work with chemicals described in references such as "Prudent Practices in the Laboratory" (The National Academies Press, Washington, D.C., 2011 www.nap.edu). All chemical waste should be disposed of in accordance with local regulations. For general guidelines for the management of chemical waste, see Chapter 8 of Prudent Practices.
These procedures must be conducted at one's own risk. Organic Syntheses, Inc., its Editors, and its Board of Directors do not warrant or guarantee the safety of individuals using these procedures and hereby disclaim any liability for any injuries or damages claimed to have resulted from or related in any way to the procedures herein.
3. Discussion
The procedure described here allows the convenient preparation of large quantities of the strong, non-nucleophilic base 2-tert-butyl-1,1,3,3-tetramethyl-guanidine (1). This reagent provides an inexpensive alternative to the amidine bases, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), which suffer from being easily alkylated.4 Additionally, the hazards of using phosgene in the previous preparations of 12,4,5 have been greatly reduced by employing triphosgene as a phosgene equivalent.6
The synthetic utility of this base (1) was demonstrated in the preparation of vinyl iodides in high yields from simple ketohydrazones and iodine (Table), a process that normally gives mixtures of vinyl iodides and geminal diiodides if less hindered bases are employed.5 This base has also been used in the elimination of sulfonic acids from the corresponding sulfonates, the alkylation of compounds containing active methylene groups, the conversion of hydrazones to vinyl selenides, and the preparation of esters from sterically hindered acids.4,5



Vinyl Iodide

% Yield









Other inexpensive, sterically hindered guanidine bases have also been synthesized and their reactivity is comparable to that described here.2,4

References and Notes
  1. Department of Chemistry, Texas A&M University, College Station, TX 77843–3255.
  2. Barton, D. H. R.; Elliott, J. D.; Géro, S. D. J. Chem. Soc., Chem. Comm. 1981, 1136.
  3. Di Grandi, M. J.; Jung, D. K.; Krol, W. J.; Danishefsky, S. J. J. Org. Chem. 1993, 58, 4989.
  4. Barton, D. H. R.; Elliott, J. D.; Géro, S. D. J. Chem. Soc., Perkin Trans. I 1982, 2085.
  5. Barton, D. H. R.; Bashiardes, G.; Fourrey, J.-L. Tetrahedron 1988, 44, 147; Barton, D. H. R.; O'Brien, R. E.; Sternhell, S. J. Chem. Soc. 1962, 470; Pross, A.; Sternhell, S. Aust. J. Chem. 1970, 23, 989.
  6. Eckert, H.; Forster, Angew. Chem., Int. Ed. Engl. 1987, 26, 894.

Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)

hydrazone of 2,2,6-trimethylcyclohexanone

ethanol (64-17-5)

potassium carbonate (584-08-7)

hydrochloric acid (7647-01-0)

diethyl ether (60-29-7)

sodium hydroxide (1310-73-2)

sodium bicarbonate (144-55-8)

sodium chloride (7647-14-5)

sodium sulfate (7757-82-6)

sodium thiosulfate (7772-98-7)

iodine (7553-56-2)

toluene (108-88-3)

sodium (13966-32-0)

phosgene (75-44-5)

hydrazine (302-01-2)

guanidine (113-00-8)

hexane (110-54-3)

triethylamine (121-44-8)

argon (7440-37-1)

calcium hydride (7789-78-8)

2-tert-butyl-1,1,3,3-tetramethyl-guanidine (34331-58-3)


triphosgene (32315-10-9)

N,N,N',N'-tetramethylurea (632-22-4)

tert-Butylamine (75-64-9)

2,2,6-trimethylcyclohexanone hydrazone (189633-82-7)

2,2,6-trimethylcyclohexanone (2408-37-9)


1,8-diazabicyclo[5.4.0]undec-7-ene (6674-22-2)