Organic Syntheses, CV 9, 147
Submitted by Derek H. R. Barton, Mi Chen, Joseph Cs. Jászberényi, and Dennis K. Taylor
1.
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.
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 CaH
2 under
argon.
7. No major temperature increase is observed.
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 (CDCl
3) 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 (CDCl
3) 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 (CDCl
3) 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, R
f = 0.75.
17. Spectral data for
2 are as follows:
1H NMR (CDCl
3) 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 (CDCl
3) 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.
Waste Disposal Information
All toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995.
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
TABLE
PREPARATION OF VINYL IODIDES FROM HYDRAZONES
|
Entry |
Hydrazone |
Vinyl Iodide |
% Yield |
|
1 |
|
|
73 |
2 |
|
|
70 |
3 |
|
|
91 |
4 |
|
|
95 |
|
Other inexpensive, sterically hindered
guanidine bases have also been synthesized and their reactivity is comparable to that described here.
2,4
Appendix
Compounds Referenced (Chemical Abstracts Registry Number)
hydrazone of 2,2,6-trimethylcyclohexanone
ethanol (64-17-5)
potassium carbonate (584-08-7)
hydrochloric acid (7647-01-0)
ether,
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)
calcium hydride (7789-78-8)
argon (7440-37-1)
2-tert-Butyl-1,1,3,3-tetramethylguanidine,
2-tert-butyl-1,1,3,3-tetramethyl-guanidine (34331-58-3)
2,2,6-TRIMETHYLCYCLOHEXEN-1-YL IODIDE (189633-81-6)
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)
1,5-diazabicyclo[4.3.0]non-5-ene
1,8-diazabicyclo[5.4.0]undec-7-ene (6674-22-2)
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