Henkel Confidential

Acrylate Platform – December 2011

Synthesis of BCHTU

Page 1

Synthesis of Benzoyl cyclohexylthiourea (BCHTU)

Method:

To a 5-Liter 4-neck round bottom flask equipped with a water condenser, thermo-probe, thermal

controller, React-IR probe, dry nitrogen purge (with desiccant), overhead stirring and pressureequilibrated addition funnel is added ammonium thiocyanate (366.20 g, 4.6904 mol) followed by

dry ethyl acetate (2000 mL). This solution/suspension is cooled near 5-10° C in an ice-water bath.

To the cooled solution/suspension is added slowly over approx. 60 minutes a solution of benzoyl

chloride (605.5 g, 500.0 mL, 4.2640 mol) in dry ethyl acetate (2000 mL). The resulting mild

exotherm is controlled with cooling and the temperature of the reaction is maintained below 20° C

during the addition. After the complete addition of the benzoyl chloride solution, the reaction is

warmed to reflux (77° C) and held at reflux minimally 2 hours. Note: Reaction progress toward the

intermediate is monitored and confirmed by FT-IR. The reaction becomes reddish with white

insoluble solids present.

External heating is removed from the reaction and the mixture is cooled again near 5-10° C. To

the cooled solution is added slowly over approx. 60 minutes a solution of cyclohexylamine (453.1

g, 4.4772 mol) in ethyl acetate (2000 mL). The resulting mild exotherm is controlled with cooling

and the temperature of the reaction is maintained below 20° C during the addition. After the

complete addition of the cyclohexylamine solution, the reaction is allowed to warm to ambient

temperature and stirred overnight Note: Alternatively the solution can be warmed to reflux for 2

hours and then cooled to ambient temperature. Reaction progress toward the target is monitored

by FT-IR. Upon confirmation of the target, the reaction mixture is washed twice with 10% HCl (2 x

4000 mL) and then deionized water (4000 mL). The organic portion is separated, dried over

anhydrous MgSO4, gravity filtered through fluted filter paper, and then concentrated in vacuo at

40° C to a pale yellow to dark orange oil. Note: The oil may solidify overnight. Crude yield is

89.4%.
Henkel Confidential

Acrylate Platform – December 2011

Synthesis of BCHTU

Page 2

Purification:

The dried crude solid is hot-filtered dual-solvent recrystallized in the following proportions; 1 part

solid: 5 parts ethanol: 1 part water. Note: These proportions are critical to the proper

crystallization of the solid.

The solid (1000 g) is dissolved in ethanol (5000 mL) at reflux. The hot solution is gravity filtered

through fluted filter paper (to remove any insoluble material). With gentle mixing, deionized water

(1000 mL) is added to facilitate precipitation. Note: Scratching of the glass will promote slow and

uniform recrystallization. The flask is allowed to cool to ambient temperature, prior to cooling in

the refrigerator overnight. In the morning the crystals are collected cold by vacuum filtration

through a glass-fritted funnel. The solid is washed with a minimal amount of cold deionized water,

suctioned to near dryness and then dried in vacuo at 40° C at <1 Torr. Additional

recrystallizations may be necessary to assure a high level of purity.

Ultimately this provides a pale yellow to slightly off-white solid that is analytically consistent with

the target structure. The overall reaction yield of BCHTU (mw 262.37 g mol-1) (after

recrystallization) is approx. 71.5%. Recrystallization yields are 60 to 80 %. Note: The filtrates

can be combined and concentrated to provide additional ‘crude’ solids (which can be combined

with subsequent batches) and then recrystallized in a separate manner to supplement the overall

yield.

Analysis:

Appearance: Visual inspection, pale yellow to off-white crystalline solid.

1H NMR: Solvent DMSOd6, į 11.25 ppm (s, HN-C=O), 10.95 ppm (d, (HN)2-C=S), 7.98 & 7.95

ppm (s, aromatic C-H), 7.6 (m, aromatic C-H), 7.45 ppm (m, aromatic C-H), 4.2 ppm (m, -CH=),

3.35 ppm (solvent exchange, water in DMSOd6), 2.50 ppm (solvent DMSO protons), 1.9 ppm (s,

ring -CH2-), 1.6 ppm (s, ring –CH2-), 1.5 ppm (s, ring –CH2-), 1.3 ppm (m, ring –CH2-).

13C NMR: Solvent DMSOd6, į 179.5 ppm (C=S), 169.0 (C=O), 134.0 (aromatic C), 133.5

(aromatic C-H), 129.0 (aromatic C), 53.5 (ring -CH=), 40.0 (DMSOd6 solvent), 31.5 (ring -CH2-),

26.0 (ring -CH2-), 24.5 (ring -CH2-).

FT-IR: ATR Accessory, 3168 cm-1 (-NH), 3047 (aromatic C-H), 2940 & 2854 (alkyl C-H), 1668

(C=O), 1600 (aromatic C-H), 1525 (C=S), 1260 (-C=O-NH-), 1167 (-(NH)2-C=S), 705 (-CH2-), 688

(aromatic C-H).

Melting point: DSC, Sharp at 67° C

Chemical Name: Benzamide, N-[(cyclohexylamino)thioxomethyl]-

Common Name: Benzoyl cyclohexylthiourea (BCHTU)

CAS Registry Number: 4921-92-0

Materials:

Ammonium thiocyanate (reagent ACS 97.5 %), CAS 1762-95-4, mw 76.12, mp 145.9° C (lit)

Benzoyl chloride (99+ %), CAS 98-88-4, mw 140.57, mp -1° C (lit), bp 197-199° C (lit)

Cyclohexylamine (98+ %), CAS 108-91-8, mw 99.17, mp -17° C (lit), bp 134° C (lit)

Ethyl acetate (reagent grade), CAS 14-78-6, bp 77° C (lit), d 0.897 g mL-1

Hydrochloric acid (concentrated), CAS 7647-01-0, 36-38 %

Ethanol (reagent grade), bp 78.4 C (lit), d 0.789 g mL-1
Henkel Confidential

Acrylate Platform – December 2011

Synthesis of BCHTU

Page 3

Mass Balance Flow Chart - Reaction, Work-up and Purification of BCHTU

Reaction

Work-up
Henkel Confidential

Acrylate Platform – December 2011

Synthesis of BCHTU

Page 4

Purification