A Publication
of Reliable Methods
for the Preparation
of Organic Compounds
Annual Volume
Org. Synth. 1968, 48, 65
DOI: 10.15227/orgsyn.048.0065
Submitted by J. Bornstein, J. E. Shields, and A. P. Boisselle1.
Checked by William G. Dauben and Harold B. Morris.
1. Procedure
In a 1-l. round-bottomed flask are placed 36.0 g. (0.132 mole) of 2-(p-tolylsulfonyl)dihydroisoindole,2 36.0 g. (0.38 mole) of phenol, 270 ml. of 48% hydrobromic acid (Note 1), and 45 ml. of propionic acid. A few boiling chips are added, and the flask is fitted with a reflux condenser in the top of which is placed a T-tube connected to a source of low-pressure nitrogen and to a mercury bubbler. The mixture is heated under reflux for 2 hours in an atmosphere of nitrogen. The deeply colored reaction mixture is cooled to room temperature, transferred to a 1-l. separatory funnel, and washed with two 200-ml. portions of ether (Note 2). The aqueous phase is then added dropwise over a 1-hour period to a vigorously stirred (Note 3) solution of 200 g. of sodium hydroxide in 600 ml. of water in a 2-l. Erlenmeyer flask immersed in an ice bath. The solution is transferred to a 3-l. separatory funnel and extracted with five 300-ml. portions of ether. The ethereal extracts are combined, dried over anhydrous potassium carbonate (Note 4), and filtered. The solvent is distilled, and the dark residual oil is transferred to a distillation flask and distilled through a low-holdup, semimicro column (Note 5). After removal of 1 or 2 drops of forerun, colorless 1,3-dihydroisoindole is collected at 96–97° (10 mm.) or 55–56° (2 mm.), n25D 1.5686, d204 1.081. The yield is 9.9–11.2 g. (63–71%) (Note 6).
2. Notes
1. The hydrobromic acid should be colorless. Reagent grade 47–49% hydrobromic acid, obtained from J. T. Baker Chemical Co., was used as supplied. A technical grade of the constant-boiling acid is suitable if purified by distillation from stannous chloride.
2. Detection of the water-ether interface may prove trouble-some; backlighting of the separatory funnel by an intense light source is recommended. The same volume of ether must be used for each washing, even when the preparation is carried out on a smaller scale, e.g., one-half or one-third the scale described here.
3. Stirring is most conveniently accomplished with a magnetic stirrer.
4. Washing of the ethereal extract with water decreases the yield of product.
5. The submitters used a 7 × 300-mm. externally heated column packed with a helix of Chromel wire and fitted with a partial reflux head.3
6. Since the product slowly darkens on exposure to air, it should be stored under nitrogen in a refrigerator. The compound solidifies on cooling; m.p. 16.0–16.5°. Nuclear magnetic resonance spectrum (neat, tetramethylsilane internal standard): singlets at δ 7.00 (aromatic protons), 3.93 (CH2), and 2.24 p.p.m. (NH).
3. Discussion
1,3-Dihydroisoindole has been prepared from phthalimide by electrolytic reduction4 and by reduction with lithium aluminium hydride.5 Other methods that have been used are reduction of 1-chlorophthalazine with zinc and hydrochloric acid6 and hydrogenolysis of 2-benzyl-1,3-dihydroisoindole.7 The present method is essentially that of Bornstein, Lashua, and Boisselle.8
4. Merits of the Preparation
This procedure illustrates a general method for the preparation of amines by reductive cleavage of sulfonamides by hydrobromic acid in the presence of phenol.9 The present synthesis makes 1,3-dihydroisoindole readily accessible and is superior in certain respects to the other two practical methods of preparation. Thus the method here described is shorter and gives a higher overall yield than the three-step synthesis of Neumeyer,7 and obviates the special apparatus and careful control required by the electrochemical process of Dunet, Rollet, and Willemart.4

References and Notes
  1. Department of Chemistry, Boston College, Chestnut Hill, Massachusetts 02167.
  2. J. Bornstein and J. E. Shields, this volume, p. 1064.
  3. C. W. Gould, Jr., G. Holzman, and C. Niemann, Anal. Chem., 20, 361 (1948).
  4. A. Dunet, J. Rollet, and A. Willemart, Bull. Soc. Chim. France, [5] 17, 877 (1950).
  5. A. Uffer and E. Schlittler, Helv. Chim. Acta, 31, 1397 (1948).
  6. S. Gabriel and A. Neumann, Ber., 26, 521 (1893).
  7. J. L. Neumeyer, J. Pharm. Sci., 53, 981 (1964).
  8. J. Bornstein, S. C. Lashua, and A. P. Boisselle, J. Org. Chem., 22, 1255 (1957).
  9. S. Searles and S. Nukina, Chem. Rev., 59, 1077 (1959).

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

potassium carbonate (584-08-7)

hydrochloric acid (7647-01-0)

ether (60-29-7)

sodium hydroxide (1310-73-2)

phenol (108-95-2)

propionic acid (79-09-4)


nitrogen (7727-37-9)

stannous chloride

zinc (7440-66-6)

Phthalimide (85-41-6)

lithium aluminium hydride (16853-85-3)

Isoindoline (496-12-8)


2-benzyl-1,3-dihydroisoindole (35180-14-4)

2-(p-Tolylsulfonyl)dihydroisoindole (32372-83-1)