5278
D. Kaufmann et al. / Tetrahedron Letters 45 (2004) 5275–5278
8H, arom H); MS (ESꢀ) m=z 266 (M)H); IR (KBr) 1714,
References and notes
1674 1439, 1340, 771 cmꢀ1. Anal. Calcd for C16H13NO3: C,
71.90; H, 4.90; N, 5.24; O, 17.96. Found: C, 71.72; H, 4.88;
N, 5.21; O, 17.98.
1. Epilepsy: A Comprehensive Textbook; Engel, J., Jr.,
Pedley, T. A., Eds.; Lippincott-Raven Publishers: Phila-
delphia, 1998; Vol. II.
2. (a) Milanese, A. WO Patent Application 9621649, 1996;
Chem. Abstr. 1996, 125, 195448; (b) Aufderhaar, E. Eur.
Patent. 28028, 1981; Chem. Abstr. 1981, 95, 115325; (c)
Schindler, W. DE Patent 2011087, 1970; Chem. Abstr.
1970, 73, 109711.
15. Complete removal of the protecting group of 4c to give 4a
was achieved by stirring crude product 4c with 1 M aq
Na2CO3, MeOH, 23 ꢂC, 30 min.
16. The tendency of 3a to cyclize to 6 is so pronounced
(Refs. 6 and 11) that only the complete blocking of the
nitrogen atom by protonation would have forced the
reaction to proceed in the direction of the desired Friedel–
Crafts reaction.
3. For a review of dibenz[b,f]azepines, see: Kricka, L. J.;
Ledwith, A. Chem. Rev. 1974, 74, 101.
17. In one process step for the industrial production of 1 the
environmentally unfriendly reagents 1,2-dichloroethane
and chlorocyanide are used. The elimination of this
process step was also an important impetus for this work.
18. Compound 4d (22.3 g, 0.083 mol) is dissolved in methanol
(112 mL) at 50 ꢂC. p-Toluenesulfonic acid (0.45 mg) is
added, followed by trimethyl orthoformate (11.5 mL). The
mixture is stirred for 5 h then methanol and formic acid
methyl ester is distilled off. Fresh methanol is added
continuously to replace the distillate. After distilling off ca.
100 mL of methanol, the mixture is cooled to 3 ꢂC and
filtered. The filter cake is washed with cold methanol and
dried under vacuum for 15 h (50 ꢂC, 50 mbar). Pure 9d is
obtained as a light yellow powder (18.0 g, 81% yield). For
experimental details using no trimethyl orthoformate see
Ref. 12.
€
4. Lohse, O.; Beutler, U.; Funfschilling, P.; Furet, P.; France,
J.; Kaufmann, D.; Penn, G.; Zaugg, W. Tetrahedron Lett.
2001, 42, 385.
5. The limitation is in particular due to the use of 2.5 equiv
LDA-TMEDA in the cyclization step.
6. The importance of choosing the right protecting group in
our system is also illustrated by the example reported by
Schulenberg and Archer. The use of the benzoyl protecting
group led solely to the formation of 6 Schulenberg, J. W.;
Archer, S. J. Am. Chem. Soc. 1960, 82, 2035.
7. Based on combustion data c-lactam 6 has a 10 kJ/mol
lower heat of formation than 4a. Furthermore, under the
applied cyclization conditions 6 is stable whereas 4a is
partly converted to 6.
8. Cyclization of 3a to 6 starts in solution at 50 ꢂC.
9. Schindler, W. DE Patent 2011087, 1970; Chem. Abstr.
1970, 73, 109711.
10. Compound 6 was prepared similarly to 1-(2,6-dichloro-
phenyl)-1,3-dihydro-indol-2-one as described by Moser,
P.; Sallmann, A.; Wiesenberg, I. J. Med. Chem. 1990, 33,
2358.
19. Examples of ammonolysis: (a) Betts, R. L.; Hammett,
L. P. J. Am. Chem. Soc. 1937, 59, 1568; (b) Porcs-Makkay,
M.; Simig, G. Org. Process Res. Dev. 2000, 4, 10;
(c) Zielinski, W.; Zaki, M. E. A. Pol. J. Chem. 1994, 68,
1569.
20. Cleavage of the carbamate function resulted when 4d or 4f
was heated with 24% aq NH3, 25 ꢂC, 24 h or NH3, MeOH,
100 ꢂC. For 9d or 9f: NH3, MeOH, 220 ꢂC, 15 h.
21. Even when using the phenyl carbamates 4f or 9f (with
phenoxy being a better leaving group than methoxy), 4a
and 5, respectively, were again obtained.
11. Cyclization 3a to 6 is observed at pH < 2.
12. Later in this investigation we found that the additional
steps via the methylester 8a could be omitted for the
preparation of 3d when the deprotonated form of 7 is
used, as described for the preparation of 3e. For details of
€
this approach see: Funfschilling, C. P.; Zaugg, W.;
22. A mixture of 9d (19 g, 67.5 mmol), polyethylene glycol 200
(20 mL) and sodium hydroxide solution 50% (13 mL,
246 mmol) is heated to 100 ꢂC for 4 h. Water (30 mL) is
added and the suspension is cooled to 20 ꢂC and filtered.
The filter cake is washed with water and dried at 60 ꢂC/
30 mbar to yield 14.7 g of 5 (98%).
23. Acetic acid (150 mL) is added dropwise to a stirred
mixture of 5 (25.0 g, 112 mmol) and NaOCN (9.25 g,
142 mmol) under a nitrogen atmosphere at 24 ꢂC. After
stirring for 7 h, water (12.5 mL, 694 mmol) and 98%
H2SO4 (ca. 7.5 mL, 140 mmol) are added to the yellow
suspension until a pH of 6 1 is achieved. After stirring for
another 17 h, water (275 mL) is added. The precipitated 1
is filtered and dried under vacuum (overall yield 78%
starting from 5).
Beutler, U.; Kaufmann, D.; Lohse, O.; Mutz, J.-P.;
Onken, U.; Reber, J.-L.; Shenton, D. Org. Process Res.
Dev. in preparation.
13. Friedel–Crafts cyclization of the corresponding acid chlo-
ride of 3d with 1.2 equiv AlCl3 in CH2ClCH2Cl at 25 ꢂC
gave 4d in 88% yield. However, from a technical point of
view the process in neat PPA was felt to be more attractive.
14. Typical reaction conditions: 3d (285.3 g, 1 mol) is added to
PPA (83% P2O5, 684 g) at 90 ꢂC and stirred at 95 ꢂC for
3 h. The reaction is cooled to 80 ꢂC, water (2500 mL) is
carefully added while the temperature is kept below 98 ꢂC.
Then the reaction mixture is extracted with toluene
(3 · 1000 mL), the combined organic phases washed with
sodium hydrogen carbonate solution (5%, 1000 mL) and
concentrated to a weight of 975 g. The solution is cooled to
0 ꢂC and stirred for 3 h to afford white crystals, which are
filtered and dried to give pure 4d (194 g, 70%): mp 139–
141 ꢂC. 1H NMR (400 MHz, CDCl3) d 3.79 (s, 3H,
COOCH3), 3.82–4.40 (2H, JAB ¼ 14:3 Hz), 7.2–8.1 (m,
24. Milanese, A. WO Patent Application 9621649, 1996;
Chem. Abstr. 1996, 125, 195448. With 4a and isocyanic
acid no reaction was observed. For further details see Ref.
12.