A facile Kf/Al2O3 mediated, selective alkylation of benzodiazepin-2,5- diones

Article abstract of DOI:10.1016/S0040-4039(00)00115-5

We have developed a new, versatile method for the selective alkylation of benzodiazepin-2,5-diones using KF on Al₂O₃. The use of a reagent on a solid support makes this process suitable for the preparation of combinatorial libraries. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00115-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2063–2066
A facile KF/Al2O3 mediated, selective alkylation of
benzodiazepin-2,5-diones
Benjamin E. Blass,∗ Thomas M. Burt, Song Liu, David E. Portlock and Erin M. Swing
Procter & Gamble Pharmaceuticals, Health Care Research Center, 8700 Mason Montgomery Road, Mason, OH 45040, USA
Received 11 November 1999; accepted 5 January 2000
Abstract
We have developed a new, versatile method for the selective alkylation of benzodiazepin-2,5-diones using KF
on Al2O3. The use of a reagent on a solid support makes this process suitable for the preparation of combinatorial
libraries. © 2000 Elsevier Science Ltd. All rights reserved.
The benzodiazepines constitute an important class of biologically active compounds that have received
a great deal of attention since their initial discovery in the late 1950s.1 Members of this class have
been identified as antihypertensives, angiotensin II antagonists, platelet aggregation inhibitors, gpIIb/IIIa
receptor antagonists, anticonvulsives, substance P inhibitors, and antimicrobial agents.2 A large number
of these have been prepared using several published synthetic protocols. The appearance of combina-
torial chemistry has increased the accessibility of benzodiazepines, as several solid phase syntheses of
benzodiazepines have been published recently. In addition, solution phase preparation of libraries of
benzodiazepines have also been reported.3 Recent work in our laboratories has led to a method for the
preparation of benzodiazepin-2,5-dione libraries using methodology that sits between these two options,
solution phase chemistry with solid supported reagents. We have found that benzodiazepin-2,5-diones
can be selectively alkylated in the presence of an alkyl bromide (or iodide) with the aid of potassium
fluoride on alumina (40% KF by weight). The choice to use a solid supported reagent provides some of
the advantages of both solid and solution phase chemistry. Like solid phase synthesis, excess support
bound reagent can be used and removed by filtration, avoiding cumbersome aqueous work-ups. In
addition, since the compound of interest is never covalently bound to the solid support, monitoring of the
reactions and analysis can be accomplished using standard methods (thin layer chromatography, solution
1H NMR, etc.). Finally, the products are isolated by filtration and removal of the solvents, eliminating
the need for a cleavage step that is required in solid phase preparations.
∗
Correponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00115-5
tetl 16395

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The use of potassium fluoride on alumina (KF/Al2O3) as a base for functionalization of amides was
initially reported in 1981 by Yamawaki, but has received very little attention since then.4 According to the
literature, this method suppresses the formation of the O-alkylated product in favor of N-alkylation. We
recently rediscovered this work during an examination of various potential methods for the preparation
of libraries of differentially dialkylated benzodiazepin-2,5-diones. In our initial attempts to apply this
chemistry to benzodiapin-2,5-diones, we expected that treatment of 1a with 2.0 equivalents of an
alkyl bromide (2a) in DMF in the presence of KF/Al2O3 would lead to the dialkylated product 3a
(Scheme 1). We were pleasantly surprised, however, to find that a single monoalkylated species (4a)
was produced under these conditions. The dialkylated product was not observed even after 10 days
under these conditions. In order to verify the site of alkylation (aniline versus benzamide nitrogen),
benzodiazepine 4d was prepared and found to be identical to that produced using Sun’s method to
prepare benzodiazepin-2,5-diones from isatoic anhydrides.5 The broad applicability of this procedure
has since been demonstrated by the successful alkylation of a number of benzodiazepin-2,5-diones with
various alkyl bromides and side chains (Table 1).6 Alkylation of a benzodiazepin-2,5-dione was readily
accomplished with 1.0 equivalent of an alkyl bromide in the presence of KF/Al2O3 in DMF at 25°C
over 48 h. Excess KF/Al2O3 was removed by simple filtration, providing the desired products in good
1
to excellent yields and with a high degree of purity (the typical crude H NMR shows little, if any,
contamination with side products). The compounds in Table 1 have been prepared from a series of
benzodiazepin-2,5-diones and alkyl bromides as part of a larger library of monoalkylated benzodiazepin-
2,5-diones.
Scheme 1.
Table 1
Representative samples of monoalkylation of benzodiazepin-2,5-diones
In order to extend the utility of this chemistry, we attempted to find a method to alkylate the
second nitrogen of a benzodiazepin-2,5-dione within a reasonable length of time. The N-methylated
benzodiazepine 5 was used as a model. Addition of sodium iodide to transiently form the alkyl iodide
did not produce any noticeable change in the rate of the alkylation of 5. Fortunately, changing solvents
had a dramatic effect on the rate of the reaction. While 1,4-dioxane showed no improvement over DMF,
both acetonitrile and dimethoxyethane (DME) demonstrated significantly better results.7 Alkylation of
5 was accomplished in 48 h when DME was used as a solvent instead of DMF, but unlike the previous
chemistry, a mixture of N- and O-alkylation was observed (Scheme 2). The identity of the two different

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benzodiazepines was established by examining the fragmentation patterns seen in the mass spectra of
each.
Scheme 2.
Since the rates of alkylation of the two amide nitrogens of 3 are very different depending on the
solvent (in DME, the dialkylated product 4 is rapidly produced), preparation of a library of differentially
substituted, dialkylated benzodiazepin-2,5-diones should be possible. We are currently in the process of
creating a library of this type containing several thousand compounds by scaling up the first step with a
single alkyl halide and then parceling out the product to multiple reaction vessels for the second step.
In summary, we have developed a new method for the selective alkylation of benzodiazepin-2,5-
diones using KF/Al2O3 that is suitable for the preparation of combinatorial libraries. The products are
obtained in good to excellent yield and purity, allowing the preparation of both the monoalkylated and
differentially dialkylated benzodiazepin-2,5-diones.
References
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C.; Thorsett, E. D.; Tischler, M.; Webb, R. R.; Venuti. M. C. J. Am. Chem. Soc. 1994, 116, 5077–5083. Cho, N. S.; Song, K.
Y.; Parkanyi, C. J. Heterocycl. Chem. 1989, 26, 1807–1810. Bauer, A.; Weber, K. H.; Danneberg, P.; Kuhn, F. J. US Patent
3 914 216. Martino, G. D.; Massa, S.; Corelli, F.; Pantaleoni, G.; Fanini, D.; Palumbo, G. Eur. J. Med. Chem. Chim. Ther.
1983, 18, 347–350. Ananthan, S.; Clayton, S. D.; Ealick, S. E.; Wong, G.; Evoniuk, G. E.; Skolnick, P. J. Med. Chem. 1993,
36, 479–490. Wong, G.; Koehler, K. F.; Skolnick, P.; Gu, Z. G.; Ananthan, S.; Schonholzer, P.; Hunkeler, W.; Zhang, W.;
Cook, J. M. J. Med. Chem. 1993, 36, 1820–1830. Wright, W. B.; Brabander, H. J.; Greenblatt, E. N.; Day, I. P.; Hardy, R.
A. J. Med. Chem. 1978, 21, 1087–1089. Jones, G. B.; Davey, C. L.; Jenkins, T. C.; Kamal, A.; Kneale, G., G.; Neidle, S.;
Webster, G. D.; Thurston, D. E. Anti-Cancer Drug Des. 1990, 5, 249–264.
3. Sun, H. H.; Barrow, C. J.; Cooper, R. J. Nat Prod. 1993, 58, 10, 1575–1580. Armstrong, R. W.; Keating, T. A. J. Org.
Chem. 1996, 61, 8935–8939. Puwen, Z.; Zhang, W.; Liu, R.; Harris, B.; Skolnick, P.; Cook, J. M. J. Med. Chem, 1995, 38,
1679–1688. Ellman, J. A. US Patent 5 288 514, 1994.
4. Yamawaki, J.; Ando, T.; Hanafusa, T. Chem. Lett. 1981, 1143–1146. Tius, M. A.; Busch-Pertersen, J. Synlett 1997, 531–532.
Nguyen, H. D.; Hiep, N. B.; Le, T. N. H.; Chu, P. N. S. C. R. Acad. Sci., Ser. 2, 1985, 300, 799–802. Blass, B. E.; Drowns,
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6. Typical experimental procedure for monoalkylation of a benzodiazepin-2,5-dione: 50.0 mg (0.19 mmol) of benzodiazepin-
2,5 dione 1a and 191 mg of KF/Al2O3 (40% by weight) are dissolved/suspended in 3.0 ml of DMF. 28.4 mg (22.5 µl, 0.19
mmol) of isoamyl bromide is added, and the reaction is stirred at room temperature for 48 h. The reaction is then filtered and
stripped to yield 51.2 mg (81%) of the desired product (4a). 1H NMR (300 MHz, CD3OD) 8.02 (1H, d, J=13 Hz), 7.91 (1H,
t, J =8.7 Hz), 7.74 (1H, d, J=13 Hz), 7.60 (1H, t, J=8.7 Hz), 7.52 (5H, m), 4.69 (1H, dt, J=13.0, 6.5 Hz), 4.26 (1H, m, J=6.5
Hz), 3.93 (1H, m, J=5.2 Hz), 3.56 (1H, m), 3.26 (1H, dd, J=10.4, 5.6 Hz), 1.69 (1H, m), 1.56 (2H, m), 1.13 (3H, d, J=6.5 Hz),
1.04 (3H, d, J=6.5 Hz). Mass spectrum m/z (%): 337 (M+, 100%).
7. Typical experimental procedure for alkylation of an N-methyl-benzodiazepin-2,5-dione: 25 mg (0.09 mmol) of benzodiazepin
2,5-dione 5 and 75 mg of KF/Al2O3 (40% by weight) are dissolved/suspended in 1.2 ml of DME, and 13.5 mg (10.7 uL, 0.09
mmol) of isoamyl bromide is added. The reaction is heated to 75–80°C and stirred for 48 h. The reaction is then cooled to

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room temperature, filtered, and stripped to yield 22.0 mg (70 %) of a mixture of the two desired products. Chromatography
with 2/1 hexane/ethyl acetate provided 11.4 mg (36%) of the N-alkylated product (6) and 10.6 mg (34 %) of the O-alkylated
product (7). 1H NMR (300 MHz, CD3OD) of 6: 7.59 (2H, m), 7.39 (1H, d, J=11.0 Hz), 7.26 (1H, t, J=11 Hz), 7.50 (5H, m),
4.28 (1H, m), 4.17 (1H, m), 3.60 (1H, m), 3.39 (3H, s), 3.21 (2H, m), 1.80 (1H, m), 1.60 (2H, m), 0.95 (6H, m, J=8.7 Hz).
Mass spectrum m/z (%): 351 (M+, 100%). 1H NMR (300 MHz, CD3OD) of 7: 7.87 (0.5H, d, J=9.1 Hz), 7.78 (0.5H, d, J=11.7
Hz), 7.72, (0.5H, t, J=11.2 Hz), 7.60 (0.5H, t, J=11.2 Hz), 7.46 (1H, m), 7.41 (1H, m), 7.26 (4H, m), 7.00 (1H, m), 4.54 (0.5H,
t, J=7.8 Hz), 4.43 (0.5H, dd, J=9.8 Hz), 4.05 (0.5H, m), 3.80 (0.5H, m), 3.47 (1/2H, m), 3.43 (1.5H, s), 3.39 (1.5H, s), 3.31
(1H, m), 3.00 (0.5H, m), 2.61 (0.5H, dd, J=11.1, 13.0 Hz), 2.52 (0.5H, dd, 11.0, 13.0 Hz), 1.48 (1H, m), 1.34 (2H, m), 1.00
(3H, t, J=9.8 Hz), 0.91 (3H, d, J=5.2 Hz). Mass spectrum m/z (%): 351 (M+, 100%).