Figure 3. Dibenz[b,f]azepines and their 10,11-dihydro deriva-
tives, potential intermediates for fluoro analogues. R = H,
CHO, COMe, Me.
Figure 2. Major metabolites of carbamazepine.
without any success. This was not a reagent problem as our
batch of SelectFluor reacted with acetanilide to give a
mixture of o- and p-fluoroacetanilide as reported.13b There
is a literature report14 of a synthesis of 2-fluorodibenz-
[b,f]azepine from 2-fluoro-9-methylacridine, via the corre-
sponding 9-chloro compound, but no synthetic details for
the latter derivative are given. We considered that the
9-acridinemethanol intermediate in that synthesis could
be conveniently accessed from the corresponding car-
boxylic acid, which itself could be obtained by base-
catalyzed rearrangement of an N-aryl isatin. The latter
rearrangement was, we believe, first reported by Stolle15
and has since been used by others.16
Through an ongoing program,7 we aim to identify by
synthesis and biological testing analogues of 1 which show
more favorable metabolic profiles and reduced hypersen-
sitivity. We have already prepared some N-substituted and
halogenated derivatives of 1: our early results have shown
that the N-substituent and 10,11-substitution are both
factors influencing hypersensitivity.7
We are currently preparing a portfolio of nuclear-
substituted analogues of 1 in order selectively to modify its
metabolic profile and to define more precisely both the
steric requirements of the T-cell receptor and the influence
of the substitution pattern.
Inany programofanalogues, fluorine substitution holds
a special place. Fluorine substitution combines a minimum
steric influence with a profound electronic effect and is
known to have a strong effect on nuclear P450-mediated
hydroxylation.8 Thus fluorine may block oxidation di-
rectly at the site of substitution;9 moreover the overall rate
of reaction of the benzene π-orbitals with P450s is
reduced.10 P450-mediated hydroxylation may still occur
at positions adjacent to CÀF and may be accompanied by
an NIH shift of fluorine or oxidative defluorination.11
We are aware of only two reports of a fluorinated analogue
of 1, namely the 10-F analogue.12 We now present the first
convenient syntheses of mono- and dibenzo-fluorinated
dibenz[b,f]azepines, employing fluorinated precursors and
utilizing a number of rather efficient rearrangements of
heterocyclic systems leading, in a few steps, to the desired
products.
Scheme 1. Synthesis of 2-Fluorodibenz[b,f]azepine
We first attempted direct fluorination of dibenz[b,f]-
azepine 7, iminodibenzyl 8, and their N-substituted analogues
(N-CHO, N-Ac, N-Me; Figure 3) using SelectFluor,6,13
Our synthesis of 15, the 2-F analogue of 7 (R = H), is
shown in Scheme 1. We slightly modified Coppola’s
procedure17 for the N-arylation of isatin 9, using N,N-
dimethylacetamide as the solvent and a reaction time of 8 h
(longer times led to slow degradation).
(7) Wu, Y.; Sanderson, J. P.; Farrell, J.; Drummond, N. S.; Hanson,
A.; Bowkett, E. R.; Berry, N. G.; Stachulski, A. V.; Clarke, S. E.; Pichler,
W. J.; Piromohamed, M.; Park, B. K.; Naisbitt, D. J. J. Allergy Clin.
Immunol. 2006, 118, 233–241.
(8) Park, B. K.; Kitteringham, N. R.; O’Neill, P. M. Ann. Rev. Pharm.
Toxicol. 2001, 41, 443–470.
After careful chromatography, the product 10 was
obtained in satisfactory yield; direct recrystallization of
(9) Morgan, P.; Maggs, J. L.; Bulman Page, P. C.; Hussain, F.; Park,
B. K. Biochem. Pharmacol. 1992, 43, 985–994.
(10) Cnubben, N. H. P.; Peelen, S.; Borst, J. W.; Verhoort, J.; De
Jager, A.; Rietjens, I. M. C. M. Chem. Res. Toxicol. 1994, 7, 590–598.
(11) Koerts, J.; Soffers, A. E. M. F.; Vervoort, J.; De Jager, A.;
Rietjens, I. M. C. M. Chem. Res. Toxicol. 1998, 11, 503–512.
(12) Szentkiralyi, I.; Mocsar, M. (Hung. Teljes) HU 41010 A2, 1987;
Chem. Abstr. 1988, 108, 94422. Allgeier, H.; Schmid, E. Ger. Offen. DE
2542335, 1976; Chem. Abstr., 1976, 85, 32888.
(13) (a) Banks, R. E. Air Products & Chemicals, Inc. USP 5,086,178,
1992. (b) Banks, R. E.; Basheesh, M. K.; Mohialdin-Khaffaf, S. N.; Sharif, I.
J. Chem. Soc., Perkin Trans. 1 1996, 2069–2076.
(14) Varma, R. S.; Whisenant, L. K.; Boykin, D. W. J. Med. Chem.
1969, 12, 913–914. Cf.:Bergman, E. D.; Rabinovitz, M. J. Org. Chem.
1960, 25, 827–828.
(15) Stolle, R. J. Prakt. Chem. Naturforsch. 1922, 105, 137–148.
(16) (a) Martinet, J.; Dansette, A. Bull. Soc. Chim. Fr. 1929, 45, 101–
109. (b) Newman, M. S.; Powell, W. H. J. Org. Chem. 1961, 26, 812–815.
(c) Razavi, Z.; McCapra, F. Luminescence 2000, 15, 239–244.
(17) Coppola, G. M. J. Heterocycl. Chem. 1987, 24, 1249–1251.
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