T. De Wit et al. / Tetrahedron Letters 42 (2001) 4919–4922
4921
CO Me
2
CO Me
2
d
a, b
c
O
76%
CN
O
O
OH
O
69 %
O
CN
88 %
Ph
12
13
14
NH2
NH2
CO Me
2
e, f, g
h, i
HO
O
HN
Ph
O
HN
Ph
HN
Ph
51 %
59 %
O
O
1
5
16
1
Scheme 4. Reagents and conditions: (a) NaH, Me CO , 110°C, 91%; (b) CH CHCN, t-BuOK (cat.), t-BuOH, 76%; (c) PhMgBr,
2
3
2
THF, −78°C, 88%; (d) MeSO H, rt, 76%; (e) 20% NaOH–THF (1:1), MeOH, DT, 70%; (f) DPPA, Et N, toluene, DT; MeOH,
3
3
9
0%; (g) i-PrOH–KOH, 83% h) BH ·Me S, THF, DT, 71%; (i) L-methionine, MeSO H, 83%.
3
2
3
with MeOH, the methyl carbamate 9 was obtained in
Acknowledgements
1
0
9
0% yield. Final treatment with i-PrOH–KOH under
11
reflux conditions afforded the amine 10 (83%).
The authors wish to thank the FWO (Fund for Scien-
tific Research, Flanders, Belgium) and the ‘Ministerie
voor Wetenschapsbeleid, IUAP’, for financial support.
We are also indebted to R. De Boer and Professor S.
Toppet for mass and NMR measurements and to the
Janssen Pharmaceutica company for microanalyses.
T.D.W. and K.V.E. would like to thank the IWT and
F.M. the FWO for fellowships received.
Obviously, bridgehead amine 10 can be used for further
functionalization. Combined with the primary pharma-
cophore already present, i.e. the 1-phenyl-1,2-
diaminoethane moiety, such derivatization allows to
incorporate structural elements characteristic of already
2
known non-peptide Substance P antagonists and
5
dopamine receptor ligands (Fig. 1: target compounds
of type C, Y=NH, NHCO). In a related application,
the acyl azide intermediate formed in the preceding
Curtius reaction could be intercepted via addition of an
amine reagent at low temperature. Thus, treatment of
acid 8 with DPPA in DMF at 0°C for 2 h, followed by
addition of benzylamine or aqueous methylamine, fur-
nished amides 11a and 11b in 81 and 67% yield, respec-
tively. Further conversion of amides 11, or the
structurally related inverse amide intermediates that
may be derived from N-acylation of 10, to the corre-
sponding target compounds C (Y=CONH, NHCO)
still requires chemoselective reduction of the lactam
carbonyl group as opposed to the amide group at the
bridgehead position.
References
1
. Van Emelen, K.; De Wit, T.; Hoornaert, G. J.; Comper-
nolle, F. Org. Lett. 2000, 2, 3083–3086.
. Snider, R. M.; Constantine, J. W.; Lowe, III, J. A.;
Longo, K. P.; Lebel, W. S.; Woody, H. A.; Drozda, S. E.;
Desai, M. C.; Vinick, F. J.; Spencer, R. W.; Hess, H.-J.
Science 1991, 251, 435.
. Harrison, T.; Williams, B. J.; Swain, C. J. Bioorg. Med.
Chem. Lett. 1994, 4, 2733–2734.
. Stevenson, G. I.; MacLeod, A. M.; Huscroft, I.; Cascieri,
M. A.; Sadowski, S.; Baker, R. J. Med. Chem. 1995, 38,
2
3
4
1264–1266.
5
. Horn, A. S. In Comprehensive Medicinal Chemistry; Han-
sch, C., Ed.; Pergamon Press, 1990; Vol. 3, pp. 229–290.
. Claudi, F.; Cingolani, G. M.; Di Stefano, A.; Giogioni,
G.; Amenta, F.; Barili, P.; Ferrari, F.; Giuliani, D. J.
Med. Chem. 1996, 39, 4238–4246.
To prepare target compound 1, a potential dopamine
receptor ligand (Fig. 1), a sequence analogous to that
described for amine 10 was applied. Starting from
6
6
-methoxyindanone 12, this proceeded via Michael
addition of the corresponding b-ketoester to form the
cyanoethyl compound 13 (yield over two steps 69%),
Grignard reaction using phenylmagnesium bromide
7
8
9
. Laganis, E. D.; Chenard, B. L. Tetrahedron Lett. 1984,
25, 5831.
. Kozikowski, A. P.; Xia, Y.; Reddy, E. R.; T u¨ ckmantel,
W.; Hanin, I.; Tang, X. C. J. Org. Chem. 1991, 56, 4636.
. In a typical experiment 0.15 g acid 8 (0.50 mmol), 0.63 ml
(
88%), and cyclization through intramolecular Ritter
reaction to produce lactam ester 14 (76%). The latter
was transformed into amino lactam 15 (combined yield
over three steps 51%). Subsequent reduction of the
DPPA (6 equiv.), and 1 ml Et N (15 equiv.) was heated at
3
reflux in 15 ml toluene for 1 h. Methanol (15 ml) was
added and the mixture was heated further at reflux for 2
h, followed by evaporation, addition of a brine solution,
extraction with ethyl acetate, and chromatographic purifi-
cation (silica gel, CH Cl : MeOH 95/5); further crystal-
lactam group was effected with BH ·DMS (71%). In the
3
last step the methoxy group was demethylated using
12,13
l-methionine in methanesulfonic acid,
corresponding 3-hydroxy target compound 1 (83%)
Scheme 4).
to give the
2
2
(
lization from EtOH gave 0.16 g (90%) of the carbamate 9