7 N. H. Martin and C. W. Jefford, Helv. Chim. Acta, 1982, 65, 762;
N. H. Martin and C. W. Jefford, Tetrahedron Lett., 1981, 22, 3949;
N. H. Martin and C. W. Jefford, Helv. Chim. Acta, 1981, 64, 2189;
N. H. Martin, S. L. Champion and P. B. Belt, Tetrahedron Lett., 1980,
21, 2613.
8 We propose that the photo-oxidation proceeds via a charge-transfer
complex. The precedent for this comes from the work of Martins et al.7
who proposed a similar mechanism in a related isoquinoline case. The
alternative concerted ene mechanism was discounted on the basis of
structure–activity studies.
To circumvent the intrinsic instability of compounds 4a–h,
purification after cyclisation of the corresponding acetamide
derivatives 3a–h was avoided, so the crude reaction product after
basic work-up of the Bischler–Napieralski reaction was irradiated
under the conditions explained in Table 1.
Using the method A (entries 1–8), regioselectivity in the
oxidation was achieved in most of the cases, yielding the dihydro-
b-carbolines 5a–h with satisfactory yields from the corresponding
tryptamine derivatives 3a–h. When d = 5 cm [method B, entries
9–13] reflux of the toluene solution occurred and, consequently,
the fully aromatic b-carbolines 6a–h were isolated with acceptable
yields from 3a–h. On other occasions the compounds 6a–h were
obtained in good yields by irradiation (d = 5 cm) of the isolated
ketoimines 5a–h [method C, entries 14–18].
9 G. Cauzzo and G. Jori, J. Org. Chem., 1972, 37, 1429.
10 That is in agreement with the known fact that the natural product
xestomanzamine B was gradually converted (at 21 uC, for 20 days)
presumably via air-oxidation to xestomanzamine A. M. Kobayashi,
C. Yin-Ju, S. Aoki, Y. In, T. Ishida and I. Kitawaga, Tetrahedron, 1995,
51, 3727.
11 Examples of general procedures A, B and C (Table 1): Method A:
synthesis of 1-(2-bromobenzoyl)-3,4-dihydro-b-carboline 5d from 2-(2-
bromophenyl)-N-[2-(1H-indol-3-yl)ethyl]acetamide 3d. The acetamide
derivative 3d (1 mmol, 357 mg) was heated in toluene until complete
dissolution was achieved. POCl3 (10 mmol, 0.93 mL) was added and the
resulting mixture refluxed for 1 hour until TLC analysis showed
completion. Afterwards, toluene was removed and the residue dissolved
in 20 mL of a 2 : 1 mixture of CH2Cl2/NaHCO3. The biphasic mixture
was then cooled and basified with aqueous NH3 to pH 9. The organic
phase was separated and the aqueous layer extracted with CH2Cl2 (2 6
25 mL). Then, the combined organic phases were dried over sodium
sulfate and the solvent evaporated. The crude product 4d obtained was
suspended in toluene with vigorous stirring; oxygen was bubbled
through the solution and the mixture was irradiated with a 500 W
halogen lamp located at 25 cm from the reaction flask (measured
temperature of the suspension ca. 30u C). The reaction was monitored
by 1H-NMR until completion. Then, the toluene was evaporated under
reduced pressure and the crude product obtained (410 mg) filtrated over
a short pad of SiO2 (2 g of SiO2) eluting with CH2Cl2 to give 5d as an
orange solid (170 mg, 48%); mp 136–137 uC (from EtOH); Found: C,
61.14; H, 3.72; N, 7.88%; C18H13BrN2O requires: C, 61.21; H, 3.71; N,
7.93%; nmax/cm21 3453, 1660, 1585, 1539, 1437, 1295, 1222, 1143, 732;
1H-NMR (300 MHz, CDCl3) d 3.0 (2H, t, J 8.9 Hz), 4.13 (2H, t, J 8.9
Hz), 7.14–7.19 (1H, m), 7.30–7.53 (4H, m), 7.61 (1H, d, J 1.2 Hz), 7.61
(1H, d, J 1.2 Hz), 7.64 (1H, d, J 1.2 Hz) and 9.48 (1H, br s, D2O exch,
NH) ppm; 13C-NMR (75 MHz, CDCl3) d 18.8 (CH2), 49.7 (CH2), 112.3
(CH), 118.2 (Cq), 120.0 (CH), 120.3 (Cq), 120.4 (CH), 124.7 (Cq), 125.2
(CH), 126.1 (Cq), 127.0 (CH), 129.8 (CH), 131.9 (CH), 133.1 (CH),
137.1 (Cq), 139.1 (Cq), 155.5 (Cq) and 196.5 (CO) ppm; m/z (ES+) 353
(MH+); m/z (FAB+) 353 (MH+) (found: MH+, 353.02897; C18H14BrN2O
requires 353). Method B: synthesis of 1-(2-bromobenzoyl)-b-carboline 6d
from 2-(2-bromophenyl)-N-[2-(1H-indol-3-yl)ethyl]acetamide 3d. The
crude product 4d obtained from the acetamide derivative 3d (1 mmol,
357 mg) as described in method A was irradiated following the protocol
described in method A with the 500 W halogen lamp located at 5 cm
from the reaction flask so reflux was achieved. The mixture was refluxed
until completion (monitored by 1H-NMR). The crude product (430 mg)
obtained after evaporation of the toluene was purified as in method A
yielding 6d (172 mg, 49%) as an orange solid; mp 215–216 uC (from
EtOH/H2O); Found: C, 61.41; H, 3.09; N 7.92%; C18H11N2OBr
requires: C, 61.56; H, 3.16; N, 7.98%; nmax/cm21 3447, 1654, 1581, 1186,
1174, 950, 792, 775, 746; 1H-NMR (300 MHz, CDCl3) d 7.35–7.42 (2H,
m), 7.47 (1H, dt, J 1.3 and 7.3 Hz), 7.56 (1H, dd, J 1.7 and 7.3 Hz), 7.63
(1H, d, J 0.9 Hz), 7.64 (1H, q, J 0.9 Hz), 7.69 (1H, dd, J 1.0 and 8.0 Hz),
8.16–8.20 (2H, m), 8.56 (1H, d, J 5 Hz) and 10.43 (1H, br s, D2O exch,
NH) ppm; 13C-NMR (75 MHz, CDCl3) d 112.1 (CH), 119.2 (CH),
120.1 (Cq), 120.7 (Cq), 121.0 (CH), 121.9 (CH), 126.9 (CH), 129.5 (CH),
129.8 (CH), 131.2 (CH), 131.9 (Cq), 133.1 (CH), 135.2 (Cq), 136.9 (Cq),
138.8 (CH), 140.4 (Cq), 141.2 (Cq) and 198.2 (CO) ppm; m/z (ES+) 351
(MH+); m/z (FAB+) 351 (MH+) (found: MH+, 351.01321; C18H12BrN2O
requires 351). Method C: synthesis of 1-(2-bromobenzoyl)-b-carboline 6d
from 1-(2-bromobenzoyl)-3,4-dihydro-b-carboline 5d. Compound 5d
(176 mg, 0.5 mmol) obtained as described in method A was irradiated
with the 500 W halogen lamp as in method B. The reaction was
monitored by 1H-NMR until completion and the resulting crude
product obtained was purified as described to yield 6d (350 mg, 99%),
which displayed spectroscopic features identical to those described
above.
Finally, a one-pot sequence for the synthesis of the target
compounds was also explored. Tryptamine was reacted with
2-bromophenylacetic chloride 2d (1.1 eq.) in toluene at reflux for
15 minutes; POCl3 (2.5 eq.) was then added to the mixture. Once
TLC analysis of a worked-up aliquot showed complete reaction,
the crude mixture was irradiated with the 500 W halogen lamp and
oxygen bubbled throughout the solution. After 24 hours at reflux,
the only isolated product was 4d in a 48% yield from tryptamine.
One probable explanation for the inhibition of the oxidation is that
the product of the Bischler–Napieralski reaction before the basic
work-up should be the hydrochloride of compound 4d. In such a
situation the imine–enamine tautomerism is inhibited, so the
charge transfer between the enamine NH and singlet oxygen
required for the oxidation does not occur.
In conclusion, we have investigated the spontaneous photo-
oxidation of the 1-(2-bromobenzyl)-4,9-dihydro-3H-b-carboline;
this has led to the development of a mild, regioselective and
practical protocol for the preparation of dihydro-b-carbolines of
type 5 and b-carbolines of type 6 from tryptamine derivatives 4 by
a sequential cyclisation-induced photo-oxidation of the non-
isolated 1-benzyl-4,9-dihydro-3H-b-carboline derivatives.
A
separate investigation into the biological activity of
compounds 5/6, and their optimization as potential inhibitors of
CDK4/Cyclin D1 is currently underway.
This work was supported by Cancer Research UK. M. D. G.
thanks the Xunta de Galicia for financial support.
Notes and references
1 D. M. Roll, C. M. Ireland, H. S. M. Lu and J. Clardy, J. Org. Chem.,
1988, 53, 3276.
2 R. Soni, L. Muller, P. Furet, J. Schoepfer, C. Stephan, S. Zumstein-
Mecker, H. Fretz and B. Chaudhuri, Biochem. Biophys. Res. Commun.,
2000, 275, 877.
3 A. Hormann, B. Chaudhuri and H. Fretz, Bioorg. Med. Chem., 2001, 9,
917.
4 C. Aubry, A. J. Wilson, P. R. Jenkins, S. Mahale, B. Chaudhuri,
J. D. Marechal and M. J. Sutcliffe, Org. Biomol. Chem., 2006, 4, 787;
C. Aubry, A. Patel, S. Mahale, B. Chaudhuri, J.-D. Marechal,
M. J. Sutcliffe and P. R. Jenkins, Tetrahedron Lett., 2005, 46, 1423;
C. Aubry, P. R. Jenkins, S. Mahale, B. Chaudhuri, J. D. Marechal and
M. J. Sutcliffe, Chem. Commun., 2004, 1696.
5 O. L. Radchenko, V. L. Novikov and G. B. Elyakov, Tetrahedron Lett.,
1997, 38, 5339.
6 This observation is not new, since related compounds of type 5/6 have
been isolated after basic work-up of the Bischler–Napieralski reaction
and it has been linked to the spontaneous oxidation of an initially
formed 4-type compound; K. M. Biswas and A. H. Jackson, J. Chem.
Soc., Perkin Trans. 1, 1989, 1981.
2588 | Chem. Commun., 2006, 2586–2588
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