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464
J . Org. Chem. 1997, 62, 6464-6465
In d oles fr om o-Ha loa n ilin es: Syn th eses of
Tr yp ta m in es a n d Tr yp top h ols via
Regioselective Hyd r ofor m yla tion of
F u n ction a lized An ilin es
Sch em e 1
Yong Dong* and Carl A. Busacca
Department of Chemical Development, Boehringer Ingelheim
Pharmaceuticals Inc., 900 Ridgebury Road, Ridgefield,
Connecticut 06877
Received J une 30, 1997
The indole ring has long been a popular synthetic
target for chemists. As in most well-investigated areas,
synthesis of indole and its derivatives has flourished into
1
a rich field with many excellent methodologies. We
formylation of 2a [H
2
/CO (1:1), 300 psi, 5 mol %
, 70 °C, 70 h]. No hydro-
report here a new synthesis of indoles from o-haloanilines
by a sequence of two transition-metal catalyzed reactions.
We believe this method provides a useful access to the
substituted tryptamines2 and tryptophols,3 which are
HRh(CO)(PPh , Ph P, PhCH
3
)
3
3
3
genation product, or hydroxypyrrolidine (a possible cy-
clization product from NHTs of the side chain) was
1
detected in the crude H NMR spectra, and only traces
4
common structural units in many indole alkaloids and
of an aldehyde were observed. N,N-di-Boc-allylamine
was used next for ease of deprotection. The results are
summarized in Table 1. At this point, conditions for the
Heck reaction and hydroformylation are not fully opti-
mized.9 The functional groups in anilines 2d -j, included
CH , CF , OCH , Br, Cl, F, which survived unscathed
possess important pharmacological properties of their
own.5
Having successfully synthesized 4-aryl-2,3-dihydropy-
rroles via Pd-catalyzed arylation of N-tosylallylamine and
the subsequent Rh-catalyzed hydroformylation of Heck
adducts,6 we reasoned that if there were an o-amino
group in the styrene-type Heck adduct, the ensuing
regioselective hydroformylation of these functionalized
anilines 2 may be followed by cyclization and dehydration
to afford the corresponding tryptamines or tryptophols
3
3
3
under the hydroformylation condition. Consequently,
tryptamines 3d -j were modified with functionalities at
10a
10b
C5, C6,
and C7.
Starting material was recovered
(ca. 80%) when aniline 2c having an o-CH
3
was subjected
to the above hydroformylation condition. Thus, the
efforts to synthesize C4-substituted tryptamine met with
no success.11 Tryptophol 3k was formed exclusively in
73% yield from aniline 2k , which was the reduction
product of methyl o-aminocinnamate (61%, iBu AlH,
THF, -78 °C). This cinnamate in turn was a Heck
3
(Scheme 1).
To test this observation, aniline 2a was first obtained
from iodoaniline 1a and N-tosylallylamine under a typi-
cal Heck condition [5 mol % Pd(OAc) , 10 mol % (o-Tol) P,
TEA, CH
CN, refluxing].7 Much to our delight, tryptamine
2
3
2
3
8
3
a
was formed smoothly in 58% yield from the hydro-
adduct (91% yield) derived from iodoaniline 1a and
methyl acrylate.
(
1) (a) Sundberg, R. J . Indoles; Academic Press: San Diego, 1996.
In summary, we have developed the first indole syn-
thesis from the hydroformylation of functionalized anilines.
By utilization of readily available o-haloanilines, syn gas,
allylamine or methyl acrylate, and by combination of two
common catalytic transformations, the overall result is
the facile construction of indoles with an aminoethyl or
hydroxyethyl side chain at C-3. We expect that this
approach is also applicable to introduce other different
C3 side chains. This new method requires only catalytic
amounts of palladium and rhodium complexes. In ad-
(
b) For a recent Pd-catalyzed indole syntheses from iodoanilines, see:
Chen, C. Y.; Liberman, D. R.; Larsen, R. D.; Verhoeven, T. R.; Reider,
P. J . J . Org. Chem. 1997, 62, 2676.
(2) (a) Speeter, M. E.; Anthony, W. C. J . Am. Chem. Soc. 1954, 76,
6
208. (b) Flaugh, M. E.; Crawell, T. A.; Clemens, J . A.; Sawyer, B. D.
J . Med. Chem. 1979, 22, 63. (c) Harrington, P. J .; Hegedus, L. S. J .
Org. Chem. 1984, 49, 2657. (d) Tidwell, J . H.; Buchwald, S. L. J . Am.
Chem. Soc. 1994, 116, 11797. (e) Chen, C. Y.; Larsen, R. D.; Verhoeven,
T. R. WO 9532197 A1, 1995.
(3) (a) Snyder, H. R.; Pilgrim, F. J . J . Am. Chem. Soc. 1948, 70,
1
962. Kotsuki, H.; Teraguchi, M.; Shimomoto, N.; Ochi, M. Tetrahe-
dron Lett. 1996, 37, 3727. (b) RajanBabu, T. V.; Chenard, B. L.; Petti,
M. A. J . Org. Chem. 1985, 51, 1704. (c) Griffen, E. J .; Roe, D. G.;
Snieckus, V. J . J . Org. Chem. 1995, 60, 1484.
(
4) (a) Saxton, J . E. Indoles, part 4, The Monoterpenoid Indole
Alkaloids; J ohn Wiley & Sons: New York, 1983. (b) Peat, A. J .;
Buchwald, S. L. J . Am. Chem. Soc. 1996, 118, 1028. (c) Sadanandan
E. V.; Pillai, S. K.; Lakshmikantham, M. V.; Billimoria, A. D.;
Culpepper, J . S.; Cava, M. P. J . Org. Chem. 1995, 60, 1800.
(9) Some recent advances for the hydroformylation of styrenes: (a)
Breit, B. J . Chem. Soc., Chem. Commun. 1996, 2071. (b) Chelucci,
G.; Cabras, M. A.; Botteghi, C.; Basoli, C.; Marchetti, M. Tetrahedron.
Asymmetry 1996, 7, 885. (c) Masdebulto, A. M.; Orejon, A.; Castellanos,
A.; Castillon, S.; Calver, C. Tetrahedron. Asymmetry 1996, 7, 1829.
(10) (a) For tryptamine 3f, a closely related compound, 6-hydrox-
ytryptamine, was recently prepared in 14 steps overall: Shinada, T.;
Miyachi, M.; Itagaki, Y.; Naoki, H.; Yoshihara, K.; Nakajima, T.
Tetrahedron Lett. 1996, 37, 7099. (b) For a recent synthesis of C7-
substituted indoles, see: Kondo, Y.; Kojima, S.; Sakamoto, T. Hetero-
cycles 1996, 43, 2741.
(5) For some recent pharmacological studies related to neurotrans-
mitters serotonin and melatonin, see: (a) Garratt, P. J .; Travard, S.;
Vonhoff, S.; Tsotinis, A.; Sugden, D. J . Med. Chem. 1996, 39, 1797. (b)
Barf, T. A.; Boer, P.; Wikstr o¨ m, H.; Peroutka, S.; Svensson, K.; Ennis,
M. D.; Ghazal, N. B.; McGuire, J . C.; Smith, M. W. J . Med. Chem.
1
996, 39, 4717. (c) Halazy, S.; Perez, M.; Fourrier, C.; Pallard, I.;
Pauwels, P. J .; Palmier, C.; J ohn, G. W.; Valentin, J .-P.; Bonnafous,
R.; Martinez, J . J . Med. Chem. 1996, 39, 4920.
(
(
6) Busacca, C. A.; Dong, Y. Tetrahedron Lett. 1996, 37, 3947.
7) Palladium Reagents in Organic Synthesis; Heck, R. F., Ed.;
(11) Attempted olefination of di-ortho-substituted bromides such as
2,6-dinitrobromobenzene, 2,6-diaminobromobenzene, 2-amino-6-nitro-
bromobenzene, and the triflate of 2-bromo-3-nitrophenol all failed.
Thus, only aniline 2c was studied for the synthesis of C4-substituted
tryptamine.
Academic Press: San Diego, 1985; pp 276-287.
8) Shono, T.; Matsumura, Y.; Tsubata, K.; Uchida, K.; Kanazawa,
T.; Tsuda, K. J . Org. Chem. 1984, 49, 3711.
(
S0022-3263(97)01179-1 CCC: $14.00 © 1997 American Chemical Society
Dong
