An expedient strategy for the synthesis of tryptamines and other heterocycles

Article abstract of DOI:10.1002/anie.200800404

(Chemical Equation Presented) Making many from one: N-Boc-protected anilines are converted into an array of useful N-heterocycles and tryptamines through an expedient, cascade-based synthetic sequence involving ortho metalation and subsequent coupling wit

Full text of DOI:10.1002/anie.200800404

Angewandte
Chemie
DOI: 10.1002/anie.200800404
Heterocycles
An Expedient Strategy for the Synthesis of Tryptamines and Other
Heterocycles**
K. C. Nicolaou,* Arkady Krasovskiy, Vincent É. TrØpanier, and David Y.-K. Chen*
The increasing number of heterocyclic natural products and
the well known applications of heterocyclic chemistry to
pharmaceutical research dictate the development of new
synthetic methods for accessing heterocycles. Novel cascade
reactions offer rapid assembly of molecular frameworks and
have been employed in natural product and other complex
molecule construction with impressive results.[1] In this
communication, we report an expedient, cascade-based
strategy for the construction of novel heterocyclic systems,
including spiro-heterocycles, ortho-substituted anilines, and
tryptamines.
Scheme 1 depicts the general concepts for the construc-
tion of spiro-heterocycles (IV), ortho-substituted anilines
(VIII), and tryptamines (XII) starting with readily available
aniline derivatives (I). Thus, bis-metalation of aniline I to
form reactive intermediate II,[2] and subsequent addition of
N-Boc pyrrolidin-3-one (A) should lead to species III, whose
ring closure as shown should offer an entry into spirocyclic
system IV and derivatives thereof as stable chemical entities.
Temporary capping of the active NH functionality within IV
should allow a second cascade sequence initiated by regiose-
lective base-induced deprotonation of intermediate V[3] to
afford anionic species VI, whose collapse as shown should
lead, sequentially, to intermediates VII (ring opening) and
ꢀ
VIII (extrusion of CO2 and hydrolysis of the N X bond). The
latter species represents a reactive class of ortho-substituted
anilines whose potential remains relatively unexplored.[4]
[*] Prof. Dr. K. C. Nicolaou, Dr. A. Krasovskiy, Dr. V. É. TrØpanier
Department of Chemistry and
The Skaggs Institute for Chemical Biology
The Scripps Research Institute
10550 North Torrey Pines Road, La Jolla, CA 92037 (USA)
and
Department of Chemistry and Biochemistry
University of California, San Diego
9500 Gilman Drive, La Jolla, CA 92093 (USA)
Fax: (+1)858-784-2469
E-mail: kcn@scripps.edu
Prof. Dr. K. C. Nicolaou, D. Y.-K. Chen
Chemical Synthesis Laboratory @ Biopolis
Institute of Chemical and Engineering Sciences (ICES)
Agency for Science, Technology and Research (A*STAR)
11 Biopolis Way, The Helios Block, #03-08, Singapore 138667
(Singapore)
E-mail: david_chen@ices.a-star.edu.sg
[**] We thank Doris Tan (ICES) for high-resolution mass spectrometry
(HRMS) assistance and Dr. T. W. C. Hoe (Institute of Molecular and
Cell Biology (IMCB), A*STAR) for X-ray crystallographic analysis.
Financial support for this work was provided by A*STAR.
Scheme 1. General, cascade-based strategy for the construction of
novel spiro-heterocycles (IV), ortho-substituted anilines (VIII), and
tryptamines (XII). X=capping group; Boc=tert-butoxycarbonyl.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2008, 47, 4217 –4220
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4217

Communications
Finally, a third cascade sequence may be initiated from ortho-
substituted aniline system VIII by acid catalysis, leading,
through fleeting intermediates IX–XI, to tryptamine XII, a
well known building block for many intents and purposes.[5]
The implementation of this plan by using N-Boc aniline
(1a) as a starting material is shown in Scheme 2. Thus,
Figure 1. X-ray derived ORTEP drawings of compounds 1c and 1d
drawn at the 50% probability level.
The generality and scope of this new methodology are
demonstrated by the examples shown in Table 1. Thus, in
addition to aniline itself (Table 1, entry 1), a number of
substituted anilines, including meta- (Table 1, entries 2 and 7)
and para-substituted anilines (Table 1, entries 3–6) were
successfully employed as starting materials leading to an
array of heterocyclic systems, including tryptamine 2e, whose
structure is related to the antipsychotic agents psilocin and
psilocybin.[10,11] Furthermore, the sequence is tolerant of
chlorine and fluorine atoms (Table 1, entries 3 and 4) as well
as trifluoromethyl groups (Table 1, entries 6 and 7), note-
worthy features for medicinal chemistry applications. Naph-
thyl (Table 1, entry 8) and biphenyl (Table 1, entry 9) deriv-
atives also enter the cascade sequence, permitting further
expansion of the scope and generality of the method. Whereas
in situ N-silylation[8] was necessary for the procurement of
free indole tryptamines, N-methylated spirocarbamate 10c
Scheme 2. Synthesis of ortho-substituted anilines 1b and 1d, spiro-
heterocycle 1c, and tryptamines 1e and 1 f. Reagents and conditions:
a) tBuLi (2.4 equiv), Et2O, ꢀ108C, 4 h; b) LaCl3·2LiCl (0.33m in THF,
1.3 equiv), ꢀ708C, 5 min; then A (1.0m in THF, 1.2 equiv), ꢀ70!
258C, 1 h, 1b (75%); c) tBuOK (0.1 equiv), THF, 708C, 4 h, 1c (90%
from 1b; 72% from 1a); d) tBuOK (1.2 equiv), TBSCl or TIPSCl
(1.2 equiv), THF, 258C, 1 h; then LDA (1.0m in THF, 5.0 equiv),
ꢀ50!ꢀ308C, 2 h, 1d (77%); e) TFA/CH2Cl2 (1:10), 0!258C, 2 h, 1e
(98%) or HCl (conc., 1 drop), CH2Cl2, 0!258C, 2 h, 1 f (98%).
TBS=tert-butyldimethylsilyl; TIPS=triisopropylsilyl; TFA=trifluoroace-
tic acid.
treatment of 1a with tBuLi in ether (ꢀ108C, 4 h) and
subsequent sequential addition of LaCl3·2 LiCl (ꢀ708C,
5 min)[6] and N-Boc pyrrolidin-3-one (A)[7] (ꢀ708C) fur-
nished, upon warming to room temperature and aqueous
workup, aniline derivative 1b in 75% yield. The latter
compound was converted into spiro-heterocycle 1c in 90%
yield upon exposure to catalytic amounts of tBuOK
(10 mol%; THF, 708C, 4 h). Alternatively, spiro-heterocycle
1c could be directly obtained from intermediate 1a in 72%
yield upon addition of catalytic amounts of tBuOK (10 mol%;
THF, 708C, 4 h) to the reaction mixture prior to the workup.
The latter observation elevates the cascade sequence from 1a
to a convenient, one-pot operation for the preparation of
spirocycle 1c. Exposure of carbamate 1c to tBuOK and
TBSCl (or TIPSCl)[8] with subsequent addition of LDA gave,
after work up with aqueous NH4Cl, ortho-substituted aniline
1d in 77% yield. Finally, treatment of the labile ortho-
substituted aniline 1d with TFA in CH2Cl2 afforded trypt-
amine 1e in 98% yield, whereas the use of concentrated HCl,
instead of TFA, led to the N-Boc protected tryptamine
derivative 1 f (98% yield).
Scheme 3. Construction of Corey and co-workers’ tryptamine 11 f.
Reagents and conditions: a) Boc2O (1.2 equiv), DMAP (1.0 equiv),
CH2Cl2, 258C, 2 h; then reflux in tBuOH, 6 h; b) NaH (1.5 equiv), MeI
(2.0 equiv), THF, 258C, 2 h, 11b (62%); c) iPrMgCl·LiCl (1.0m in THF,
1.1 equiv), THF, ꢀ708C, 2 h; then LaCl3·2LiCl (0.33m in THF,
1.1 equiv), ꢀ708C, 1 h; then A (1m in THF, 1.0 equiv), ꢀ70!258C,
1 h, 11c (78%); d) TFA (0.1 equiv), CH2Cl2, 08C, 1 h, 11d (96%);
e) LDA (1.0m in THF, 1.1 equiv), ꢀ50!ꢀ308C, 3 h, 11e (92%); f)
TFA (0.1 equiv), CH2Cl2, 0!258C, 2 h, 11 f (96%). DMAP=4-dimethyl-
aminopyridine; LDA=lithium diisopropylamide.
Heterocycles 1c (m.p. 176–1778C, EtOAc) and 1d (m.p.
124–1258C, EtOAc) afforded crystals suitable for X-ray
crystallographic analysis that proved their structure beyond
question[9] (see ORTEP drawings, Figure 1).
4218
www.angewandte.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2008, 47, 4217 –4220

Angewandte
Chemie
Table 1: Synthesis of spiro-heterocycles and tryptamines.
Entry
N-Boc aniline
Spiro-heterocycle[a]
Yield[b] [%]
Tryptamine[c]
Yield[b] [%]
1
72
76
2
3
76
81
84
80
4
5
6
70
74
72
71
66
68
7
74
77
8
79
41
87
65
9
80
10
71[d]
[a] Reactions were carried out on 3.0-mmol scale in anhydrous ether. [b] Yield of isolated product. [c] Reactions were carried out on 0.1-mmol scale in
anhydrous THF. [d] Obtained by in situ N-methylation of the anion of spirocycle 1c with MeI prior to quenching.
Angew. Chem. Int. Ed. 2008, 47, 4217 –4220
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
4219

Communications
[3] For the metalation of N-Boc pyrrolidines, see: a) P. Beak, D. B.
Reitz, Chem. Rev. 1978, 78, 275 – 316; b) P. Beak, W. J. Zajdel,
D. B. Reitz, Chem. Rev. 1984, 84, 471 – 523; c) D. J. Gallagher, P.
Beak, J. Org. Chem. 1995, 60, 7092 – 7093; d) K. M. B. Gross, P.
Beak, J. Am. Chem. Soc. 2001, 123, 315 – 321.
[4] For an elegant use of such an enamine derivative in total
synthesis, see: V. H. Rawal, S. Iwasa, J. Org. Chem. 1994, 59,
2685 – 2686.
[5] For the synthesis and biological activity of tryptamines, see:
a) A. Shulgin, A. Shulgin, PIHKAL, Transform Press, Berkeley,
CA, USA, 1991; b) R. J. Sundberg, Indoles, Best Synthetic
Methods Series, Academic Press, London, 1996; c) S. Freeman,
J. F. Alder, J. Med. Chem. 2002, 37, 527 – 539.
[6] A. Krasovskiy, F. Kopp, P. Knochel, Angew. Chem. 2006, 118,
511 – 515; Angew. Chem. Int. Ed. 2006, 45, 497 – 500.
[7] J. C. Barrow, P. G. Nantermet, H. G. Selnick, K. L. Glass, P. L.
Ngo, M. B. Young, J. M. Pellicore, M. J. Breslin, J. H. Hutch-
inson, R. M. Freidinger, C. Condra, J. Karczewski, R. A. Bednar,
S. L. Gaul, A. Stern, R. Gould, T. M. Connolly, Bioorg. Med.
Chem. Lett. 2001, 11, 2691 – 2696.
(obtained from 1a by in situ N-methylation of the corre-
sponding anion with MeI) afforded 1-methyltryptamine 10e
directly upon treatment with LDA (Table 1, entry 10).
As a first application of the described methodology, we
report a short and efficient synthesis of 6,7-dimethoxy-1-
methyltryptamine (11 f), a compound used by Corey and co-
workers in the synthesis of aspidophytine[12] (Scheme 3). Thus,
N-Boc protection (Boc2O, DMAP; then tBuOH, reflux)[13]
and subsequent methylation (NaH, MeI) of known iodoani-
line 11a[14] afforded iodide 11b (62% yield), which was
reacted sequentially, and in one pot, with iPrMgCl·LiCl,[15]
LaCl3·2 LiCl,[6] and N-Boc pyrrolidin-3-one (A) to give
aniline derivative 11c, in 78% yield. Exposure of the latter
compound to TFA in CH2Cl2 then furnished spirocycle 11d in
quantitative yield. Since the nitrogen atom of the cyclic
carbamate has no acidic protons, in this case, the rupture of
spirocycle 11d was performed directly by treatment with
LDA and led to bicycle 11e, whose rearrangement/depro-
tection to tryptamine 11 f was accomplished through the
action of TFA in 96% yield.
[8] Since it was more convenient to transfer small amounts of
TIPSCl than TBSCl under inert atmosphere, the former was
favored throughout this work.
[9] CCDC 675373 (1c) and 675374 (1d) contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
[10] a) F. Yamada, M. Tamura, A. Hasegawa, M. Somei, Chem.
Pharm. Bull. 2002, 50, 92 – 99; b) F. Yamada, M. Tamura, M.
Somei, Heterocycles 1998, 49, 451 – 457; c) H. Sakagami, K.
Ogasawara, Heterocycles 1999, 51, 1131 – 1135; d) D. E. Nichols,
S. Frescas, Synthesis 1999, 935 – 938.
The chemistry described herein provides facile and direct
entries into a variety of novel N-heterocycles and substituted
tryptamines. This general method is expected to find appli-
cations in chemical synthesis in general, and in the construc-
tion of tryptamine-based complex molecules in particular.
Received: January 25, 2008
Published online: April 11, 2008
[11] a) A. Stoll, F. Troxler, J. Peyer, A. Hofmann, Helv. Chim. Acta
1955, 38, 1452 – 1472; b) A. Hofmann, R Heim, A. Brack, H.
Kobel, A. Frey, H. Ott, T. Petrzilka, F. Troxler, Helv. Chim. Acta
1959, 42, 1557 – 1572; c) R. W. Brimblecombe, R. M. Pinder,
Hallucinogenic Agents, Wright-Scientechnica, Bristol, 1975,
pp. 106 – 108.
[12] F. He, Y. Bo, J. D. Altom, E. J. Corey, J. Am. Chem. Soc. 1999,
121, 6771 – 6772.
[13] H.-J. Knꢀlker, T. Braxmeier, G. Schlechtingen, Angew. Chem.
1995, 107, 2746 – 2749; Angew. Chem. Int. Ed. Engl. 1995, 34,
2497 – 2500.
Keywords: heterocycles · indoles · metalation ·
synthetic methods · tryptamines
.
[1] K. C. Nicolaou, D. J. Edmonds, P. G. Bulger, Angew. Chem. 2006,
118, 7292 – 7344; Angew. Chem. Int. Ed. 2006, 45, 7134 – 7186.
[2] For use of the tert-butoxycarbonyl moiety as an ortho-directing
group in arene metalations, see: a) P. Stanetty, H. Koller, M.
Mihovilovic, J. Org. Chem. 1992, 57, 6833 – 6837; b) J. N. Reed,
V. S. Snieckus, Tetrahedron Lett. 1984, 25, 5505 – 5508; The
original procedure from J. M. Muchowski, M. C. Venuti, J. Org.
Chem. 1980, 45, 4798 – 4801 gave, in our hands, repeatedly low
yields.
[14] J. M. Mejia-Oneto, A. Padwa, Org. Lett. 2006, 8, 3275 – 3278.
[15] A. Krasovskiy, P. Knochel, Angew. Chem. 2004, 116, 3396 – 3399;
Angew. Chem. Int. Ed. 2004, 43, 3333 – 3336.
4220 www.angewandte.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2008, 47, 4217 –4220