A novel one-pot four-component access to tetrahydro-β-carbolines by a coupling-amination-aza-annulation-Pictet-Spengler sequence (CAAPS)

Article abstract of DOI:10.1039/b404559a

The four-component coupling-amination-aza-annulation-Pictet-Spengler (CAAPS) sequence of acid chlorides 1, terminal alkynes 2, tryptamine derivatives 6, and acryloyl chloride derivatives 4 represents a facile and rapid one-pot access to tetrahydro-β-carbolines 7 in moderate to good yields.

Full text of DOI:10.1039/b404559a

A novel one-pot four-component access to tetrahydro-b-carbolines by a
coupling-amination-aza-annulation-Pictet–Spengler sequence (CAAPS)†
Alexei S. Karpov, Thomas Oeser and Thomas J. J. Müller*
Organisch-Chemisches Institut der Ruprecht-Karls-Universität Heidelberg, Im Neuenheimer Feld 270,
D-69120 Heidelberg, Germany. E-mail: Thomas_J.J.Mueller@urz.uni-heidelberg.de;
Fax: ++49(0)6221546579; Tel: ++49(0)6221546207
Received (in Cambridge, UK) 29th March 2004, Accepted 27th April 2004
First published as an Advance Article on the web 25th May 2004
The four-component coupling-amination-aza-annulation-Pic-
tet–Spengler (CAAPS) sequence of acid chlorides 1, terminal
alkynes 2, tryptamine derivatives 6, and acryloyl chloride
derivatives 4 represents a facile and rapid one-pot access to
tetrahydro-b-carbolines 7 in moderate to good yields.
data corroborate the suggested molecular structure of these aza-
annulation products.
However, upon applying tryptamine (6a) or (S)-(2)-tryptophane
methylester (6b) as primary amines in the CAA sequence the
lactams 5 were not the final reaction products, but as a result of a
subsequent Pictet–Spengler reaction,10 only the indolo[2,3-a]qui-
nolizin-4-ones 7 were isolated in moderate to good yields as
colorless crystals (Scheme 2, Table 1).11 Thus, a N-acyliminium
cyclization12 terminates the CAA reaction by a Pictet–Spengler
cyclization13 in the sense of a four-component coupling-aza-
annulation-Pictet–Spengler sequence (CAAPS) and generates a
maximum of structural complexity and diversity in a one-pot
fashion.
The successful formation of the indolo[2,3-a]quinolizin-4-one
core is unambiguously supported by 1H NMR, 13C NMR, 2D
NOESY experiments, IR spectroscopy, MS spectrometry, combus-
tion analytical data and, additionally, it is corroborated by
numerous X-ray structure analyses (for 7h see Fig. 1).‡
Interestingly, however, is the excellent diastereoselectivity of the
CAAPS sequence where the R2, acyl-R1, and R5 substituents are
exclusively placed in a syn–syn arrangement (Table 1, entries 1–5,
7, 8), whereas with an R4 substituent other than hydrogen, epimers
are formed at that position with moderate selectivity (entry 6, d.r. =
4.5 : 1). Most surprisingly, with (S)-(2)-tryptophan methyl ester
(6b) as tryptamine derivative the only cyclization product isolated
in 45% yield is the tetrahydro-b-carboline 7h (entry 8, Fig. 1) that
is formed as a single diastereomer.
Tetrahydro-b-carbolines not only constitute subunits in numer-
ous alkaloids14 but they are also templates for drug discovery and
have been used as scaffolds for combinatorial libraries. They
display a pronounced antitumor and antiviral activity15 and some of
them have been shown to efficiently inhibit monoamine oxidase
A16 and bind with nanomolar affinity to serotonin receptors in the
central nervous system.
In conclusion, the four-component CAAPS sequence where five
bonds are formed in a one-pot reaction proceeds with reasonable
yields and delivers, starting from electronically diverse acid
chlorides and aliphatic, aromatic alkynes as well as (TMS)acety-
lene, a broad variety of tetrahydro-b-carbolines 7. Studies scouting
the scope and limitation of this novel tetrahydro-b-carboline
Multicomponent and sequential one-pot processes address very
fundamental principles of synthetic efficiency and reaction design1
and they are steadily gaining a considerable and increasing
academic, economic and ecological interest. Additionally, the
aspect of a modular chemistry of one-pot reactions can be readily
expanded into combinatorial and solid phase syntheses1,2 promis-
ing manifold opportunities for developing novel lead structures of
pharmaceuticals, catalysts and even novel molecule based materi-
als. Therefore, we are designing novel multicomponent syntheses
by alkyne activation3 initiated by transition metal catalyzed CC-
bond forming processes4 like the Sonogashira coupling.5
Just recently, we could show that the Sonogashira coupling of
acid chlorides and alkynes generating alkynones, that now open a
new mode of consecutive reactions, gives rise to the formation of
enaminones and pyrimidines in sequential three-component trans-
formations.6,7 In particular, the newly generated enaminone
functionality6,7 is electronically amphoteric and can be addressed in
Michael additions, at its enamine reactivity, or even in their
combination. Here, we communicate the design of the first four-
component aza-annulations and a novel rapid coupling-amination-
aza-annulation-Pictet–Spengler (CAAPS) sequence as a new
modular entry to tetrahydro-b-carboline frameworks.
(Hetero)aryl acid chlorides 1, terminal alkynes 2 and primary
amines react in the sense of a one-pot coupling-amination (CA)
sequence to furnish Z-configured enaminones in excellent yields.7
Encouraged by this facile access to enaminones which are key
intermediates in heterocyclic syntheses8 we set out to probe the
compatibility of a subsequent aza-annulation reaction9 with the
conditions of the CA sequence. Hence, after performing the CA
reaction with thienoyl chloride (1a), 1-hexyne (2a), and benzyl
amine (3a) or homoveratryl amine (3b), acryloyl chloride (4a) was
added and after gentle heating the intermediate enaminones were
smoothly converted into 5-acyl dihydropyrid-2-ones 5 that were
isolated in moderate to good yield as colorless oils (Scheme 1).
The structure of the lactams 5 is unambiguously supported by the
expected appearance of the characteristic proton and carbon
resonances and multiplicities in the NMR spectra. Additionally, the
mass spectrometric, IR spectroscopic, and combustion analytical
Scheme 1 One-pot four-component coupling-amination-aza-annulation
(CAA) sequence.
† Electronic supplementary information (ESI) available: Experimental
details and X-ray structure data for 7h. See http://www.rsc.org/suppdata/cc/
b4/b404559a/
Scheme 2 One-pot four-component coupling-aza-annulation-Pictet–Spen-
gler sequence (CAAPS).
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C h e m . C o m m u n . , 2 0 0 4 , 1 5 0 2 – 1 5 0 3
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

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Table 1 Coupling-amination-aza-annulation-Pictet–Spengler (CAAPS) sequence to indolo[2,3-a]quinolizin-4-ones 7
a,b-Unsaturated acid
Entry Acid chloride 1
Alkyne 2
Tryptamine 6 chloride 4
Tetrahydro-b-carboline 7 (yield)
1a
2a
3a
4a
5a
R1 = 2-thienyl (1a)
R2 nBu (2a) R3 = H (6a)
6a
6a
R2 = Ph (2b) 6a
=
R4 = R5 = H (4a) 7a (R1 = 2-thienyl, R2
=
7b (R1 = p-O2NC6H4, R2
7c (R1 = p-MeOC6H4, R2
nBu , R3 = R4 = R5 = H, 52%)
=
=
R1 = p-O2NC6H4 (1b) 2a
4a
4a
4a
nBu , R3 = R4 = R5 = H, 43%)
nBu, R3 = R4 = R5 = H, 59%)
R1 = p-MeOC6H4 (1c) 2a
1a
1a
7d (R1 = 2-thienyl, R2 = Ph, R3 = R4 = R5 = H, 41%)
2a
6a
R4 = H, R5 = CH3 7e (R1 = 2-thienyl, R2
(4b)
=
nBu, R3 = R4 = H, R5 = CH3, 50%)
6a
1a
2a
6a
R4 = CH3, R5 = H 7f (R1 = 2-thienyl, R2
(4c)
4a
=
nBu, R3 = R5 = H, R4 = CH3, 54%,
syn–syn/syn–anti = 4.5 : 1)b
7a
8d
1a
1a
R2 = TMS (2c) 6ac
2a
7g (R1 = 2-thienyl, R2 = R3 = R4 = R5 = H, 32%)
R3 = CO2CH3 4a
7h (R1 = 2-thienyl, R2 nBu, R3 = CO2Me, R4 = R5 = H,
=
(6b)e
45%)
a In THF. b The mixture of diastereomers was separated by column chromatography. c After the coupling step 1.00 mmol of an aqueous TBAF solution was
added prior to the addition of 6a. d In toluene. e Additionally, together with 2.00 mmol of 6b (as a hydrochloride), 0.28 mL (2.00 mmol) of triethylamine were
added.
5 For a recent review, see e.g.: K. Sonogashira, J. Organomet. Chem.,
2002, 653, 46.
6 A. S. Karpov and T. J. J. Müller, Org. Lett., 2003, 5, 3451.
7 A. S. Karpov and T. J. J. Müller, Synthesis, 2003, 2815.
8 For recent reviews on the synthetic potential of enaminones in
heterocycle syntheses, see e.g.: Y. V. Smirnova and Z. A. Krasnaya,
Russ. Chem. Rev., 2000, 69, 1021; J. P. Michael, C. B. De Koning, D.
Gravestock, G. D. Hosken, A. S. Howard, C. M. Jungmann, R. W. M.
Krause, A. S. Parsons, S. C. Pelly and T. V. Stanbury, Pure Appl. Chem.,
1999, 71, 979; P. Lue and J. V. Greenhill, Adv. Heterocycl. Chem., 1997,
67, 207.
9 For recent examples of aza-annulations, see e.g.: K. Paulvannan and T.
Chen, J. Org. Chem., 2000, 65, 6160; P. Benovsky, G. A. Stephenson
and J. R. Stille, J. Am. Chem. Soc., 1998, 120, 2493.
10 For a recent review, see e.g.: E. D. Cox and J. M. Cook, Chem. Rev.,
1995, 95, 1797.
11 Typical procedure (Compound 7c): in a screw cap pressure vessel 14 mg
(0.02 mmol) of Pd(PPh3)2Cl2, and 7 mg (0.04 mmol) of CuI were
Fig. 1 Molecular structure of 7h (R1 = 2-thienyl, R2 = nBu, R3
CO2CH3, R4 R5
H). For a better overview only one of both
independent host molecules is shown.
=
dissolved in 5 mL of degassed THF or toluene. Then 0.14 mL (1.00
mmol) of triethylamine, as well as 171 mg (1.00 mmol) of 1c and 0.12
mL (1.05 mmol) of 2a were successively added to the solution. The
reaction mixture was stirred at room temperature for 1 h. Then, 320 mg
(2.00 mmol) of tryptamine (6a) were added and the reaction mixture
was heated to 70 °C and maintained at this temperature over 10 h. Then,
0.41 mL (5.00 mmol) of acryloyl chloride (4a) was added and the
reaction mixture was heated to 70 °C and maintained at this temperature
over 3 h. The reaction mixture was diluted with methanol and stirred for
10 min. Then, after workup and chromatography (silica gel, diethyl
ether) 254 mg (59%) of the analytically pure tetrahydro-b-carboline 7c
was obtained as colorless crystals, mp. 201–202 °C, [a]D24 +178° (c =
2.0, CH2Cl2). Rf = 0.25 (diethylether). 1H NMR (CDCl3, 300 MHz): d,
0.85 (t, J, = 7.0 Hz, 3 H), 1.05–1.40 (m, 4 H), 1.96–2.12 (m, 1 H),
2.20–2.40 (m, 2 H), 2.75–3.07 (m, 6 H), 3.74 (s, 3 H), 3.93 (dd, J, =
13.2 Hz, J, = 4.9 Hz, 1 H), 5.23–5.31 (m, 1 H), 6.74 (d, J, = 9.0 Hz,
2 H), 7.04–7.17 (m, 3 H), 7.46–7.52 (m, 1 H), 7.66 (d, J, = 9.0 Hz, 2 H),
8.27 (s, 1 H). 13C NMR (CDCl3, 75 MHz): d, 13.9 (CH3), 20.9 (CH2),
21.5 (CH2), 23.2 (CH2), 27.2 (CH2), 29.6 (CH2), 35.7 (CH2), 39.8
(CH2), 52.6 (CH), 55.3 (CH3), 62.0 (Cquat), 110.7 (Cquat), 111.0 (CH),
113.7 (CH), 118.0 (CH), 119.3 (CH), 121.8 (CH), 125.9 (Cquat), 129.4
(Cquat), 130.3 (CH), 134.3 (Cquat), 135.7 (Cquat), 163.7 (Cquat), 169.6
(Cquat), 201.5 (Cquat). Anal. calcd. for C27H30N2O3 (430.6): C 75.32, H
7.02, N 6.51. Found: C 74.93, H 7.01, N 6.46%.
=
=
synthesis and the concomitant enhancement of molecular diversity
in pharmaceutically interesting targets are currently underway.
The authors gratefully acknowledge the financial support by
DFG (Graduiertenkolleg 850), MORPHOCHEM AG, München,
Fonds der Chemischen Industrie, and Dr.-Otto-Röhm Gedächt-
nisstiftung.
Notes and references
‡ Crystal data 7h: C26H28N2O4S·CH2Cl2, M = 549.5, monoclinic, space
group P21, a = 12.022(1), b = 14.950(1), c = 14.663(1) Å, a = 90.0, b
= 94.869(2), g = 90.0°, V = 2625.9(4) Å3, T = 100(2) K, Z = 4, r =
1.390 g cm23, crystal dimensions 0.21 3 0.15 3 0.12 mm3, Mo Ka
radiation, m = 0.364 mm21, l = 0.71073 Å. Data were collected on a
Bruker Smart APEX diffractometer and a total of 10561 of the 23151
reflections were unique [R(int) = 0.0423]. Refinement on F2, wR2 = 0.107
(observed reflections), R1 = 0.050 for [I > 2s(I)]. CCDC 235421. See
http://www.rsc.org/suppdata/cc/b4/b404559a/ for crystallographic data in
.cif or other electronic format.
12 For a recent review on cyclization of N-acyliminium ions, see e.g.: B. E.
Maryanoff, H.-C. Zhang, J. H. Cohen, I. J. Turchi and C. A. Maryanoff,
Chem. Rev., 2004, 104, 1431.
13 The aza-annulation-Pictet–Spengler reaction was reported last year
independently from our group: M. M. Abelman, J. K. Curtis and D. R.
James, Tetrahedron Lett., 2003, 44, 6527.
1 For recent reviews, see e.g.: I. Ugi, A. Dömling and B. Werner, J.
Heterocycl. Chem., 2000, 37, 647; L. Weber, K. Illgen and M.
Almstetter, Synlett, 1999, 366.
2 S. Kobayashi, Chem. Soc. Rev., 1999, 28, 1.
3 See e.g.: A. S. Karpov, F. Rominger and T. J. J. Müller, J. Org. Chem.,
2003, 68, 1503; T. J. J. Müller, J. P. Robert, E. Schmälzlin, C. Bräuchle
and K. Meerholz, Org. Lett., 2000, 2, 2419; T. J. J. Müller, M. Ansorge
and D. Aktah, Angew. Chem., Int. Ed., 2000, 39, 1253.
4 For recent reviews on transition metal assisted sequential transforma-
tions, see e.g.: G. Balme, E. Bossharth and N. Monteiro, Eur. J. Org.
Chem., 2003, 4101; G. Battistuzzi, S. Cacchi and G. Fabrizi, Eur. J. Org.
Chem., 2002, 2671.
14 For overviews, see e.g.: E. Breitmaier, Alkaloide, Teubner Stud-
ienbücher, Stuttgart, 1997, p. 52; K. Stuart and R. Woo-Ming,
Heterocycles, 1975, 3, 223.
15 For reviews, see e.g.: S. Urban, S. J. H. Hickford, J. W. Blunt and M. H.
G. Munro, Curr. Org. Chem., 2000, 4, 765; J. B. Hudson, Antiviral Res.,
1989, 12, 55; D. J. McKenna and G. H. Towers, J. Psychoact. Drugs,
1984, 16, 347.
16 B. T. Ho, J. Pharm. Sci., 1972, 61, 821.
C h e m . C o m m u n . , 2 0 0 4 , 1 5 0 2 – 1 5 0 3
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