Synthesis of 1,1-disubstituted tetrahydro-β-carbolines from 2-methyleneaziridines

Article abstract of DOI:10.1016/j.tetlet.2008.03.095

Ring opening of indole functionalised methyleneaziridines (3a-c, 7) with alcohols in the presence of boron trifluoride etherate leads to the formation of 1,1-disubstituted tetrahydro-β-carbolines in moderate to good yields (37-83%).

Full text of DOI:10.1016/j.tetlet.2008.03.095

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Tetrahedron Letters 49 (2008) 3489–3491
Synthesis of 1,1-disubstituted tetrahydro-b-carbolines
from 2-methyleneaziridines
Peter M. Mumford a, Jason J. Shiers a, Gary J. Tarver b, Jerome F. Hayes c,
Michael Shipman a,*
a Department of Chemistry, University of Warwick, Gibbet Hill Road, Coventry CV4 7AL, UK
b Organon Laboratories Ltd, part of the Schering Plough Corporation, Newhouse, Scotland ML1 5SH, UK
c GlaxoSmithKline, Old Powder Mills, Tonbridge TN11 9AN, UK
Received 27 February 2008; accepted 17 March 2008
Available online 25 March 2008
Abstract
Ring opening of indole functionalised methyleneaziridines (3a–c, 7) with alcohols in the presence of boron trifluoride etherate leads to
the formation of 1,1-disubstituted tetrahydro-b-carbolines in moderate to good yields (37–83%).
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Nitrogen heterocycles; Strained compounds; Ring opening; Pictet–Spengler; Aziridines
The tetrahydro-b-carboline (THBC) unit is a common
constituent of many naturally occurring alkaloids, which
display interesting biological activities.1 Examples include
harmicine,2 fumitremorgin C3 and haploscleridamine.4
The THBC nucleus is also an important template in drug
discovery,5 and approved drugs such as tadalafil6 possess
this heterocyclic ring system. THBCs have also been found
in many foods, and it is postulated that these compounds
are important in the prevention of diseases associated with
oxidative damage.7
reactive ketones such as a-ketoesters but the reactions are
often slow and low yielding with simple ketones. In the
latter case, steric and electronic factors presumably slow
down the rate of iminium ion formation, and make it less
reactive towards further cyclisation. As a consequence,
the preparation of 1,1-disubstituted tetrahydro-b-carbo-
lines by this approach is generally rather inefficient.
Recently, Lingam reported that molecular iodine can
act as an effective catalyst for Pictet–Spengler reactions
involving simple unactivated ketones.10 Titanium (IV)
The important biological effects of THBCs have made
them key targets for chemical synthesis. The most com-
monly used approach to this ring system is based upon
the Pictet–Spengler cyclisation.8,9 The classical Pictet–
Spengler reaction is a two-step process that involves the
condensation of a b-arylethyl amine with a carbonyl com-
pound to form an electrophilic iminium ion, which under-
goes further ring closure by way of electrophilic aromatic
substitution. The reaction works well with aldehydes and
R
R
Lewis acid (LA)
N
N
LA
N
H
N
H
NuH
R
R
Electrophilic
cyclisation
NH
Nu
N
LA
Nu
N
H
N
H
Me
*
Corresponding author. Tel.: +44 247 652 3186; fax: +44 247 652 4112.
Scheme 1. New route to 1,1-disubstituted tetrahydro-b-carbolines.
E-mail address: m.shipman@warwick.ac.uk (M. Shipman).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.03.095

3490
P. M. Mumford et al. / Tetrahedron Letters 49 (2008) 3489–3491
isopropoxide has also been used successfully as the iminat-
ing agent.11
X
R1OH (2.0 eq),
BF3 OEt2 (1.0 eq),
CH2Cl2, —30 °C→ rt, 15 h
X
As an alternative solution to the problems associated
with slow iminium ion formation from ketones, we decided
to explore a new route to 1,1-disubstituted tetrahydro-b-
carbolines using a strategy based upon the ring opening
of an indole substituted methyleneaziridinium ion with an
appropriate nucleophile under Lewis acid catalysis
(Scheme 1). By analogy with the Pictet–Spengler reaction,
further cyclisation of the resultant iminium ion to the
THBC nucleus was anticipated under the reaction condi-
tions. By variation in the structure of the methyleneazir-
idine and nucleophile components, it was anticipated
that a wide variety of 1,1-disubstituted THBCs could be
produced using this approach. In this Letter, we establish
the scope and limitations of this chemistry using alcohol-
based nucleophiles.
Initially, a series of methyleneaziridines containing
an indole nucleus tethered to the aziridine nitrogen were
prepared. The alkylation of 2,3-dibromopropene with
2.0 equiv of tryptamine (1a) afforded the monoalkylated
derivative 2a in 94% yield. Further ring closure12 of 2a
using sodium amide in liquid ammonia gave methyleneaz-
iridine 3a in 87% yield after bulb-to-bulb distillation
(Scheme 2). Methyleneaziridine 3b was prepared from 5-
methoxytryptamine (1b) in 85% overall yield using an iden-
tical sequence. Similarly, 3c was made in 62% yield from
N-2-(1-methyl-1H-indol-3-yl)ethylamine (1c).13
Earlier work on the ring opening reactions of methyl-
eneaziridines had established that BF3ÁOEt2 promotes
nucleophilic attack at C-3 with carbon-based nucleophiles
such as RMgCl.14 Thus, we reasoned that this Lewis acid
might induce the required ring opening/Pictet–Spengler
cyclisation (Scheme 1). The treatment of 3a (1.0 equiv) in
CH2Cl2, at À30 °C with an equimolar quantity of
BF3ÁOEt2 then benzyl alcohol as nucleophile (2 equiv)
and the subsequent warming of the reaction mixture to
room temperature overnight afforded 4a in an optimised
73% yield after column chromatography (Scheme 3 and
Table 1, entry 1). Lower yields were observed when the
reaction was conducted in chloroform (32%), toluene
(38%), dichloroethane (39%), or MeCN (52%). By using
just 1.1 equiv of benzyl alcohol in CH2Cl2, the yield of 4a
N
NH
OR1
N
R
N
R
37-83%
Me
4a-f
3a-c
Scheme 3. Synthesis of 1,1-disubstituted tetrahydro-b-carbolines 4a–i.
Table 1
Synthesis of 1,1-disubstituted tetrahydro-b-carbolines
Entry
Aziridine
R
X
R1OH
Product Yield
(%)
1
2
3
4
5
6
7
8
9
3a
3a
3a
3a
3a
3a
3b
3c
3c
H
H
H
H
H
H
H
Me
Me
H
H
H
H
H
H
PhCH2OH
nPrOH
c-HexOH
tBuOH
4a
4b
4c
4d
73
83
63
58
80
71
66
43
37
H2C@CHCH2OH 4e
HC„C(CH2)3OH 4f
OMe PhCH2OH
4g
4h
H
H
PhCH2OH
H2C@CHCH2OH 4i
was reduced to 54%. Having optimised the conditions for
the reaction, a range of alcohol-based nucleophiles were
examined in order to evaluate its scope. These reactions
proceeded in moderate to good yields, and a small set of
tetrahydro-b-carbolines 4a–i were produced (Scheme 3
and Table 1). It is notable that the substitution of the
indole nitrogen leads to lower product yields (Table 1,
entry 1, cf. entry 8). Preliminary results indicate that the
reaction tolerates additional functionality contained within
the alcohol or attached indole nucleus.
As the reaction generates a new quaternary asymmetric
centre, we sought to ascertain if any asymmetric induction
could be achieved. As an initial test, ( )-a-methyl-trypt-
amine (5) was converted into methyleneaziridine 7 via vinyl
bromide 6 in 92% yield over the two steps (Scheme 4). The
reaction of this aziridine with benzyl alcohol in the pres-
ence of BF3ÁOEt2 led to the isolation of 8 in 63% yield as
a single diastereomer. The analysis of the crude reaction
Br
Br
Br
X
X
Br
K2CO3, THF
Br
NH2
K2CO3, THF
88-98%
HN
N
H
Br
98%
N
H
NH2
HN
2a-c
N
5
6
N
R
R
1a-c
NaNH2, NH3
—33 °C
94%
X
NaNH2, NH3
—33 °C
BnOH,
3
BF3 OEt2, CH2Cl2,
N
—30 ºC → rt, 18 h
N
70-87%
1
NH
N
3a-c
N
H
R
N
H
63%
OBn
7
a (X = H. R = H); b (X = OMe, R = H); c (X = H, R = Me).
Scheme 2. Synthesis of indole substituted 2-methyleneaziridines 3a–c.
8
Scheme 4. Stereoselective cyclisation to 1,1,3-trisubstituted-b-carbolines.

P. M. Mumford et al. / Tetrahedron Letters 49 (2008) 3489–3491
3491
1
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mixture by H NMR indicated the presence of a second
component tentatively assigned as the minor diastereomer
(dr = 8:1) which was not isolated. The relative stereo-
chemistry of 8 was deduced by NOESY experiments.15
In summary, a new approach to 1,1-disubstituted tetra-
hydro-b-carbolines has been devised based upon the ring
opening of indole substituted methyleneaziridines. Studies
to extend this reaction to other types of nucleophiles are
ongoing in our laboratories and will be disclosed in due
course.
4. Patil, A. D.; Freyer, A. J.; Carte, B.; Taylor, P. B.; Johnson, R. K.;
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Acknowledgements
6. (a) Daugan, A.; Grondin, P.; Ruault, C.; Le Monnier de Gouville,
This work was supported by the Engineering and
Physical Sciences Research Council, the Biotechnology
and Biological Sciences Research Council (BBSSL-
200512206), Organon and GlaxoSmithKline. We are
indebted to the EPSRC National Mass Spectrometry
Service Centre for performing some of the mass measure-
ments, and to EPSRC (EP/C007999/1) for the provision
of additional mass spectrometers.
`
A.-C.; Coste, H.; Kirilovsky, J.; Hyafil, F.; Labaudiniere, R. J. Med.
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Le Monnier de Gouville, A.-C.; Coste, H.; Linget, J.-M.; Kirilovsky,
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Chem. Soc. 2006, 128, 1424–1425 and references cited therein.
10. Lingam, Y.; Rao, D. M.; Bhowmik, D. R.; Santu, P. S.; Rao, K. R.;
Islam, A. Tetrahedron Lett. 2007, 48, 7243–7245.
Supplementary data
Supplementary data (experimental procedures and
characterisation data for 2a–c, 3a–c, 4a–i and 6–8) associ-
ated with this article can be found, in the online version,
at doi:10.1016/j.tetlet.2008.03.095.
11. Horiguchi, Y.; Nakamura, M.; Kida, A.; Kodama, H.; Saitoh, T.;
Sano, T. Heterocycles 2003, 59, 691–705.
12. Shiers, J. J.; Shipman, M.; Hayes, J. F.; Slawin, A. M. Z.; Twin, H. J.
Am. Chem. Soc. 2004, 126, 6868–6869 and references cited therein.
13. Prepared by adaption of a recent synthesis of N-benzyltryptamine by:
Liu, Y.; Luo, S.; Fu, X.; Fang, F.; Zhuang, Z.; Xiong, W.; Jia, X.;
Zhai, H. Org. Lett. 2006, 8, 115–118.
References and notes
14. Hayes, J. F.; Shipman, M.; Twin, H. J. Org. Chem. 2002, 67, 935–942.
15. Strong NOESY cross-peaks were seen between the Me group at C-1
and H-3, and between the CH2OBn group and the methyl group at
C-3. These data are consistent with the depicted (1R*,3R*)-
diastereomer.
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