Synthesis of new cyclopropanated tryptamine analogues

Article abstract of DOI:10.1055/s-2008-1078426

A series of tryptamine analogues bearing a cyclopropyl-amine unit was prepared, starting from 3-indolyl acetonitriles, through a MeTi(Oi-Pr) ₃-mediated cyclopropanation. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1078426

LETTER
1479
Synthesis of New Cyclopropanated Tryptamine Analogues
Cyclopropanated
l
Trypta
a
mine
A
nalo
u
gues de Szalata,a Janos Sapi,a Jan Szymoniak,b Philippe Bertus,*b,c Stéphane Gérard*a
a
Institut de Chimie Moléculaire de Reims, UMR CNRS 6229, Faculté de Pharmacie, Université de Reims-Champagne-Ardenne,
51 rue Cognacq-Jay, 51096 Reims Cedex, France
E-mail: stephane.gerard@univ-reims.fr
Institut de Chimie Moléculaire de Reims, UMR CNRS 6229, UFR Sciences, Université de Reims-Champagne-Ardenne, BP 1039, 51687
Reims Cedex 2, France
CNRS and Université du Maine, UMR 6011, UCO2M, 72085 Le Mans Cedex 9, France
Fax +33(2)43833902; E-mail: philippe.bertus@univ-lemans.fr
b
c
Received 17 March 2008
In a previous study, we noticed a promising 5-HT6 bind-
ing activity of N,N-dimethyl-N-arylsulfonyl-2-vinyl-
tryptamines 5.8 With the aim to increase the potency and/
or selectivity of our derivatives, we have chosen to intro-
duce conformational restrictions to their structure.
Abstract: A series of tryptamine analogues bearing a cyclopropyl-
amine unit was prepared, starting from 3-indolyl acetonitriles,
through a MeTi(Oi-Pr)3-mediated cyclopropanation.
Key words: cyclopropanes, indoles, titanium, transition metals,
tryptamines
Herein we describe the synthesis of the first representa-
tives of a new class of tryptamine compounds possessing
cyclopropane core at the a position of the tryptamine side
chain (general formulae of 6 and 7 are shown in Figure 1).
This design reflects the main structural requirements for
potent 5-HT6 receptor ligands. Namely, a sulfamide phar-
macophore is incorporated between two hydrophobic re-
gions and separated from a basic amine by a linker. In this
context, structure–activity relationship (SAR) studies
have also showed that N,N-dimethyl substitution slightly
increased the affinity for 5-HT6 receptors.9
In the last decades substantial efforts have been devoted to
the design and the synthesis of cyclopropane analogues of
biologically active compounds.1 Cyclopropanes are com-
monly used in drug design to impart conformational re-
striction to flexible molecules.2 Several examples of
biologically active compounds including a cyclopropane
moiety are known.3 For instance, tranylcypromine (1) is a
potent monoamine oxidase inhibitor and an efficient tran-
quilizing drug.4 The four conformationally constrained
glutamate analogues 2a–d were found to exhibit distinct
affinities for glutamate receptors, depending on the cyclo-
propane moiety configuration.5 Some serotonin analogues
3 were tested for affinity with 5-HT1A and 5-HT2 recep-
tors,6 while recently, the melatonin analogue 4 was used
to investigate the nature of the binding site of the melato-
nin receptor.7
The synthetic approach to these structures is straightfor-
ward, as depicted in Scheme 1. It involves only three steps
from commercially available 3-indolylacetonitrile (8) or
from 2-vinyl-3-indoleacetonitrile (9), prepared according
to a well-known method.10 After a protection of the indole
nitrogen, the titanium-mediated cyclopropanation of
nitriles11 would afford the corresponding primary cyclo-
propylamines, which will be converted into the final N,N-
dimethyl-substituted tryptamines analogues 6 and 7.12
NH2
R2
NH2
CN
NH2
R
NMe2
*
HO2C
CO2H
1) protection
*
N
R
R
2) cyclopropanation
3) N,N-dimethylation
N
H
N
R1
SO2Tol
1
2a–d
3
8 (R = H)
9 (R = vinyl)
6a–d (R = H)
7a,b (R = vinyl)
NHCOPr
NMe2
R2
NMe2
MeO
Scheme 1
R
N
N
N
The synthesis of substituted N,N-dimethylcyclopropyl-
tryptamines 6a–d and 2-vinyl-N,N-dimethylcyclopropyl-
tryptamines 7a,b started with the protection of the indole
nitrogen. It was performed at room temperature by treat-
ment of nitriles 8 and 9 with sodium hydroxide in a bipha-
sic system (CH2Cl2–H2O) and reaction with the
appropriate arylsulfonyl chlorides, benzyl bromide or
methyl iodide. After purification by column chromatogra-
R1
6 (R = H)
7 (R = vinyl)
Me
SO2Ar
4
5
Figure 1
SYNLETT 2008, No. 10, pp 1479–1482
Advanced online publication: 16.05.2008
DOI: 10.1055/s-2008-1078426; Art ID: G09608ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
0
8

1480
C. Szalata et al.
LETTER
phy or recrystallization, N-functionalized nitriles 10a–c bered metallacycle intermediates B. The ring contraction
and 11a,b were isolated in 45–70% yields.
of B was efficiently achieved by the addition of BF3·OEt2,
and the corresponding cyclopropylamines were obtained
after hydrolysis. Whereas this reaction was studied with a
variety of nitriles,11b including carbohydrates,13 the use of
We next turned to the cyclopropanation step.11 In this re-
action, transient titanacyclopropanes A, generated from
Ti(Oi-Pr)4 and two equivalents of Grignard reagents
(Scheme 2, path i), added to nitriles to afford five-mem-
Table 1 Preparation of Primary Cyclopropylamines 12 and 13 from Nitriles 10 and 11
R2
R2
NMe2
CN
R
MgBr
MeTi(Oi-Pr)3
R2
HCHO
NaBH3CN
NH2
R
R
THF
then BF3⋅OEt2
AcOH, MeOH
N
R1
N
R1
N
R1
10a–c, 11a,b
12a–d, 13a,b
6a–d, 7a,b
Entry
1
Nitrile
R2
H
Primary cyclopropylamine
Yield (%)a,b Tryptamine analogue
66
Yield (%)a,b
82
10a (R = H, R1 = SO2Ph)
NH2
NMe2
N
N
SO2Ph
SO2Ph
12a
6a
2
3
4
10b (R = H, R1 = SO2p-Tol)
10c (R = H, R1 = Bn)
10a
H
H
Et
59
97
92
94
NMe2
NH2
N
N
SO2Tol
SO2Tol
12b
6b
46
NH2
NMe2
N
Bn
N
Bn
12c
6c
57
Et
NMe2
Et
NH2
N
SO2Ph
N
SO2Ph
6dc
12dc
5
6
11a (R = vinyl, R1 = Me)
H
H
40
47
76
60
NH2
NMe2
N
Me
N
Me
13a
7a
7b
11b (R = vinyl, R1 = Bn)
NMe2
NH2
N
N
Bn
Bn
13b
a Yields refer to isolated products.
b All compounds gave satisfactory 1H NMR, 13C NMR, IR, MS and HRMS or elemental analysis data.
c A mixture of diastereoisomers (1:1) was obtained.
Synlett 2008, No. 10, 1479–1482 © Thieme Stuttgart · New York

LETTER
Cyclopropanated Tryptamine Analogues
1481
nitriles bearing indole or sulfonamide moieties was un-
precedented.
Acknowledgment
The authors thank the ‘Conseil Régional de Champagne-Ardenne’
for a Ph.D. fellowship (C.S.) and the CNRS for financial support.
Mass spectroscopic measurements by P. Sigaut and D. Harakat and
NMR analyses by C. Petermann and H. Baillia are gratefully ack-
nowledged.
Nitrile 10a (R = H, R1 = SO2Ph) was used as a model com-
pound to determine the optimal conditions for the cyclo-
propanation reaction. When ethylmagnesium bromide (2
equiv) was added to a solution of 10a and Ti(Oi-Pr)4 (1.1
equiv) in THF, followed by the addition of BF3·OEt2 (2
equiv), the cyclopropylamine 12a was obtained, albeit in
a moderate yield (37%). The direct addition of the Grig-
nard reagent to 10a was also observed, leading to the cor-
responding ketone in a significant yield (21%).14 Efforts
to increase the yield of 12a by modifying the solvent or
the temperature failed.
References and Notes
(1) (a) Vilsmaier, E. In The Chemistry of the Cyclopropyl
Group; Rappoport, Z., Ed.; Wiley: New York, 1987, 1341.
(b) Houben-Weyl, Vol. E17a-c; de Meijere, A., Ed.;
Thieme: Stuttgart, 1997.
(2) (a) Suckling, C. J. Angew. Chem., Int. Ed. Engl. 1988, 27,
537. (b) Salaün, J. Top. Curr. Chem. 2000, 207, 1.
(3) (a) Wise, R.; Andrews, J. M.; Edwards, L. J. Antimicrob.
Agents Chemother. 1983, 23, 559. (b) Todo, Y.; Nitta, J.;
Miyajima, M.; Fukuoka, Y.; Yamashiro, Y.; Nishida, N.;
Saikawa, I.; Narita, H. Chem. Pharm. Bull. 1994, 42, 2063.
(c) Brighty, K. E.; Castaldi, M. J. Synlett 1996, 1097.
(d) Högberg, M.; Sahlberg, C.; Engelhardt, P.; Noréen, R.;
Kangasmetsä, J.; Johansson, N. G.; Öberg, B.; Vrang, L.;
Zhang, H.; Sahlberg, B.-L.; Unge, T.; Lövgren, S.; Fridborg,
K.; Bäckbro, K. J. Med. Chem. 1999, 42, 4150. (e) Daluge,
S. M.; Martin, M. T.; Sickles, B. R.; Livingston, D. A.
Nucleosides Nucleotides 2000, 19, 297. (f) Tichenor, M. S.;
MacMillan, K. S.; Stover, J. S.; Wolkenberg, S. E.; Pavani,
M. G.; Zanella, L.; Zaid, A. N.; Spalluto, G.; Rayl, T. J.;
Hwang, I.; Baraldi, P. G.; Boger, D. L. J. Am. Chem. Soc.
2007, 129, 14092; and references therein.
We recently observed that MeTi(Oi-Pr)3 can be a valuable
alternative to Ti(Oi-Pr)4 in the cyclopropanation of
nitriles13c and imides.15 This reagent, which was intro-
duced by de Meijere for the cyclopropanation of tertiary
amides, requires only one equivalent of Grignard reagent
to generate the titanacyclopropane (Scheme 2, path ii).16
In this way side reactions due to an excess of the Grignard
reagent can be limited.
Ti(Oi-Pr)4
+
R
(i)
MeTi(Oi-Pr)3
+
(ii)
Ti(Oi-Pr)2
– MeH
–
R
MgX
R
A
2
MgX
R
(4) (a) Fujita, T. J. Med. Chem. 1973, 16, 923. (b) N-
Cyclopropyltryptamine was also described as a potent
monoamine oxidase inhibitor. See: Winn, M.; Horrom, B.
W.; Rasmussen, R. R.; Chappell, E. B.; Plotnikoff, N. P.
J. Med. Chem. 1975, 18, 437.
BF3
R'
R'
BF3⋅OEt2
N
A
N
R'CN
Ti(Oi-Pr)2
Ti(Oi-Pr)2
R
B
R
(5) Shimamoto, K.; Ishida, M.; Shinozaki, H.; Ohfune, Y.
J. Org. Chem. 1991, 56, 4167.
R
(6) Vangveragong, S.; Kanthasamy, A.; Lucaites, V. L.; Nelson,
D. L.; Nichols, D. E. J. Med. Chem. 1998, 41, 4995.
(7) Tsotinis, A.; Vlachou, M.; Papahatjis, D. P.;
Calogeropoulou, T.; Nikas, S. P.; Garratt, P. J.; Piccio, V.;
Vonhoff, S.; Davidson, K.; Teh, M.-T.; Sugden, D. J. Med.
Chem. 2006, 49, 3509.
(8) Raoul, M.; Patigny, D.; Fabis, F.; Dauphin, F.; Rault, S.;
Sapi, J.; Laronze, J.-Y. J. Enzym. Inhib. Med. Chem. 2006,
251.
(9) (a) Glennon, R. A. J. Med. Chem. 2003, 46, 2795.
(b) Holenz, J.; Mercè, R.; Diaz, J. L.; Guitart, X.; Codony,
X.; Dordal, A.; Romero, G.; Torrens, A.; Mas, J.; Andaluz,
B.; Hernandez, S.; Monroy, X.; Sanchez, E.; Hernandez, E.;
Pérez, R.; Cubi, R.; Sanfeliu, O.; Bushchmann, H. J. Med.
Chem. 2005, 48, 1781.
(10) Sapi, J.; Grébille, Y.; Laronze, J.-Y.; Lévy, J. Synthesis
1992, 383.
(11) (a) Bertus, P.; Szymoniak, J. Chem. Commun. 2001, 1792.
(b) For a review, see: Bertus, P.; Szymoniak, J. Synlett 2007,
1346.
(12) An alternative approach involving the titanium-mediated
cyclopropanation of N,N-dialkylamides should be
envisioned, but requires the preparation of the amides. For
the reaction, see: (a) Chaplinski, V.; de Meijere, A. Angew.
Chem., Int. Ed. Engl. 1996, 35, 413. (b) de Meijere, A.;
Kozhushkov, S. I.; Savchenko, A. I. J. Organomet. Chem.
2004, 689, 2033. For related applications, see: (c) Cao, B.;
Xiao, D.; Joullié, M. M. Org. Lett. 1999, 1, 1799.
(d) Ouhamou, N.; Six, Y. Org. Biomol. Chem. 2003, 1,
R'
NH2
Scheme 2
When MeTi(Oi-Pr)3 (1.2 equiv) and EtMgBr (1.2 equiv)
were used, 12a was obtained in an increased yield (59%),
but 10% of 10a remained unreacted. Increase of the
amount of both reagents to 1.5 equivalents led to the total
consumption of the starting material giving 12a in 66%
isolated yield. This procedure was used for the nitriles 10
and 11, to afford the primary cyclopropylamines 12a–d
and 13a,b (Table 1).17,18 An additional substitution at the
cyclopropane moiety is possible, as exemplified by the
use of n-BuMgBr (entry 4). The presence of the vinyl
moiety on the indole core is quite well tolerated, as shown
by the formation of 13a and 13b (entries 5 and 6).19
The final N,N-dimethylation of the cyclopropylamines 12
and 13 using HCHO–NaBH3CN–AcOH–MeOH system
furnished the corresponding cyclopropanated tryptamines
6a–d and 7a,b in fair to high yields (Table 1, step 2).20,21
In conclusion, a new class of N,N-dimethyltryptamines
was prepared by a MeTi(Oi-Pr)3-promoted cyclopropana-
tion. Evaluation of its 5-HT6 binding activity and other
structural modifications are currently in progress.
Synlett 2008, No. 10, 1479–1482 © Thieme Stuttgart · New York

1482
C. Szalata et al.
LETTER
3007. (e) Gensini, M.; de Meijere, A. Chem. Eur. J. 2004,
10, 785. (f) Larquetoux, L.; Kowalska, J. A.; Six, Y. Eur. J.
Org. Chem. 2004, 3517. (g) Larquetoux, L.; Ouhamou, N.;
Chiaroni, A.; Six, Y. Eur. J. Org. Chem. 2005, 4654.
(h) Faler, C. A.; Joullié, M. M. Org. Lett. 2007, 9, 1987.
(250 MHz, CDCl3): d = 0.46–0.63 (m, 4 H), 1.50 (br s, 2 H,
NH2), 2.72 (s, 2 H), 7.13–7.47 (m, 7 H), 7.78 (d, J = 7.7 Hz,
2 H), 7.94 (d, J = 8.3 Hz, 1 H). 13C NMR (63 MHz, CDCl3):
d = 14.5, 33.7, 35.7, 113.7, 119.8, 120.8, 123.2, 123.7, 124.7,
126.5, 129.1, 131.3, 133.7, 135.2, 137.9. HRMS (ES): m/z
[M + H]+ calcd for C18H19N2O2S 327.1167; found: 327.1169.
(19) The cyclopropanation of unprotected 8 gave only a low yield
of the primary cyclopropylamine.
(20) Street, L. J.; Baker, R.; Castro, J. L.; Chambers, M. S.;
Guiblin, A. R.; Hobbs, S. C.; Matassa, V. G.; Reeve, A. J.;
Beer, M. S.; Middlemiss, D. N.; Noble, A. J.; Stanton, J. A.;
Scholey, K.; Hargreaves, R. J. J. Med. Chem. 1993, 36,
1529.
(21) Selected data: N,N-Dimethyl-1-[(1-benzenesulfonyl-1H-
indol-3-yl)methyl]cyclopropylamine (6a): yellow oil. IR
(neat): 3365, 2916, 2845, 1634, 1445, 1264, 1119 cm–1. 1H
NMR (300 MHz, CDCl3): d = 0.25–0.57 (m, 4 H), 2.45 (s, 6
H), 3.01 (s, 2 H), 7.25–7.52 (m, 7 H), 7.80–7.83 (m, 2 H),
7.98 (d, J = 8.1 Hz, 1 H). 13C NMR (75 MHz, CDCl3): d =
13.3, 21.1, 40.9, 43.7, 113.9, 119.6, 120.3, 123.3, 124.2,
124.7, 126.5, 129.1, 131.7, 133.7, 135.1, 138.0. HRMS (EI):
m/z [M+·] calcd for C20H22N2O2S: 354.1402; found:
354.1398. N,N-Dimethyl-1-[(1-methyl-2-vinyl-1H-indol-
3-yl)methyl]cyclopropylamine (7a): yellow oil. IR (neat):
3054, 2986, 2845, 1628, 1437, 1262 cm–1. 1H NMR (300
MHz, CDCl3): d = 0.30–0.55 (m, 4 H), 2.63 (s, 6 H), 3.30 (s,
2 H), 3.70 (s, 3 H), 5.50 (dd, J = 1.2, 11.9 Hz, 1 H), 5.69 (dd,
J = 1.2, 17.9 Hz, 1 H), 7.07 (dd, J = 11.9, 17.9 Hz, 1 H),
7.02–7.38 (m, 3 H), 7.54 (d, J = 7.4 Hz, 1 H). 13C NMR (75
MHz, CDCl3): d = 12.2, 18.6, 30.7, 40.4, 44.7, 109.1, 117.3,
118.9, 119.3, 122.1, 125.9, 128.6, 128.7, 135.2, 137.2.
HRMS (ES): m/z [M + H+] calcd for C17H23N2: 255.1861;
found: 255.1855.
(13) (a) Laroche, C.; Behr, J. B.; Szymoniak, J.; Bertus, P.;
Plantier-Royon, R. Eur. J. Org. Chem. 2005, 5084.
(b) Laroche, C.; Plantier-Royon, R.; Szymoniak, J.; Bertus,
P.; Behr, J.-B. Synlett 2006, 223. (c) Pearson, M.; Plantier-
Royon, R.; Szymoniak, J.; Bertus, P.; Behr, J. B. Synthesis
2007, 3589.
(14) The ketone by-product might also be obtained by the
hydrolysis of metallacycle B (Scheme 2). This assumption
was ruled out by deuterolysis of the reaction media (no trace
of deuterium was observed on the methyl moiety).
(15) Bertus, P.; Szymoniak, J. Org. Lett. 2007, 9, 659.
(16) Chaplinski, V.; Winsel, H.; Kordes, M.; de Meijere, A.
Synlett 1997, 111.
(17) General Procedure for the MeTi(Oi-Pr)3-Mediated
Cyclopropanation of Nitriles 10a–c and 11a,b (Table 1):
To a solution of the nitrile (1 mmol) and MeTi(Oi-Pr)3 (1.5
mmol) in THF (10 mL) was added dropwise under argon the
Grignard reagent (1.5 mmol). The yellow solution darkened
gradually within 5 min. After stirring for 1.5 h, BF3·OEt2 was
added (2 mmol). After 30 min, the dark mixture was
quenched with 1 M HCl (10 mL). EtOAc (20 mL) was
added, followed by 3 M NaOH (10 mL). The mixture was
stirred until the blue aqueous solution become white. The
aqueous phase was extracted with EtOAc (2 × 20 mL). After
drying (MgSO4) and evaporation of the solvents, the crude
material was purified by flash chromatography (EtOAc).
(18) Selected data: 1-[(1-Benzenesulfonyl-1H-indol-3-
yl)methyl]cyclopropylamine (12a): pale yellow solid; mp
97–98 °C. IR (neat): 3385, 1447, 1361, 1175 cm–1. 1H NMR
Synlett 2008, No. 10, 1479–1482 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.