Facile Synthesis of 7-Amino-1,2,3,4-tetrahydro-β-carboline

Article abstract of DOI:10.1081/SCC-120025179

7-Amino-1,2,3,4-tetrahydro-β-carboline has been prepared by a short efficient synthetic sequence based on a regioselective nitration of a fully protected 1,2,3,4-tetrahydro-β-carboline.

Full text of DOI:10.1081/SCC-120025179

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Facile Synthesis of 7-Amino-1,2,3,4-tetrahydro-β-
carboline
Barbara Forte a , Andrea Lombardi-Borgia a & Gianluca Papeo a
a Discovery Research Oncology , Department of Chemistry , Pharmacia Italia S.p.A. ,
Nerviano (MI), Italy
Published online: 16 Aug 2006.
To cite this article: Barbara Forte , Andrea Lombardi-Borgia & Gianluca Papeo (2003) Facile Synthesis of 7-Amino-1,2,3,4-
tetrahydro-β-carboline, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 33:21, 3707-3716, DOI: 10.1081/SCC-120025179
To link to this article: http://dx.doi.org/10.1081/SCC-120025179
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 21, pp. 3707–3716, 2003
Facile Synthesis of
7-Amino-1,2,3,4-tetrahydro-b-carboline
*
Barbara Forte, Andrea Lombardi-Borgia, and Gianluca Papeo
Discovery Research Oncology,
Department of Chemistry, Pharmacia Italia S.p.A.,
Nerviano (MI), Italy
ABSTRACT
7-Amino-1,2,3,4-tetrahydro-b-carboline has been prepared by a
short efficient synthetic sequence based on a regioselective nitration
of a fully protected 1,2,3,4-tetrahydro-b-carboline.
Key Words: Tetrahydro-b-carboline; Regioselective; Nitration;
Phase-transfer.
In the process of searching for new biologically active compounds,
we became interested in the preparation of 7-amino-1,2,3,4-tetrahydro-b-
carboline on a multigram scale. Tetrahydro-b-carbolines are a class of
*Correspondence: Barbara Forte, Discovery Research Oncology, Department
of Chemistry, Pharmacia Italia S.p.A., Viale Pasteur 10, 20014 Nerviano (MI),
Italy; E-mail: barbara.forte@pharmacia.com.
3707
DOI: 10.1081/SCC-120025179
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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3708
Forte, Lombardi-Borgia, and Papeo
compounds that have been widely investigated due to their biological
properties. In fact, molecules belonging to this class are known as
analgesics, anxiolytics, antidepressants, antihypertensives[1] etc. This
notwithstanding, very few examples of amino-1,2,3,4-tetrahydro-
b-carbolines are reported in the literature[2] and in particular 5- and
7-nitro and 5- and 7-amino-1,2,3,4-tetrahydro-b-carbolines have not
been yet reported in the literature. Therefore we set out to devise a
synthetic procedure to obtain 7-amino-1,2,3,4-tetrahydro-b-carboline
on a 10 g scale. As a first approach to prepare our target compound,
we considered the nitration of the commercially available noreleagnine (1).
Treatment of compound 1 with different nitrating agents, under a
variety of conditions, gave the expected 7-nitro and 5-nitro isomers,[2]
but with unsatisfactory yield and low regioselectivity (Sch. 1). Moreover,
regioisomers 2a and 2b could not be separated with standard chromato-
graphic procedure.[3] As an attempt to improve the recovery of the
regioisomers we converted noreleagnine into its 2-acetyl derivative 3
(Sch. 2).
Compound 3 was subjected to nitration under various reaction con-
ditions (Table 1). The desired 7-nitro derivative 4a was obtained in only
12% isolated yield by using nitronium tetrafluoborate,[4] generated in situ
reacting nitric acid with trifluoromethansulfonic acid and dichloro-
methane as solvent. The regioisomer ratio was 2:1 in favor of the
7-nitro derivative. However, the yield of compound 4a was far too low
for our purposes.
Degradation of compound 3 was observed under all experimental
conditions, possibly due to instability of the unprotected indole moiety
in an acidic/oxidative environment.[6] Therefore, we turned our attention
toward the nitration of the fully protected 1,2,3,4-tetrahydro-b-carboline
system 6 (Sch. 3).
The acetyl group on the tetrahydropyridine nitrogen 4a proved to be
resistant to acid and alkaline hydrolysis, and was therefore replaced by
the more labile trifluoroacetyl group. Trifluoroacetamide 5 was obtained
4
3
NO2
5
8
NH2
NH
NH
6
7
1
+
N 9
H
N
N
O2N
H
H
1
2b
2a
Scheme 1.

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7-Amino-1,2,3,4-tetrahydro-b-carboline
3709
NH
a
N
b
O
N
N
H
N
H
3
1
NO2
N
O
O
+
N
N
H
O2N
H
4a
4b
a) Ac2O, Py, 98%; b) see Tab. 1
Scheme 2.
Table 1.
Nitrating agent
CF3SO3NO2
Solvent
Temperature
Result
a
CH2Cl2
ꢁ78 to ꢁ30ꢀC
18% of a mixture
of 7-nitro and
5-nitro isomers (2:1)
12% of a mixture of
isomers
b
c
e
BF4NO2
CH2Cl2
ꢁ78 to ꢁ20ꢀC
to RT
0 to RT
d
NH4NO3
TFAA
,
CH2Cl2
Only traces of
product
aWhen the reaction was carried out in CH3CN, DME, or AcOEt only degrada-
tion of 3 was observed.
bSee Ref.[4]
cOnly degradation of 3 was observed using DME as solvent.
dSee Ref.[5]
eOnly degradation of 3 was observed using TFAA as solvent.
from 1 in 98% yield applying a standard procedure (TFAA, DCM, 0ꢀC
to R.T.). Compound 5 was then acetylated at the indole nitrogen under
phase transfer conditions, as reported by Illi[7] and Ottoni et al.,[8] in
almost quantitative yield. The phase-transfer procedure, run in the
absence of water, prevented the reversion of the reaction, due to
the high reactivity of N-acyl indoles towards nucleophiles, as well as

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3710
Forte, Lombardi-Borgia, and Papeo
CF3
NH
a
N
O
N
H
N
H
1
5
CF3
N
b
O
N
O
6
c
NO2
CF3
O
CF3
O
N
N
+
N
N
O2N
O
O
(4 : 1)
7a
7b
d
NH
NH
e
N
N
H2N
O2N
.
H
H
2HCl
2a
8
a) TFAA, DCM, 0˚C to rt, 98%; b) NaOH pellets, cetrimide, DCM, 96%; c) CF3SO3NO2,
DCM, -78˚C to 0˚C,40%; d)NaOH (1N), EtOH, 90%; e) H2, Pd/C, MeOH, HCl (1N), 85%.
Scheme 3.
the cleavage of the alkaline-labile trifluoroacetamide. Compound 6
turned out to be more stable than 2-acetyl noreleagnine 3 under nitrating
conditions. Nitration of 6 was carried out by treatment with 1.1 equiv. of
CF3SO3NO2 in CH2Cl2 at ꢁ78ꢀC, then allowing the reaction mixture to
warm up to 0ꢀC. The two regioisomers were obtained in 40% isolated
yield. Moreover, a higher degree of regioselectivity was observed, the
ratio of 7-NO2 vs. 5-NO2 being increased to 4:1.
The pure regioisomer 7a was isolated by flash chromatography
and, after simultaneous removal of the protective groups (1N NaOH/

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7-Amino-1,2,3,4-tetrahydro-b-carboline
3711
EtOH; 96% yield), the 7-nitro-1,2,3,4-tetrahydro-b-carboline 2a was
catalytically hydrogenated in acidic medium (50 psi H2, Pd/C 10%,
MeOH, 1N HCl) to afford pure 7-amino-1,2,3,4-tetrahydro-b-carboline
dihydrochloride 8 in 84% yield.
CONCLUSION
In this communication we disclosed a convenient procedure suitable
for a large-scale preparation of 7-amino-1,2,3,4-tetrahydro-b-carboline.
Starting from the commercially available 1,2,3,4-tetrahydro-b-carboline
(noreleagnine), we were able to obtain, in five steps, and with only one
chromatographic purification, the pure 7-amino-1,2,3,4-tetrahydro-
b-carboline in 31% overall yield.
EXPERIMENTAL
1H-NMR and 13C-NMR spectra were recorded on Varian Mercury-
Vx 600 MHz, 500 MHz, 400 MHz, or 300 MHz, spectrometers. Mass
spectra were recorded on a Finnigan LCQ ion trap mass spectrometer
using the electrospray (ESI) ionization technique with positive and
negative ion detection. Elemental analyses were recorded by EA 1110
CHNS-O C.E. Instruments Elemental Analyzer. Melting points have
been measured on a Buchi 510 apparatus and are uncorrected.
2-(Trifluoroacetyl)-1,2,3,4-tetrahydro-9H-b-carboline (5)
In a three-necked round-bottomed flask, equipped with a mechan-
ical stirrer, a suspension of 1,2,3,4-tetrahydro-9H-b-carboline (25 g,
0.145 mol) in dichloromethane (1.3 L) was stirred and cooled to 0ꢀC.
To this suspension TFAA (174 mL, 1.25 mol) was then added dropwise.
After the addition was completea, the reaction mixture was stirred and
cooled for an additional hour, then neutralized by slow addition of a
pre-cooled NaHCO3 saturated aqueous solution (1.6 L). The organic
phase was then separated, washed with water (100 mL), dried over
aInitial formation of TFA salt of unreacted 1,2,3,4-tetrahydro-b-carboline gave
rise to a white precipitate that disappeared once the addition of TFAA was
complete.

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3712
Forte, Lombardi-Borgia, and Papeo
Na2SO4, and evaporated to afford 38.12 g (98%) of pure 2-(trifluoro-
acetyl)-1,2,3,4-tetrahydro-9H-b-carboline (5) as white solid.
1H-NMR (300 MHz, CDCl3) (syn/anti mixture): 2.95 (m, 2H),
3.95–4.06 (two t, J ¼ 5.7 Hz, 2H, syn/anti 1/2.5), 4.83–4.88 (two s, 2H),
7.0–7.6 (m, 4H), 7.9 (bs, 1H). 13C-NMR (75 MHz, CDCl3) (syn/anti
mixture): 22.22, 42.20, 44.58, 107.99, 111.39, 114.93, 118.49, 118.74,
120.10, 122.48, 122.67, 126.73, 126.78, 128.44, 136.52, 156.24, 156.63,
157.11, 157.59. MS: m/z ¼ 260 (MꢁH)ꢁ. CHN: Anal. calcd. for
C13H11F3N2O: C, 58.21%; H, 4.13%; N, 10.44%. Found: C, 57.66%;
H, 4.13%; N, 10.18%. M.p. ¼ 135–140ꢀC decomposition.
9-Acetyl-2-(trifluoroacetyl)-1,2,3,4-
tetrahydro-b-carboline (6)
In
a three-necked round-bottomed flask, equipped with a
mechanical stirrer, NaOH pelletsb (190 g, 4.75 mol) and N-cetyl-N,N,N-
trimethyl-ammonium bromide (4.68 g, 0.013 mol) were suspended in dry
dichloromethane (1.5 L). After cooling to 0ꢀC, 2-(trifluoroacetyl)-1,2,3,4-
tetrahydro-9H-b-carboline (2) (36.5 g, 0.136 mol) was added under vigor-
ous stirring. To the mixture was then added acetyl chloride (173 mL,
2.4 mol) dropwise, and the reaction mixture was kept under stirring
and cooling until no starting material was left. The reaction mixture
was then filtered, the filtrate was washed with water (100 mL) and the
pH adjusted to neutrality by slow addition of NaHCO3 saturated aqu-
eous solution. Finally, the organic phase was separated, washed with
brine (300 mL), dried over Na2SO4 and evaporated to afford 40.5 g
(96%) of pure 9-acetyl-2-(trifluoroacetyl)-1,2,3,4-tetrahydro-b-carboline
(6) as yellowish solid.
1H-NMR (400 MHz, d 6-DMSO) (syn/anti mixture): 2.76–2.78 (two s,
3H), 2.82 (m, 2H), 3.89–3.93 (two t, J ¼ 5.5 Hz, 2H, syn/anti 1/2.5),
5.05–5.08 (two s, 2H), 7.2–7.6 (m, 3H), 7.89–7.92 (two d, J ¼ 7.3 Hz,
1H). 13C-NMR (75 MHz, d 6-DMSO) (syn/anti mixture): 22.07, 27.22,
41.05, 44.50, 111.34, 115.16, 115.54, 118.98, 119.08, 122.80, 123.62,
125.02, 129.41, 131.34, 135.34, 154.98, 155.44, 155.90, 156.36, 170.48.
MS: m/z 310 (Mþ). CHN: Anal. calcd. for C15H13F3N2O2: C, 8.07%;
H, 4.22%; N, 9.03%. Found: C, 59.13%; H, 4.55%; N, 8.99%. M.p. ¼
99–102ꢀC.
bCAUTION using finely grounded NaOH instead of pellets led to a strongly
exothermic reaction when acetyl chloride was added.

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7-Amino-1,2,3,4-tetrahydro-b-carboline
3713
9-Acetyl-7-nitro-2-(trifluoroacetyl)-1,2,3,4-
tetrahydro-b-carboline (7a)
In a three-necked round-bottomed flask, equipped with a mechanical
stirrer, trifluoromethanesulfonic acid (22.9 mL, 0.26 mol) was dissolved in
dichloromethane (1.3 L) under nitrogen at room temperature. To the
milky solution, 90% nitric acid (6.1 mL, 0.13 mol) was added, and the
mixture was stirred at room temperature until the initially formed white
precipitate was dissolved, giving rise to a yellow–green solution. The mix-
ture was cooled to ꢁ50ꢀC, then a solution of 9-acetyl-2-(trifluoroacetyl)-
1,2,3,4-tetrahydro-b-carboline (6) (40 g, 0.13 mol) in dichloromethane
(500 mL) was added dropwise. Once the addition was completed, the
reaction mixture was allowed to warm to 0ꢀC then quenched by pouring
it into a vigorously stirred saturated aqueous solution of NaHCO3 (3 L).
After 15 min, the organic layer was separated, washed with brine
(2 ꢂ 200 mL) and dried. Separation of the two regioisomers was performed
by flash chromatography of the crude residue (40 g) using AcOEt as eluent
and afforded 4.6 g of 5-nitro and 19.02 g of 7-nitro-regioisomer that was
further purified by suspending it in AcOEt (200 mL); the solid was then
collected and dried to give 18.41 g (40%) of pure 9-acetyl-7-nitro-2-(tri-
fluoroacetyl)-1,2,3,4-tetrahydro-b-carboline as yellow solid.
7a. 1H-NMR (400 MHz, d 6-DMSO) (syn/anti mixture): 2.84–2.87
(two s, 3H), 2.91 (m, 2H), 3.95 (m, 2H), 5.14 (s, 2H), 7.77 (m, 1H), 8.17
(m, 1H), 8.77–8.85 (two d, J ¼ 1.8 Hz, 1H, syn/anti 2.5/1). 13C-NMR
(75 MHz, d6-DMSO) (syn/anti mixture): 22.00, 27.06, 41.05, 44.46,
111.28, 111.85, 115.08, 115.65, 118.88, 118.89, 119.42, 122.68, 133.99,
134.29, 137.15, 144.73, 155.03, 155.50, 155.97, 156.44, 170.49. MS: m/z
353 (MꢁH)ꢁ. CHN: Anal. calcd. for C15H12F3N3O4: C, 50.71%; H,
3.40%; N, 11.83%. Found: C, 50.73%; H, 3.44%; N, 11.56%.
M.p. ¼ 168–171ꢀC.
7b. 1H-NMR (300 MHz, CDCl3) (syn/anti mixture): 2.84–2.87 (two s,
3H), 3.03 (m, 2H), 3.87–3.92 (two t, J ¼ 5.7 Hz, 2H), 5.15–5.17 (two s,
2H), 7.42 (m, 1H), 7.9 (dd, J ¼ 0.7 Hz, J ¼ 8.1 Hz, 1H), 8.03–8.16 (two
dd, J ¼ 0.7 Hz, J ¼ 8.6 Hz, 1H, syn/anti 0.4/1.1). 13C-NMR (150 MHz,
CDCl3) (syn/anti mixture): 25.32, 27.58, 43.39, 44.52, 113.81, 119.45,
120.20, 122.32, 123.90, 135.60, 137.27, 142.92, 155.87, 156.11, 156.35,
156.59, 168.94. MS: m/z 353 (MꢁH)ꢁ. CHN: Anal. calcd. for
C15H12F3N3O4: C, 50.71%; H, 3.40%; N, 11.83%. Found: C, 50.75%;
H, 3.45%; N, 11.52%.
Along the same procedure, products 4a and 4b were prepared:
1
4a. (as yellow solid). H-NMR (300 MHz, CDCl3): 2.28 (s, 3H), 2.92
(m, 2H), 3.86 (m, 2H), 4.90 (s, 2H), 7.50 (d, 1H, J ¼ 8.8), 8.03 (dd, 1H,

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3714
Forte, Lombardi-Borgia, and Papeo
J ¼ 2.15, 8.8), 8.32 (d, 1H, J ¼ 2.15), 9.00 (bs, 1H). 13C-NMR (150 MHz,
d 6-DMSO): 21.89, 22.04, 22.61, 44.44, 108.50, 114.74, 118.30, 118.75,
131.96, 134.96, 139.27, 139.69, 169.82. MS: m/z 258 (MꢁH)-. CHN:
Anal. calcd. for C13H13N3O3: C, 60.23%; H, 5.05%; N, 16.21%.
Found: C, 60.20%; H, 4.97%; N, 16.15%.
1
4b. (as yellow solid). H-NMR (300 MHz, CDCl3): 2.28 (s, 3H), 3.19
(m, 2H), 3.76 (m, 2H), 4.90 (s, 2H), 7.20 (t, 1H, J ¼ 8.09), 7.62 (d, 1H,
J ¼ 8.09), 7.94 (d, 1H, J ¼ 8.09), 9.00 (bs, 1H). 13C-NMR (150 MHz, d 6-
DMSO): 21.13, 21.95, 25.25, 44.70, 109.21, 117.40, 118.36, 120.40,
131.83, 135.14, 137.92, 142.17, 169.82. MS: m/z 258 (MꢁH)ꢁ. CHN:
Anal. calcd. for C13H13N3O3: C, 60.23%; H, 5.05%; N, 16.21%.
Found: C, 60.21%; H, 4.95%; N, 16.18%.
7-Nitro-1,2,3,4-tetrahydro-9H-b-carboline (2a)
To a stirred suspension of 9-acetyl-7-nitro-2-(trifluoroacetyl)-1,2,3,4-
tetrahydro-b-carboline (7a) (11.9 g, 0.0335 mol) in ethanol (1.2 L), under
nitrogen at room temperature, aqueous 2 M NaOH (149 mL) was added
over 5 min, thus obtaining a deep red solution that was stirred for an
additional hour. The reaction mixture was then diluted with water (1 L)
and filtered. The orange solid obtained was washed with water (100 mL),
collected, and dried to afford 6.54 g (90%) of pure 7-nitro-1,2,3,4-tetra-
hydro-9H-b-carboline (2a) as yellow solid.
1H-NMR (300 MHz, d 6-DMSO): 2.62 (m, 2H), 2.95 (m, 2H), 3.9 (s,
2H), 7.4 (d, 1H, J ¼ 9.1), 7.83 (dd, 1H, J ¼ 2.3, 9.1), 8.2 (d, 1H, J ¼ 2.3),
11.55 (bs, 1H). 13C-NMR (150 MHz, d 6-DMSO): 22.54, 43.40, 43.63,
108.21, 111.45, 114.52, 117.76, 132.66, 134.48, 141.67, 142.96. MS: m/z
218 (MþH)þ. CHN: Anal. calcd. for C11H11N3O2: C, 60.82%; H, 5.10%;
N, 19.34%. Found: C, 60.86%; H, 5.15%; N, 19.30%.
7-Amino-1,2,3,4-tetrahydro-9H-
b-carboline Dihydrochloride (8)
To a solution of 7-nitro-1,2,3,4-tetrahydro-9H-b-carboline (2a)
(3.4 g, 0.016 mol) and aqueous 1M HCl (40 mL) in methanol (610 mL),
10% Pd/C (0.7 g) was added and the suspension was shaken in a Parr
hydrogenation apparatus under hydrogen atmosphere (50 psi) for 2 h.
The suspension was then filtered over CeliteÕ, the volume of the filtrate
was reduced in vacuo, than submitted to an azeotropic removal of
residual water with absolute ethanol (2 ꢂ 250 mL).

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7-Amino-1,2,3,4-tetrahydro-b-carboline
3715
Finally, the crude was suspended in absolute ethanol (200 mL),
filtered, collected, and dried to afford 3.46 g (85%) of pure 7-amino-
1,2,3,4-tetrahydro-9H-b-carboline (8) as dihydrochloride salt (white
solid).
1H-NMR (400 MHz, d 6-DMSO): 2.93 (m, 2H), 3.40 (m, 2H), 4.33 (s,
2H), 7.01 (dd, J ¼ 1.9, 8.3 Hz, 1H), 7.46 (d, J ¼ 1.9, 1H), 7.54 (d, J ¼ 8.3,
1H), 9.67 (bs, 2H), 10.3 (bs, 3H), 11.44 (s, 1H). 13C-NMR (75 MHz, d 6-
DMSO): 18.61, 41.01, 41.87, 106.49, 106.98, 114.91, 119.42, 126.08,
126.14, 128.98, 136.25. MS: m/z 188 (M þ H)þ. CHN: Anal. calcd. for
C11H13N3: 2HCl: C, 50.78%; H, 5.81%; N, 16.15%. Found: C, 50.80%;
H, 5.86%; N, 16.12%. M.p.>280ꢀC.
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Balon, M.; Hidalgo, J.; Carmona, C.; Pappalardo, R.R.; Sanchez
´ ´
Marcos, E. J. Chem. Soc. Perkin Trans. 2 1991, 1729; (e)
Lounasmaa, M.; Berner, M.; Tolvanene, A. Heterocycles 1999, 50, 243.
3. The mixture of 2a and 2b, obtained in 7% yield by reaction of 1 with
CF3SO3NO2 at 0ꢀC in CH2Cl2, was hydrogenated, affording a crude
mixture of amino derivatives which was treated with BOC anhydride
to give 2-(tert-butoxycarbonyl)-7-[(tert-butoxycarbonyl)amino]-
1,2,3,4 -tetrahydro-b-carboline and 2-(tert-butoxycarbonyl)-5-[(tert-
butoxycarbonyl)amino]-1,2,3,4-tetrahydro-b-carboline (40% over
two steps). The two isomers could be easily separated by conven-
tional column chromatography regioisomer ratio 2:1 of 7-NO2 vs.
5-NO2) and the desired isomer reconverted quantitatively to the
amino derivative 8 (1.8% overall yield).
4. For a review on nitronium salts in organic chemistry, see Guk, Yu. V.;
Ilyushin, M.A.; Golod, E.L.; Gidaspov, B.V. Russ. Chem. Rev. 1983,
52, 284.

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Forte, Lombardi-Borgia, and Papeo
5. Crivello, J.V. J. Org. Chem. 1981, 46, 3056.
6. For a general discussion on indole chemistry, see: Remers, W.A.;
Brown, R.K. The Chemistry of Heterocyclic Compounds; 1972; Vol.
25, Part I.
7. Illi, V.O. Synthesis 1979, 387.
8. Ottoni, O.; Cruz, R.; Alves, R. Tetrahedron 1998, 54, 13915.
Received in the UK November 19, 2002