Syntheses of 4-, 5-, 6-, and 7-substituted tryptamine derivatives and the use of a bromine atom as a protecting group

Article abstract of DOI:10.1016/j.tetlet.2013.12.025

Orthogonal syntheses of 4-, 5-, 6-, and 7-chloro substituted tryptamine derivatives were performed under the Grandberg-Zuyanova-modified Fisher indole-synthesis conditions. In the 4- and 6-substituted tryptamine cases, a bromine atom was utilized as an easily cleavable protecting group, which allowed complete regiocontrol. In addition, a chlorine substituent was preserved in the debromination step and could be utilized as a synthetic handle for late-stage diversification under modern Pd(0) catalysis conditions.

Full text of DOI:10.1016/j.tetlet.2013.12.025

Accepted Manuscript
Syntheses of 4-, 5-, 6- and 7-Substituted Tryptamine Derivatives and the Use of
a Bromine Atom as a Protecting Group
Olivier René, Benjamin P. Fauber
PII:
S0040-4039(13)02100-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.12.025
TETL 43939
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
11 November 2013
3 December 2013
6 December 2013
Please cite this article as: René, O., Fauber, B.P., Syntheses of 4-, 5-, 6- and 7-Substituted Tryptamine Derivatives
and the Use of a Bromine Atom as a Protecting Group, Tetrahedron Letters (2013), doi: http://dx.doi.org/10.1016/
j.tetlet.2013.12.025
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Syntheses of 4-, 5-, 6- and 7-Substituted Tryptamine
Derivatives and the Use of a Bromine Atom as a
Protecting Group
Olivier René* and Benjamin P. Fauber
Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080,
USA
PHONE +1(650) 467-0236; FAX +1(650) 467-8922; E-mail: rene.olivier@gene.com
Graphical Abstract.
Abstract.
Orthogonal syntheses of 4-, 5-, 6- and 7-chloro substituted tryptamine derivatives were
performed under the Grandberg-Zuyanova-modified Fisher indole-synthesis conditions. In the 4- and 6-
substituted tryptamine cases, a bromine atom was utilized as an easily cleavable protecting group,
which allowed complete regiocontrol. In addition, a chlorine substituent was preserved in the

debromination step and could be utilized as a synthetic handle for late-stage diversification under
modern Pd(0) catalysis conditions.
keywords: tryptamine; Fisher indole synthesis; bromine; protecting group; late-stage functionalization
Tryptamines are of pharmaceutical significance due to their presence in multiple biologically-
active natural products as well as several marketed drugs.1 In addition, 4,6-dichloro-2-methyl-3-
aminoethylindole (DCAI), a dichlorinated tryptamine derivative, was recently identified through an
NMR-based fragment screen as a small-molecule ligand binding to a distinct pocket in oncogenic K-ras
(G12D) and inhibited SOS-mediated nucleotide exchange activity.2 Further exploration of the tryptamine
scaffold and synthesis of a diversified variety of 4-, 5-, 6- and 7-substituted analogs is therefore of
interest.
Following the initial report of the tryptamine synthesis by Ewins,3 other classical syntheses
include the Abramovitch-Shapiro tryptamine synthesis,4 and tryptophan decarboxylation.5 More
generally, tryptamine derivatives may be synthesized from a pre-formed indole scaffold, followed by C-3
functionalization under electrophilic aromatic substitution conditions using oxalyl chloride,6
nitroethylene7 or N-acetylaminoacetaldehyde dimethyl acetal8 as electrophiles. Alternatively, the
Grandberg-Zuyanova modification of the Fisher indole synthesis9 is an efficient one-step process
wherein the indole ring and the C-3 aminoethyl substituent are installed in a single step. However, the
above-mentioned tryptamine synthesis reports do not describe concise and orthogonal syntheses of 4-,
5-, 6- and 7-substituted tryptamine derivatives that would allow for late-stage diversification at all four
isomeric benzo- positions. Furthermore, substitution at the 4- and 6-positions cannot be installed on an

arylhydrazine precursor prior to a Fisher indolization10 due to the limited regioselectivity typically
observed at the cyclization step.11
Consequently, we decided to harness the intrinsic lability of the carbon-bromine bond under
reductive conditions12 and utilize it as a protecting group13 in the Grandberg-Zuyanova modification of
the Fisher indole synthesis. Positioned appropriately, a bromine atom would enable the indolization step
to occur with the desired regiochemistry, followed by a debromination step, giving access to 4- and
6-substituted tryptamines as single isomers with complete regiocontrol. Additionally, due to its lower
reactivity, a chloro substituent could be used in addition to the bromine as a synthetic handle for further
diversification of the tryptamine scaffold upon removal of the bromine. 5- And 7-substituted tryptamine
derivatives would not require such a protecting group, as in each case, cyclization could only afford a
single product (Scheme 1).
Scheme 1. The traditional syntheses of 4- and 6-chloro-2-methyl-3-aminoethylindole syntheses via
Fisher indolization are poorly regioselective. Using bromine as a protecting group to block reactivity on
the aromatic ring, followed by debromination, can overcome this limitation.

Hence, for the cases in which no protecting group was required, 5-Chlorotryptamine derivative 2
was synthesized from commercially available (4-chlorophenyl)hydrazine 1 and 5-chloropentan-2-one
under refluxing ethanol conditions. A one-pot t-butylcarbamate formation on the aminoethyl chain was
subsequently performed in order to facilitate the purification and further functionalization, and gave
product 2 in 75% yield over 2 steps (Scheme 2A). Similarly, the 7-chloro substituted analog 4 was
obtained from commercially available (2-chlorophenyl)hydrazine 3, followed by a Boc-group installation
on the primary amine substituent, and afforded tryptamine derivative 4 in 69% yield over 2 steps
(Scheme 2B).

Scheme 2. Syntheses of Boc-Protected 5-chloro-2-methyl-3-aminoethylindole 2 (A) and 7-chloro-2-
methyl-3-aminoethylindole 4 (B).
A.
O
NHBoc
Cl
i.
Cl
Cl
EtOH, reflux
NH2
ii.
N
H
Boc2O, Et3N
DCM, 23 °C
75% (2 steps)
N
H
2
1
O
NHBoc
B.
Cl
i.
EtOH, reflux
Boc2O, Et3N
NH2
ii.
N
H
4
N
H
DCM, 23 °C
69% (2 steps)
Cl
Cl
3
As discussed previously, the syntheses of 4-chloro-2-methyl-3-aminoethylindole 8 and 6-chloro-
2-methyl-3-aminoethylindole 12 required the use of the bromine atom as a protecting group to ensure
proper regiochemistry at the cyclization step (Scheme 3). Hence, the synthesis of 8 began with 1-bromo-
4-chloro-2-fluorobenzene 5, which underwent a nucleophilic aromatic substitution of the fluorine atom
with hydrazine monohydrate, and gave arylhydrazine intermediate 6 in excellent yield. Cyclization of the
arylhydrazine intermediate under the typical indole cyclization conditions with 5-chloropentan-2-one,
followed by tert-butylcarbamate formation on the aminoethyl substituent, gave the desired 7-bromo-4-
chlorotryptamine derivative 7 in 36% yield over 2 steps. An effective de-bromination protocol in the
presence of a chloride had been reported, using tris(2,4-di-t-butylphenyl)phosphite L1 as the ligand.14
Subjection of intermediate 7 to these catalytic reductive conditions successfully provided the 4-

chlorotryptamine product 8 in 56% yield. Of note, standard catalytic hydrogenation conditions were also
attempted to remove the bromine selectively, but led to unsatisfactory conversions or poor selectivity.15
Scheme 3. Synthesis of Boc-protecting 4-chloro-2-methyl-3-aminoethylindole 8.
Analogously, the synthesis of 6-chloro-2-methyl-3-aminoethylindole 12 also necessitated the
use of the bromine atom as a protecting group (Scheme 4). (2-Bromo-3-chlorophenyl)hydrazine 10 was
first obtained from 2-bromo-1-chloro-3-fluorobenzene 9 under nucleophilic aromatic substitution
conditions with hydrazine monohydrate in 99% yield. In the next step, the hydrazine intermediate 10
underwent Fisher-indole cyclization, followed by aminoethyl Boc-protection, to afford the desired 7-
bromo-6-chloro intermediate 11 in 49% yield over 2 steps. Finally, treatment of compound 11 with
cyclohexanol under established Pd(0)-catalysis de-bromination conditions led to the desired 6-
chlorotryptamine derivative 12 in 70% yield.

Scheme 4. Synthesis of Boc-protected 6-chloro-2-methyl-3-aminoethylindole 12.
Having completed the orthogonal syntheses of Boc-protected 4-, 5-, 6- and 7-chloro-2-methyl-3-
aminoethylindole (compounds 8, 2, 12 and 4, respectively), we had set the stage for a divergent
derivatization to transform the chlorine atom to other functional groups.16 Under Pd(0)-catalyzed
conditions,17 the chloride successfully underwent arylation, cyanation, etherification, alkylation and
amination reactions (Scheme 5). For example, aminopyrimidine 13 was uneventfully obtained via a
Suzuki-Miyaura coupling18 in 71% yield. The reaction proceeded smoothly and efficiently in the presence
of four unprotected hydrogen-bond donors and two heterocyclic rings. Also, the carbon-chlorine bond
could undergo a facile cyanation with potassium ferrocyanide trihydrate19 under Pd(0) catalysis
conditions to afford 4-cyanotryptamine compound 14 in 72% yield. Additionally, we demonstrated the
possibility of performing etherification chemistry20 with n-butanol, giving rise to ether product 15, albeit
in low yield (10% yield) under un-optimized conditions.21 Moreover, the use of potassium
cyclopentyltetrafluoroborate22 under Pd(0) catalysis successfully gave cyclopentyl-tryptamine product

16 in a synthetically useful yield of 37%. Finally, a Buchwald-Hartwig coupling23 was also performed with
N-acetylpiperazine and afforded the desired amine product 17 in 35% yield.
Scheme 5. Late-stage diversification of 6-chloro-2-methyl-3-aminoethylindole
NHBoc
N
H
N
14
K4[Fe(CN)6]•3H2O
X-Phos palladacycle (5 mol%)
X-Phos (5 mol%)
KOAc (0.125 equiv)
1,4-dioxane/H2O, 100 o
72%
C
B(pin)
N
-Butanol
n
H2N
N
X-Phos palladacycle (2.5 mol%)
X-Phos (2.5 mol%)
Pd(OAc)2 (10 mol%)
Beller's L (20 mol%)
Cs2CO3 (1.5 equiv)
NHBoc
NHBoc
NHBoc
K3PO4 ( 3 equiv)
THF/H2O, 65 o
C
Toluene, 110 o
C
N
H
N
N
H
N
H
12
O
71%
Cl
10%
13
H2N
N
15
O
N
NH
BF3K
Pd(OAc)2 (5 mol%)
-BuP(Ad)2 (10 mol%)
Cs2CO3 (3 equiv)
Pd(OAc)2 (5 mol%)
RuPhos (10 mol%)
n
NaO -Bu (1.5 equiv)
t
toluene/H2O, 110 o
C
1,4-dioxane, 110 o
35%
C
37%
NHBoc
NHBoc
N
H
17
N
N
H
N
16
O
In conclusion, we have shown that a bromine atom can be used as an easily cleavable protecting
group in the presence of a chlorine substituent, allowing for the orthogonal syntheses of 4-, 5-, 6- and 7-
chloro substituted tryptamine derivatives under the Grandberg-Zuyanova-modified Fisher indole-

synthesis conditions. In addition, the chlorine atom can be utilized as a versatile synthetic handle for
late-stage diversification under Pd(0) catalysis conditions.
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Takano, S.; Hibino, S.; Takeshita, M. Synthesis 1972, 475. (c) Kametani, T.; Suzuki, T.; Takahashi, K.;
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R.; Grey, T. F.; Lockhart, I. M.; Ralph, R. S. J. Chem. Soc. 1959, 3388. (c) Friedrich, A.; Brase, S.; O’Connor, S.
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