Synthesis of C-1 indol-3-yl substituted tetrahydroisoquinoline derivatives via a Pictet-Spengler approach

Article abstract of DOI:10.1016/j.tetlet.2012.07.017

A protocol for the diastereoselective synthesis of C-1 indol-3-yl substituted tetrahydroisoquinoline derivatives via Pictet-Spengler condensation with L-DOPA or l-DOPA derivatives and 1H-indole-3-carbaldehydes is presented. The protocol is used for the successful synthesis of several tetrahydroisoquinolines as well as diketopiperazine fused analogues.

Full text of DOI:10.1016/j.tetlet.2012.07.017

Tetrahedron Letters 53 (2012) 4966–4970
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Tetrahedron Letters
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Synthesis of C-1 indol-3-yl substituted tetrahydroisoquinoline derivatives
via a Pictet–Spengler approach
⇑
Rikard Larsson, Narda Blanco, Martin Johansson, Olov Sterner
Centre for Analysis and Synthesis, Lund University, PO Box 124, SE 22100, Sweden
a r t i c l e i n f o
a b s t r a c t
Article history:
A protocol for the diastereoselective synthesis of C-1 indol-3-yl substituted tetrahydroisoquinoline deriv-
Received 10 April 2012
Revised 20 June 2012
Accepted 4 July 2012
Available online 20 July 2012
atives via Pictet–Spengler condensation with L-DOPA or L-DOPA derivatives and 1H-indole-3-carbaldehy-
des is presented. The protocol is used for the successful synthesis of several tetrahydroisoquinolines as
well as diketopiperazine fused analogues.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Pictet–Spengler condensation
L-DOPA
1H-Indole-3-carbaldehydes
C-1 Indolyl tetrahydroisoquinolines
Diketopiperazine fused
tetrahydroisoquinolines
Tetrahydroisoquinolines have received considerable interest as
synthetic targets in the field of medicinal chemistry due to their
biological activities, for example, antitumor and antimicrobial
activities.1
The most widely used, and probably the most convenient, reac-
tion for the synthesis of substituted tetrahydroisoquinolines is the
Pictet–Spengler condensation,2 first described in 1911 by Amé Pic-
tet and Theodore Spengler.3 Since its discovery its usefulness has
been demonstrated in numerous syntheses of biologically active
compounds, natural products and synthetic compounds.4 Although
the reaction has been known for 100 years, reports on successful
An indication of the usefulness of the Pictet–Spengler approach
towards the synthesis of C-1 indol-3-yl substituted tetrahydroiso-
quinolines was reported by Bogza and coworkers,5who described
the synthesis of an elimination product, possibly formed after
elimination of the indole moiety following a Pictet–Spengler con-
densation between an aminopyrazole derivative and a substituted
indole-3-carboxaldehyde. Numa and coworkers6 reported the suc-
cessful condensation between the HCl salt of 5-hydroxydopamine
and indole-3-carboxaldehyde, however, without isolating or pro-
viding any analytical data for the claimed product. Additional re-
search is therefore needed, and we decided to develop a protocol
for the synthesis of C-1 indol-3-yl substituted tetrahydroisoquino-
lines via a Pictet–Spengler approach (see Scheme 1), that could
provide derivatives which would enable our synthesis of diketopi-
perazine fused analogues and a subsequent structure–activity rela-
tionship study.
Pictet–Spengler condensations between
L-3,4-dihydroxyphenylala-
nine ( -DOPA) and heteroaromatic aldehydes resulting in tetrahy-
L
droisoquinolines substituted with a heteroaromatic moiety at the
C-1 position are scarce. In 2006, Aubry and coworkers reported
the successful synthesis of thiophene substituted tetrahydroiso-
quinolines, from, among others,
L
-DOPA via a Pictet–Spengler
The diastereoselectivity of the Pictet–Spengler condensation
has been discussed in several reports7 and reviews,8 and it has
been demonstrated that the formation of the cis diastereomer is
favoured over the thermodynamically more stable trans diastereo-
mer when the reaction is under kinetic control in acidic media,9
and that the cis/trans ratio depends on the nature of the aldehyde
employed3,9 and the substitution pattern at C-3.10 Also, cis to trans
epimerisation at C-1 has been observed, and is a key step in Cook’s
synthesis of mitragunine11 via a Pictet–Spengler reaction.
condensation,2 in moderate to good yields. The scope of that inves-
tigation was limited to substituted phenyl and thiophene
aldehydes, and there is obviously a need for further studies with
N-heteroaromatic aldehydes. As we were studying the biological
effects of compounds possibly formed via C-1 indol-3-yl substi-
tuted tetrahydroisoquinolines, Pictet–Spengler condensations with
1H-indole-3-carbaldehydes were of particular interest to us.
L-DOPA (1) was converted into its corresponding methyl ester
according to a standard procedure leading directly to the Pictet–
Spengler precursor 2 (see Scheme 2). However, stirring 2, NaOAc
⇑
Corresponding author. Tel.: +46 4622228213; fax: +46 462228209.
E-mail address: Olov.Sterner@organic.lu.se (O. Sterner).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.07.017

R. Larsson et al. / Tetrahedron Letters 53 (2012) 4966–4970
4967
H
O
O
O
O
H
H
N
HO
HO
HO
HO
HO
HO
OH
H
OH
OH
+
NH2
NH
NH
NH
NH
Scheme 1. C-1 indol-3-yl substituted tetrahydroisoquinolines formed via a Pictet–Spengler condensation.
O
O
O
O
H
H
HO
HO
HO
HO
HO
HO
O
O
O
O
OH
O
a
NH
NH
a
NH2
NH2
2
1
5
6
N
N
H
O
Boc
Boc
O
O
O
O
H
N
H
9
N
O
O
H
O
O
O
O
N
Boc
3
N
N
H
HO
HO
HO
5
b, c
d
O
O
3
3
+
b
1
NH
1
NH
HO
7
8
4
5
N
NH
2'
2'
Boc
N
N
Boc
Boc
Scheme 3. Reagents and conditions: (a) BrCH2Cl, Cs2CO3, DMF, 95 °C, 5 h, 40%. (b)
chloroacetyl chloride, pyridine, DMAP, CH2Cl2, room temperature, overnight. (c)
MeNH2, MeOH, 50 °C, overnight, 23% (over two steps). (d) DMF, 150 °C, 3 h, 15%.
Scheme 2. Reagents and conditions: (a) SOCl2, MeOH, 0 °C – room temperature, (b)
NaOAc, AcOH, room temperature, overnight, 67% (1:9, trans:cis).
2 M HCl in Et2O or TFA in CH2Cl2 at room temperature only led
to the total degradation of the starting material. However, we
found that heating 7 for 3 h in DMF at 150 °C afforded 8 as a single
diastereomer. The relative configuration of 8 was determined by
NOESY experiments in the same way as discussed for 4 and 5.
and indole-3-carboxaldehyde12 in AcOH at room temperature for
24 h failed to give the desired product. Reasoning that protecting
the nitrogen on indole-3-carboxaldehyde with an electron-with-
drawing group would facilitate both the formation of the interme-
diate Schiff base and the subsequent ring-closure, we tried the
same reaction with N-Boc-protected indole-3-carboxaldehyde 3
(see Scheme 2). The desired indolyl substituted tetrahydroisoquin-
oline was isolated as a separable 1:9 (trans:cis) diastereomeric
mixture in a total yield of 67%. The configurations of 4 and 5 were
determined by NMR NOESY experiments; a correlation between 20-
H and 3-H was observed for diastereomer 4, demonstrating that
the protons were on the same face of the tetrahydroisoquinoline
ring, while no correlation was observed between 1-H and 3-H.
With 5, no correlation was observed between 20-H and 3-H, dem-
onstrating that these protons were on opposite faces, while a
strong correlation was observed between 1-H and 3-H. The diaste-
reomeric outcome was in full agreement with previous observa-
tions which indicated that the cis isomer was the preferred
diastereomer under the reaction conditions used.9
Compound 8 was optically active ([
and as the absolute configuration at C-9 is determined from L-
a
]
D = ꢀ34 (c = 0.43, DMSO)),
DOPA the absolute configuration of 8 is 5R, 9S.
As the synthesis of 8 from 5 only proceeded in moderate yields,
we decided to investigate an alternative route.
N-Boc protection of L-DOPA (1) (Scheme 4), according to stan-
dard procedure gave 9 in excellent yield. BOPCl mediated amide
coupling between 9 and methyl sarcosine, followed by non-aque-
ous (due to the hydrophilic nature of 10) Boc deprotection yielded
the optically active ([
a]D = 50 (c = 0.86, MeOH)) Pictet–Spengler
precursor 10.
O
O
HO
HO
HO
We were interested in the further derivatisation of the tetrahy-
droisoquinoline scaffold via the introduction of a fused diketopi-
perazine ring, as well as protection of the catechol moiety with a
methylene dioxy bridge, to obtain diketopiperazine fused tetrahy-
droisoquinoline derivatives such as 8 after removal of the N-Boc
protecting group.
OH
OH
Boc
a
NH2
HN
HO
1
9
O
HO
HO
O
N
Treating
5 with bromochloromethane at 95 °C in DMF
b, c
NH2
HCl
O
yielded the methylene dioxy protected tetrahydroisoquinoline 6
(Scheme 3). The diketopiperazine ring was formed in moderate
yield via N-acylation with chloroacetyl chloride, followed by treat-
ment with methylamine and heating overnight to give the N-Boc
protected intermediate 7. The Boc protecting group was resilient
to removal. Heating 7 with Cs2CO3 in DMF at 150 °C, stirring 7 in
10
Scheme 4. Reagents and conditions: (a) Boc2O, NaOH, 1,4-dioxane/H2O, room
temperature, quant. (b) Sarcosine methyl ester hydrochloride, BOPCl, Et3N, NaHCO3,
CH2Cl2, room temperature, overnight, (c) 2 M HCl in Et2O, 0 °C, 1 h, 21% (over two
steps).

4968
R. Larsson et al. / Tetrahedron Letters 53 (2012) 4966–4970
H
O
O
3
O
N
H
HO
HO
O
HO
HO
O
Boc
N
N
a
NH
O
NH2
HCl
O
10
11
N
Boc
O
H
O
O
N
9
b
N
5
O
12
2'
NH
Scheme 5. Reagents and conditions: (a) NaOAc, AcOH, room temperature, overnight, 50%. (b) BrCH2Cl, Cs2CO3, DMF, 150 °C, 2.5 h, 31%.
O
O
O
O
O
O
H
N
H
N
H
N
O
O
O
O
O
O
N
N
N
N
N
NH
H
H CO3
2-CO3
CO3
H
2-
CO3
O
O
O
O
H
N
H
N
O
O
O
O
O
N
N
N
N
O
O
O
N
H
NH
N
H
Scheme 6. Suggested mechanism for the racemisation of 12.
H
O
X
O
O
N
Boc
H
13a-c
HO
HO
O
HO
HO
O
N
N
a
NH2
HCl
O
NH
O
14a-c
10
N
X
Boc
O
O
H
O
N
b
N
O
15a-c
NH
X
Scheme 7. Reagents and conditions: (a) NaOAc, AcOH, room temperature, overnight, (b) BrCH2Cl, Cs2CO3, DMF, 150 °C, 2.5 h.

R. Larsson et al. / Tetrahedron Letters 53 (2012) 4966–4970
4969
Stirring a mixture of 10, N-Boc protected indole-3-carboxalde-
hyde 3 and NaOAc in AcOH at room temperature overnight re-
sulted in the formation of a new product (Scheme 5). We
propose the structure to be that of tetrahydroisoquinoline 11, but
its identification proved difficult as we could not obtain good qual-
ity NMR spectra (possibly due to the existence of rotamers).
Assuming that the product we obtained was in fact the Pictet–
Spengler condensation product 11 between 10 and N-Boc
protected indole-3-carboxaldehyde 3, we applied the previously
described conditions for the protection of the catechol moiety
and deprotection of the N-Boc group. Heating 11, BrCH2Cl and
Cs2CO3 in DMF at 150 °C for 2.5 h yielded 12 as a single diastereo-
mer, although the yield was still only moderate. The configuration
H
O
X
O
O
N
H
13a-c
HO
HO
HO
HO
Boc
O
O
a
NH2
NH
16a-c
2
N
X
Boc
Scheme 8. Reagents and conditions: (a) NaOAc, AcOH, room temperature,
overnight.
Table 1
Analogue synthesis
Pictet–Spengler precursor
Indole derivative
Product
Yield (%)
H
O
H
N
O
O
O
N
Cl
10
16a
13a
N
Boc
O
O
Cl
15a
NH
H
H
O
O
O
N
O
N
10
31a
13b
N
O
O
Boc
O
15b
NH
H
H
O
O
O
N
N
13c
N
10
5a
O
Boc
15c
NH
H
O
H
O
HO
HO
Cl
O
Cl
NH
2
13a
72 (8:1) (cis/trans)
N
Boc
16a
N
Boc
O
H
H
O
HO
HO
O
O
O
NH
13b
2
66 (5:1) (cis/trans)
N
Boc
16b
N
Boc
O
H
H
O
HO
HO
O
NH
13c
N
2
75 (3:1) (cis/trans)
Boc
16c
N
Boc
a
The low yield is mainly due to the Boc deprotection step.

4970
R. Larsson et al. / Tetrahedron Letters 53 (2012) 4966–4970
of 12 was determined by the NOESY correlation between proton
20-H and 9-H (Scheme 5). No trace of 8 was observed. Interestingly,
product 12 was optically inactive.
derivatives involved the transformation of L-DOPA into the Pic-
tet–Spengler precursor 10 and the condensation of this with N-
Boc protected 1H-indole-3-carbaldehydes.
The racemisation of 12 could be explained by considering
two mechanisms, base-catalysed breaking of the C-5–N bond
(Scheme 6, top) leading to a ring-opening/closure to the thermody-
namically most stable diastereomer (trans), and a base-catalysed
keto–enol tautomerisation of C-9 (Scheme 6, bottom), resulting
in 12 as a racemate. It is possible that somewhat milder conditions
for the transformation of 11 into 12 would avoid the racemisation,
but this was not investigated.
To investigate further the usefulness of the Pictet–Spengler pro-
tocol with 1H-indole-3-carbaldehydes, we attempted the reaction
with both Pictet–Spengler precursors 2 and 10 and the three addi-
tional N-Boc protected 1H-indole-3-carbaldehydes 13a, 13b and
13c (Schemes 7 and 8, Table 1).
Acknowledgements
Financial support from the Swedish Natural Science Research
Council and the KAW foundation is gratefully acknowledged.
Supplementary data
Supplementary data (1H NMR, 13C NMR HRMS, optical activity)
associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2012.07.017.
References and notes
The initial Pictet–Spengler condensation products obtained
from 10, and believed to be 14a–c were not isolated, but after a
simple filtration through SiO2 were further reacted to yield 15a–c
(see Scheme 7 and Table 1). The corresponding reactions with 2
yielded the substituted tetrahydroisoquinolines 16a–c (see
Scheme 8 and Table 1).
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hydroisoquinoline derivatives such as 8, in a process that retains
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