Diversity-oriented approach to 1,2,3,4-tetrahydroiso-quinoline-3-carboxylic acid (Tic) derivatives using diethyl acetamidomalonate as a glycine equivalent: Further expansion by Suzuki-Miyaura cross-coupling reaction

Article abstract of DOI:10.3987/COM-09-S(S)103

Synthesis of diverse l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic) derivatives and its higher analogues are reported using diethyl acetamidomalonate as a glycine equivalent. In addition, various substituted Tic derivatives are assembled by application of SuzukiMiyaura cross-coupling reaction as a key step.

Full text of DOI:10.3987/COM-09-S(S)103

HETEROCYCLES, Vol. 80, No. 2, 2010
847
HETEROCYCLES, Vol. 80, No. 2, 2010, pp. 847 - 854. © The Japan Institute of Heterocyclic Chemistry
Received, 3rd August, 2009, Accepted, 4th September, 2009, Published online, 11th September, 2009
DOI: 10.3987/COM-09-S(S)103
DIVERSITY-ORIENTED APPROACH TO 1,2,3,4-TETRAHYDROISO-
QUINOLINE-3-CARBOXYLIC ACID (TIC) DERIVATIVES USING
DIETHYL ACETAMIDOMALONATE AS A GLYCINE EQUIVALENT :
FURTHER EXPANSION BY SUZUKIMIYAURA CROSS-COUPLING
REACTION†
Sambasivarao Kotha,a* Shilpi Misra,a Nimita Gopal Krishna,a Nagaraju
Devunuri,a Henning Hopf,b and Abhilash Keecherikunnelb
a) Department of Chemistry, Indian Institute of Technology-Bombay, Mumbai,
400076, India Fax: (+91)-22-2572-3480; phone: (+91)-22-2576-7160; e-mail:
srk@chem.iitb.ac.in b) Institut für Organische Chemie, Technical University of
Braunschweig, Germany; Fax: +49 531-391-5388; e-mail: h.hopf@tu-bs.de
Abstract – Synthesis of diverse 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid
(Tic) derivatives and its higher analogues are reported using diethyl
acetamidomalonate as a glycine equivalent. In addition, various substituted Tic
derivatives are assembled by application of SuzukiMiyaura cross-coupling
reaction as a key step.
Constrained -amino acid (AAA) derivatives play a critical role in the design of biologically active
peptides and peptidomimetics.1 1,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid (Tic) is considered as
a constrained analogue of phenylalanine (Phe), where its dihedral angle is limited to a small range (χ =
+60o, -60o).2 In addition, Tic has also been employed as a useful building block for the synthesis of
various biologically active alkaloid derivatives.3 Peptides containing Tic are also used as -opioid
receptor antagonists.4 Interestingly, the Tic residue adopts different conformations depending on
whether it is incorporated at the N-terminus or at a central location of the peptide chain. Recent studies
indicate that by incorporation of Tic residues, the resulting peptide can adopt both helical and -bonded
structures. Generally, Tic derivatives are assembled by PictetSpengler or BischlerNapieralski
reactions as a key step.5 In order to expand the synthetic routes to Tic derivatives, development of other
approaches is desirable.6 In connection with the studies related to the bioactive conformation of peptide
† This paper is dedicated to Emeritus Professor Akira Suzuki on the occasion of his 80th birthday

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HETEROCYCLES, Vol. 80, No. 2, 2010
ligands, various Tic derivatives were assembled (Figure 1).7 In continuation of our efforts to design
various Tic derivatives by a building block approach,11 we conceived a general strategy to several Tic
derivatives involving diethyl acetamidomalonate (DEAM) as a glycine equivalent. Although DEAM is
used for the construction of various unusual amino acid derivatives, its utility towards the preparation of
Tic derivatives however is less explored.12
CO2H
CO2H
NH
Benzo(f)Tic 3
CO2H
NH
CO2H
NH2
NH
Benzo(g)Tic 4
Tic 2
Phe 1
CO2H
NH
CO2H
NH
CO2H
NH
CO2H
NH
Sic 6
Benzo(h)Tic 5
Nic 8
Hic 7
Figure 1. Various constrained AAA derivatives related to Tic
Here we describe the synthesis of various Tic derivatives, by treating ,-dibromo-o-xylenes, with
DEAM in presence of a mild base such as K2CO3 (Scheme 1). By choosing an appropriate dibromo
derivative one can prepare Tic and its higher analogues (Eq. 1 – Eq. 3).
Br
CO2Et
EtO2C
CO2Et
NHAc
CO2Et
N
Eq. 1
Ac
Br
CO2Et
CO2Et
Ac
Ac
Br
Br
N
N
Eq. 2
CO2Et
CO2Et
Br
Br
Eq. 3
Scheme 1. Retrosynthetic approach to Tic and its higher analogues

HETEROCYCLES, Vol. 80, No. 2, 2010
849
The required dibromo derivatives can be obtained from the corresponding dimethyl aromatic
compounds with the aid of benzylic bromination using N-bromosuccinimide (NBS)13 under free radical
condition or by bromination of the corresponding diols with PBr3 (Scheme 2).14 The required diols were
assembled by a [2+2+2]cycloaddition reaction and reduction as key steps.15 Alternatively, a
bromomethylation16 strategy can also be adopted for this purpose.
HCHO
HBr
Br
Br
NBS
CO2Me
CO2Me
CO2Me
CO2Me
[2+2+2]
reaction
OH
OH
reduction
Scheme 2. Synthetic approaches to ,-dibromo-o-xylene derivatives
Reaction of ,-dibromo-o-xylene derivatives (Table 1) with DEAM in presence of K2CO3 gave
various Tic derivatives in moderate yields. In a typical experimental procedure, a solution of dibromide
(1 equivalent) in dry acetonitrile was treated with DEAM (1.1 equivalent), powdered potassium
carbonate (6 equivalents) and tetrabutylammonium hydrogen sulfate (0.2 equivalent) as a phase-transfer
catalyst. At the conclusion of the reaction (TLC monitoring), the reaction mixture was passed through a
small pad of celite. The filtrate was concentrated and extracted with ethyl acetate (3 × 25 mL). The
crude product obtained was purified by silica-gel column chromatography. Elution of the column with
ethyl acetate-petroleum ether mixture furnished the required Tic derivative.
This methodology was also extended for the synthesis of higher analogues of Tic. Towards the
preparation of Sic derivative 26, the required dibromide was prepared from the corresponding
anhydride.17 Later, treatment of the dibromide 25 with DEAM in the presence of K2CO3 gave Sic
derivative 26. Along similar lines, Hic derivative 28 was assembled starting with the commercially
available 2,2-bis(bromomethyl)-1,1-biphenyl 27 (Table 2).
CO2Et
CO2Et
Ac
EtO2C
Ac
CO2Et
Br
Br
N
Br
Br
DEAM
K2CO3
Br
Br
CO2Et
CO2Et
N
N
Ac
29
(35%)
31
(40%)
30
Scheme 3. Cyclophane based Tic derivative

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HETEROCYCLES, Vol. 80, No. 2, 2010
Table 1. Preparation of various Tic derivatives
starting material
entry
1
product
yield (%)
condition
CO2Et
CO2Et
A
I
I
41
I
I
Br
Br
N
Ac
9
10
12
CO2Et
CO2Et
Br
2
B
B
42
42
Br
N
Ac
11
CO2Et
CO2Et
Br
Br
3
N
Ac
14
N
13
CO2Et
N
Br
CO2Et
75
72
4
5
B
B
Br
N
N
N
Ac
15
16
CO2Et
CO2Et
Cl
Cl
N
Cl
N
Br
Br
N
N
Cl
N
Ac
17
18
CO2Et
Br
CO2Et
45
A
6
7
N
Br
Ac
20
19
CO2Et
CO2Et
Br
Br
B
48
N
Ac
22
21
Br
Br
S
CO2Et
CO2Et
Cl
Cl
S
B
56
8
N
Ac
23
Br
Br
24
aConditions A: DEAM (1 equiv.), K2CO3 (5 equiv.), MeCN reflux, 24 h.
Conditions B: DEAM (1.1 equiv.), K2CO3 (6 equiv.), TBAHS (0.2 equiv.), MeCN reflux, 20-22 h.

HETEROCYCLES, Vol. 80, No. 2, 2010
851
Table 2. Preparation of Sic and Hic derivatives
starting material
entry
1
product
conditiona yield (%)
CO2Et
Br
Br
Ac
N
CO2Et
64
A
25
26
CO2Et
CO2Et
Ac
Br
Br
N
2
A
64
27
28
Table 3. Expansion of Tic derivatives by Suzuki cross-coupling reaction
product
entry
1
yield (%)
substrate boronic acid
conditiona
CF3
B(OH)2
10
CO2Et
CO2Et
A
35
CF3
N
Ac
32
33
CF3
B(OH)2
MeO
CO2Et
CO2Et
2
10
A
49
N
OMe
34
Ac
35
MeO
B(OH)2
CO2Et
CO2Et
A
B
30
37
3
10
N
Ac
36
37
CO2Et
CO2Et
O
B(OH)2
N
O
18
4
N
O
Ac
N
38
39
aConditions A: [Pd2(dba)3], Buchwald Ligand (5 mol%), Na2CO3, THF/toluene/H2O, 70 oC.
Conditions B: [Pd2(dba)3], LiCO3, dioxane:H2O (3:1), MW, 5 min.

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It is interesting to note that this strategy could also be extended to cyclophane derivative 29.
Accordingly, when tetrabromide 2918 was reacted with DEAM under the above condition to give di-Tic
derivative 30 along with mono-Tic derivative 31 in 40% and 35% yields, respectively. The
regiochemistry of compound 30 has been established by single crystal X-ray diffraction analysis.19 In
view of various recent applications of [2.2] paracyclophane chemistry these results may found useful
application in bioorganic chemistry.20
Having prepared various Tic derivatives and its higher analogues, diiodo Tic derivative 10 was chosen
as a suitable precursor to realize the SuzukiMiyaura (SM) cross-coupling step. We found that the
corresponding tetrabromo derivative is not a friendly precursor. To this end, we prepared various SM
cross-coupling products by reaction of 10 with various boronic acids under Pd catalyst conditions.
Several derivatives prepared by SM coupling reaction are included in Table 3.
In a typical reaction procedure, the diiodo Tic derivative 10 was reacted with an appropriate boronic
o
acid, THF/toluene/H2O (1:1:1) in presence of Na2CO3, at 70 C for 15-20 min followed by addition of
[Pd2(dba)3] (1.5 mol%) and Buchwald ligand21 (5 mol%) (condition A). At the end of the reaction (TLC
monitoring), the reaction mixture was concentrated and the crude product obtained was purified by
silica-gel column chromatography. Elution of the column with an ethyl acetate-petroleum ether mixture
gave the cross-coupling product. In some cases, the SM cross-coupling reaction was also carried out in
the absence of a ligand by using [Pd2(dba)3] (1.5 mol%), dioxane:H2O = 3:1) in the presence of LiCO3
under microwave irradiation (condition B). All new compounds were characterized on the basis of high
resolution 1H NMR and mass spectral data.
In conclusion, we have shown that DEAM is a useful glycine equivalent to prepare diverse Tic
derivatives under mild reaction conditions. Further, we have shown that SM cross-coupling reaction is
useful to generate various functionalized Tic derivatives. Since a large number (>900) of boronic acids
are commercially available, the present strategy can be easily extended to generate a library of Tic
derivatives by applying SM cross-coupling reaction. Since the development of new synthetic methods
for the preparation of unusual AAA derivatives is important for designing peptide-based drugs, our
methodology may be of interest to medicinal and bioorganic chemists.
ACKNOWLEDGEMENTS
We thank CSIR, New Delhi for financial support and SAIF, Bombay for recording spectral data. S.
Misra thanks CSIR, New Delhi for the award of research fellowship. N. G. Krishna thanks Department
of Chemistry, IIT-Mumbai for awarding the research fellowship. Abhilash Keecherikunnel thanks the
Alexander von Humboldt foundation for a postdoctoral fellowship.

HETEROCYCLES, Vol. 80, No. 2, 2010
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