Substrate controlled, regioselective carbopalladation for the one-pot synthesis of C4-substituted tetrahydroisoquinoline analogues

Article abstract of DOI:10.1039/d0ra01539c

6-Exo-trig cyclization reaction through regioselective carbopalladation was demonstrated with N-(2-halobenzyl)-N-allylamines to furnish the corresponding C4-substituted tetrahydroisoquinoline derivatives. The scope of the reaction was extended to the synt

Full text of DOI:10.1039/d0ra01539c

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Substrate controlled, regioselective
carbopalladation for the one-pot synthesis of C4-
Cite this: RSC Adv., 2020, 10, 15794
substituted tetrahydroisoquinoline analogues†
a
a
Singarajanahalli Mundarinti Krishna Reddy, Pavithira Suresh,
b
Jagadeesh Babu Nanubolu, Surisetti Suresh *d
c
Subbiah Thamotharan,
a
and Subramaniapillai Selva Ganesan
*
6
-Exo-trig cyclization reaction through regioselective carbopalladation was demonstrated with N-(2-
halobenzyl)-N-allylamines to furnish the corresponding C4-substituted tetrahydroisoquinoline
derivatives. The scope of the reaction was extended to the synthesis of C4-quaternary
tetrahydroisoquinoline derivatives also. The nature of the substituent on the olefin moiety dictates the
course of the carbopalladation sequence. Regioselective carbopalladation is substantiated by performing
the reaction with unsymmetrical diallylated amine substrates.
Received 18th February 2020
Accepted 11th April 2020
DOI: 10.1039/d0ra01539c
rsc.li/rsc-advances
substituted isoquinoline analogue used as antidepressant
agent without any sedative side effect. C4-substituted
Introduction
3
Tetrahydroisoquinolines are one of the key nitrogen heterocy- analogues are also used as serotonin reuptake inhibitors with
1
a–i
4
cles with innumerable biological activities.
Noscapine, sal- histamine H
examples
3
antagonist activity and function as 4-hydrox-
5
solinol, gigantine are representative
of ytamoxifen analogues. Cherylline is a C4-substituted tetrahy-
tetrahydroisoquinolines with anticancer, antihistaminic and droisoquinoline isolated from the natural sources.
6
2
hallucinogenic activities. A representative list of bioactive tet-
rahydroisoquinoline derivatives is given in Fig. 1.
Among tetrahydroisoquinolines, C4-substituted analogues
are well-acclaimed subset due to their highly desirable phar-
macologically relevant properties. Nomifensine is
a C4-
Fig. 1 Selected bioactive tetrahydroisoquinoline analogues.
a
Department of Chemistry, School of Chemical and Biotechnology, SASTRA Deemed
University, Thanjavur-613401, Tamil Nadu, India. E-mail: selva@biotech.sastra.edu
b
Biomolecular Crystallography Laboratory, Department of Bioinformatics, School of
Chemical and Biotechnology, SASTRA Deemed University, Thanjavur 613401, India
c
Centre for X-ray Crystallography, CSIR-Indian Institute of Chemical Technology,
Room No 150, Hyderabad-500007, India
d
Organic Synthesis
& Process Chemistry, CSIR-Indian Institute of Chemical
Technology, Hyderabad-500007, India
Electronic supplementary information (ESI) available. CCDC 1912875. For ESI
and crystallographic data in CIF or other electronic format see DOI:
0.1039/d0ra01539c
†
Chart
1 Methods for the synthesis of C4-substituted tetrahy-
1
droisoquinolines and our methodology.
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Despite several signicances, only a limited number of
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examples are available for the one-pot synthesis of C4-
substituted tetrahydroisoquinoline derivatives. These were
7
a
prepared by the palladium catalysed [4+2] annulation reaction
or superacid-catalyzed Pictet–Spengler cyclization reactions
7
b
(
Chart 1). Hu et al., reported palladium mediated amino-
alkenylation of alkenes for the synthesis of C4-substituted tet-
7c
rahydroisoquinoline derivatives. Nandakumar et al., reported
the synthesis of similar tetrahydroquinoline by the intra-
7d
molecular cyclization of more reactive alkynes. Broggini and
co-workers reported palladium catalysed synthesis of C4-
8
spiroannulated tetrahydroisoquinoline derivatives. However,
the scope of the reaction was largely conned to N-allyl
derivative.
Unlike N-allyl derivatives, 6-exo-trig cyclization of N-cin-
namyl/N-crotyl derivatives is challenging due to the plausible
formation of a mixture of isomers due to the regio- and
stereochemical scrambling (vide infra). Since the generation of
a convenient method to access these valuable pharmacophores
is highly appreciated, it was decided to perform 6-exo-trig
cyclization of terminal carbon substituted acyclic N-allylic
amine derivatives with palladium catalysis (Chart 1).
Scheme 1 Plausible products in Pd catalysed cyclization of 1a–l.
Gratifyingly, changing of palladium complex from Pd(dppf)Cl
2
2+
0
to Pd (dba) (Pd to Pd ) improved the product yield to 90%
2
3
(Table 1, entry 2). Replacing the non-polar solvent toluene with
polar aprotic solvents such as DMF or DMSO reduced the yield
of the product 3a (Table 1, entries 3 and 4). Changing of base to
Results and discussion
2 3
K CO or reducing the reaction temperature drastically affected
the yield of the product 3a (Table 1, entries 6 and 7). Interest-
ingly, replacing pre-functionalized palladium complexes with in
situ generated palladium phosphine complexes using Pd(OAc)2/
To obtain the highest level of stereocontrol in palladium
catalysis, directing functional groups needs to be anchored on
the alkene or the use of Ag or Tl salts is required.
9
a,b
In the
PPh gave the desired product 3a with 95% yield (Table 1, entry
3
absence of any directing group or metal salt additive, it is
difficult to secure a single isomeric product from the mixture of
stereo-/regio-isomers (Scheme 1).
Apart from the formation of a mixture of isomers as shown in
Scheme 1, the competitive deallylation reaction of the substrate
8
). Hence, it was decided to perform the reaction with Pd(OAc)
PPh . Aer optimizing the reaction conditions, the scope of the
reaction was screened with diverse alkyl/aryl substituents.
2
/
3
The carbopalladation/cyclization reaction was found to be
general for both N-(n-butyl) and N-ethyl amine derivatives
1
0
1
a-1l is yet another challenge. To suppress deallylation, allyl
(Fig. 2). The products 3a and 3b were obtained in appreciable
11
moiety needs to be tethered to a heterocyclic ring or reaction
must be performed with N-allyl amides.
yields. The replacement of N-ethyl substituent on the nitrogen
atom with sterically more demanding tert-butyl substituent
didn't show much effect on the yield of the product [3b (87%) vs.
12a,b
These constraints
limit the synthetic utility of the 6-exo-trig cyclization for
accessing C4-substituted tetrahydroisoquinoline analogues.
It was previously reported in the literature that the nature of
the substituent on the double bond plays a pronounced role in
3c (78%)]. These results show that the nature of the aliphatic
substituent on the nitrogen atom doesn't inuence much on the
yield of the isoquinoline products 3.
Replacing the phenyl group on the terminal olen with
a relatively electron richer 4-methoxyphenyl group also did not
affect the carbopalladation/cyclization sequence. The products
13
determining the type of the product formed in the reaction.
Likewise, the use of alkyl amine would also facilitate the cycli-
zation reaction by suppressing the undesired deallylation
reaction. Hence, tertiary amine derivative 1a was designed to
have a cinnamyl group anchored on the aliphatic amine.
Reaction conditions were optimized with substrate 1a (Table 1).
Reaction performed with commercially available, pre-
functionalized palladium phosphine complexes such as
3
d–f were obtained in high yields. In the case of benzylamine
derivatives, the presence of methoxy substituent on the olen
aromatic moiety or amine did not alter the yield of the products
3
ocally by single crystal XRD and it revealed that the product 3g
adopts (Z)-conguration (Fig. 2). As speculated, the replacement
of aliphatic substituent on the nitrogen atom with an aromatic
moiety resulted in more amounts of unreacted substrate 1i in
the reaction medium. An increase in the reaction time or
reaction temperature did not improve the yield of the product
g–h. The structure of the product 3g was conrmed unequiv-
Pd(dppf)Cl
2
gave the corresponding tetrahydroisoquinoline
product 3a in 60% yield (Table 1, entry 1). It is of interest to
mention here that the exclusive formation of the isomer 3a with
an exocyclic double bond was observed in the reaction medium.
The migration of exocyclic double bond to the corresponding
stable endocyclic double bond through the reinsertion of the
palladium followed by second elimination was not observed.
Encouraged by this result, we decided to investigate further the
role of palladium on the 6-exo-trig cyclization reaction.
3i. Interestingly, the reaction carried out with N-aryl-N-allyl
derivative gave the product 3j in 80% yield. Reaction performed
with N,N-diallylated substrate gave the product 3k in 75% yield.
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a
Table 1 Optimization of reaction conditions
ꢀ
b
Entry
1
Catalyst
Base
Temp. ( C)
Solvent
Time (h)
Yield (%) 3a
Pd(dppf)Cl
2
Cs
Cs
Cs
Cs
Cs
2
2
2
2
2
CO
CO
CO
CO
CO
3
3
3
3
3
100
110
120
120
130
110
80
NMP
Toluene
DMF
DMSO
Xylene
Toluene
Toluene
Toluene
26
24
26
24
24
24
30
24
60
90
74
65
75
60
60
95
c
2
Pd
2
Pd
2
Pd
2
Pd
2
Pd
2
Pd
2
(dba)
(dba)
(dba)
(dba)
(dba)
(dba)
3
3
3
3
3
3
3
4
5
6
7
2 3
K CO
Cs
Cs
2
CO
CO
3
d
8
Pd(OAc)
2
2
3
110
a
Unless otherwise mentioned, all the reactions were performed with aryl halide 1a (0.1 mmol), Pd catalyst (0.01 mmol) and base (0.2 mmol) in 3 mL
b
c
d
3
of solvent. Isolated Yield. Presence of unreacted 1a was observed if the reaction mixture was quenched before 24 h. PPh (0.02 mmol) was used
as ligand.
Mechanistic investigations and
quantum chemical calculations
It was previously reported in the literature that the facial
selectivity of the olen and the subsequent carbopalladation
14
plays a crucial role in determining the product selectivity.
Oxidative addition of palladium onto the aryl bromide could
result in the formation of aryl palladium complex (Fig. 3). For
the 6-exo-trig cyclization, intramolecular coordination of palla-
dium with olen moiety is necessary. We presume, during the
carbopalladation, the phenyl substituent on the olen tends to
move away from the sterically more hindered triphenylphos-
phine ligand tethered palladium. This could have been resulted
in the preferential formation of (Z)-isomer over (E)-isomer
(
Fig. 3). A detailed plausible mechanism is given in Scheme 3.
If steric factor plays a crucial role in the carbopalladation,
Fig. 2 Substrate scope for 6-exo-trig cyclization reaction.
then the use of unsymmetrical diallylated substrate 1m–p or 1s
would lead to regioselective carbopalladation at sterically less
Likewise, lipophilic N-octyl-N-allyl derivative also yielded the
product 3l in good yields. In the synthesis of both 3k and 3l,
cyclization proceeded with substituent-free allyl moiety itself.
The formation of deallylated product was not observed even in
the absence of any substituent at the terminal double bond. To
demonstrate the practical utility of this method as a synthetic
tool, we have performed a larger scale synthesis of 3c with
1
0 mmol of substrate 1c. It is imperative to mention that the
desired product 3c was formed in 76% yield in this scale-up
3 4
reaction. In addition, 3c synthesis performed with Pd(PPh )
also gave the product in 70% yields. This shows that Pd(0) plays
a crucial role in this cyclization sequence.
Fig. 3 Plausible cyclization pathway.
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hindered olen moiety. To check this hypothesis, acyclic amine
substrates 1m–p were designed to have both substituted allyl
and cinnamyl moieties tethered on to the nitrogen atom
(Scheme 2(i) and (ii)). In the case of substrates 1m/1n, cycliza-
tion prefers sterically less hindered allyl moiety rather than
relatively more steric cinnamyl moiety and the products 3m/3n
are formed in good yields. Likewise, for the substrates 1o/1p,
cyclization proceeds through sterically less hindered cinnamyl/
allyl moiety than sterically more crowded 2,3-dimethylallyl
moiety. Hence, products 3o/3p form in good yields. In scheme
0
0
0
0
(
i) and (ii), the formation of products 3m /3n and 3o /3p are not
observed. The carbopalladation at 2,3-dimethyl allyl derivative Fig. 4 (I) HOMO of 1o; (II) HOMO of 1m.
q is challenging due to (i) the presence of sterically more
demanding methyl groups, (ii) lack of b-hydrogen on the ring
Scheme 2(iii)). Interestingly, reaction performed with 1q gave
1
(
the corresponding C4-quaternary isoquinoline derivative 3q.
Thus the proposed method offers a facile method for the
synthesis of C4-quaternary derivatives. However, the reaction
performed with 1r failed to yield the desired product 3r. Lack of
product selectivity was observed if the substrate (1s) possesses
two cinnamyl groups with similar steric inuence but varies in
electronic effect (Scheme 2(iv)).
The carbopalladation/cyclization reaction performed under
open-air reaction conditions also gave the product 3a in 74%
yield (Scheme 2(v)). To further conrm the absence of radical
pathway, the reaction was performed in the presence of radical
quencher TEMPO (Scheme 2(v)). As predicted, TEMPO did not
interfere with the course of the reaction and product 3a was
obtained in 46% yield.
Scheme 3 Plausible mechanism for Pd-catalysed regioselective 6-
exo-trig cyclization.
Quantum chemical calculations were performed using
15
Gaussian09 program with B3LYP/6-311++G(d,p) level of theory
for 1m and 1o. The result revealed that the electron density of
the highest occupied molecular orbitals (HOMO) is localized
over allyl and cinnamyl moieties and they are comparable
(Fig. 4). Hence, the products 3o and 3m formed from 1o and 1m
are largely driven by the steric factor. Studies performed on both
(
2
E) and (Z)-isomers of 3g revealed that the (Z)-isomer is
.6 kcal mol more stable form than the corresponding (E)-
ꢁ
1
isomer (Fig. S1, ESI†). Based on the results obtained from
mechanistic studies and quantum chemical calculations, we
propose a plausible mechanism for the formation of the
product.
The addition of both Pd(OAc)
formation of anionic palladium complex A (Scheme 3).
2 3
and PPh could result in the
16
Oxidative addition of anionic palladium on to the aryl halide
followed by the coordination with olen would result in the
formation of palladium complex B or B
1
2.
The nature of the substituent on the olen dictates this
13
crucial carbopalladation step. If R ¼ Me, the carbopalladation
might proceed through sterically less hindered cinnamyl
derivative via cycle I to form B
tion of the olen on to the aryl palladium would result in the
formation of complex C
. Likewise, if R ¼ H, the reaction could
proceed through cycle II and C is formed. The syn coplanar
1
. In cycle I, the migratory inser-
1
2
arrangement of the metal center and the b-hydrogen atom is
required for the b-hydride elimination to take place in C and
1
17
C . The b-hydride elimination of the complex C and C could
2
1
2
Scheme 2 Regioselective carbopalladation and mechanistic studies.
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result in the formation of the product 3m and 3o respectively.
Interestingly, the re-insertion of the palladium on to the
product was not observed under the reaction conditions. Hence
the formation of the product with endocyclic double bond was
not found.
orally efficacious RORgt inverse agonists. part 2: design,
synthesis,
and
biological
evaluation
of
novel
tetrahydroisoquinoline derivatives, Bioorg. Med. Chem.,
2018, 26, 470–482; (g) M. Kairuki, Q. Qiu, M. Pan, Q. Li,
J. Zhou, H. Ghaleb, W. Huang, H. Qian and C. Jiang,
Designed
P-glycoprotein
inhibitors
with
triazol-
tetrahydroisoquinoline-core increase doxorubicin-induced
mortality in multidrug resistant K562/A02 cells, Bioorg.
Med. Chem., 2019, 27, 3347–3357; (h) Y. S. Li, X. Y. Liu,
D. S. Zhao, Y. X. Liao, L. H. Zhang, F. Z. Zhang, G. P. Song
Conclusion
In conclusion, we have developed an intramolecular sequential
carbopalladation and cyclization methodology for the synthesis
of highly biologically relevant C4-substituted tetrahy-
droisoquinoline analogues. The prime advantages of this
transformation are being the exclusive formation of (Z)-exo
olen group containing tetrahydroisoquinoline derivatives. The
possibility for the generation tetrahydroisoquinolines with all
carbon quaternary stereogenic centers at C4 carbon atom is also
demonstrated.
and
Z.
N.
Cui,
Tetrahydroquinoline
and
tetrahydroisoquinoline derivatives as potential selective
PDE4B inhibitors, Bioorg. Med. Chem. Lett., 2018, 28, 3271–
3275; (i) H. Watanabe, K. Fukui, Y. Shimizu, Y. Idoko,
Y. Nakamoto, K. Togashi, H. Saji and M. Ono, Synthesis
and
biological
evaluation
of
F-18
labeled
tetrahydroisoquinoline derivatives targeting orexin
1
receptor, Bioorg. Med. Chem. Lett., 2019, 29, 1620–1623.
2
3
I. P. Singh and P. Shah, Tetrahydroisoquinolines in
therapeutics: a patent review (2010–2015), Expert Opin.
Ther. Pat., 2017, 27, 17–36 and references cited therein.
Z. L. Zhao, Q. L. Xu, Q. Gu, X. Y. Wu and S. L. You,
Conflicts of interest
There are no conicts to declare.
Enantioselective
tetrahydroisoquinolines
synthesis
via
of
4-substituted
Acknowledgements
palladium-catalyzed
Financial support from the Council of Scientic and Industrial
Research, CSIR (80(0085)/16/EMR-II) is gratefully acknowledged
by S. S. G. The authors thank the SASTRA Deemed University for
providing lab space and the NMR facility. We thank Director,
CSIR-IICT for the support (IICT/Pubs./2019/315).
intramolecular Friedel–Cras type allylic alkylation of
phenols, Org. Biomol. Chem., 2015, 13, 3086–3092 and
references cited therein.
4 X. Deng, J. T. Liang, J. Liu, H. McAllister, C. Schubert and
N. S. Mani, A practical synthesis of enantiopure 7-alkoxy-4-
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a dual serotonin reuptake
3
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