Palladium catalyzed, heteroatom-guided C-H functionalization in the synthesis of substituted isoquinolines and dihydroisoquinolines

Article abstract of DOI:10.1039/c4cc03165b

A new approach for the functionalization of C-4 of isoquinolines is reported. The method utilizes palladium catalyzed, hetero-atom guided (or electrophilic metalation) direct arylation via regioselective C-H functionalization of dihydroisoquinolines.

Full text of DOI:10.1039/c4cc03165b

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Palladium catalyzed, heteroatom-guided C–H
functionalization in the synthesis of substituted
isoquinolines and dihydroisoquinolines†‡
Cite this: Chem. Commun., 2014,
50, 7322
Received 28th April 2014,
Accepted 19th May 2014
Virendra Kumar Tiwari, Govind Goroba Pawar, Himanshu Sekhar Jena and
Manmohan Kapur*
DOI: 10.1039/c4cc03165b
www.rsc.org/chemcomm
A new approach for the functionalization of C-4 of isoquinolines is
reported. The method utilizes palladium catalyzed, hetero-atom
guided (or electrophilic metalation) direct arylation via regioselective
C–H functionalization of dihydroisoquinolines.
Direct arylation via C–H activation reactions is a very important
substitute to arylation reactions via prefunctionalization.1
Synthesis of substituted nitrogen heterocycles like pyridines,
quinolines, isoquinolines, pyrazines, among others via C–H
functionalization is not a straightforward task due to the fact that the
heterocycles are electron-deficient.2 Due to this, C–H functionaliza-
tions involving electrophilic metalation on these heteroaromatics are
quite rare. Studies directed towards the functionalization of such
heteroaromatics have utilized directing groups in the form of
Fig. 1 4-Aryl isoquinoline containing biologically important molecules.
N-oxides, acyl groups, or tethers, amongst others, to direct the are important pharmaceutical agents, such as protein kinase B
regioselectivity.3 Other methods include employment of electrophilic (PKB) inhibitors, anti-Parkinsonian drugs, anti-depressants, anti-
metalation of non-aromatic heterocycles using the nucleophilicity of histamines, selective serotonin reuptake inhibitors (SSRI).9 Some
the olefinic bond to which an electron-donating heteroatom is are important starting materials in the synthesis of complex
attached.4 In some cases, Boron–Heck reactions have also been natural products.10 Due to their broad array of biological signi-
employed for functionalization of endocyclic olefins of heterocycles.5 ficance, these building blocks have been the target of synthetic
In a related study, Loh and co-workers have reported regioselective chemists since quite some time.
functionalization of enamides.6 We have recently reported the C-3
Synthetic methodologies for the direct functionalization of the
functionalization of quinolines in which the concept of electrophilic C-4 position of isoquinoline are limited, with almost all approaches
palladation was utilized for a regioselective direct arylation reaction.7 relying on pre-installation of the substituent before the cyclization to
We report herein, our results for a regioselective direct arylation of obtain the isoquinoline ring. Some approaches utilize selective
dihydroisoquinolines in the synthesis of 4-arylisoquinolines and 1,4- halogenations of C-4 as a prelude to metal catalyzed cross-coupling
disubstituted dihydroisoquinolines.
reactions for C-4 functionalization of isoquinolines or dihydroiso-
The isoquinoline core is an important constituent in several quinolines. Recently, nucleophilic addition of b-amino carbanions to
alkaloid natural products, especially the amaryllidaceae alkaloids.8 arynes has been reported by Singh and co-workers for the synthesis
In particular, naturally occurring isoquinolines with a 4-aryl sub- of 4-aryl tetrahydroisoquinolines.11 Wang and co-workers have
stituent (Fig. 1) possess very important biological properties and reported a Lewis acid mediated [3+3] annulation approach for the
same class of molecules.12 The direct arylation of isoquinoline
Department of Chemistry, Indian Institute of Science Education and Research Bhopal,
Indore Bypass Road, Bhauri, Bhopal 462066, India. E-mail: mk@iiserb.ac.in;
Fax: +91-755-6692 392; Tel: +91-755-6692-324
N-oxide leads to the expected C-1 functionalization.3 To the best of
our knowledge, a direct arylation of the C-4 position of dihydroiso-
quinolines to obtain 4-arylisoquinolines is not known in the literature.
Our efforts started with screening for the best conditions for
the transformation. The dihydroisoquinoline starting material was
synthesized either by reduction of isoquinoline and concomitant
† Dedicated to Professor Ganesh Pandey on the occasion of his 60th birthday.
‡ Electronic supplementary information (ESI) available. CCDC 994242 and
994243. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c4cc03165b
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Table 1 Efforts in screening various catalyst systems
Catalyst
Additive/base/oxidant
Solvent/temp.
Result
t
None
None
CuI, AgOAc, BuOK
Toluene, 100 1C
Toluene, 100 1C
Toluene, 100 1C
Toluene, 60 1C
PivOH, 70 1C
Toluene, 100 1C
Toluene, 70 1C
Toluene, 70 1C
Toluene, 70 1C
Dioxane, 100 1C
Toluene, 60 1C
Toluene, 100 1C
Toluene, 100 1C
Toluene, 110 1C
TFA, 70 1C
Only homocoupling of ArB(OH)2
Only homocoupling
Only homocoupling
Only homocoupling
Only homocoupling
10%b
Cu(OTf)2, Ag2O
BQ, Ag2O
K3PO4, AgOAc
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2(MeCN)2
PdCl2(PhCN)2
PdCl2(dppf)
Pd(OAc)2
Pd(OPiv)2
Pd(OAc)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
K2CO3 (3 equiv.)
Cu(OAc)2, AgOAc
Cu(OTf)2, Ag2O
Cu(OTf)2, Ag2O
Cu(OTf)2, Ag2O
Cu(OTf)2, Ag2O
Cu(OTf)2, Ag2O
Cu(OTf)2, Ag2O
Cu(OTf)2, Ag2O
Cu(OTf)2, Ag2O, 1, 10-Phen
Cu(OTf)2, Ag2O
25%b
45%b
Only homocoupling
Messy reaction
40% (unseparated 3 : 1 mix of C4 : C3 isomers)b
67% (unseparated 3 : 1 mix of C4 : C3 isomers)a
38% (unseparated 2.5 : 1 mix of C4 : C3 isomers)a
Only homocoupling
52% (single C4 isomer)a
a
b
Isolated yield. GC yields.
Table 2 Substrate scope with arylboronic acids
acylation or by addition of an organolithium or a magnesium
reagent followed by quenching with an acylating agent. Unlike the
case of quinolines,7 the initial attempts towards direct arylation of
N-acyldihydroisoquinoline resulted in varying amounts of regioiso-
meric products (C-4 versus C-3 arylated). The reaction conditions were
accordingly standardized and after a considerable amount of ligand
and catalyst screening, the best conditions for C-1-unsubstituted
dihydroisoquinolines were found to be Pd(TFA)2/Ag2O in TFA
(Table 1). However, in the case of C-1 substituted substrates, use of
this highly electrophilic Pd(TFA)2 in TFA resulted in regioisomers
(C-4 vs. C-3). The direct arylation of C-1-substituted dihydroisoquino-
lines was best obtained using Pd(OAc)2/Ag2O/Cu(OTf)2 in toluene.
Therefore, in order to generalize, we used Pd(OAc)2/Ag2O/Cu(OTf)2 in
toluene for all the substrates.7 Without a palladium catalyst, the
reaction yielded only homocoupling products of the arylboronic
acids. The use of Cu(OTf)2 was essential as the oxidant. Use of other
different copper sources or other oxidants did not give desirable
results. Changing the catalyst to the more reactive Pd(OPiv)2 also did
not improve the result of transformation. Use of other Pd(II)
catalysts did not yield better results than Pd(OAc)2. Use of more
polar solvents seemed to be detrimental to the reaction. Several
bases were scanned, however best results were obtained only with
Ag2O. The substrate scope is depicted in Table 2. The reaction
worked decently well under the standardized conditions with
electron neutral and electron-rich arylboronic acids. In the case
of the N-acyldihydroquinolines which are unsubstituted at C-1, the
reaction did not work well with arylboronic acids with electron
withdrawing substituents.
All yields are isolated yields of the C-4 aryl product; general reaction
In contrast, in the case of the dihydroisoquinolines substituted conditions: Pd(OAc)2 (5 mol%), ArB(OH)2, Cu(OTf)2, Ag2O, toluene,
a
100 1C. Ratio of the C-4:C-3 aryl product in a crude reaction mixture
at C-1, the reaction worked decently well in most cases. Even with
b
c
analyzed by GC-MS. Isolated yield of the C-3 isomer. Only the proto-
deboronation product was obtained.
arylboronic acids containing electron withdrawing groups, the
reaction worked quite well, with the exception of 3-nitrophenyl
boronic acid which gave only a trace amount of product. In this
case and others that did not work out, the primary side-reaction
A plausible mechanism is depicted below in Scheme 1. The
obtained was the protodeboronation of the arylboronic acids, reaction could either proceed via the transmetallation of the aryl-
along with varying quantities of aromatized starting material.
boronic acid as the first step followed by the heteroatom-guided
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Scheme 1 Plausible reaction mechanism.
electrophilic palladation or vice versa. At this moment it is difficult to
conclude what would be the correct sequence for the palladation.
After intermediate (C) is formed, a fast reductive elimination would
lead to the C-4 C–H functionalization product. In the case of the C-1
substituted dihydroquinolines, the N-deacetylation is a slow process
and the concomitant aromatization via the pathway depicted in
Scheme 1 is therefore expected to be retarded. This has also been
observed experimentally. Under the same reaction conditions, the
C-4 arylated dihydroquinolines aromatize quickly, whereas in the
case of 1,4-disubstituted dihydroisoquinolines, only trace amounts of
aromatized products were observed. The aromatization reaction in
the case of the 4-aryl dihydroisoquinolines could be mediated by the
oxidant or could be a result of the syn b-hydride elimination from (F).
We were successful in aromatizing the C-1 substituted products (7)
in quantitative yields by simply deacylating them by warming in an
aq. HCl–Dioxane mixture. The crude reaction mixture, containing 7,
upon a preliminary work-up was directly subjected to acid-hydrolysis
and aromatization to yield 6. The regiochemistry of the major isomer
was easily proved by simple spectroscopic techniques and X-ray data
of some of the unaromatized substrates.13,14
An interesting observation was made when large excess
(4 equiv.) of arylboronic acid was used in the reaction with
substrate 1. In this case, a C-3, C-4-diarylated product was
observed in 35% isolated yield, along with the regular C-4 aryl
product. In a way, this indicated that the arylation at C-3 was a
result of a domino-type reaction pathway which could involve a
transition state of the type (G) (formed after C-4 arylation) in
which the N-acyl group is acting as a directing group for a
concerted metalation deprotonation (CMD) type mechanism.
A similar transition state has been proposed by Loh and
co-workers in the arylation of exocyclic enamides.6 Unfortunately
for us, we were unable to isolate substantial quantities of 3 so as
to use it as a starting material to try an arylation reaction at C-3
and confirm whether the C-3 arylation was indeed directed by the
N-acyl group. This diarylation was not observed in significant
quantities in the case of 1,4-disubstituted dihydroquinolines even
when 4 equiv. of the arylboronic acid were used (Scheme 2). This
type of transition state is also able to explain why selectivity for
C-4 versus C-3 arylation is slightly lower with Pd(OAc)2 in the
case of unsubstituted dihydroisoquinolines.
Scheme 2 Plausible transition state for second arylation at C-3.
In order to prove the regioselectivity of palladation, NMR
experiments were undertaken.4d,15 In this substrate (1), the C-4
palladated species was not observed in NMR using DMSO-d6 or
toluene-d8 or THF-d8. A comparative NMR plot of the substrate
upon isolation after reaction in TFA/D2O with 1 equiv. of Pd(TFA)2,
taken at different intervals, is shown in Fig. 2. Upto 64% deuterium
content at C-4 was observed in isolated starting material.14 Similarly,
under these highly acidic conditions, the starting material 1
deacetylated and aromatized to 4, which was found to be with 15%
deuterium content upon isolation.14 Initially, we assumed that this
was due to deuterodemetallation; however, in our case, it turned
out to be a totally wrong assumption, a similar level of deuteration
was obtained under the same conditions even without a palladium
source. This deuteration could be due to the endocyclic enamide
picking up a D+ at electron-rich C-4 followed by elimination of H+
to generate the C-4 deuterated starting material.
Fig. 2 Attempts to determine regioselectivity.
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4 For selected references, see: (a) Y. Bai, J. Zeng, S. Cai and X.-W. Liu,
Org. Lett., 2011, 13, 4394; (b) D. Kim and S. Hong, Org. Lett., 2011,
13, 4466; (c) L. Bi and G. Georg, Org. Lett., 2011, 13, 5413; (d) Y.-Y. Yu,
M. J. Niphakis and G. Georg, Org. Lett., 2011, 13, 5932; (e) Y. Moon,
D. Kwon and S. Hong, Angew. Chem., Int. Ed., 2012, 51, 11333;
( f ) N. Gigant and I. Gillaizeau, Org. Lett., 2012, 14, 3304; (g) N. Gigant,
L. Chausset-Boissarie, M.-C. Belhomme, T. Poisson, X. Pannecoucke and
I. Gillaizeau, Org. Lett., 2013, 15, 278; (h) Y.-Y. Yu, L. Bi and G. Georg,
J. Org. Chem., 2013, 78, 6163 and references cited therein; ; (i) G. G. Pawar,
G. Singh, V. K. Tiwari and M. Kapur, Adv. Synth. Catal., 2013, 355, 2185.
5 Y. W. Kim and G. I. Georg, Org. Lett., 2014, 16, 1574 and references
cited therein.
6 (a) H. Zhou, Y.-H. Xu, W.-J. Chung and T.-P. Loh, Angew. Chem., Int.
Ed., 2009, 48, 5355; (b) S. Pankajakshan, Y.-H. Xu, J. K. Cheng,
M. T. Low and T.-P. Loh, Angew. Chem., Int. Ed., 2012, 51, 5701;
(c) H. Zhou, W.-J. Chung, Y.-H. Xu and T.-P. Loh, Chem. Commun.,
2009, 3472; (d) Y.-H. Xu, Y. K. Chok and T.-P. Loh, Chem. Sci., 2011,
2, 1822.
In conclusion, we have developed a new methodology for the
regioselective direct arylation of dihydroisoquinolines for the
synthesis of 4-arylisoquinolines and 1,4-disubstituted dihydro-
isoquinolines. This represents a regioselective two-step direct
arylation of isoquinoline itself. The reaction is proposed to
proceed via heteroatom-guided electrophilic palladation. This
synthetic methodology shall be useful in the synthesis of
4-arylisoquinoline-containing pharmacologically significant
heterocycles. Further utilization of this approach in natural
product synthesis is currently underway.
Financial support from DST-SERB, India, is acknowledged.
GGP and VKT thank CSIR-India for a doctoral fellowship. We
thank Dr Sanjit Konar (IISERB) for the assistance in X-ray
analysis. We thank the Director, IISERB for funding and infra-
structure. We also thank the Referees for useful suggestions.
7 V. K. Tiwari, G. G. Pawar, R. Das, A. Adhikary and M. Kapur,
Org. Lett., 2013, 15, 3310.
8 (a) N. R. Candeias, L. C. Branco, P. M. P. Gois, C. A. M. Afanso and
A. F. Trindade, Chem. Rev., 2009, 109, 2703; (b) V. Sridharan, P. A.
´
Suryavanshi and J. C. Menendez, Chem. Rev., 2011, 111, 2703;
Notes and references
(c) J. A. Joule and K. Mills, Heterocycl. Chem., Wiley, UK, 5th edn,
2010; (d) Comprehensive Heterocyclic Chemistry, ed. A. R. Katrizky and
C. W. Rees, Pergamon, New York, 1984.
1 (a) D. Alberico, M. E. Scott and M. Lautens, Chem. Rev., 2007, 107,
174; For selected reviews and special issues on C–H Functionaliza-
tion, see: (b) J. A. Labinger and J. E. Bercaw, Nature, 2002, 417, 507;
(c) R. H. Crabtree, Chem. Rev., 2010, 110, 575; (d) J. A. Gladysz, Chem.
Rev., 2011, 111, 1167; (e) M. Beller, Chem. Soc. Rev., 2011, 40, 4891;
( f ) M. P. Doyle and K. I. Goldberg, Acc. Chem. Res., 2012, 45, 777;
(g) C–H Activation, ed. J. -Q. Yu and Z. Shi, Topics in Current
Chemistry 292, Springer, Berlin, 2010; (h) Activation and Function-
alization of C–H Bonds, ed. K. I. Goldberg and A. S. Goldman, ACS
Symposium Series 885, American Chemical Society, 2004; (i) Y. Wu,
J. Wang, F. Mao and F. Y. Kwong, Chem. – Asian J., 2014, 9, 26.
2 (a) J. C. Lewis, R. G. Bergman and J. A. Ellman, Acc. Chem. Res., 2008,
´
9 (a) J. Crecente-Campo, M. P. Vazquez-Tato and J. A. Seijas, Tetra-
hedron, 2009, 65, 2655 and references cited therein; (b) L. A. Bonner,
B. R. Chemel, V. J. Watts and D. E. Nichols, Bioorg. Med. Chem.,
2010, 18, 6763; (c) A. D. Pechulis, J. P. Beck, M. A. Curry, M. A. Wolf,
A. E. Harms, N. Xi, C. Opalka, M. P. Sweet, Z. Yang, A. S. Vellekoop,
A. M. Klos, P. J. Crocker, C. Hassler, M. Laws, D. B. Kitchen,
R. E. Olson, S. Liu and B. F. Molino, Bioorg. Med. Chem. Lett.,
2012, 22, 7219.
10 X. Bao, Y.-X. Cao, W.-D. Chu, H. Qu, J.-Y. Du, X.-H. Zhao, X.-Y. Ma,
C.-T. Wang and C.-H. Fan, Angew. Chem., Int. Ed., 2013, 52, 14167.
41, 1013; (b) A. Petit, J. Flygare, A. T. Miller, G. Winkel and D. H. Ess, 11 K. N. Singh, P. Singh, P. Singh and Y. S. Deol, Org. Lett., 2012,
Org. Lett., 2012, 14, 3680. 14, 2202.
3 (a) K. Fagnou, Top. Curr. Chem., 2010, 292, 35; For some represen- 12 S. Wang, Z. Chai, S. Zhou, S. Wang, X. Zhu and Y. Wei, Org. Lett.,
tative examples see: (b) L.-C. Campeau, S. Rousseaux and K. Fagnou, 2013, 15, 2628.
J. Am. Chem. Soc., 2005, 127, 18020; (c) J.-P. Leclerc and K. Fagnou, 13 Crystal Structures submitted to Cambridge Cystallographic Data
Angew. Chem., Int. Ed., 2006, 45, 7781; (d) B. Xiao, Z.-J. Liu,
L. Liu and Y. Fu, J. Am. Chem. Soc., 2013, 135, 616; (e) R. Suresh,
Centre, CCDC deposition number: CCDC 994242 (Compound 7d)
and CCDC 994243 (Compound 7f) respectively.
S. Muthusubramanian, R. S. Kumaran and G. Manickam, Asian 14 See ESI‡ for details.
J. Org. Chem., 2014, 3, 604; see also: ( f ) I. B. Seiple, S. Su, 15 (a) M. Min, Y. Kim and S. Hong, Chem. Commun., 2013, 49, 196;
R. A. Rodriguez, R. Gianatassio, Y. Fujiwara, A. L. Sobel and
P. S. Baran, J. Am. Chem. Soc., 2010, 132, 13194–13196.
(b) M. J. Da Silva, J. A. Gonçalves, R. B. Alves, O. W. Howarth and
E. V. Gusevskaya, J. Organomet. Chem., 2004, 689, 302.
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