A metal-free cyclic iminium induced one-pot double annulation cascade: Access to dihydroisoquinolinium (DHIQ) salts

Article abstract of DOI:10.1039/c6ob02089e

A reactive cyclic iminium induced one-pot Groebke-Blackburn-Bienayme (GBB) double annulation cascade (DAC) for the synthesis of skeletally diverse DHIQ salts has been described. The key features of this protocol are transition-metal and solvent-free, mild reaction conditions, robust method, one-step construction of two privileged heterocyclic rings, clean reaction profile and operational simplicity.

Full text of DOI:10.1039/c6ob02089e

View Article Online
View Journal
Organic &
Biomolecular
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: S. A., N. B.
Venkata, A. H. Shinde and S. S. Duddu, Org. Biomol. Chem., 2016, DOI: 10.1039/C6OB02089E.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the Ethical guidelines still
apply. In no event shall the Royal Society of Chemistry be held
responsible for any errors or omissions in this Accepted Manuscript
or any consequences arising from the use of any information it
contains.
www.rsc.org/obc

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 1 of 5
View Article Online
DOI: 10.1039/C6OB02089E
Journal Name
ARTICLE
Metal-Free Cyclic Iminium Induced One-pot Double Annulation
Cascade: Access to Dihydroisoquinolinium (DHIQ) Salts
A. Sagar,‡ Venkata Nagarjuna Babu,‡ Anand H. Shinde‡ and Duddu S. Sharada*
Received 00th January 20xx,
Accepted 00th January 20xx
A reactive cyclic iminium induced one-pot Groebke-Blackburn-Bienayme (GBB) double annulation cascade (DAC) for the
synthesis of skeletally diverse DHIQ salts has been described. The key features of this protocol are transition-metal and
solvent-free, mild reaction conditions, robust method, one-step construction of two privileged heterocyclic rings, clean
reaction profile and operational simplicity.
DOI: 10.1039/x0xx00000x
www.rsc.org/
Introduction
structure6 of natural products and pharmaceuticals (Figure 1),
however, very few methods7 have been reported for DHIQ
derivatives.
The ubiquity of the isoquinoline (IQ) framework1 in
biologically active natural products, besides its applications as
pharmaceuticals, functional organic materials and ligands for
asymmetric catalysis have turned the attention of synthetic
organic chemists in recent years. Among IQ derivatives, fused
IQ salts are naturally occurring alkaloids2 and promising lead
Figure 1 Representative examples of bioactive molecules and
natural products.
Scheme 1 Various approaches to imidazopyridine based drug-like
molecules via GBB reaction.
structures in drug discovery.3 The iminium moiety in these
derivatives was found to be essential for significant biological
activities.4 Though several reports have been documented for
the synthesis of these derivatives, most of the methods5 involve
starting material with preformed IQ skeleton, expensive metal
catalysts, multiple steps, lack of diversity, scalability, and
tedious routes to access starting material. Beside isoquinoline
motif dihydroisoquinolinium (DHIQ) ion and pyrido-
Recently, Shen et al. have developed an efficient approach
to pyridoimidazoisoquinolinium compounds via Yb(OTf)3
/AgOTf catalyzed one-pot synthesis (Scheme 1a).8 However, it
involves use of expensive two metal catalysts, inaccessible
starting material, lack of generality and lengthy synthetic steps.
Though there is a convenient approach reported for the
synthesis of imidazoisoquinolinium salts, it involves
preconstructed isoquinoline substrate rather than constructing
the same.9
imidazo[5,1-a]isoquinolinium ion also form an important core
Department of Chemistry, Indian Institute of Technology Hyderabad, Kandi 502285,
Sangareddy, Telangana, INDIA
Phone: (040) 2301 7058; Fax: (040) 2301 6032, E-mail: sharada@iith.ac.in
† Footnotes relaꢀng to the ꢀtle and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
The versatility of 2-(2-bromoethyl)benzaldehyde (1a) as a
promising bifunctional reactant in various organic
transformations has been well documented, especially leading
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 2 of 5
View Article Online
DOI: 10.1039/C6OB02089E
ARTICLE
Journal Name
to tetrahydroisoquinoline (THIQ) motifs based natural products
and their analogues (Scheme 2).10 However, utilization of 1a in
the synthesis of fused dihydroisoquinolinium salts is not
explored to date. Very recently, in our lab, we have
documented some interesting cascade strategies employing 1a
for the synthesis of skeletally diverse THIQ skeletons (Scheme
2).10a-c Moreover, we have also reported step-economic and
sustainable methods for the synthesis of imidazopyridines via
GBB reaction.11
Groebke-Blackburn-Bienayme (GBB) reaction12 is an
elegant example involving [4+1] cycloaddition as a key step
between activated imine i.e. 1,3-diazadiene (1,3-DD) and
isocyanide resulting in drug-like imidazopyridine heterocyclic
entities which are further cyclized by post-GBB modifications
(Scheme 1b).13,8 However, most of the methods were realized
by either use of stoichiometric or catalytic amount of Bronsted
acids or bases, Lewis acids and metal catalysts for the
generation of 1,3-DD and its activation.
entry
solvent
MeOH
MeOH
MeOH
MeOH
temp (°C)
time (h)
10
20
22
20
yield (%)
1
2
3
4
rt
10
20
54
64
50
70
90
5
6
7
8
9
10
11
12
13
EtOH
H2O
DCE
DCM
CH3CN
THF
1,4 dioxane
No solvent
No solvent
100
100
100
50
90
90
110
rt
50
20
20
23
14
21
14
10
10
20
67
0
40
32
43
35
55
trace
40
14
15
16
17
No solvent
No solvent
No solvent
No solvent
60
2
66
91
70
66
80
10 min
10 min
10 min
90
100
a Reaction conditions: 1a (0.23 mmol), 2a (0.23 mmol) and 3a (0.23 mmol). b
Yield of isolated product after column chromatography.
afforded the desired product 4aaa, albeit in low yield (Table 1,
entry 1). Encouraged by this result, and to further explore, we
increased the temperatures which resulted in improvement of
yields up to 64% (Table 1, entries 2-4). Moreover, in protic and
aprotic polar solvents, even after continuing the reaction for
long hours the starting materials were not completely consumed
(Table 1, entries 5-11). From the perspective of twelve
principles of green chemistry,15 solvent-free reactions have seen
tremendous growth both in academia and industry.16 Our
continued interests in development of sustainable methods for
synthesis of diverse heterocyclic frameworks17,10a-c,11a,b
prompted us to perform the reaction under solvent-free
conditions. Not surprisingly, higher temperatures resulted in
improved yields of the products with drastic reduction in time
(Table 1, entries 13-15). However, beyond 80 °C we have seen
drop in the yields (Table 1, entries 16 and 17), which could be
due to decomposition of reaction mixture.
Scheme 2 Various approaches to THIQ motifs starting from 2-(2-
bomoethyl) benzaldehyde.
Encouraged by our recent reports10a-c on employing 1a in
various organic cascade transformations, we envisioned that the
bifunctional reactivity of 1a could be tapped further (Scheme
1c). In this scenario, we conceptualized that 1a on reaction with
2-aminopyridine 2a would result in cyclic iminium via pre-
GBB modification (imine formation and alkylation), which can
be employed in GBB reaction as activated 1,3-DD under
metal/catalyst-free conditions14 (Scheme 1c). Herein, we
disclose the cyclic iminium induced GBB double annulation
cascade reaction leading to pyridoimidazo-DHIQ salts for the
first time.
With the reaction at 80 °C as optimized condition (Table 1,
entry 15) for double annulation cascade (DAC) in hand we
planned to evaluate the scope of our strategy. In this direction,
we extended it to various aminoazines
keeping the aldehyde component constant to obtain
corresponding pyridoimidazoisoquinolinium derivatives
2 and isocyanides 3,
1
Results and discussion
(Scheme 3, 4aaa-4ace) in good to excellent yields. The
structure of 4aab was further confirmed by single crystal X-ray
To test the above hypothesis, a preliminary reaction of
equimolar mixture of 2-(2 bromoethyl) benzaldehyde 1a, 2-
aminopyridine 2a and cyclohexylisocyanide 3a was performed
at ambient temperature (35 °C) in methanol for 10h, which
Table 1 Double annulation cascade to pyridoimidazo-DHIQ
salt 4aaaa,b
crystallography as shown in Scheme
3 (see ESI). The
aminoazine bearing electron withdrawing group (EWG), for
example chloro substituent gave 4aha in moderate yield (64%)
compared to other aminoazines. We next investigated
employing a variety of 2-(2-bromoethyl)benzaldehydes
1 and
aminoazines with EWG and electron donating groups (EDG),
2
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 3 of 5
View Article Online
DOI: 10.1039/C6OB02089E
Journal Name
ARTICLE
Scheme 4 Synthesis of skeletally diverse DHIQ scaffolds a,b
which did not show any significant difference in the outcome of
the reaction. Gratifyingly, even when both aminoazines and
aldehydes were employed with EWG, it resulted in good yield
of the product (4bga, Scheme 3).
Scheme 3 Synthesis of pyridoimidazo-DHIQ scaffolds a,b
a
Reactions were performed with 1 (0.23 mmol), 2 (0.23 mmol) and
3 (0.23 mmol) at 80 oC. Yield of isolated product after column
b
chromatography.
After having successfully developed one-pot double
annulation cascade (DAC) strategy for the synthesis of diverse
pyridoimidazo-DHIQ scaffolds via GBB reaction, we
envisaged to examine the scalability of the process.
Consequently, we have performed the reaction on 2 g scale and
isolated the product 4aaa as white solid in very good yield
(86%) by direct filtration without the need for any tedious
column purification (Scheme 5). As synthesized DHIQ
compounds contain some privileged heterocyclic motifs present
in drug molecules,19 the scalability of our method should prove
industrially applicable.
Scheme 5 Scalability of present DAC protocol
Scheme 6 Plausible reaction mechanism for 4aaa
a Reactions were performed with 1 (0.23 mmol), 2 (0.23 mmol) and
b
3 (0.23 mmol) at 80 oC. Yield of isolated product after column
chromatography. c See ESI for X-ray crystal data
.
Our pursuit for diversity oriented synthesis (DOS) impelled
us to examine diversity of our present strategy. Accordingly,
we probed with structurally and skeletally different
aminoazines, which to our delight provided interesting and
diverse tetra- and pentacyclic IQ scaffolds (Scheme 4).18 When
we have used other heterocyclic aminoazines we have not
observed any detrimental effect on reaction outcome.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 4 of 5
View Article Online
DOI: 10.1039/C6OB02089E
ARTICLE
Journal Name
Based on our reports,10a-c experimental20 and other
3
4
M. Jayaraman, B. M. Fox, M. Hollingshead, G. Kohlhagen, Y.
Pommier and M. Cushman, J. Med. Chem., 2002, 45, 242.
(a) F. Miao, X. J. Yang, L. Zhou, H. J. Hu, F. Zheng, X. D. Ding,
literatures,4a,10d we have proposed a plausible mechanism for
the formation of pyridoimidazo-DHIQ salt 4aaa in Scheme 6.
Initially, the reaction of 2-(2-bromoethyl)benzaldehyde 1a and
D. M. Sun, C. D. Zhou and W. Sun, Nat. Prod. Res., 2011, 25
,
863. (b) F. Miao, X. J. Yang, Y. N. Ma, F. Zheng, X. P. Song and
L. Zhou, Chem. Pharm. Bull., 2012, 60, 1508.
2-aminopyridine 2a reacts to give intermediate imine I, which
5
(a) G. Lahm, J. G. Deichmann, A. L. Rauen and T. Opatz, J.
Org. Chem., 2015, 80, 2010. (b) Z. Qi, S. Yu and X. Li, J. Org.
Chem., 2015, 80, 3471. (c) G. Zhang, L. Yang, Y. Wang, Y. Xie
and H. Huang, J. Am. Chem. Soc., 2013, 135, 8850. (d) A. M.
on intramolecular nucleophilic substitution will afford the
highly reactive cyclic iminium II. Further, the cyclic iminium
II on [4+1] cycloaddition with cyclohexylisocyanide 3a will
lead to pyridoimidazo-DHIQ bromide 4aaa
.
Nauth, N. Otto and T. Opatz, Adv. Synth. Catal. 2015, 357
,
In summary, we have developed a mild, efficient and metal-
free protocol for the synthesis of fused IQ derivatives under
solvent-free conditions. We have demonstrated an
unprecedented cyclic iminium induced GBB leading to
construction of two privileged heterocyclic rings in one-pot.
This double annulation cascade provided pyridoimidazo-
DHIQs in excellent yields by easy isolation without tedious
workup. In addition, readily accessible starting material,
remarkably short reaction time, simplicity in operation, scope
of skeletal diversity, H2O as sole byproduct and scalability
makes this approach greener, cost effective, and better
alternative to existing ones. On the other hand, the scalability of
the method should prove appealing for industrial applications.
Further studies on biological activity of these scaffolds are
currently under way in our laboratory.
3424. (e) K. Parthasarathy, N. Senthilkumar, J. Jayakumar and
C. H. Cheng, Org. Lett., 2012, 14, 3478.
6
7
(a) L. Grycova, J. Dosta and R. Marek, Phytochemistry, 2007,
68, 150. (b) B. Juskowiak, E. Galezowska, N. Koczorowska and
T. W. Hermann, Bioorg. Med. Chem. Lett., 2004, 14, 3627. (c)
G. Bringmann, T. Gulder, B. Hertlein, Y. Hemberger and F. J.
Meyer, Am. Chem. Soc., 2010, 132, 1151. (d) X. Yu and J. Wu,
J. Comb. Chem., 2010, 12, 238.
(a) H. J. Deiseroth, A. Granzhan, H. Ihmels, M. Schlosser and
M. Tian, Org. Lett., 2008, 10, 757. (b) R. Yang, Z. F. Gao, J. Y.
Zhao, W. B. Li, L. Zhou and F. Miao, J. Agric. Food
Chem., 2015, 63, 1906. (c) K. Iwasa, M. Moriyasu, Y.
Tachibana, H. S. Kim, Y. Wataya, W. Wiegrebe, K. F. Bastow,
L. M. Cosentino, M. Kozukab and K. H. Lee, Bioorg. Med.
Chem., 2001, 9, 2871.
8
9
H. Zhou, W. Wang, O. Khorev, Y. Zhang, Z. Miao, T. Meng and
J. Shen, Eur. J. Org. Chem., 2012, 28, 5585.
A. Shaabani, E. Soleimani and H. R. Khavasi, J. Comb. Chem.,
2008, 10, 443.
10 (a) D. S. Sharada, A. H. Shinde, S. M. Patel and S.
Vidyacharan, J. Org. Chem., 2016, 81, 6463. (b) A. H. Shinde,
N. Archith, S. M. patel and D. S. Sharada, Tetrahedron Lett.,
2014, 55, 6821. (c) A. H. Shinde, S. Vidyacharan and D. S.
Acknowledgements
We gratefully acknowledge Council of Scientific and
Industrial Research (CSIR), New Delhi, India and Indian
Institute of Technology Hyderabad (IITH) for financial support.
AS thank to CSIR, VNB and AHS thank to UGC, New Delhi,
India for the award of research fellowship.
Sharada, Org. Biomol. Chem., 2016, 14, 3207. (d) S.
Dhanasekaran, A. Suneja, V. Bisai and V. K. Singh, Org. Lett.,
2016, 18, 634 and references cited therein. (e) S. Milosevic
and A. Togni, J. Org. Chem., 2013, 78, 9638. (f) T. Hashimoto,
Y. Maeda, M. Omote, H. Nakatsu and K. Maruoka, J. Am.
Chem. Soc., 2010, 132, 4076. (g) I. Coldham, S. Jana, L.
Notes
Watson and N. G. Martin, Org. Biomol. Chem., 2009, 7, 1674.
11 (a) S. Vidyacharan, A. H. Shinde, B. Satpathi and D. S.
Sharada, Green Chem., 2014, 16, 1168. (b) A. H. Shinde, M.
Srilaxmi, B. Satpathi and D. S. Sharada, Tetrahedron Lett.,
2014, 55, 5915.
Corresponding Author
* E-mail: sharada@iith.ac.in
Author Contributions
12 (a) Z.-Q. Liu, Curr. Org. Synth., 2015, 12, 20. (b) N. Devi, R. K.
Rawal and V. Singh, Tetrahedron, 2015, 71, 183. (c) T. Kaur,
P. Wadhwa, S. Bagchi and A. Sharma, Chem. Commun., 2016,
52, 6958.
‡ AS, VNB and AHS contributed equally.
13 (a) A. El Akkaoui, M. A. Hiebel, A. Mouaddib, S. Berteina-
Raboin and G. Guillaumet, Tetrahedron, 2012, 68, 9131. (b)
Z. Tber, M. A. Hiebel, A. El Hakmaoui, M. Akssira, G.
References
1
(a) C. Philip, B. Page, B. R. Buckley, H. Heaney and A. J.
Blacker, Org. Lett., 2005, , 375. (b) Y. Nishiyama, M.
Moriyasu, M. Ichimaru, K. Iwasa, A. Kato, S. G. Mathenge, P.
B. Chalo Mutiso and F. D. Juma, Phytochemistry, 2004, 65
Guillaumet and S. Berteina-Raboin, J. Org. Chem., 2015, 80
6564.
,
7
14 (a) C.-L. Sun and Z.-J. Shi, Chem. Rev., 2014, 114, 9219. (b) X.
Xiao, Y. Xie, S. Bai, Y. Deng, H. Jiang and W. Zeng, Org. Lett.,
2015, 17, 3998. (c) T. Kaicharla, M. Thangaraj and A. T. Biju,
Org. Lett., 2014, 16, 1728.
,
939. (c) E. Badarau, S. Dilly, F. Dufour, S. Poncin, V. Seutinand
and J. F. Lie´geois, Bioorg. Med. Chem. Lett., 2011, 21, 6756.
(d) T. Tanahashi, Y. Su, N. Nagakura and H. Nayeshiro, Chem.
Pharm. Bull., 2000, 48, 370. (e) F. Durola, J. P. Sauvage and
15 P. T. Anastas, J. C. Warner, Green Chemistry: Theory and
Practice, Oxford University Press, Oxford, 1998
16 (a) A. Loupy and L. N. Thach, Synth. Commun., 1993, 23
.
O. S. Wenger, Chem. Commun., 2006,
2, 171. (f) S.
,
Möcklinghoff, W. V. Otterlo, R. Rose, S. Fuchs, T.
Zimmermann, M. D. Seoane, H. Waldmann, C. Ottmann and
L. Brunsveld, J. Med. Chem., 2011, 54, 2005. (g) J. D. Winkler,
T. Allyn, L. Mark and T. Hamann, Org. Lett., 2007,
A. Padwa and H. Zhang., J. Org. Chem., 2007, 72, 2570.
2571. (b) A. Sarkar, S. Santra, S. K. Kundu, A. Hajra, V. Z.
Grigory, N. C. Oleg, N. C. Valery and A. Majee, Green Chem.,
2016, DOI: 10.1039/C6GC01279E.
9, 4467. (h)
17 (a) S. Vidyacharan, A. Sagar, N. C. Chaitra and D. S. Sharada,
RSC Adv., 2014,
S. Sharada, RSC Adv., 2014,
and D. S. Sharada, RSC Adv., 2015,
4
, 34232. (b) A. Sagar, S. Vidyacharan and D.
, 37047. (c) A. Sagar, V. N. Babu
, 29066.
2
(a) J. Brioche, J.; C. Meyer and J. Cossy, Org. Lett., 2015, 17
2800. (b) G. T. Tan, M. John, A. D. Kinghorn and S. H. Hughes,
J. Nat. Prod., 1991, 54, 143.
,
4
5
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 5 of 5
View Article Online
DOI: 10.1039/C6OB02089E
Journal Name
ARTICLE
18 (a) Z. Lin, M. Koch, M. H. A. Aziz, R. Galindo-Murillo, M. D.
Tianero, T. E. Cheatham, L. R. Barrows, C. A. Reilly and E. W.
Schmidt, Org. Lett., 2014, 16, 4774. (b) N. T. Patil, V. S.
Shinde and B. Sridhar, Angew. Chem., Int. Ed., 2013, 52
2251.
,
19 (a) G. K. M. Verzijl, A. H. M. D. Vries, J. G. D. Vries, P. Kapitan,
T. Dax, M. Helms, Z. Nazir, W. Skranc, C. Imboden, J. Stichler,
R. A. Ward, S. Abele and L. Lefort, Org. Process Res.
Dev., 2013, 17, 1531. (b) M. Sera, M. Yamashita, Y. Ono, T.
Tabata, E. Muto, T. Ouchi and H. Tawada, Org. Process Res.
Dev., 2014, 18, 446.
20 When we performed the reaction of 2-(2-bromoethyl)-
benzaldehyde (1a) with aniline at 80 oC afforded the
product 2-phenyl-3,4-dihydroisoquinolin-2-ium
bromide
salt, which was characterised by the NMR spectroscopy,
thus supporting the proposed mechanism.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
Please do not adjust margins