Iodine-Catalyzed Metal-Free Oxidative Ring Opening of 1-Aryltetrahydro-β-carbolines: Facile Synthesis of C-2 Aroyl and Aryl Methanimino Indole Derivatives

Article abstract of DOI:10.1002/ejoc.201800879

Indole derivatives bearing C-2 substituents have garnered a lot of attention due to their diverse biological activities. Various methods forthe synthesis of these compounds have been reported. Inspired by the hydrolysis of imines, an oxidative ring-opening reaction of 1-aryltetrahydro-β-carbolines with catalytic iodine in aqueous hydrogen peroxide, and also in the presence of appropriate amines, is described for the generation of 2-aroyl and arylmethanimine indole derivatives. The reaction proceeds under mild reaction conditions with ethanol as the solvent or under solvent-free conditions, respectively. This metal-free strategy facilitates the formation of the desired substituted C-2 indoles in moderate to excellent yields. The utility of this reaction is demonstrated by a facile multigram-scale synthesis of Luzindole, a selective melatonin receptor antagonist and an investigational drug against depression and disruption of the circadian rhythm.

Full text of DOI:10.1002/ejoc.201800879

A Journal of
Accepted Article
Title: An iodine catalyzed metal free oxidative ring opening of 1-
aryltetrahydro-ꢀ-carbolines: Facile synthesis of C2 aroyl and aryl
methanimino indole derivatives
Authors: Subhabrata Sen, Jyoti Chauhan, and Tania Luthra
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800879
Link to VoR: http://dx.doi.org/10.1002/ejoc.201800879
Supported by

10.1002/ejoc.201800879
European Journal of Organic Chemistry
An iodine catalyzed metal free oxidative ring opening of 1-aryltetrahydro--carbolines:
Facile synthesis of C2 aroyl and aryl methanimino indole derivatives
Jyoti Chauhan,‡ Tania Luthra,‡ and Subhabrata Sen*
Department of Chemistry, School of Natural Sciences, Shiv Nadar University,
Chithera, Dadri, Gautam Budh Nagar, Uttar Pradesh 201314, India
subhabrata.sen@snu.edu.in
‡ Equal contributors
Table of content graphic
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800879
European Journal of Organic Chemistry
Abstract
C2 substituted indole compounds have garnered a lot of attention due to their diverse biological
activities. Various methods have been reported to access these compounds. Inspired from
hydrolysis of imines, an oxidative ring opening reaction of 1-aryltetrahydro--carboline with
catalytic iodine in aqueous hydrogen peroxide and also in presence of appropriate amines has been
reported for the generation of 2-aroyl and arylmethanimine indole derivatives under mild reaction
condition with ethanol as the solvent and under solvent free conditions respectively. This metal
free strategy facilitates the formation of the desired substituted C2 indoles in moderate to excellent
yield. The utility of this reaction is demonstrated by a facile multigram scale synthesis of
Luzindole, a selective melatonin receptor antagonist and an investigational drug against depression
and circadian rhythm.
Introduction
By virtue of their presence in plethora of diverse natural products and biologically active
compounds, C2 functionalized indole derivatives occupy a niche position in synthetic organic and
medicinal chemistry.[1] Among them C2 aroyl and amino methyl compounds are extremely
significant. Precisely, C2 aroyl moieties are available as calmadulin-dependent protein kinase II
(CAMKII) receptors, 1, histone deacetylase receptors 2, antagonists for tubulin polymerization
3/4, cyclooxygenase-2 (COX-2) receptors, indoleamine-2, 3-dioxygenase (IDO) receptors 5,
platelet derived growth factor (PDGF) kinase receptors and agonists for peroxisome proliferator-
activated receptors (PPAR) (Figure 1).[2-7] They can also be envisioned as a suitable precursor for
the synthesis of Luzindole 7, a selective inhibitor of melatonin receptors MT1 over MT2 and is an
investigational drug for anti-depression and disruption of circadian rhythm (Figure 1).[8]
Additionally the C2-arylmethanimine analogs of indoles can be conceived as precursors for C2-
aminomethyl indoles a key motif that exists in several biologically active compounds, including
calindol 6, a Ca2+ sensing receptor and various melatonin receptor antagonists.[9-11]
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800879
European Journal of Organic Chemistry
Figure 1. Representative biologically active 2-aroyl or benzyl derivatives
Despite being an important building block, there are fewer available strategies to access 2-aroyl
and 2-arylmethanimine indoles. The available methods include a combination of visible light
(photoredox) and palladium (II) catalyzed dehydrogenative C2 aroylation of indoles at room
temperature, n-butyl lithium mediated C2-aroylation of N-phenylsulfonyl indole with aroyl
chlorides and N-bromosuccinimide (NBS) promoted oxidative ring opening of 1-aryltetrahydro-
-carbolines in presence of water and acetic acid in tetrahydrofuran (THF).[5], [12-13] It is noteworthy
that these process involve toxic metal catalysts, environmentally harmful solvents and harsh
conditions (such as strong bases) which evidently, provides opportunity for the development of a
practical and mild approach for 2-aroylation and arylmethanimination of indole derivatives. And
if such indole derivatives are based on tryptamines then it further augments the utility of the
protocol, as natural products and drug candidates gleaned from tryptamines are important for their
biological efficacy and activity.[14-17]
Results and discussion
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800879
European Journal of Organic Chemistry
To generate an efficient strategy for the C2 aroylation and arylmethanamination of indoles we
envisioned a catalytic oxidative ring opening of C1-substituted tetrahydro--carbolines to
functionalize the C2-H of the indole. We took a cue from the acid catalyzed hydrolysis of diaryl
imines (Scheme 1) and realized that a transient imine formation at C1-N bond of the 1-
aryltetrahydro--carbolines could facilitate a ring opening of the substrate in presence of an
appropriate aqueous source (Scheme 1a). Realizing iodine’s rich heritage as a green catalyst and
an alternative to transition metals in organic synthesis we envisaged that catalytic molecular iodine
in the presence of an appropriate terminal oxidant and water/amine could facilitate a ring cleavage
on 1-aryltetrahydro--carbolines which could afford our desired products (Scheme 1b).[18]
Scheme 1. The concept of our C2 aroylation or aminomethylation of indole derivatives
For the optimization of C2 aroylation reaction we began with molecular iodine as catalyst and
aqueous hydrogen peroxide as the oxidant. The table below (Table 1), depicts the reaction
condition for oxidative ring opening of the 1-(4-chlorophenyl)-N-carbomethoxytetrahydro--
carboline, 7a as the model substrate (synthesized from 6a) in dimethyl sulfoxide (DMSO) as the
solvent. The desired aroyl indole 8a was obtained in poor yield of 12% with 0.1 equiv of molecular
iodine and two equiv of aq. hydrogen peroxide (aq. H2O2) as the oxidant at 40 °C (entry 1).
Changing the solvent to methanol, dimethyl formamide or isopropanol, could not improve the
yield (entry 2-4). However, by increasing the amount of the molecular iodine to 0.3 equiv in
DMSO improved the yield of 8a to 25% (entry 5). Interestingly, changing the solvent to
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800879
European Journal of Organic Chemistry
acetonitrile and then to tetrahydrofuran improved the yields further to 40 and 65% respectively
(entry 6 and 7). Conducting the reaction at higher temperature viz. 70 and 90 °C proved detrimental
as it increased the formation of byproducts. Finally, we were extremely gratified to obtain 8a in
~82% yield when the reaction was conducted with 0.3 equiv of molecular iodine, 2 equiv of aq.
H2O2 in ethanol as the solvent at 40 °C (entry 10) for 6h.
Table 1. Optimization of reaction condition
Solventb
DMSO
MeOH
DMF
IPA
Yield (%)a
Entry Temperature (T °C) Catalyst equivalent
Time (h)
1
2
40
0.1
16
12
8
̎
̎
̎
3
̎
̎
̎
10
4
4
̎
̎
̎
5
̎
0.3
DMSO
ACN
THF
̎
10
25
42
65
37
21
82
6
̎
̎
̎
̎
̎
̎
7
7
̎
̎
8
70
90
40
16
9
̎
̎
10
EtOH
6
[a] Isolated yield (reaction scale 50mg); [b] DMSO: Dimethyl sulfoxide; MeOH: Methanol; DMF:
Dimethyl formamide; IPA: Isopropanol; ACN: Acetonitrile; THF: Tetrahydrofuran; EtOH:
Ethanol.
Scheme 2 depicts the scope and limitation of the oxidative ring opening reaction of 1-aryl-N-
carbomethoxytetrahydro--carbolines 7a-l and N-acetyl-1-aryltetrahydro--carbolines 7m-r
under the optimized reaction condition. The substrates 7a-l and m-r where obtained by protecting
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800879
European Journal of Organic Chemistry
tetrahydro--carbolines, 6a-l which in-turn were synthesized via Pictet-Spengler reaction of
tryptamine and its derivatives with appropriate aldehydes (Experimental).[19-21] The substrates 7a-
r obtained from the reactions were clean enough to be taken forward without any purification.
Molecular iodine catalyzed ring opening of 7a-r in presence of hydrogen peroxide, afforded the
corresponding C2-aroyl indole products 8a-r in moderate to excellent yields (62-88%), irrespective
of the presence of electron withdrawing or electron donating groups on the C1 aryl moiety of the
tetrahydro--carbolines and N-acetyl or carbomethoxy functionalities on the carboline nitrogen
(Scheme 2). The reaction condition was also amenable to promote C2-aroylation with aliphatic
7p/r and heteroaromatic 7q substituted tetrahydro--carbolines to afford the desired compounds
8p-r in excellent yield. This is perhaps one of the very few examples where C2 position of the
indoles are functionalized under metal free catalytic condition. The final compounds were purified
by flash column chromatography and were characterized by nuclear magnetic resonance
spectroscopy (1H and 13C) and high resolution mass spectroscopy. The structure of these C2-
arolylated indole derivatives were confirmed by singly crystal X-ray of compound 8a (Scheme 2).
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800879
European Journal of Organic Chemistry
Scheme 2. Demonstration of the generic nature of molecular iodine catalyzed, aq. H2O2
mediated oxidative ring opening of 1-aryltetrahydro--carbolines
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800879
European Journal of Organic Chemistry
Several control experiments were conducted to propose a putative reaction mechanism for this
transformation. It is reported that 1-aryltetrahydro--carbolines underwent oxidative ring opening
to provide C2 aroylated indole derivatives with stoichiometric quantity of NBS, in water, acetic
acid and tetrahydrofuran.[13] Taking a cue from this, performing the reaction with 1 equiv of
molecular iodine in the absence of aq. H2O2 in ethanol yielded compound 8a in ~ 10% yield and
80% unreacted 7a (Scheme 3, eq. 1). This indicated the possibility that the oxidative ring opening
of the tetrahydro--carbolines required both iodine and hydrogen peroxide. It is also well
documented in the literature that iodine catalyzed oxidations are facilitated by aq. H2O2, where
few of the examples suggested that hypoiodous acid (HOI) can be considered as an active
species.[22] Interestingly, treatment of 7a with one equiv of sodium iodide, aq. H2O2 in
trifluoroacetic acid medium (which is known to generate either HOI or its protonated version) [23]
facilitated the oxidative ring opening to afford the desired product 8a in 52% yield (Scheme 3, eq.
2). Additionally, in a bid to assess any involvement of radical in the reaction, it was conducted in
the presence of the radical inhibitor BHT (3, 5-di-tert-4-butylhydroxytoluene), which barely had
any effect on the rate of the reaction (Scheme 3, eq. 3).
Scheme 3. Control experiments to decipher the reaction mechanism
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800879
European Journal of Organic Chemistry
Based on the observation from the control experiments and literature, Scheme 4 depicts the
putative reaction mechanism for the oxidative ring opening of 1-aryltetrahydro--carbolines, We
believe the secondary amine of the 1-aryltetrahydro--carboline 7a is oxidized to the
corresponding iminium ion A by HOI (generated by the reaction of molecular iodine and aq.
hydrogen peroxide). A nucleophilic attack A at C1 with water (as nucleophile) generated B. Ring
cleavage of B, facilitated by keto formation at C1 leads to the formation of 8a. The hydrogen iodide
generated by the addition of water at A is reoxidized to HOI by hydrogen peroxide (Scheme 4).
Scheme 4. Putative reaction mechanism
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800879
European Journal of Organic Chemistry
To support the putative mechanism of oxidative ring opening, we performed density functional
theory calculations to rationalize the conversion of intermediate B into 8a. All calculations were
executed in gas phase calculations based on their ab initio and crystal (Fig. 2) geometries,
respectively, using Gaussian 09, revision D.01. [24-26] Both molecules were optimized (Fig 2) using
density functional theory method and with B3LYP exchange correlation functional.[29] The basis
set used was 6-311G (d, p). The corresponding change in molecular energies between the
intermediate B and the product 8a was estimated to be of -13.54 kcal/mol, with product 8a at lower
energy (Figure 2). This suggested that 8a is energetically more stable than B, thereby facilitating
the oxidative ring opening reaction.
Figure 2. Optimized molecular structure of the proposed intermediates and the crystal structure
of 8a
In a bid to demonstrate the synthetic utility of our protocol we synthesized Luzindole, a drug used
in investigating the function of melatonin in the body. It has nearly 15 fold more binding affinity
for MT2 receptor over MT1 and in in vivo study it has demonstrated that it interferes the circadian
rhythm and also exhibit anti-depressant effect.[27] Accordingly, 2 gm of 8o was reduced at 0 ºC in
ethanol and the crude intermediate was then treated with triethyl silane in presence of
trifluoroacetic acid from 0 °C to r.t., to afford the crude Luzindole, 9 which was purified through
column chromatography, to provide the desired product in 76% yield over two steps (Scheme 5).
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800879
European Journal of Organic Chemistry
Scheme 5. Synthesis of Luzindole 10a
To extend the utility of our strategy next we focused on demonstrating the generation of C2-
arylmethanimine indole through our procedure, by incorporating appropriate amines in the
reaction mixture. These arylmethanimine indoles can be suitable precursor for accessing
aminomethyl indoles which have myriad biological activities.[28] Accordingly, carboline 7a was
treated with molecular iodine (0.3 equiv) and aqueous hydrogen peroxide in methyl amine as
solvent at 40 C. The desired 2-(4-chlorophenylmethanimine)indole 10a was obtained in 56%
yield (Scheme 6). To assess the robustness of the protocol carbolines 7b, g-i and p-s were treated
with ethyl and methyl amines under the optimized reaction conditions to afford the final
compounds 10b-i in decent yields (Scheme 6). Similar to C2-aroyl derivatives, the protocol was
equally amenable for accessing C2-arylmethanamine indoles with aromatic moieties encrusted
with electron withdrawing and electron donating functionalities 10b-h and heteroaromatic analog
10i. It was noteworthy that the reaction with ethyl amine was generally poor yielding compared to
the methyl analog. We assume the nucleophilic nature of the amines plays an important role in the
formation of the final compound as depicted in the mechanism for the formation of C2-aroyl
derivatives in Scheme 3. The structure of these compounds were confirmed by the representative
single crystal X-ray of 10h (Scheme 6).
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800879
European Journal of Organic Chemistry
Scheme 6. Synthesis of C2 arylalkanimine indoles
Conclusions
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800879
European Journal of Organic Chemistry
In conclusion we report an efficient protocol for the synthesis of C2-aroyl and arylmethanimine
indole derivatives via iodine catalyzed oxidative ring opening of 1-aryltetrahydro--carboline.
This C2 functionalization strategy is environmentally benign as it utilizes catalytic molecular
iodine with aq. H2O2 and methyl/ethylamine in ethanol (a class III) solvent. Diverse analogs with
variety of functionalities include aromatic, heteroaromatic and aliphatic moiety at C1 position of
the tetrahydro--carbolines were converted to the desired products 8a-r and 10a-h. The synthetic
applicability of the strategy was demonstrated by the multigram synthesis of Luzindole (5 mg
@150 USD in Aldrich). This unique strategy inspired from imine hydrolysis provides access to
diversely C2-functionalized indoles bioactive scaffolds from 1-aryltetrahydro--carbolines and can
be successfully applied in accessing Luzindole an investigational drug molecule which could cure
millions of people globally suffering from depression and sleep disorder.
Acknowledgments
This work was supported by Shiv Nadar University
Notes and References
1. a) D. S. Wenholz, M. Zeng, C. Ma, M. Mielczarek, X. Yang, M. Bhadbhade, D. S. Black,
P. J. Lewis, R. Griffith, N. Kumar, Bioorg. Medchem. Lett. 2017, 27, 4302. b) N. D. Franz,
J. M. Belardinelli, M. A. Kaminski, L. C. Dunn, V. C. N. de Moura, M. A. Blaha, D. D.
Truong, W. Li, M. Jackson, E. J. North, Bioorg. Medchem. Lett. 2017, 25, 3746. c) M.
Arthius, R. Pontikis, G. C. Chabot, L. Quentin, D. Scherman, J-C. Florent, Eur. J. Med.
Chem. 2011, 46, 95. d) P-C. Diao, Q. Li, M-J. Hu, Y-F. Ma, W-W. You, K. H. Hong, P-L.
Zhao, Eur. J. Med. Chem. 2011, 46, 95. e) Y. Oh, S. H. Han, N. K. Mishra, U. De, J. Lee,
H. S. Kim, Y. H. Jung, I. S. Kim, Eur. J. Org. Chem., 2017, doi:10.1002/ejoc.201701001.
2. T. Beckers, T. Reissmann, M. Schmidt, A. M. Burger, H. H. Fiebig, U. Vanhoefer, H.
Pongratz, H. Hufsky, J. Hockemeyer, M. Frieser, S. Mahboobi, Cancer Res. 2002, 62,
3113.
3. O. Cruz-López, J. J. Díaz-Mochón, J. M. Campos, A. Entrena, M. T. Núñez, L. Labeaga,
A. Orjales, M. A. Gallo, A. Espinosa, ChemMedChem, 2007, 2, 88.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800879
European Journal of Organic Chemistry
4. E. Dolusić, P. Larrieu, S. Blanc, F. Sapunaric, J. Pouyez, L. Moineaux, D. Colette, V.
Stroobant, L. Pilotte, D. Colau, T. Ferain, G. Fraser, M. Galleni, J. Frère, B. Masereel, B.
V. Eynde, J. Wouters and R. Frédérick, Eur. J. Med. Chem., 2011, 46, 3058.
5. (a) M. Komiya, S. Asano, N. Koike, E. Koga, J. Igarashi, S. Nakatani, Y. Isobe, Bioorg.
Med. Chem. 2012, 20, 6840. (b) H. Wang, A. Ganesan, J. Org. Chem. 2000, 65, 4685.
6. S. Mahboobi, S. Teller, H. Pongratz, H. Hufsky, A. Sellmer, A. Botzki, A. Uecker, T.
Beckers, S. Baasner, C. Schächtele, F. Uberall, M. U. Kassack, S. Dove and F. D. Böhmer,
J. Med. Chem., 2002, 45, 1002.
7. T. M. Willson, P. J. Brown, D. D. Sternbach, B. R. Henke, J. Med. Chem., 2000, 43, 527.
8. D. P. Zlotos, M. I. Attia, J. Julius, S. Sethi, P. A. Witt-Enderby, J. Med. Chem. 2009, 52,
826.
9. J. A. Morón, M. Campillo, V. Perez, M. Unzeta, L. Pardo, J. Med. Chem. 2000, 43, 1684.
10. G. Spadoni, C. Balsamini, G. Diamantini, A. Tontini, G. Tarzia, J. Med. Chem. 2001, 44,
2900 – 2912.
11. a) S. Rivara, M. Mor, C. Silva, V. Zuliani, F. Vacondio, G. Spadoni, A. Bedini, G. Tarzia,
V. Lucini, M. Pannacci, F. Fraschini, P. V. Plazzi, J. Med. Chem. 2003, 46, 1429 – 1439;
b) K. Ray, J. Tisdale, R. H. Dodd, P. Dauban, M. Ruat, J. K. Northup, J. Biol. Chem. 2005,
280, 37013 – 37020.
12. M. K. Manna, G. Bairy, R. Jana, Org. Biomol. Chem. 2017, 15, 5899.
13. T. N. Van, P. Claes, N. De Kimpe, Synlett, 2013, 24, 1006.
14. a) J. B. Hendrickson, in: R. H. F. Manske, H. L. Holmes (Eds.), The Alkaloids, vol. 6,
Academic Press, New York, 1960, p. 179. b) N. Neuss, in: J.D. Philipson, M.H. Zenk
(Eds.), Indole and Biogenetically Related Alkaloids, Academic Press, London, 1980, p.
293.
15. J. M. Müller, E. Schlittler, H. J. Bein, Experientia 1952, 8, 338. d) R. van der Heijden, D.
I. Jacobs , W. Snoeijer, D. Hallard, R. Verpoorte., Curr. Med. Chem. 2004, 11, 607.
16. N. Neuss, M. Gorman, W. Hargrove, N. J. Cone, K. Biemann, G. Buchi, R. E. Manning, J.
Am. Chem. Soc. 1964, 86, 1440.
17. T.W. Southin, J. Buckingham, Dictionary of Alkaloids, vol. 3, Chapman & Hall, London,
1979.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800879
European Journal of Organic Chemistry
18. (a) V. V. Zhdankin, Hypervalent Iodine Chemistry: Preparation, Structure and Synthetic
Applications of Polyvalent Iodine Compounds, Wiley, Chichester, UK, 2003. b) M.
Yusubov, V. V. Zhdankin, Curr. Org. Synth. 2012, 9, 247. c) M. S. Yusubov, V. V.
Zhdankin, Mendeleev Commun. 2010, 20, 185.
19. M. Muthukrishnan, S. V. More, D. R. Ganesh, C. V. Ramana, R. R. Joshi, R. A. Joshi, J.
Heterocyclic Chem. 2006, 43, 767.
20. A. Spindler, K. Stefan, M. Wiese, J. Med. Chem. 2016, 59, 6121.
21. J. Chauhan, T. Luthra, R. Gundla, A. Ferraro, U. Holzgrabe, S. Sen, Org. Biomol. Chem.
2017, 15, 9108.
22. (a) J. Pavlinac, M. Zupan, S. Stavber, Org. Biomol. Chem. 2007, 5, 699. (b) J. Pavlinac,
M. Zupan, S. Stavber, J. Org. Chem. 2006, 71, 1027. (c) J. Pavlinac, M. Zupan, S. Stavber,
Synthesis 2006, 2603. (d) M. Jereb, M. Zupan, S. Stavber, Chem. Commun. 2004, 5, 2614.
(e) K. Omura, J. Org. Chem. 1996, 61, 2006. (f) H. Ohta, T. Motoyama, T. Ura, Y. Ishii,
M. Ogawa, J. Org. Chem. 1989, 54, 1668. (g) I. Lengyel, I. R. Epstein, K. Kustin, Inorg.
Chem. 1993, 32, 5880. (h) I. Barnes, K. H. Bedker, J. Starcke, Chem. Phys. Lett. 1992, 196,
578. (i) J. Paquette, B. L. Ford, Can. J. Chem. 1985, 63, 2444.
23. J. Barluenga, M. Marco-Arias, F. Gonzalez-Bobes, A. Ballesteros, J. M. Gonzalez, Chem.
Commun. 2004, 2616. (b) J. Barluenga, M. Marco-Arias, F. Gonzalez-Bobes, A.
Ballesteros, J. M. Gonzalez, Chem. Eur. J. 2004, 10, 1677.
24. M.J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman,
G. Scalmani, V. Barone, B. Mennucci, G. A. Petersson, H. Nakatsuji, M. Caricato, X. Li,
H.P. Hratchian, A. F. Izmaylov, J. Bloino, G. Zheng, J. L. Sonnenberg, M. Hada, M. Ehara,
K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai,
T. Vreven, J.A. Montgomery, Jr., J. E. Peralta, F. Ogliaro, M. Bearpark, J.J. Heyd, E.
Brothers, K.N. Kudin, V. N. Staroverov, R. Kobayashi, J. Normand, K. Raghavachari, A.
Rendell, J. C. Burant, S. S. Iyengar, J. Tomasi, M. Cossi, N. Rega, J. M. Millam, M. Klene,
J. E. Knox, J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R. E. Stratmann,
O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli, J.W. Ochterski, R.L. Martin, K.
Morokuma, V.G. Zakrzewski, G.A. Voth, P. Salvador, J. J. Dannenberg, S. Dapprich, A.
D. Daniels, Ö. Farkas, J. B. Foresman, J. V. Ortiz, J. Cioslowski, and D. J. Fox, Gaussian,
Inc.: Wallingford CT, USA; 2009.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800879
European Journal of Organic Chemistry
25. (a) A. D. Becke Phys Rev A. 1988, 38, 3098; (b) P. J. Stephens, F. J. Devlin, C. F.
Chabalowski, M. J. Frisch, J. Phys Chem. 1994, 98, 11623; (c) C. Lee, W. Yang, R. G.
Parr, Phys Rev B. 1988, 37, 785.
26. (a) A. C. Neto, E. P. Muniz, R. Centoducatte, F. E. Jorge J. Mol. Struct. (Theochem). 2005,
718, 219; (b) G. C. Camiletti, S. F. Machado, F. E. Jorge. J. Comp. Chem. 2008, 29, 2434;
(c) C. L. Barros, P. J. P. De Oliveira, F. E. Jorge, A. C. Neto, M. Campos, Mol. Phys. 1965,
2010, 108; (d) R. C. De Berredo, F. E. Jorge, J. Mol. Struct (Theochem). 2010, 961, 107;
(e) A. C. Neto, F. E. Jorge, Chem. Phys. Lett. 2013, 582, 158.
27. a) D. Heckman, M. I. Attia, M. A. M. Behnam, A. M. Y. Mohsen, C. Markl, J. Julius, S.
Sethi, P. A. Witt-Enderby, D. P. Zlotos, Med. Chem. Comm. 2011, 2, 991. b) D. P. Zlotos,
R. Jockers, E. Cecon, S. Rivara, P. A. Witt-Enderby, J. Med. Chem. 2014, 57, 3161.
28. a) A. O. Stewart, M. D. Cowart, R. B. Moreland, S. P. Latshaw, M. A. Matulenko, P. A.
Bhatia, X. Wang, J. F. Daanen, S. L. Nelson, M. A. Terranova, M. T. Namovic, D. L.
Donnelly-Roberts, L. N. Miller, M. Nakane, J. P. Sullivan, J. D. Brioni, J. Med. Chem.
2004, 47, 2348; b) A. Kessler, H. Faure, C. Petrel, M. Ruat, P. Dauban, R. J. Dodd, Bioorg.
Med. Chem. Lett. 2004, 14, 3345; c) C. Petrel, A. Kessler, P. Dauban, R. H. Dodd, D.
Rognan, M. Ruat, J. Biol. Chem. 2004, 279, 18990.
29. a) A.D. Becke, 1993, J. Chem. Phys. 98, 5648; b) C. Lee, W. Yang, R.G. Parr, Phys. Rev.
B 1988, 3, 785.
This article is protected by copyright. All rights reserved.