Mild, rapid and efficient metal-free synthesis of 2-aryl-4-aryloxyquinolines via direct Csp2[sbnd]O bond formation by using diaryliodonium salts

Article abstract of DOI:10.1016/j.tetlet.2016.11.093

An efficient ligand- and transition metal-free procedure for the direct C_sp²[sbnd]O bond formation for the arylation of 2-aryl-4-quinolones was developed. The synthesis of the starting quinolones was carried out under our optimized C

Full text of DOI:10.1016/j.tetlet.2016.11.093

Accepted Manuscript
Mild, Rapid and Efficient Metal-Free Synthesis of 2-Aryl-4-aryloxyquinolines
via Direct Csp 2-O Bond Formation by Using Diaryliodonium Salts
Pradip D. Nahide, César R. Solorio-Alvarado
PII:
S0040-4039(16)31575-1
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.11.093
TETL 48379
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
18 October 2016
19 November 2016
21 November 2016
Please cite this article as: Nahide, P.D., Solorio-Alvarado, C.R., Mild, Rapid and Efficient Metal-Free Synthesis of
2-Aryl-4-aryloxyquinolines via Direct Csp 2-O Bond Formation by Using Diaryliodonium Salts, Tetrahedron
Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.11.093
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Graphical Abstract
Mild, Rapid and Efficient Metal-Free
Synthesis of 2-Aryl-4-aryloxyquinolines via
2
Direct Csp -O Bond Formation by Using
Diaryliodonium Salts
Pradip D. Nahide and César R. Solorio-Alvarado*

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Mild, Rapid and Efficient Metal-Free Synthesis of 2-Aryl-4-aryloxyquinolines via
2
Direct Csp -O Bond Formation by Using Diaryliodonium Salts
Pradip D. Nahide and César R. Solorio-Alvarado ∗
Departamento de Química, División de Ciencias Naturales y Exactas, Campus Guanajuato, Universidad de Guanajuato. Cerro de la Venada S/N, 36040,
Guanajuato, Gto., México.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient ligand- and transition metal-free procedure for the direct Csp2-O bond formation for
the arylation of 2-aryl-4-quinolones was developed. The synthesis of the starting quinolones was
carried out under our optimized Cu-catalyzed C-N bond formation conditions between
2´-bromoacetophenone and benzamide derivatives followed by cyclization. Easily prepared
diaryliodonium salts were used as aryl source. Highly functionalized 4-aryloxyquinolines were
obtained in a mild and operationally simple protocol, which involves conventional heating and
short periods of time. The method shows good to excellent yields and broad toleration of
functional groups like fluorine or trifluoromethyl, which are important in medicinal chemistry.
The Csp2-O bond formation process herein described for the quinolone functionalization offers
an excellent non-toxic alternative to the transition metal-catalyzed reactions that not only can
potentially contaminate the final compounds but also can be enviromental pollutants.
Available online
Keywords:
2-Aryl-4-aryloxyquinolines
Iodonium salts
Direct Csp2-O bond formation
Ligand- and Metal-Free reactions
Non-toxic reactions
2009 Elsevier Ltd. All rights reserved.
The quinoline nucleus is an important fragment for the human
life.1 Relevant biological activities like antimalarial,2
antibacterial,3 antiparasitary,4 antifungal,5 antiinflammatory,6
analgesic,7 cardiovascular8 and hypoglycemic9 among the most
important have been described. It is ubiquitous in nature and
usually sought after in medicinal chemistry10 and organometallic
chemistry11 among other relevant areas. Specifically 2-aryl-4-
aryloxy functionalized quinolines represent a tremendously
important core in clinical and medicinal research.12 Essentially,
the recent trends about the anti-diabetic,13 anti-cancer14 and anti-
viral15 investigation points towards a combined synthetic and
computational calculations strategy. In such a way is possible to
find easier a properly drug for a plausible treatment in the short-
or medium-term. In this sense, the 2-aryl-4-aryloxyquinoline
moiety has been widely used (Figure 1).
the change of carbonyl group for the corresponding chlorine or
fluorine. Afterwards, a direct nucleophilic aromatic substitution
with
a naphthol derivative in basic media affords the
incorporation of the desired C-O bond in the aryloxy group. This
approach is a two-step procedure.16
Described protocols for C-O bond formation in aryl derivatives,
usually imply the use of Cu-17 or Pd-catalyzed18 cross-coupling
reactions. These procedures commonly require costly ligands and
are often low yielding or not tolerant in presence of heterocyclic
groups. Additionally, they can contaminate the final compounds.
Recently hypervalent λ3-iodane19 derivatives have emerged as an
excellent alternative in transition metal-free reactions.
Specifically the Olofsson method20 for the C-O bond formation
by using diaryliodonium salts is efficient, mild and shows broad
toleration of functional groups, including heterocyclic systems.
In this regard during our quest towards the total synthesis of the
naturally occurring graveoline from Rutta sp., we needed the
methylation at 4-position in the 2-phenyl-4-quinolone. We
questioned ourselves about the use of some other groups like an
aryl to be attached in the oxygen of the quinolone for
synthesizing analogues of this natural compound. We found in
the diaryliodonium chemistry an excellent, direct and non-toxic
tool for this transformation. It is important to mention that during
the experimental course of our work, Karade21 and Kumar22
reported a closely related idea. Karade described the direct
arylation of 4-aryl-6-methyl-pyrimidine-2(1H)-one derivatives.
On the other hand Kumar prepared in one-pot procedure 2- and
4-aryloxyquinolines based on a microwave-assisted O-arylation
Figure 1. Representative anti-diabetic and anti-viral developed
drugs containing the 2-aryl-4-aryloxyquinoline structure.
Representative methods to synthesize 2-aryl-4-aryloxyquinolines
i—nv—olv—e the starting synthesis of 2-aryl-4-quinolones followed by
∗ Corresponding author. Tel.: +52-473-732-0006, ext 1418; e-mail: csolorio@ugto.mx

2
Tetrahedron
of quinolones. While various diaryliodonium salts were
The described conditions23 gave low to moderate yields (37-61%)
even changing the amount of ligand and copper (entries 1-3).
Keeping 20 mol% of copper iodide and 40 mol% of DMEDA but
increasing the equivalents of benzamide (1.5-2.5) gave rise to
significantly better yields (50-75%) (entries 4-6). Some other
ligands like o-phenathroline, trans-1,2-dicyclohexylamine and
different copper sources did not produce higher yields (entries 7-
11). The optimized conditions for this cross-coupling reaction are
described in entry 5. Even though entry 6 shows a slightly better
yield, this required a big amount of benzamide (See SI for full
details).
investigated in the preparation of 4-aryloxyquinolines, the
synthesis of 2-aryl-4-aryloxyquinolines was limited to one
example. In light of the importance of such framework in
bioactive compounds, we described herein an easy, mild and
efficient procedure for synthesizing in one pot 2-aryl-4-
aryloxyquinolines starting from the corresponding functionalized
4-quinolones by using conventional heating and non-symmetrical
iodonium salts.
We started with the synthesis of 2-aryl-4-quinolones via an one-
pot Buchwald procedure.23 However after several attempts we
could not reproduce the methodology, obtaining only poor yields
in the C-N coupling step (Scheme 1).
With the optimized conditions in hand, we were ready to prepare
the series of 2-aryl-4-quinolones (Table 2).
Table 2. Synthesis of 2-aryl-4-quinolones under optimized
conditions for the C-N coupling reaction.
Structure Entry 1a-k, %a
-R
-H
2a-k, %a
2a, 88
2b, 93
2c, 96
2d, 90
2e, 93
2f, 85
1
2
3
4
5
6
7
8
1a, 67
1b, 69
1c, 70
1d, 62
1e, 65
1f, 70
1g, 68
1h, 34
Scheme 1. Synthesis of 2-aryl-4-quinolones by using the Buchwald
procedure.
-Me
-OMe
-Cl
Then we decided to optimize this sequence starting with the C-N
coupling to develop a robust and general procedure (Table 1).
R
Table 1. Optimization of the C-N coupling to get
acetylphenylbenzamide 1a.
-F
-Cl
R
-CF3
-OMe
2g, 90
2h, 91
R
R
F
9
1i, 69
-Cl
2i, 93
Entry
PhCONH2
(equiv)
1.2
Cu
(mol%)
CuI (10)
L
Yield of 1
%
a,b
(mol%)
L1 (20)
1
2
37
10
1j, 72
3,5-F
2j, 87
1.2
1.2
1.5
2.0
2.5
2.0
2.0
2.0
2.0
2.0
CuI (20)
CuI (40)
L1 (40)
L1 (80)
L1 (40)
L1 (40)
L1 (40)
L3 (40)
L2 (40)
L1 (40)
L1 (40)
L3 (40)
61
F
3
45
O
4
CuI (20)
50
O
12
1k, 44
2k, 91
5
CuI (20)
67
a Isolated yields
6
CuI (20)
75
5c
< 5c
37c
60c
13c
Several 2-aryl-4-quinolones were synthesized in excellent yields
(87-96%) with different groups at the 2-aryl fragment. Thus,
electron-donor (entries 2-3, 8 and 12), electron-attractor (entries
4-7, and 9-10) as well as electron-neutral (entry 1) substituents
were incorporated. We considered important the former
optimization, which was carried out. This in the context to
describe a complete, robust and reproducible procedure for the
synthesis of highly functionalized 2-aryl-4-aryloxyquinolines
starting from simple and/or commercial starting materials.
7
CuI (20)
8
CuI (20)
9
CuBr (20)
Cu(OAc)2 (20)
Cu(OAc)2 (20)
10
11
a All of the reactions were carried out using benzamide (1.0 equiv), K2CO3 (2
equiv) in toluene (0.3 M).
At this point we were ready to test our hypothesis. Then it was
decided to optimize the direct O-arylation in 2c as model. The
use of acetonitrile and potssium tert-butoxide were the starting
conditions based upon previous reports24 (Table 3). Also fixed
the reaction temperature at 60 ºC was crucial to get shorter
reaction times. Usually overnight period was necessary to
complete the starting material at 40 ºC. In the initial screening it
was considered the use of hexafluorophosphate, triflate, chlorine
and nitrate iodonium salts maintaining 1.2 equiv of base (entries
b Isolated yields.
c The yields were determined using anisole as internal standard.
The table illustrates representative experiments. See SI for full details.

3
1-4). All entries yielded good results, highlighting triflate 72%
(entry 2) and nitrate 69% (entry 4) as the best anions.
Table 3. Optimization of the direct Csp2-O bond formation in
All of the reactions were carried out by using conventional
heating under very mild temperature conditions. Also very short
reaction times (20-30 min) were observed to complete the starting
material. Additionally good to excellent yields (77-92%) were
obtained after chromatography purification. This procedure
tolerates electron-neutral (3a), electron-rich (3b-d, 3j) and
electron-poor (3e-i) functional groups at the 2-aryl fragment of
the quinolone.
the metal-free one-pot synthesis of 4-aryloxiquinolines.
To complete the scope of the developed procedure, we decided to
test different iodonium salts25 with the 2-arylquinolones 2a-k
(Scheme 3).
Entry
tBuOK Equiv
XΘ (Equiv)
PF6 (1.2)
OTf (1.2)
Cl (1.2)
Yield %a
60
1
2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.5
Scheme 3. Scope at the iodonium salt for the direct C-O
arylation in 2-arylquinolones 2a-k.
72
3
65
4
NO3 (1.2)
OTf (1.5)
OTf (2.0)
NO3 (1.5)
NO3 (1.8)
NO3 (2.0)
NO3 (2.0)
69
5
77
6
80
7
72
8
76
9
78
85b
10
a Isolated yields. b Complicate chromatographic purification.
Then, we focused our attention to optimize the reaction using
these two salts. On the treatment with 1.2-1.5 equiv of triflate salt
the yield increases from 77% until 80% (entries 5 and 6).
Regarding to the nitrate, a slightly bigger amount of salt (1.5-2
equiv) was necessary. Thus with 1.5 equiv, 72% of yield was
observed (entry 7), and with 1.8 and 2.0 equiv (entries 8 and 9)
76% and 78%, respectively, were obtained. Finally, in the
increase to 1.5 equiv of base, we found an excellent 85% of yield.
In this way, the entries 6 and 10 were the best conditions and
they validated our hypothesis. With optimal conditions for the
direct Csp2-O bond formation, the scope in the 1,4-quinolone was
explored with 2a-k as starting materials (Scheme 2).
a
b
Iodonium salt 4 was used. Iodonium salt 5 was used. Reaction times in
brackets.
Scheme 2. Scope at the 2-arylquinolone for the direct C-O
arylation by using iodonium salts.
Iodonium salts 4-7 were synthesized and used. As shown for the
phenyl group (Scheme 2), p-nitrophenyl, p-trifluorophenyl and
2-bromophenyl groups were transfered directly to electron-
neutral (3k, 83%), electron-rich (3l, 77%) and electron-poor (3m-
3l, 65-83%) 2-aryl-4-quinolones (Scheme 3). The yields of the 4-
aryloxyquinolines obtained were moderate to good. In this part, it
is of crucial importance to mention three points: 1) The
procedure in general is totally regioselective, since only O-
arylation was observed at least by the NMR detection limit. 2)
The protocol is totally chemoselective the electron-poor aryl is
exclusively transfered. This result was in the same for all of the
examples (Scheme 3) and is in agreement with the DiMagno26,27
observation. Additionally, our procedure avoids the use of
symmetrical iodonium salts, which is an strong limitation in
previous reports.22 This implies the use of pre-functionalized
substrates to access into this class of symmetric salts and is
wasted the half of such functionalized molecule in the reaction
process. 3) The procedure tolerates important substituents like
chlorine, fluorine or trifluoromethyl which are relevant in
medicinal chemistry. In fact, we focused on the application of the
developed procedure to the synthesis of these potentially
biological active of derivatives.
a
t
b
t
Ph2INO3 (2 equiv), BuOK (1.5 equiv). Ph2IOTf (2 equiv), BuOK (1.2
equiv). Reaction times in brackets.
In order to test the application of the synthesized compounds by
our procedure, we decide to carry out the following short

4
Tetrahedron
sequence of reactions to prepare the iodinated quinoline 3l as
Acknowledgments
potential starting building block in different organic reactions
(Scheme 4).
We gratefully thank to CONACyT (CB-2013/220836),
FOMIX (CONACyT-CONCyTEG GTO-2012-C03-194610) for
financial support. We acknowledge the facilities from the
DCNyE, Chemistry Department, the National Laboratory UG-
CONACyT (LACAPFEM) in Guanajuato University for full
characterization. We thank to CONACyT for the fellowship to P.
D. Nahide.
Scheme 4. Application of the developed procedure to the
synthesis of quinoline 3u.
References and notes
1. Angali,; Pathak, D.; Singh, D. IJPSR, 2016, 7, 1-13.
2. a) Containing ferrocenyl group: Chibale, K.; Moss, J. R.; Blackie,
M.; Schalkwyk, D.; Smith, P. J. Tetrahedron Lett. 2000, 41,6231-
6235. b) Containing tiourea moiety: Mahajan, A.; Yeh, S.; Nell,
M.; Rensburg, C. E. J.; Chible, K. Bioorg. Med. Chem. Lett. 2007,
17, 5683-5685. c) Huo, Z.; Gridnev, I. D.; Yammamoto, Y. J.
Org. Chem. 2010, 75, 1266-1270. d) Containing triazines: Kumar,
A.; Srivastava, K.; Kumar, S. R.; Puri, S. K.; Chauhan, P. M. S.
Bioorg. Med. Chem. Lett. 20008, 18, 6530-6533. e) Containing
Tetrazole: Pandeya, S.; Agarwalb, P.; Srivastavab, K.;
Rajakumarb, S.; Purib, S. K.; Vermac, P.; Saxenac, J. K.;
Sharmad, A.; Lald, J.; Chauhana, S. E. J. Med. Chem. 2013, 66,
69-81.
The quinolone 2a was iodinated to yield 2l28 in good 82% of
yield. This compound was arylated under our optimized
conditions giving rise to the quinoline 3u in excellent 87% of
yield. The presence of a bulky iodine close to the arylation center
did not affect the reaction.
Finally according to the precedents of the iodonium salts
chemistry,19,29-30 it is plausible to propose the following
mechanism of reaction (Scheme 5).
Scheme 5. Proposed mechanism of reaction for the direct C-O
arylation of 2-aryl-4-quinolones by using iodonium salts.
3. Ma, X.; Zhou, W.; Brun, R. Bioorg. Med. Chem. Lett. 2009, 19,
986-989.
4. Rossiter, S.; Peron, S.J.; Whitfield, P.J.; Jones, K. Bioorg. Med.
Chem. Lett. 2005, 15, 4806–4808.
5. Gholap, A.R.; Toti, K.S.; Shirazi, F.; Kumari, R.; Bhat, M.K.;
Deshpande, M.V.; Srinivasan, K.V. Bioorg. Med. Chem. 2007,
15, 6705–6715.
6. Chen, Y.; Zhao, Y.; Lu, C.; Tzeng, C.; Wang, J. P. Bioorg. Med.
Chem. 2006, 14, 4373–4378.
7. Abadi, A.H.; Hegazy, G.H.; Zaher, A. A.E. Bioorg. Med. Chem.
2005, 13, 5759–5765.
8. Hu, B.; Jetter, J.; Kaufman, D.; Singhaus, R.; Bernotas, R.;
Unwalla, R.; Quinet, E.; Savio, D.; Halpern, A.; Basso, M.; Keith,
J.; Clerin, V.; Chen, L.; Liu, Q.Y.; Feingold, I.; Huselton, C.;
Azam, F.; Nilsson, A.G.; Wilhelmsson, A.; Nambi, P.; Wrobel, J.
Bioorg. Med. Chem. 2007, 15, 3321–3333.
9. Edmont, D.; Rocher, R.; Plisson, C.; Chenault, J. Bioorg. Med.
Chem. Lett. 2000, 10, 1831– 1834.
10. Evans, J. F.; Leveille, C.; Mancini, J.A.; Prasit, P., Therien, M.,
Zamboni, R., Gauthier, J.Y., Fortin, R., Charleson, P., Maclntyre,
D.E., 1991. 5-lipooxygenase-activating protein is the target of a
quinoline class of leukotriene synthesis inhibitors. Mol. Pharm.
40, 22–27.
The mechanism starts with the deprotonation of quinolone by
potassium tert-butoxide to generate I. This bidentade anion
regioselectively attacks at the electrophilic iodine center in the
salt giving rise to II. The evolution of this intermediate via
reductive elimination yields compounds 3a-t with a concomitant
releasing of iodobenzene.
11. Youliang, W.; Zhitong, Z.; Liming, Z. J. Am. Chem.
Soc., 2015, 137, 5316–5319
12. Örtqvist, P.; Peterson, S. D.; Åkerblom, E.; Gossas, T.; Sabnis, Y.
A.; Fransson, R.; Linderberg, G.; Danielson, U. H.; Karlen, A.;
Sandström, A. Bioorg. Med. Chem. 2007, 15, 1448-1474.
13. Jin, M.; Petronella, B. A.; Cooke, A.; Kadalbajoo, M.; Siu, K. W.;
Kleinberg, A.; May, E. W.; Gokhale, P. C.; Schulz, R.; Kahler, J.;
Bittner, M. A.; Foreman, K.; Pachter, J. A.; Wild, R.; Epstein, D.;
Mulvihill, M. J. ACS Med. Chem. Lett. 2013, 4, 627-631.
14. Marganakop, S. B.; Kamble, R. R.; Taj, T.; Kariduraganvar, M. Y.
Med. Chem. Res. 2012, 21, 185-191.
15. Massari, S.; Daelemans, D.; Manfroni, G.; Sabatini, S.; Tabarrini,
O.; Pannecouque, C.; Cecchetti, V. Bioorg. Med. Chem. 2009, 17,
667–674.
16. a) Andersen, K. E.; Lundt, B. F.; Jøegensen, A. S.; Braestrup, C.
Eur. J. Med. Chem. 1996, 31, 417-425. b) Cope, H.; Mutter, R.;
Heal, W.; Pascoe, C.; Brown, P.; Pratt, S.; Chen, B Eur. J. Med.
Chem. 2006, 41, 1124-1143. c) Hoekstra, W. J.; Paterl, H. S.;
Liang, X.; Blanc, J. B. P.; Heyer, D. O.; Willson, T. M.; Iannone,
M. A.; Kadwell, S. H.; Miller, L. A.; Pearce, K. H.; Simmons, C.
A.; Searin, J. J. Med. Chem. 2005, 48, 2243-2247.
In summary we developed a mild, efficient and operationally
simple procedure for the direct arylation of 2-aryl-4-quinolones,
to produce in one-pot a new Csp2-O bond under metal- and
ligand-free conditions. To the best of our knowledge, this is the
first work with a wide application totally directed to the synthesis
of functionalized bioactive 2-aryl-4-aryloxyquinoline core,
containing groups like -Cl, -F or –CF3 relevant in medicinal
chemistry. The procedure was carried out with the use of
conventional heating. Additionally, it shows totally regio- and
chemoselectivity allowing for synthesizing exclusively
O-arylquinolines by using simple non-symmetrical iodonium
salts. This represents a more atom-economical protocol regarding
to those previously described,22 which use symmetrical salts. The
procedure has a broad scope and tolerates different functional
groups nature.
17. D´Angelo, N. D.; Peterson, J. J.; Booker, S. J.; Fellows, I.;
Domínguez, C.; Hungate, R.; Reider, P. J.; Kim, T. S. Tetrahedron
Lett. 2006, 47, 5045-5048.
18. Burgos, C. H.; Barder, T. E.; Huang, X.; Buchwald, S. L. Angew.
Chem. Int. Ed. 2006, 45, 4321-4326.
19. Zhdankin, V. ARKIVOC, 2009, i, 1-62.

5
20. a) Jalalian, N.; Ishikawa, E. E.; Sila-Jr., L. F.; Olofsson, B. Org.
Lett. 2011, 13, 1552-1555. b) Tolnai, G. L.; Nilsson, U. J.;
Olofsson, B. Angew. Chem. Int. Ed. 2016, 55, 11226-11230.
21. Thorat, P. B.; Waghmode, N. A.; Karade, N. N Tetrahedron Lett.
2014, 55, 5718-5721.
22. Mehara, M. K.; Tantak, M. P.; Kumar, I.; Kumar, D. Synlett 2016,
27, 604-610.
23. Jones, C.P.; Anderson, K. W.; Buchwald, S. L. J. Org. Chem.
2007, 72, 7968-7973.
24. Zhdankin, V.; Stang, P. J. Chem. Rev. 2002, 102, 2523-2584.
25. Bielawski, M.; Zhu, M.; Olofsson, B. Adv. Synth. Cat. 2007, 349,
2610-2618.
26. Wang, B.; Graskemper, J. W.; Qin, L.; DiMagno, S. G. Angew.
Chem. Int. Ed. 2010, 49, 4079-4083.
27. Malmgren, J.; Santoro, S.; Jalalian, N.; Himo, F.; Himo, F.;
Olofsson, B. Chem. Eur. J. 2013, 19, 10334-10342.
28. Mphahlele, M. J.; Nwamadi, M.S.; Mabeta, P. J. Heterocyclic.
Chem., 2006, 46, 255-260.
29. Yoshimura A.; Zhdankin, V. Chem. Rev. 2016, 116, 3328-3435.
30. Merrit, E. A.; Olofsson, B. Angew. Chem. Int. Ed. 2009, 48, 9052-
9070.
Supplementary Material
Full details about experimental procedures, optimization protocols as well as
copies of 1H and 13C NMR, for unknown compounds are available.

6
Tetrahedron
HIGHLIGHTS
 The first genral method for synthesizing in
one pot 2-aryl-4-aryloxyquinolines, which is
a tremendous important pharmacophore.
 A metal- and ligand-free procedure for the
direct formation of a C-O bond giving rise
to functionalized quinolines.
 A totally, regio- and chemioselective O-
arylation procedure for the functionalization
of quinolines.
 The use of non symetrical bisaryliodonium
salts expending only PhI as organic
byproduct of the reaction.