Cascade Knoevenagel and aza-Wittig reactions for the synthesis of substituted quinolines and quinolin-4-ols

Article abstract of DOI:10.1039/c8gc03180k

A [4 + 2] annulation involving cascade Knoevenagel, aza-Wittig and dehydrofluorination reactions is developed for the synthesis of substituted quinolin-4-ols including analogs bearing CF₂H, CF₃, and C₂F₅ groups. This simple and highly efficient method is also applicable for the synthesis of substituted quinolines. A number of reported biologically active compounds can be readily prepared by this one-pot synthesis. Green chemistry metrics analysis of the new reaction processes provided favorable results.

Full text of DOI:10.1039/c8gc03180k

Green Chemistry
View Article Online
View Journal
PAPER
Cascade Knoevenagel and aza-Wittig reactions for
the synthesis of substituted quinolines and
Cite this: DOI: 10.1039/c8gc03180k
quinolin-4-ols†‡
a
Xiaofeng Zhang,a Xiaoming Ma,a,b Weiqi Qiu,a Jason Evansa and Wei Zhang
*
A [4 + 2] annulation involving cascade Knoevenagel, aza-Wittig and dehydrofluorination reactions is
developed for the synthesis of substituted quinolin-4-ols including analogs bearing CF2H, CF3, and
C2F5 groups. This simple and highly efficient method is also applicable for the synthesis of substituted
quinolines. A number of reported biologically active compounds can be readily prepared by this one-
pot synthesis. Green chemistry metrics analysis of the new reaction processes provided favorable
results.
Received 10th October 2018,
Accepted 18th December 2018
DOI: 10.1039/c8gc03180k
rsc.li/greenchem
multi-step reactions, need special starting materials, and have
low regioselectivity for making substituted quinolin-4-ols.
Introduction
Quinoline is a privileged structure which can be found in Introduced in this paper is a new method for pot, atom, step
many natural and synthetic compounds with desirable biologi- and economic (PASE) synthesis of 2,3-substituted quinolin-4-
cal, fluorescence, and phosphorescence properties.1 As an ols (Scheme 1C).6,7
important member in the quinoline family, quinolin-4-ol
2-Azidobenzaldehyde is a versatile synthon for making
derivatives, such as cabozantinib, anlotinib, subtype-2 agonist, nitrogen-heterocyclic compounds such as benzisoxazoles
lenvatinib, and MC1823 (Fig. 1), have significant biological and quinolines.8 We have recently reported 2-azidobenzalde-
and medicinal utilities.2–4 Aniline-based [3 + 3] annulation hyde-based one-pot synthesis of quinolinedicarboxylates
(Gloud-Jacobs)5a and [4 + 2] annulation3,5b are common and pyrroloquinolinediones through a reaction sequence of
methods for making 2,3-disubstituted quinolin-4-ols denitrogenation of 2-azidobenzaldehyde, cyclization, aza-
(Scheme 1A and B). However, these two protocols require Diels–Alder reaction, and dehydrative aromatization
(Scheme 2A).9 In this work, a new sequence including
Knoevenagel reaction, aza-Wittig reaction, and dehydro-
fluorinative aromatization was introduced for the one-pot
synthesis of quinolin-4-ols (Scheme 2B). CF2H-, CF3-, and
C2F5-substituted quinolin-4-ols could be readily synthesized
by using corresponding fluorinated ketones as starting
materials.
Fig. 1 Representative bioactive quinolin-4-ol derivatives.
aDepartment of Chemistry, University of Massachusetts Boston, 100 Morrissey
Boulevard, Boston, MA 02125, USA. E-mail: wei2.zhang@umb.edu
bSchool of Pharmaceutical Engineering and Life Science, Changzhou University,
Jiangsu 213164, P. R. China
†Dedicated to Professor Dennis P. Curran on the occasion of his 65th birthday.
‡Electronic supplementary information (ESI) available. See DOI: 10.1039/
c8gc03180k
Scheme 1 Synthesis of 2,3-substituted quinolin-4-ols.
This journal is © The Royal Society of Chemistry 2018
Green Chem.

View Article Online
Paper
Green Chemistry
Table 2 Synthesis of substituted quinolin-4-ols 4 and quinolines 5a
Scheme 2 2-Azidobenzaldehyde-initiated one-pot synthesis.
Results and discussion
The development of the reaction conditions for the one-pot
synthesis of 2,3-disubstituted quinolin-4-ol 4a and 2,3-di-
substituted quinoline 5a was carried out by conducting the
reaction of α-fluoro-β-ketoester 2a or β-ketoester 3a with 2-azi-
dobenzaldehyde 1a and PPh3 (Table 1). Without using a base,
the reaction of 2a in MeCN at 95 °C for 48 h gave 4a in 11% LC
yield (entry 1). Changing of the reaction time and using a base
like LiOH, K2CO3, DBU or Et3N increased the yield of 4a from
76% to 99% (entries 2–5) except for the reaction using DBU as
a base, which only gave a trace amount of product (entry 6).
Reactions using toluene or EtOH as a solvent at 110 °C and
95 °C gave 4a in 74% and 89% yield, respectively (entries 7
and 8). Thus, the optimized condition for 2,3-disubstituted
quinolin-4-ol 4a was to conduct the reaction using Et3N (1.0
equiv.) and PPh3 (1.2 equiv.) and 1 : 1.1 of 1a and 2a in MeCN
at 95 °C for 12 h, which afforded 4a in 90% isolated yield
(entry 3). Similarly, after screening bases including Et3N,
Et2NH, DIPEA, and LiOH (entries 9–14), changing the reaction
time (6–12 h) and the amount of 1-ethoxybutane-1,3-dione 3a,
the optimized condition for the synthesis of 2,3-disubstituted
a Isolated yield. Reaction conditions are same as Table 1, entries 3 and
11.
quinoline 5a was to use 1.0 : 1.2 of 1a and 3a to react with
Et2NH (1.0 equiv.) and PPh3 (1.2 equiv.) at 95 °C for 6 h, which
afforded 5a in 89% isolated yield (entry 11).
With the optimized reaction conditions in hand, the one-
pot reactions with different sets of 2-azidobenzaldehydes 1,
and 2-fluoro-1,3-dicarbonyls
2 or 1,3-dicarbonyls 3 were
carried out for the synthesis of products 4 and 5 bearing
different R1, R2 and R3 groups (Table 2). Products 4a–l were
obtained in 77–91% isolated yields, and products 5a–d in
79–91% isolated yields. It is worth noting that most 1,3-dicar-
bonyls 2 or 3 used for the reactions were β-keto esters. Only
1,3-diketons were used in the synthesis of 4b and 5d.
Table 1 Optimization of reaction conditionsa
There are increased numbers of biologically active com-
pounds are fluorinated.10 Our reaction scope was then
extended by using β-keto esters 6 containing CF3, CHF2, or
C2F5 groups to afford fluorinated quinolin-4-ols 8a–h in
73–89% yields (Table 3). Similarly, fluorinated quinolines 9a–j
were synthesized in 70–90% yields. Further extension of the
reaction scope by conducting the reactions using ketone 10a
or 11a afforded 2,3-substituted quinolines 12a and 13a,
respectively (Scheme 3). Formation of 12a indicates that for
the reaction of fluorinated ketone, the dehydrative aromatiza-
tion is more favourable than the dehydrofluorination process
since no quinolin-4-ol product was detected. Reactions of
diethyl β-keto phosphonates 14a and 15a afforded phospho-
nate quinolin-4-ol 16a in a trace amount, but 17a in 79% yield.
Products 4a, 5a and 5c shown in Table 2 are histone acetyl-
transferase (HAT) inhibitors,11 and 4k is an intermediate for
making HMG-CoA reductase inhibitors.4c We also applied the
one-pot synthesis for the reparation of a series of reported bio-
logically active quinolin-4-ol and quinoline compounds shown
2a or 3a Base
(eq.)
T
4aa
(1.0 eq.) (°C) t (h) (%)
5aa
(%)
Entry Solvent
1
2
3
4
5
6
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
2a (1.1)
2a (1.1)
2a (1.1)
2a (1.1)
2a (1.1)
2a (1.1)
—
LiOH
Et3N
K2CO3
Et3N
DBU
Et3N
95
95
95
95
95
95
48
6
12
6
11
76
99 (90)
79
—
—
—
—
—
—
—
—
59
99
99 (89)
81
88
91
6
6
88
Trace
74
7
8
Toluene 2a (1.2)
110 12
EtOH
2a (1.2)
3a (1.2)
3a (1.2)
3a (1.2)
3a (1.2)
3a (1.2)
3a (1.1)
Et3N
Et3N
Et2NH
Et2NH
DIPEA
LiOH
Et2NH
95
95
95
95
95
95
95
12
12
12
6
89
—
—
—
9
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
10
11
12
13
14
6
—
6
12
—
—
a LC yield, isolated yield in parenthesis.
Green Chem.
This journal is © The Royal Society of Chemistry 2018

View Article Online
Green Chemistry
Paper
Table 3 Synthesis of 2-fluorinated quinolin-4-ols 8 and quinolines 9a
Scheme 4 Proposed mechanism for making substituted quinolin-4-ols
and quinolines.
The mechanisms for the one-pot synthesis of quinolin-4-ols
4 and 8 as well as quinolines 5 and 9 are proposed in
Scheme 4. An aza-Wittig reagent 19 are readily generated from
the reaction of
a 2-azidobenzaldehyde with PPh3. The
Knoevenagel addition of 19 with a fluorinated 1,3-dicarbonyl
compound affords intermediate 20 which then undergoes aza-
Wittig reaction to form quinolin-4-ol 4 or 8 after dehydrofluori-
nation.17 The Knoevenagel reaction of 19 with a non-fluori-
nated 1,3-dicarbonyl compound affords quinoline 5 or 9 after
dehydration. Similar reaction mechanism applies to the reac-
tion process in the formation of products shown in Scheme 3
and Table 4.
a Isolated yield. Reaction conditions are same as Table 1, entries 3 and
11.
Green chemistry metrics analysis of the one-pot synthesis
of quinolin-4-ol 4a (Process C) and comparison with two litera-
ture methods (Processes A and B) shown in Scheme 5 was con-
ducted (Tables 5 and 6).18,19 The metrics include atom
economy (AE), atom efficiency (AEf), carbon efficiency (CE),
reaction mass efficiency (RME), optimum efficiency (OE),
process mass intensity (PMI), E-factor (E), solvent intensity
(SI), and water intensity (WI) (see SupInf for the definition of
metrics and calculations). Process A starting from diethyl mal-
onate 21 has intermediate 23 which was not isolated, it was
considered as a two-step synthesis for calculation.4a Process B
is also a two-step synthesis starting from 2-aminobenzoic acid
24.4b The AE for Process C has inherited high atom economy
(78%) and atom efficiency (70%) which is clearly better than
Scheme 3 Synthesis of other quinoline analogs.
Table 4 Synthesis of bioactive quinolin-4-ols and quinolines
in Table 4, such as HTLV-1 inhibitors 13b and 13c,12 antileish-
manial agent 13d,13 CF3- and CHF2-bearing quinolines 13e
and 13f,14 antibacterial agent 18a,15 and anticancer agent
18b.16 Cyclic 1,3-dicarbonyl compounds were used in the syn-
thesis of 18a and 18b.
Scheme 5 Processes A–C for the synthesis of quinolin-4-ol 4a.
This journal is © The Royal Society of Chemistry 2018
Green Chem.

View Article Online
Paper
Green Chemistry
Table 5 Green metrics (AE, AEf, CE, RME, OE and MP) for processes A–C
Process
Isolation steps
Yield (%)
AE (%)
AEf (%)
CE (%)
RME (%)
OE (%)
MP (%)
A
B
C
2
2
1
26
55
90
56
41
78
16
23
70
10
39
86
9
16
67
16
39
85
0.7
1.0
2.8
The higher the value (closer to 100%), the greener the reaction process
Table 6 Green metrics (PMI, E factor, SI and WI) for processes A–C
Conclusions
Process
PMI (g/g)
E (g/g)
SI (g/g)
WI (g/g)
A straightforward and highly efficient [4 + 2] annulation
method for substituted quinolin-4-ols including analogues
containing CF3, CHF2, and C2F5 groups is introduced through
a one-pot synthesis involving the process of formation of an
aza-Wittig reagent, Knoevenagel addition, aza-Wittig reaction,
and dehydrofluorination. A similar reaction sequence invol-
ving the formation of aza-Wittig reagents, Knoevenagel con-
densation and aza-Wittig aromatization is developed for the
preparation of substituted quinolines. The method has been
demonstrated in the synthesis of a number of bioactive com-
pounds such as histone acetyltransferase (HAT) inhibitors,
HTLV-1 inhibitors, antileishmanial, antibacterial and anti-
cancer agents. Green chemistry metrics analysis of the one-pot
synthesis of 4a was conducted and favourably compared with
two reported methods for its high synthetic efficiency, oper-
ational simplicity, and low waste generation.
A
B
C
149
100
36
148
99
35
138
30
33
0
64
0
The lower the value, the better the reaction process.
those of Process I (56% and 16%) and Process B (41% and 23%)
(Table 5).20 CE (86%) for Process C justifies for excess stoichio-
metry in reaction conditions and 90% yield of the product even
though number of carbons remains the same. RME is the most
direct metric to identify the greenness of the process, since it
evaluates the reactant mass, yield and atom economy.
Calculations of RME for Process C (67%) gave even more posi-
tive results compared to Process A (9%) and Process B (16%). In
addition, OE evaluation also showed Process C (85%) is superior
to Process A (16%) and Process B (39%). Mass productivity is a
significant metric for industry as it takes into account resource
consumption. The MP for Process C (3.0%) is also better than
those of Processes A (0.7%) and B (1.0%).
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
X. M. acknowledges the sponsorship of Jiangsu oversea
Visiting Scholar Program for University Prominent Youth &
Middle-aged Teachers and Presidents.
PMI of Process A (149) and B (100) are much worse com-
pared to Process C (36) (Table 6). Meanwhile, solvent intensity
(SI) and water intensity (WI) values were also evaluated. A large
excess of solvent was used in process A compared to process B
and C. WI for Process A and C is 0 because no water was used,
which is significantly better than Process B (64).
Notes and references
1 Selected reviews: (a) S. M. Prajapati, K. D. Patel,
R. H. Vekariya, S. N. Panchala and H. D. Patel, RSC Adv.,
2014, 4, 24463–24476; (b) O. Afzal, S. Kumar, M. R. Haider,
M. R. Ali, R. Kumar, M. Jaggi and S. Bawa, Eur. J. Med.
Green Chem.
This journal is © The Royal Society of Chemistry 2018

View Article Online
Green Chemistry
Paper
Chem., 2015, 97, 871–910; (c) P. F. Salas, C. Herrmann and
C. Orvig, Chem. Rev., 2013, 113, 3450–3492;
(d) V. R. Solomon and H. Lee, Curr. Med. Chem., 2011, 18,
1488–1508; (e) J. P. Michael, Nat. Prod. Rep., 2008, 25,
166–187; (f) S. M. A. Hussaini, Expert Opin. Ther. Pat., 2016,
26, 1201–1221; (g) J. P. Michael, Nat. Prod. Rep., 2007, 24,
223–246; (h) J. Wiesner, R. Ortmann, H. Jomaa and
M. Schlitzer, Angew. Chem., Int. Ed., 2003, 42, 5274–
5293.
2 (a) B. H. Han, K. Li, Y. Z. Zhao, B. L. Li, Y. Cheng,
J. Y. Zhou, Y. Lu, Y. K. Shi, Z. H. Wang, L. Y. Jiang, Y. Luo,
Y. P. Zhang, C. Huang, Q. Li and G. M. Wu, Br. J. Cancer,
2018, 118, 654–661; (b) S. E. Wolkenberg, Z. J. Zhao,
C. Thut, J. W. Maxwell, T. P. McDonald, F. Kinose,
M. Reilly, C. W. Lindsley and G. D. Hartman, J. Med. Chem.,
2011, 54, 2351–2358; (c) M. Kudo, R. S. Finn, S. Qin,
K. H. Han, K. Ikeda, F. Piscaglia, A. Baron, J. W. Park,
G. Han, J. Jassem, J. F. Blanc, A. Vogel, D. Komov,
T. R. J. Evans, C. Lopez, C. Dutcus, M. Guo, K. Saito,
S. Kraljevic, T. Tamai, M. Ren and A. L. Cheng, Lancet,
2018, 391, 1163–1173; (d) F. J. Candel and M. Penuelas,
Drug Des., Dev. Ther., 2017, 11, 881–891; (e) H. X. Ding,
C. A. Leverett, R. E. Kyne, K. K. C. Liu, S. M. Sakya,
A. C. Flick and C. J. O’Donnell, Bioorg. Med. Chem., 2014,
22, 2005–2032.
6 X. F. Zhang and W. Zhang, Curr. Opin. Green Sustain.
Chem., 2018, 11, 65–69.
7 (a) P. A. Clarke, S. Santos and W. H. C. Martin, Green
Chem., 2007, 9, 438–440; (b) D. Bhuyan, R. Sarma,
Y. Dommaraju and D. Prajapati, Green Chem., 2014, 16,
1158–1162; (c) X. F. Zhang, S. J. Zhi, W. Wang, S. Liu,
J. P. Jasinski and W. Zhang, Green Chem., 2016, 18, 2642–
2646.
8 Representative examples: (a) S. J. Gharpure, S. K. Nanda,
P. A. Adate and Y. G. Shelke, J. Org. Chem., 2017, 82, 2067–
2080; (b) J. G. Harrison, O. Gutierrez, N. Jana, T. G. Driver
and D. J. Tantillo, J. Am. Chem. Soc., 2016, 138, 487–490;
(c) J. R. Donald, R. R. Wood and S. F. Martin, ACS Comb.
Sci., 2012, 14, 135–143; (d) J. T. Hu, Y. F. Cheng, Y. Q. Yang
and Y. Rao, Chem. Commun., 2011, 47, 10133–10135;
(e) F. Qu, P. He, R. F. Hu, X. H. Cheng, S. Wang and J. Wu,
Synth. Commun., 2015, 45, 2802–2809; (f) J. R. Donald and
S. F. Martin, Org. Lett., 2011, 13, 852–855;
(g) K. G. Guggenheim, H. Toru and M. J. Kurth, Org. Lett.,
2012, 14, 3732–3735; (h) H. H. Nguyen, T. A. Palazzo and
M. J. Kurth, Org. Lett., 2013, 15, 4492–4495; (i) R. Mossetti,
D. Saggiorato and G. C. Tron, J. Org. Chem., 2011, 76,
10258–10262; ( j) Z. Huo, I. D. Gridnev and Y. Yamamoto,
J. Org. Chem., 2010, 75, 1266–1270; (k) C. Xu, F. C. Jia,
Z. W. Zhou, S. J. Zheng, H. Li and A. X. Wu, J. Org. Chem.,
2016, 81, 3000–3006.
3 (a) A. Mai, D. Rotili, D. Tarantino, A. Nebbioso,
S. Castellano, G. Sbardella, M. Tini and L. Altucci, Bioorg.
Med. Chem. Lett., 2009, 19, 1132–1135; (b) A. Mai, D. Rotili,
9 X. F. Zhang, G. Dhawan, A. Muthengi, S. Liu, W. Wang,
M. Legris and W. Zhang, Green Chem., 2017, 19, 3851–3855.
D. Tarantino, P. Ornaghi, F. Tosi, C. Vicidomini, 10 (a) S. B. Rosenblum, T. Huynh, A. Afonso, H. R. Davis,
G. Sbardella, A. Nebbioso, M. Miceli, L. Altucci and
P. Filetici, J. Med. Chem., 2006, 49, 6897–6907; (c) Q. Shen,
L. Wang, J. Yu, M. Liu, J. Qiu, L. Fang, F. Guo and J. Tang,
Synth., 2012, 44, 389–392; (d) X. C. Ji, H. W. Huang, Y. B. Li,
H. J. Chen and H. F. Jiang, Angew. Chem., Int. Ed., 2012, 51,
7292–7296; (e) C. S. Li, J. X. Li, Y. N. An, J. W. Peng,
N. Yumibe, J. W. Clader and D. A. Burnett, J. Med. Chem.,
1998, 41, 973–980; (b) M. Rowley, D. J. Hallett, S. Goodacre,
C. Moyes, J. Crawforth, T. J. Sparey, S. Patel, R. Marwood,
S. Patel, S. Thomas, L. Hitzel, D. O’Connor, N. Szeto,
J. L. Castro, P. H. Hutson and A. M. MacLeod, J. Med.
Chem., 2001, 44, 1603–1614.
W. Q. Wu and H. F. Jiang, J. Org. Chem., 2016, 81, 12189– 11 A. Lenoci, S. Tomassi, M. Conte, R. Benedetti,
12196.
V. Rodriguez, S. Carradori, D. Secci, S. Castellano,
G. Sbardella, P. Filetici, E. Novellino, L. Altucci, D. Rotili
and A. Mai, ChemMedChem, 2014, 9, 542–548.
4 Represent Examples, see: (a) I. P. J. Hoglund, S. Silver,
M. T. Engstrom, H. Salo, A. Tauber, H. K. Kyyronen,
P. Saarenketo, A. M. Hoffren, K. Kokko, K. Pohjanoksa, 12 (a) M. A. Fakhfakh, A. Fournet, E. Prina, J. F. Mouscadet,
J. Sallinen, J. M. Savola, S. Wurster and O. A. Kallatsa,
J. Med. Chem., 2006, 49, 6351–6363; (b) V. Goncalves,
J. A. Brannigan, D. Whalley, K. H. Ansell, B. Saxty,
A. A. Holder, A. J. Wilkinson, E. W. Tate and
R. J. Leatherbarrow, J. Med. Chem., 2012, 55, 3578–3582;
X. Franck, R. Hocquemiller and B. Figadere, Bioorg. Med.
Chem., 2003, 11, 5013–5023; (b) A. Fournet, R. Mahieux,
M. A. Fakhfakh, X. Franck, R. Hocquemiller and
B. Figadere, Bioorg. Med. Chem. Lett., 2003, 13,
891–894.
(c) S. K. Zhao, W. C. Zhou and J. Liu, Bioorg. Med. Chem., 13 V. S. Gopinath, J. Pinjari, R. T. Dere, A. Verma,
2009, 17, 7915–7923; (d) A. R. Hamann, C. de Kock,
P. J. Smith, W. A. L. van Otterlo and M. A. L. Blackie,
Bioorg. Med. Chem. Lett., 2014, 24, 5466–5469;
(e) E. J. Rastelli and D. M. Coltart, Angew. Chem., Int. Ed.,
2015, 54, 14070–14074.
5 (a) R. G. Gould and W. A. Jacobs, J. Am. Chem. Soc., 1939,
61, 2890–2895; (b) N. G. Jentsch, J. D. Hume, E. B. Crull,
S. M. Beauti, A. H. Pham, J. A. Pigza, J. J. Kessl and
M. G. Donahue, Beilstein J. Org. Chem., 2018, 14, 2529–
2536.
P. Vishwakarma, R. Shivahare, M. Moger, P. S. K. Goud,
V. Ramanathan, P. Bose, M. V. S. Rao, S. Gupta, S. K. Puri,
D. Launay and D. Martin, Eur. J. Med. Chem., 2013, 69, 527–
536.
14 (a) S. Y. Lee, J. Jeon and C. H. Cheon, J. Org. Chem., 2018,
83, 5177–5186; (b) X. K. Zhou, Z. S. Qi, S. J. Yu, L. H. Kong,
Y. Li, W. F. Tian and X. W. Li, Adv. Synth. Catal., 2017, 359,
1620–1625; (c) V. V. Kouznetsov, F. A. R. Ruiz,
L. Y. V. Mendez and M. P. Gupta, Lett. Drug Des. Discovery,
2012, 9, 680–686; (d) K. Gopaul, S. A. Shintre and
This journal is © The Royal Society of Chemistry 2018
Green Chem.

View Article Online
Paper
Green Chemistry
N. A. Koorbanally, Anti-Cancer Agents Med. Chem., 2015, 15,
631–646.
17, 752–768; (b) C. Jiménez-González, D. J. C. Constable
and C. S. Ponder, Chem. Soc. Rev., 2012, 41, 1485–1498;
(c) C. Jimenez-Gonzalez, C. S. Ponder, Q. B. Broxterman
and J. B. Manley, Org. Process Res. Dev., 2011, 15, 912–917;
(d) J. Augé, Green Chem., 2008, 10, 225–231; (e) J. Andraos,
15 (a) N. Marquise, P. J. Harford, F. Chevallier, T. Roisnel,
V. Dorcet, A. L. Gagez, S. Sable, L. Picot, V. Thiery,
A. E. H. Wheatley, P. C. Gros and F. Mongin, Tetrahedron,
2013, 69, 10123–10133; (b) R. R. Rajawinslin,
S. D. Gawande, V. Kavala, Y. H. Huang, C. W. Kuo,
T. S. Kuo, M. L. Chen, C. H. He and C. F. Yao, RSC Adv.,
2014, 4, 37806–37811.
Org.
Process
Res.
Dev.,
2005,
9,
149–163;
(f) D. J. C. Constable, A. D. Curzons and
V. L. Cunningham, Green Chem., 2002, 4, 521–527.
19 Representative
examples:
(a)
C.
R.
McElroy,
16 N. Mulakayala, D. Rambabu, M. R. Raja, M. Chaitanya,
C. S. Kumar, A. M. Kalle, G. R. Krishna, C. M. Reddy,
M. V. B. Rao and M. Pal, Bioorg. Med. Chem., 2012, 20, 759–
768.
17 Representative examples of dehydrofluorinative aromatiza-
tion: (a) Z. Song, X. Huang, W.-B. Yi and W. Zhang, Org.
Lett., 2016, 18, 5640–5643; (b) J. Qian, W.-B. Yi, X. Huang,
Y. Miao, J. Zhang, C. Cai and W. Zhang, Org. Lett., 2015, 17,
1090–1093; (c) F. Massicot, A. M. Iriarte, T. Brigaud,
A. Lebrun and C. Portella, Org. Bio. Chem., 2011, 9, 600–
603; (d) R. Surmont, G. Verniest, F. Colpaert,
A. Constantinou, L. C. Jones, L. Summerton and
J. H. Clark, Green Chem., 2015, 17, 3111–3121;
(b) T. V. T. Phan, C. Gallardo and J. Mane, Green Chem.,
2015, 17, 2846–2852; (c) N. J. Willis, C. A. Fisher,
C. M. Alder, A. Harsanyi, L. Shukla, J. P. Adams and
G. Sandford, Green Chem., 2016, 18, 1313–1318;
(d) S. Abou-Shehada, P. Mampuys, B. U. W. Maes,
J. H. Clark and L. Summerton, Green Chem., 2017, 19, 249–
258; (e) A. Muthengi, X. F. Zhang, G. Dhawan, W. S. Zhang,
F. Corsini and W. Zhang, Green Chem., 2018, 20, 3134–
3139.
G. Macdonald, J. W. Thuring, F. Deroose and N. De Kimpe, 20 2-Azidobenzaldehyde is not commercially available. It can
J. Org. Chem., 2009, 74, 1377–1380; (e) W. R. Dolbier,
J. J. Keaffaber, C. R. Burholder, H. Koroniak and
J. Pradhan, Tetrahedron, 1992, 48, 9649–9660.
be
readily
prepared
from
2-nitrobenzaldehyde.
A. Capperucci, A. Degl’Innocenti, M. Funicello,
G. Mauriello, P. Scafato and P. Spagnolo, J. Org. Chem.,
1995, 60, 2254–2256. See ESI‡ for green metrics analysis for
the synthesis of 2-azidobenzaldehyde.
18 Representative green metrics reviews: (a) F. Roschangar,
R. A. Sheldon and C. H. Senanayake, Green Chem., 2015,
Green Chem.
This journal is © The Royal Society of Chemistry 2018