Utilizing Solubility differences to achieve regiocontrol in the synthesis of substituted quinoline-4-carboxylic acids

Article abstract of DOI:10.1055/s-0035-1561395

A practical method for the regiocontrolled synthesis of substituted quinoline-4-carboxylic acids is described. Solubility differences between the product quinoline regioisomers enable their facile separation, thus avoiding any challenging chromatographic purifications and allowing access to highly substituted quinoline compounds in three steps from commercially available anilines.

Full text of DOI:10.1055/s-0035-1561395

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–E
letter
A
P. J. Lindsay-Scott, H. Barlow
Letter
Synlett
Utilizing Solubility Differences to Achieve Regiocontrol in the Syn-
thesis of Substituted Quinoline-4-carboxylic Acids
CO2H
Peter J. Lindsay-Scott*
R2
Helen Barlow
cyclization
R2
Eli Lilly and Company Limited, Erl Wood Manor,
Windlesham, Surrey GU20 6PH, UK
lindsay-scott_peter@lilly.com
R1
R2
N
O
(i) H2SO4, 80 °C
+
N
R1
N
OH
(ii) KOH (aq)
acetone, 70 °C
then HCl (aq)
R1
CO2H
H
cyclization
N
Facile purification by utilizing
solubility differences?
Received: 14.01.2016
Accepted: 04.02.2016
Published online: 04.03.2016
DOI: 10.1055/s-0035-1561395; Art ID: st-2016-d0029-l
line-4-carboxylic acids that bear substituents on the ben-
zene ring (e.g., in the 5- or 7-positions), the Pfitzinger
methodology requires isatin starting materials that have
been synthesized in a regiocontrolled fashion. Many classi-
cal methods have been described for the synthesis of isat-
ins,8 including those of Gassman9 and Stolle,10 but perhaps
the most widely adopted method for their construction was
Abstract A practical method for the regiocontrolled synthesis of sub-
stituted quinoline-4-carboxylic acids is described. Solubility differences
between the product quinoline regioisomers enable their facile separa-
tion, thus avoiding any challenging chromatographic purifications and
allowing access to highly substituted quinoline compounds in three
steps from commercially available anilines.
cyclization path a
R2
Key words heterocycles, quinolones, isatins, regioisomers, cyclization
R2
R1
isonitroso-
acetanilide
formation
O
N
R1
N
OH
Quinolines are an important class of heterocyclic com-
pounds that have become a privileged structural motif in
drug discovery, displaying widespread biological activity in
numerous settings.1 The classical synthetic approaches that
have been developed for their construction from anilines
fall broadly into two categories: (i) those methods that cy-
clize anilines (or their derivatives) onto a carbon atom adja-
cent to the nitrogen-bearing carbon of the benzene nucleus,
typified by the Skraup2 and Combes3 methods – this ap-
proach can lead to mixtures of regioisomers if unsymmetri-
cal aniline precursors are employed; (ii) those methods that
pre-build the desired substitution into the starting aniline
derivatives to avoid potential issues around the formation
of regioisomeric mixtures, typified by the Friedlander4
method. More modern synthetic approaches to build up
quinoline scaffolds (including the use of catalytic metal
complexes5 and green chemistry1a) similarly have the po-
tential to generate mixtures of regioisomers if they utilize
the cyclization of unsymmetrical aniline precursors.6 In
contrast, the Pfitzinger method,7 first discovered at the end
of the 19th century, allows access to quinoline-4-carboxylic
acids directly from isatin precursors, with the pre-built
substitution of the isatins being transferred faithfully to the
quinoline products. Therefore, to access substituted quino-
NH2
H
1
2
cyclization path b
H2SO4
80 °C
cyclization
O
CO2H
R2
R1
R2
R1
O
KOH (aq)
acetone, 70 °C
then HCl (aq)
N
H
N
4a
3a
+
+
R1
Pfitzinger
reaction
R1
CO2H
O
R2
R2
O
N
H
N
4b
3b
Facile purification by utilizing
solubility differences?
Challenging
regiosiomer separation
Scheme 1 General route for the formation of quinolines 4a and 4b
from anilines 1
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

B
P. J. Lindsay-Scott, H. Barlow
Letter
Synlett
developed by Sandmeyer,11 who showed that the cycliza-
tion of isonitrosoacetanilides 2 occurred at elevated tem-
peratures in the presence of strong acid to give isatins 3 in a
reliable fashion, with the requisite starting materials being
readily prepared from the corresponding anilines 1 (see
Scheme 1).
any chromatographic purifications. Consequently, this
methodology might allow access to highly substituted
quinolines as single regioisomers in a more facile manner.
Thus, a range of electronically and sterically diverse iso-
nitrosoacetanilides 2 (prepared in one step from the corre-
sponding commercially available anilines 1; see the Sup-
porting Information) were subjected to cyclization in sulfu-
ric acid at 80 °C by following Sandmeyer’s protocol to give
isatin products 5–17 on multigram scale as mixtures of re-
gioisomers (Scheme 2).21 The effect of ring-substitution on
the regioisomeric ratio of the product isatins was clearly
For symmetrical isonitrosoacetanilides (e.g., 2 when R1
= H), isatins are formed as single regioisomers because cy-
clization can occur through two equivalent carbon atoms
adjacent to the nitrogen-bearing carbon of the benzene nu-
cleus. However, for unsymmetrical isonitrosoacetanilides
(e.g., 2 when R1 ≠ H), the formation of two regioisomeric
products is possible because cyclization can occur through
two different carbon atoms (see ‘cyclization path a’ and ‘cy-
clization path b’ in Scheme 1), with the nature of the sub-
stituents R1 and R2 playing a key role in determining the ra-
tio of isatin regioisomers. To tackle this problem, alterna-
tive methods for the synthesis of isatins have been reported
in which the desired substitution has been pre-built into
the starting materials to generate isatin products as single
regioisomers, by utilizing SNAr,12 lithiation,13 N-heteroan-
nulation14 and ylide-mediated carbonyl homologation
methodologies.15 More recently, a regioselective carbonyla-
tive approach was described by Lei and co-workers.16 De-
spite these recent advances, the classical approaches for
isatin synthesis are still widely employed and, as such,
some limited methods for the separation of isatin regioiso-
mers formed from unsymmetrical cyclization precursors
have been reported,17 including counter-current chroma-
tography18 and separation based on pKa differences,19 with
varying levels of success. Isatin regioisomer separations by
traditional silica-gel chromatographic methods (which can
be time-consuming and wasteful in terms of solvent con-
sumption)18 are hampered by the fact that isatins are often
insoluble in common chromatography solvents.12
O
R2
R2
H2SO4
80 °C
O
O
N
R1
N
OH
H
R1
N
H
+
2
R1
O
R2
O
N
H
5–17
Cl
Br
O
O
O
O
O
O
O
N
N
N
F
H
H
H
5, 65%
10:1 r.r.
6, 67%
1.3:1 r.r.
7, 77%
2.3:1 r.r.
Cl
Cl
O
O
O
F
F
F
Cl
O
O
N
N
H
N
H
H
8, 86%
>19:1 r.r.
9, 42%
5.9:1 r.r.
10, 51%
1.1:1 r.r.
A recent report from the Kaila group showed that an in-
separable mixture of isatin regioisomers (produced by the
Sandmeyer method) could be converted into the corre-
sponding quinoline-4-carboxylic acids using the Pfitzinger
reaction and that the quinoline regioisomers displayed
more marked differences in physical properties than their
isatin counterparts, rendering them separable by column
chromatography in some cases.20 We were intrigued
whether it would be possible to access substituted quino-
line-4-carboxylic acids 4 as single regioisomers from mix-
tures of isatin regioisomers 3a and 3b, by exploiting this
apparent greater difference in physical properties between
the corresponding quinoline regioisomers (Scheme 1). This
approach would avoid the tedious separation of isatin re-
gioisomers and obviate the need to pre-build the desired
substitution pattern into the starting anilines. Furthermore,
we hypothesized that it might be possible to readily purify
the quinoline-4-carboxylic acids by utilizing solubility dif-
ferences between the regioisomers 4a and 4b, thus avoiding
O
O
O
MeO
F
MeO
Br
MeO
Me
O
O
O
N
N
N
H
H
H
11, 80%
>19:1 r.r.
12, 64%
1.7:1 r.r.
13, 61%
>19:1 r.r.
O
O
O
F
Cl
Br
O
O
O
N
H
N
N
MeO
MeO
MeO
H
H
14, 89%
>19:1 r.r.
15, 71%
>19:1 r.r.
16, 64%
>19:1 r.r.
Br
O
Me
O
N
H
17, 88%
4:1 r.r.
Scheme 2 Formation of isatins 5–17 from isonitrosoacetanilides 2; the
structure of the major isatin regioisomer is depicted
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

C
P. J. Lindsay-Scott, H. Barlow
Letter
Synlett
evident. Thus, the 6-substituted fluoroisatin 5 was formed
over its 4-substituted counterpart in a 10:1 ratio, whereas
the formation of chloro- and bromoisatins 6 and 7 was less
selective, in agreement with reported data.17 The majority
of the disubstituted isatins investigated were formed with a
preference for the 5,6-regioisomer (through cyclization
path a), with selectivities over the 4,5-regioisomer ranging
from a modest 1.7:1 for isatin 12 up to >19:1 for isatins 8,
11, and 13–16. Of the disubstituted compounds tested, only
the dichloroisatin 9 and the bromo-methyl compound 17
showed a marked preference for the formation of the 4,5-
regioisomer (through cyclization path b), whereas chloro
fluoroisatin 10 was formed as a 1.1:1 mixture. During the
course of this study, we found that the isatin mixtures could
be readily purified from minor impurities by triturating
them in isopropanol, although the crude regioisomer ratios
were preserved during this process.
With a range of isatins 5–17 in hand, we subjected these
regioisomeric mixtures to the Pfitzinger reaction condi-
tions on a multigram scale, utilizing acetone in aqueous po-
tassium hydroxide at 70 °C (Scheme 3).22 Upon cooling and
neutralization of these reactions mixtures, the product
quinoline-4-carboxylic acids 4 precipitated from the reac-
tion mixtures and were readily isolated by filtration. These
could be further purified by trituration to remove minor
impurities (see the Supporting Information), with little
change in the regioisomer ratio. Interestingly, quinolines
18–20 were all isolated as predominantly the 7-substituted
quinoline regioisomer. This selectivity was remarkable,
considering the starting chloro- and bromoisatins 6 and 7
had been enriched in the 4-substituted isomers; LCMS
analysis revealed that the mother liquors had been corre-
spondingly enriched in the 5-substituted quinoline regio-
isomers during the precipitations. Likewise, quinolines 21
and 23–29 were all isolated as predominantly the 6,7-
disubstituted regioisomers. Whereas the high ratios of isat-
in regioisomers were preserved in the formation and isola-
tion of quinolines 21, 24, and 26–29, the chloro-fluoro
compound 23, bromo-methoxy compound 25 and bromo-
methyl compound 30 all showed some rejection of the cor-
responding 5,6-disubstituted quinoline regioisomers into
the mother liquors to varying extents during their respec-
tive precipitations. Only the dichloroquinoline 22 was fur-
ther enriched in the 5,6-regioisomer after the Pfitzinger re-
action and trituration process.
O
CO2H
R2
R1
R2
R1
O
O
KOH (aq)
acetone, 70 °C
N
N
H
+
+
R1
R1
CO2H
then HCl (aq)
O
R2
R2
N
H
N
5–17
18–30
CO2H
N
18, 65%
>19:1 r.r.
(isatin 10:1 r.r.)
CO2H
CO2H
N
20, 29%
10:1 r.r.
(isatin 2.3:1 r.r.)
F
Cl
Cl
N
Br
19, 23%
14:1 r.r.
(isatin 1.3:1 r.r.)
CO2H
Cl
CO2H
CO2H
F
F
F
N
N
Cl
N
21, 41%
>19:1 r.r.
(isatin >19:1 r.r.)
22, 71%
11:1 r.r.
(isatin 5.9:1 r.r.)
23, 35%
2.6:1 r.r.
(isatin 1.1:1 r.r.)
CO2H
CO2H
CO2H
MeO
F
MeO
Br
MeO
Me
N
N
N
24, 95%
>19:1 r.r.
(isatin >19:1 r.r.)
25, 61%
>19:1 r.r.
(isatin 1.7:1 r.r.)
26, 64%
>19:1 r.r.
(isatin >19:1 r.r.)
CO2H
CO2H
CO2H
F
Cl
Br
MeO
N
MeO
N
MeO
N
27, 85%
>19:1 r.r.
(isatin >19:1 r.r.)
28, 77%
>19:1 r.r.
(isatin >19:1 r.r.)
29, 88%
>19:1 r.r.
(isatin >19:1 r.r.)
Br CO2H
Me
N
30, 41%
2.6:1 r.r.
(isatin 4:1 r.r.)
Scheme 3 Conversion of isatins 5–17 into quinolines 18–30; the struc-
ture of the major quinoline regioisomer is depicted
We hypothesize that the marked solubility differences
exhibited by the quinoline regioisomers may be due, in
part, to their different packing in the solid state. A crystal
structure of quinoline-4-carboxylic acid has been reported
by Dobson and Gerkin, in which various hydrogen-bonding
interactions were proposed.23 Substituents on the quino-
line ring in the 5-position might disrupt these interactions
to a greater extent than those in the 7-position, leading to
less effective packing and a lower tendency towards precip-
itation for the 5-substituted regioisomers, allowing them to
be washed into the mother liquors more readily upon neu-
tralization from the Pfitzinger reaction. During the course
of our studies, we observed that the isatin regioisomers
typically showed small differences in retention time of
0.03–0.06 minutes during a standard 2-minute LCMS meth-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

D
P. J. Lindsay-Scott, H. Barlow
Letter
Synlett
od, whereas the corresponding quinoline regioisomers
showed larger differences in retention time of 0.12–0.25
minutes on the same LCMS method. This LCMS data is
therefore consistent with the challenging separation of isat-
in regioisomers that has been reported previously and the
more facile separation of the corresponding quinoline re-
gioisomers that we observed was due to their greater dif-
ferences in physical properties.20
In summary, we have developed a simple three-step
process for the practical synthesis of substituted quinoline-
4-carboxylic acids from anilines in a regiocontrolled fash-
ion, avoiding any challenging separations of regioisomers
by chromatographic methods. Thus, the Sandmeyer isatin
synthesis was employed to generate mixtures of isatin re-
gioisomers, which were subjected to the Pfitzinger reaction
with acetone. Solubility differences in the product quino-
line-4-carboxylic acids were sufficient in many cases to al-
low the preferential precipitation of 7- and 6,7-substituted
quinoline regioisomers (even when only present as the mi-
nor regioisomer), while rejecting 5- and 5,6-substituted
quinolines into the mother liquors. This method therefore
provides efficient access to these substituted quinoline-4-
carboxylic acids and is likely to find applications in the syn-
thesis of pharmacologically relevant molecules as a result.
(10) Stolle, R.; Bergdoll, R.; Luther, M.; Auerhahn, A.; Wacker, W.
J. Prakt. Chem. 1930, 128, 1.
(11) Sandmeyer, T. Helv. Chim. Acta 1919, 2, 234.
(12) Kraynack, E. A.; Dalgard, J. E.; Gaeta, F. C. A. Tetrahedron Lett.
1998, 39, 7679.
(13) Hewawasam, P.; Meanwell, N. A. Tetrahedron Lett. 1994, 35,
7303.
(14) Söderberg, B. C. G.; Gorugantula, S. P.; Howerton, C. R.; Petersen,
J. L.; Dantale, S. W. Tetrahedron 2009, 65, 7357.
(15) Lollar, C. T.; Krenek, K. M.; Bruemmer, K. J.; Lippert, A. R. Org.
Biomol. Chem. 2014, 12, 406.
(16) Li, W.; Duan, Z.; Zhang, X.; Zhang, H.; Wang, M.; Jiang, R.; Zeng,
H.; Liu, C.; Lei, A. Angew. Chem. Int. Ed. 2015, 54, 1893.
(17) Sadler, P. W. J. Org. Chem. 1956, 21, 169.
(18) Almeida, M. R.; Leitão, G. G.; Silva, B. V.; Barbosa, J. P.; Pinto, A.
C. J. Braz. Chem. Soc. 2010, 21, 764.
(19) Varma, R. S.; Singh, A. P. Indian J. Chem., Sect. B: Org. Chem. Incl.
Med. Chem. 1990, 29, 578.
(20) Kaila, N.; Janz, K.; DeBernardo, S.; Bedard, P. W.; Camphausen,
R. T.; Tam, S.; Tsao, D. H. H.; Keith, J. C. Jr.; Nickerson-Nutter, C.;
Shilling, A.; Young-Sciame, R.; Wang, Q. J. Med. Chem. 2007, 50,
21.
(21) 4-Bromo-5-methylindoline-2,3-dione (17); Typical Proce-
dure: To a stirred solution of aqueous sulfuric acid (18.1 M, 42.0
mL) at 60 °C, was added (2E)-N-(3-bromo-4-methylphenyl)-2-
(hydroxyimino)acetamide (15.8 g, 61.8 mmol) portionwise. The
reaction mixture was stirred in a heating block for 30 min at an
internal temperature of 80 °C, then the mixture was cooled to
room temperature. The solution was added slowly to a satu-
rated water/ice mixture (79.5 mL) and stirred for 10 min at
room temperature, then filtered. The resultant solid was dried
under vacuum at 40 °C for 40 h, then added to isopropyl alcohol
(10 mL), stirred at room temperature for 15 min, filtered and
dried under vacuum at 40 °C for 16 h to give isatin 17 (13.0 g,
54.4 mmol, 88% yield, 4:1 r.r. in favor of the 4-bromo-5-methyl
isomer over the 5-methyl-6-bromo isomer) as an orange solid.
Data listed for both regioisomers: mp 236–238 °C. IR (thin
film): 3289, 1728, 1605, 1458, 1273, 1211, 1152, 1042, 995,
980, 824, 635 cm–1. 1H NMR (400 MHz, DMSO-d6): δ = 11.07 (s,
0.8 H), 11.04 (s, 0.2 H), 7.53–7.51 (m, 2 H), 7.11 (s, 0.2 H), 6.81
(d, J = 8.0 Hz, 0.8 H), 2.30 (s, 0.6 H), 2.29 (s, 2.4 H). 13C NMR (100
MHz, DMSO-d6): δ = 183.6, 182.0, 159.4, 158.6, 150.6, 149.2,
Acknowledgment
We thank Christopher Reutter (Eli Lilly) for his assistance with high-
resolution mass spectrometry samples and Nicholas A. Magnus (Eli
Lilly) for useful discussions during the preparation of this manuscript.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1561395.
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References and Notes
139.3, 133.9, 132.1, 131.6, 126.3, 121.7, 117.4, 116.6, 115.6,
+
111.2, 21.7, 20.7. HRMS (ESI+): m/z [M]+ calcd for C9H6BrNO2
:
(1) (a) Chung, P.-Y.; Bian, Z.-X.; Pun, H.-Y.; Chan, D.; Chan, A. S.-C.;
Chui, C. H.; Tang, J. C.-O.; Lam, K.-H. Future Med. Chem. 2015, 7,
947. (b) Foley, M.; Tilley, L. Pharmacol. Ther. 1998, 79, 55.
(c) Michael, J. P. Nat. Prod. Rep. 2005, 22, 627.
(2) Denmark, S. E.; Venkatraman, S. J. Org. Chem. 2006, 71, 1668.
(3) Yamashkin, S. A.; Yudin, L. G.; Kost, A. N. Chem. Heterocycl.
Compd. (N. Y., NY, U. S.) 1992, 28, 845.
(4) Muchowski, J. M.; Maddox, M. L. Can. J. Chem. 2004, 82, 461.
(5) Khusnutdinov, R. I.; Bayguzina, A. R.; Dzhemilev, U. M. J. Organomet.
Chem. 2014, 768, 75.
(6) (a) Prajapati, S. M.; Patel, K. D.; Vekariya, R. H.; Panchala, S. N.;
Patel, H. D. RSC Adv. 2014, 4, 24463. (b) Kouznetsov, V. V.;
Mendez, L. Y. V.; Gomez, C. M. M. Curr. Org. Chem. 2005, 9, 141.
(7) Sangshetti, J. N.; Zambare, A. S.; Gonjari, I.; Shinde, D. B. Mini-
Rev. Org. Chem. 2014, 11, 1.
238.9582; found: 238.9575 (+2.99 ppm).
(22) 5-Bromo-2,6-dimethylquinoline-4-carboxylic Acid (30);
Typical Procedure: To a stirred solution of KOH (15.3 g, 272
mmol) in H2O (52.2 mL) in an ice-water bath was added isatin
17 (13.0 g, 54.4 mmol, 4:1 r.r. in favor of the 4-bromo-5-methyl
isomer over the 5-methyl-6-bromo isomer) portionwise. The
reaction mixture was stirred at room temperature for 10 min,
then cooled in an ice-water bath and acetone (52.2 mL) was
added dropwise. The reaction mixture was stirred in a 70 °C
heating block for 5 h, then cooled in an ice-water bath and a
solution of aqueous HCl (5 M, 49.0 mL, 245 mmol) was added
dropwise until the mixture reached pH 5–6. The reaction
mixture was stirred at room temperature for 10 min and then
filtered. The resultant solid was dried under vacuum at 40 °C for
16 h, then added to isopropyl alcohol (10 mL), stirred at room
temperature for 15 min, filtered, and dried under vacuum at
40 °C for 16 h. The solid was then added to ethyl acetate (10
mL), stirred at room temperature for 15 min, filtered, and dried
under vacuum at 40 °C for 6 h to give quinoline 30 (6.26 g, 22.3
(8) da Silva, J. F. M.; Garden, S. J.; Pinto, A. C. J. Braz. Chem. Soc. 2001,
12, 273.
(9) Gassman, P. G.; Cue, B. W. Jr.; Luh, T.-Y. J. Org. Chem. 1977, 42,
1344.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

E
P. J. Lindsay-Scott, H. Barlow
Letter
Synlett
mmol, 41% yield, 2.6:1 r.r. in favor of the 5-bromo-6-methyl
isomer over the 6-methyl-7-bromo isomer) as a golden brown
solid. Data listed for both regioisomers: mp 245–251 °C
(decomp.). IR (thin film): 1705, 1587, 1558, 1458, 1333, 1256,
(s, 2.2 H), 2.55 (s, 0.8 H). 13C NMR (100 MHz, DMSO-d6): δ =
169.9, 167.2, 159.3, 158.2, 147.4, 147.4, 141.2, 137.6, 135.9,
135.6, 132.5, 131.3, 128.5, 126.6, 126.1, 123.5, 122.1, 121.9,
121.3, 119.5, 24.6, 24.1, 24.0, 23.0. HRMS (ESI+): m/z [M]+ calcd
for C12H10BrNO2+: 278.9895; found: 278.9901 (−2.09 ppm).
(23) Dobson, A. J.; Gerkin, R. E. Acta Crystallogr., Sect. C: Cryst. Struct.
Commun. 1998, 54, 1883.
1188, 1149, 1036, 910, 880, 826, 785, 733, 689 cm–1 1H NMR
.
(400 MHz, DMSO-d6): δ = 13.80 (br. s, 1 H), 8.59 (s, 0.3 H), 8.25
(s, 0.3 H), 7.94 (d, J = 8.6 Hz, 0.7 H), 7.86 (s, 0.3 H), 7.78 (d, J =
8.6 Hz, 0.7 H), 7.52 (s, 0.7 H), 2.70 (s, 0.8 H), 2.68 (s, 2.2 H), 2.57
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E