Highly regioselective ring opening of quinolinic[2,3]anhydrides under mild conditions

Article abstract of DOI:10.1016/j.tetlet.2013.10.020

We report a study of the influence of Lewis acids upon the regioselectivity of ring opening of quinolinic[2,3]anhydrides to provide 2-(isopropoxycarbonyl)- nicotinic acids. In the presence of stoichiometric amounts of indium trifluoromethanesulfonate or lanthanum trifluoromethanesulfonate, the desired 2-position ester was generated with greater than 95:5 regioselectivity. This methodology was also applied to 6-methyl-[2,3]-quinoline to provide similar results.

Full text of DOI:10.1016/j.tetlet.2013.10.020

Accepted Manuscript
Highly regioselective ring opening of quinolinic [2,3] anhydrides under mild
conditions
Sammy E. Metobo, Salman Y. Jabri, Evangelos Aktoudianakis, Jared Evans,
Haolun Jin, Choung U. Kim
PII:
S0040-4039(13)01746-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.10.020
TETL 43658
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
16 September 2013
1 October 2013
6 October 2013
Please cite this article as: Metobo, S.E., Jabri, S.Y., Aktoudianakis, E., Evans, J., Jin, H., Kim, C.U., Highly
regioselective ring opening of quinolinic [2,3] anhydrides under mild conditions, Tetrahedron Letters (2013), doi:
http://dx.doi.org/10.1016/j.tetlet.2013.10.020
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We report a study of the influence of Lewis acids upon the regioselectivity of ring
opening of quinolinic [2,3] anhydrides to provide 2-(isopropoxycarbonyl)-nicotinic acids.
In the presence of stoichiometric amounts of indium trifluoromethanesulfonate or
lanthanum trifluoromethanesulfonate, the desired 2-position ester was generated with
greater than 95:5 regioselectivity. This methodology was also applied to 6-methyl-[2,3]-
quinoline to provide similar results.
Keywords: regioselective; ring opening; quinolinic [2,3] anhydrides; naphthyridines;
Lewis-acid catalysis.
Highly regioselective ring opening of quinolinic [2,3]
anhydrides under mild conditions.
Sammy E. Metobo*, Salman Y. Jabri1, Evangelos Aktoudianakis, Jared Evans, Haolun
Jin, Choung U. Kim2.
Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA.
1Amgen, Inc., 1120 Veterans Blvd, South San Francisco, CA 94080, USA.
2 Kainos Medicine, Inc., 88, Olympic-ro 43-gil, Seoul 138-736, Korea.
Introduction
Quinolinic anhydrides have been used extensively as versatile intermediates in the
synthesis of various heterocyclic systems including naphthyridines,1 nicotinamides2 and
isotoic derivatives.3 Recently, they have been exploited in antiviral,4 dementia,5 anti-
allergy6 and antitumor targets.7
Quinolinic anhydrides are readily generated from the corresponding pyridine-2,3-
dicarboxylic acids 1 (Scheme 1) via heating at reflux in acetic anhydride.8 Pioneering
work by Kenyon and Thaker fifty years ago established that treatment of the resultant
anhydride 2 with an alcohol furnishes mixtures of the regioisomeric acid-esters 3 and 4,

and this remains the most common method to access these valuable intermediates.9 In
favorable cases, crystallization enables the separation of the isomers, albeit in low yield.10
It is then possible to recycle the undesired isomer. However, this requires several
synthetic steps (hydrolysis of undesired regioisomer to 1, followed by repetition of the
sequence). This is particularly disadvantageous when more elaborate anhydrides are
utilized.11
Scheme 1. Thermal ring opening of quinolinic anhydrides with alcohols. For R=iPr, ratio of 3:4 is 67:33.
Chelation as a means of influencing the regioselectivity of synthetic transformations of
cyclic anhydrides has been demonstrated in a variety of contexts. Succinimides have been
shown to be regioselectively reduced using sodium borohydride in the presence of a
chelating metal complex.12 Little and Cochran have demonstrated the use of a Lewis acid
to catalyze the Friedel-Crafts regioselective opening and acylation of anhydrides.13 Goto
and co-workers have shown that coordination with a metal Lewis acid can help promote
the subsequent sodium borohydride reduction of quinolinimides to provide high
regioisomeric ratios.14 Baruah reported that metal complexes could be utilized to effect
formation of dicarboxylate metal complexes.15
We have previously reported that substituted quinolinic anhydrides serve as useful
synthetic intermediates for an HIV integrase active site inhibitor program.16 As expected
from literature precedent, the thermal ring opening of these intermediates with various
alcohols proceeds to provide the corresponding acid-esters as mixtures of regioisomers.17
We were interested in developing a more efficient method for the generation of the
desired 2-position ester, and herein report the regioselective ring opening esterification of
a quinolinic anhydride via a Lewis acid metal chelate complex under mild conditions.
Results
The synthesis of anhydride 5 was recently reported.18 We explored the ring opening of 5
with isopropanol in the presence of various Lewis acids (Scheme 2; Table 1) to obtain the
two isomers 6a and 6b.
Scheme 2. a) Lewis acid (1 equiv.), THF, 0 ˚C b) isopropanol, 0 ˚C to rt.
Table 1. Results obtained when anhydride 5 is exposed to isopropanol and methanol in the presence of
different Lewis acids. 19 Ratio of isomers determined by 1H NMR analysis of crude reaction mixtures. a
Also contains 18% of diacid. b also contains 9% of diacid. c 1.1 equiv. used for each reagent.
In all cases, the rate of reaction was enhanced by the Lewis acid such that the ring-
opening could conveniently be carried out at ambient temperature. The results in Table 1
indicate that the reaction outcome is influenced both by the metal and the counterion in
the additive. The monochelating metals Li+ and Ag+ provided little differentiation from

the regioselectivity observed under thermal conditions (entries 3-5 versus 1 and 2), with
incomplete reaction (as indicated by the generation of the diacid upon quenching) with
LiOTf. The results with magnesium salts were more encouraging with Mg(ClO4)2 (entry
6) in particular providing a significant enhancement in the formation of the desired
isomer. Sc(OTf)3 (entry 12) improved the regioselectivity further providing a 81:19 ratio
of isomers. One of the best outcome was obtained with In(OTf)3 (entry 10) which
provided only a single isomer of the desired isomer in high yields and high
regioselectivity (>95:5).19 When catalytic amounts of In(OTf)3 were used (entry 11), an
erosion of the selectivity was observed (79:21). Lanthanide metals also provided high
regioselectivity comparable to those shown with stoichiometric In(OTf)3 with La(OTf)3
and Yb(OTf)3 provided >95:5 and 93:7 ratios respectively.
Less coordinating counterions tended to favor the formation of the desired isomer 6a,
with perchlorate superior to triflate in the case of magnesium (6 versus 7). However, the
improved regioselectivity observed with magnesium perchlorate and triflate was negated
with magnesium bromide and even reversed, relative to the thermal conditions, with
magnesium chloride. A similar reversal in selectivity was observed with indium chloride
(entry 13). We speculate that the nucleophilic character of the chloride anion is involved
in reducing chelation of the cation to the pyridyl nitrogen. However, this might also be
due to reduced Lewis acidity of the counterion. Interestingly, when In(OTf)3 was used
together with LiCl (entry 14), high regioselectivity was still attained.
We next looked at a different anhydride (6-methyl-[2,3]-quinoline, 7). Under thermal
conditions the regioselectivity was similar to that seen for 5 (8a:8b, 64:36; Scheme 3).
Here also the use of In(OTf)3 was extremely effective, providing the desired 8a in high
regioselectivity (>95:5). The results were similar when methanol was used instead of
isopropanol (9a and 9b).
Scheme 3. Ring opening of 6-methyl-[2,3]-quinolin. 1. a. isopropanol, 80 ˚C, 64:36 ratios of 8a:8b. b. In(OTf)3 (1.1
equiv.), IPA, THF, 0 ˚C to rt. >95: 5 8a:8b, R = iPr. 2. c. methanol, 80 ˚C, 65:35 ratios of 8c:8d. b. In(OTf)3 (1.1
equiv.), MeOH, THF, 0 ˚C to rt. >95: 5 9a:9b R = Me.
Summary and Conclusions
In summary, we have demonstrated a practical, regioselective and high yielding method
for generation of nicotinic acid 2-carboxy esters by the ring-opening of quinolinic-[2,3]
anhydrides using indium (III) trifluoromethanesulfonate or lanthanum (III)
trifluoromethanesulfonate.
Acknowledgments
The authors would like to thank Will Watkins and Randy Vivian for useful comments
and discussions. This work is dedicated to Professor Robert M Williams, Colorado State
University, Fort Collins, CO on the occasion of his 60th birthday.
Supplementary Material

Supplemental data (spectroscopic data) of selected entries from Table 1 are attached.
References and Notes
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19
The anhydride 5 (100 mg, 1 equiv., 0.39 mmol) is dissolved in THF (6 mL) and cooled to 0 ˚C. To this was
added the Lewis acid (0.42 mmol, 1.1 equiv.) followed by IPA (6 mL). The reaction was allowed to warm up and
stir overnight at room temperature. After the reaction was complete, it was diluted with water and ethyl acetate.
The organic layer was washed with water and saturated NH4Cl before being dried over MgSO4, filtered and

concentrated in vacuo. Silica gel chromatography was the carried out with Hexanes : EtOAc to obtain 6a. (For
entry 9, 112 mg, 91%).

Scheme 1

Scheme 2

Scheme 3