Quinolines from the cyclocondensation of isatoic anhydride with ethyl acetoacetate: Preparation of ethyl 4-hydroxy-2-methylquinoline-3-carboxylate and derivatives

Article abstract of DOI:10.3762/bjoc.14.229

A convenient two-step synthesis of ethyl 4-hydroxy-2-methylquinoline-3-carboxylate derivatives has been developed starting from commercially available 2-aminobenzoic acids. In step 1, the anthranilic acids are smoothly converted to isatoic anhydrides using solid triphosgene in THF. In step 2, the anhydride electrophiles are reacted with the sodium enolate of ethyl acetoacetate, generated from sodium hydroxide, in warm N,N-dimethylacetamide resulting in the formation of substituted quinolines. A degradation–buildup strategy of the ethyl ester at the 3-position allowed for the construction of the α-hydroxyacetic acid residue required for the synthesis of key arylquinolines involved in an HIV integrase project.

Full text of DOI:10.3762/bjoc.14.229

Quinolines from the cyclocondensation of isatoic
anhydride with ethyl acetoacetate: preparation of ethyl
4-hydroxy-2-methylquinoline-3-carboxylate and derivatives
Nicholas G. Jentsch, Jared D. Hume, Emily B. Crull, Samer M. Beauti, Amy H. Pham,
Julie A. Pigza, Jacques J. Kessl and Matthew G. Donahue*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2018, 14, 2529–2536.
Department of Chemistry and Biochemistry, University of Southern
Mississippi, 118 College Drive #5043, Hattiesburg, MS 39406, USA
doi:10.3762/bjoc.14.229
Received: 11 June 2018
Email:
Accepted: 04 September 2018
Published: 28 September 2018
Matthew G. Donahue* - matthew.donahue@usm.edu
* Corresponding author
Associate Editor: I. R. Baxendale
Keywords:
© 2018 Jentsch et al.; licensee Beilstein-Institut.
License and terms: see end of document.
cyclodehydration; HIV integrase; isatoic anhydride; masked acyl
cyanide; quinoline
Abstract
A convenient two-step synthesis of ethyl 4-hydroxy-2-methylquinoline-3-carboxylate derivatives has been developed starting from
commercially available 2-aminobenzoic acids. In step 1, the anthranilic acids are smoothly converted to isatoic anhydrides using
solid triphosgene in THF. In step 2, the anhydride electrophiles are reacted with the sodium enolate of ethyl acetoacetate, generated
from sodium hydroxide, in warm N,N-dimethylacetamide resulting in the formation of substituted quinolines. A degradation–build-
up strategy of the ethyl ester at the 3-position allowed for the construction of the α-hydroxyacetic acid residue required for the syn-
thesis of key arylquinolines involved in an HIV integrase project.
Introduction
In stark contrast to the prevalence of the quinoline heterocycle strand transfer inhibitors (INSTIs) dolutegravir, elvitegravir,
in natural products [1], quinolines are only present in approxi- and raltegravir, arylquinolines 1 and 2 bind to a non-catalytic
mately 2% of FDA approved prescription pharmaceuticals [2]. site of integrase (NCINI) via allosteric binding inhibition.
Recently, 2,3,4-trisubstituted arylquinolines such as BI 224436
1 [3,4] and 2 [5,6] have been shown to exhibit inhibitory activi- Structure–activity relationship studies have indicated that the
ty against HIV-1 integrase that is essential for viral replication 2-methyl and 3-acetic acid residues are crucial to maintaining
through integration of viral DNA into host cell chromatin the potency of this scaffold [10]. The Boehringer Ingelheim
(Figure 1) [7-9]. In contrast to the FDA approved integrase chemical development route toward the synthesis of quinoline 1
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matic substitution; and (3) the aqueous work-up of this method
which does not reliably produce a precipitate that can be filtered
easily.
Figure 1: Investigational non-catalytic HIV-1 Integrase inhibitors.
is shown in Scheme 1 [11]. The northern tricyclic heterocycle at
position 4 is installed by Suzuki coupling with iodide 3a that is
synthesized in three steps from ethyl aryl oxalate 4a. The
α-ketoester side chain at position 3 was installed by selective
halogen-metal exchange of iodide 5a with isopropylmagnesium
chloride lithium chloride complex followed by quenching with
ethyl chlorooxolate furnishing ethyl oxalate 4a in 29–79% yield
[12]. This sequence works well with the unsubstituted benzene
ring of the series a compounds where R = H. However, to
access quinoline 2 with scaffolds such as 4b with halogen sub-
Scheme 2: Quinoline ring condensation strategies.
stitution in the benzene ring at the 5-, 6-, 7- or 8-positions Given the regioselectivity issues and practical challenges asso-
would require a different strategy due to regioselectivity issues ciated with the aniline cyclocondensation (7→8), along with the
encountered in the Grignard acylation step (5b→4b).
scarcity of commercially available highly substituted quino-
lines, we sought to employ an entirely different tactic by
As part of an ongoing research program investigating new utilizing 2H-3,1-benzoxazine-2,4(1H)-dione (isatoic anhydride)
assays toward integrase inhibition, we desired to synthesize chemistry [16,17]. Isatoic anhydrides 9 are readily prepared
quinoline derivatives such as 2 with substitution in the benzene from inexpensive, commercially available 2-aminobenzoic acid
ring of the quinolone [13]. The known synthesis of quinoline derivatives (anthranilic acids) with a variety of carbonyl transfer
core 8 has been published in a one-pot, two-step reaction from reagents such as phosgene, triphosgene, carbonyldiimidazole, or
4-bromoaniline (7) and diethyl acetylsuccinate in 36% yield diethyl carbonate. We therefore employed a modified Coppola
(Scheme 2) [14,15]. However, our attempts to repeat and scale- quinoline synthesis method through the one-pot acylation of
up this procedure beyond a few hundred milligrams were met ethyl acetoacetate with isatoic anhydrides followed by dehydra-
with inconsistent results and variable yields. In our experience, tive intramolecular cyclization to access the desired quinoline
this route is less advantageous due to: (1) the need for a scaffold 10 [18]. We replaced sodium hydride as the base re-
prolonged room temperature condensation reaction time quired to generate the enolate of ethyl acetoacetate with sodium
(>5 days in a desiccator with phosphorus pentoxide) to form the hydroxide [19,20]. The use of sodium hydride is of particular
initial vinylogous amide; (2) the use of expensive diphenyl concern upon reaction scale-up due to limited solubility in
ether, which has a nauseating odor, at 0.01 molar dilution at organic solvents and the production of flammable hydrogen gas
reflux (259 °C) to effect the ring closure via electrophilic aro- [21,22]. Sodium hydroxide avoids the off-gassing of hydrogen
Scheme 1: Boehringer Ingelheim retrosynthesis of quinoline 1.
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and produces water instead, thereby avoiding the use of any 8-positions (9b, 9c, 9f, 9h). The unprotected hydroxy group in
special safety precautions.
9d gave reasonably high yield as did electron-withdrawing nitro
groups in the 6- and 7-positions (9e, 9g).
Results and Discussion
The anhydrides 9a–h were readily accessible by treatment of The substituted isatoic anhydrides from Scheme 3 were then
anthranilic acids AA with one equivalent of triphosgene in subjected to the modified Coppola conditions for the synthesis
refluxing tetrahydrofuran at 0.36 molar concentration of 2-methylquinoline derivatives 10a–h (Scheme 4). Most sig-
(Scheme 3). This procedure is an alternative to the existing nificantly, the investigation found that one equivalent of solid
published protocol that relies on the use of toxic phosgene gas sodium hydroxide in 0.6 molar N,N-dimethylacetamide at
[23] as the acylating agent by replacing it with the non-volatile 100 °C was able to achieve the same result as the Coppola
and weighable solid triphosgene [24,25]. After stirring for protocol (NaH, DMA, 120 °C). While the use of sodium
12 hours, the reaction mixtures were quenched by pouring into hydroxide results in the production of water in the reaction me-
approximately 30 volumes of water (1 volume = 10 mL of dium, we observed no evidence of hydrolysis of the ethyl esters
water per 1 gram of substrate) with subsequent stirring at room even at elevated temperatures. The reaction is operationally
temperature for one hour. The isatoic anhydride products 9a–h robust and can be carried out without rigorous exclusion of
typically precipitate out of solution and are readily collected by moisture or degassing protocols. As with the isatoic anhydride
vacuum filtration. This reverse aqueous quench provides suffi- step, the crude reaction mixtures were poured directly into
ciently pure material without the need for extraction with approximately 30 volumes of water and produced solid materi-
organic solvent or additional purification. The reactions typical- al that was readily collected via vacuum filtration. It should be
ly produced high purity products with some colored impurities noted that addition of water directly to the reaction vessel did
that were removed by slurring the crude filter cake in methanol
followed by vacuum filtration. HPLC analysis of the filtrate
showed minuscule loss of product due to this trituration. The
reaction is tolerant to halide substitution at the 6-, 7-, and
Scheme 4: Substituted 2-methyl-4-hydroxyquinolines from isatoic
Scheme 3: Isatoic anhydrides from anthranilic acids with triphosgene.
anhydrides and ethyl acetoacetate.
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Beilstein J. Org. Chem. 2018, 14, 2529–2536.
not have the same outcome, typically resulting in oiling out of agent. The resulting sodium enolate regioselectively attacks the
the product, and requiring organic solvent extraction. The yields more electrophilic ester carbonyl of the isatoic anhydride
ranged from modest (47%) to excellent (97%) on scales from forming tetrahedral intermediate A. Subsequent collapse of the
1 gram up to 25 gram batches with spectral data matching sp3-hybridized carbon to the ketone B with concomitant
known quinolones [26].
expulsion of carbon dioxide and enolization affords the
ketone C. The anion of the aniline nitrogen then attacks the
A plausible mechanism for the formation of the quinoline is ketone carbonyl via intramolecular 6-exo-trig cyclization
shown in Scheme 5 [27]. After initial formation of the enolate and subsequent proton transfer to the aminal oxygen D. Elimi-
of ethyl acetoacetate with sodium hydroxide, water is generated nation of the 2-hydroxy group from D then affords the
in the reaction mixture, which then serves as a proton transfer 4-quinolone E that tautomerizes via [1,5]-hydride shift to form
quinoline 10.
Given the success of employing ethyl acetoacetate in the quino-
line cyclocondensation reaction (Scheme 4, 9→10), we hypoth-
esized that ethyl acetopyruvate could install the desired ethyl
2-oxoacetate residue at the 3-position as in 11 that is required
for the synthesis of quinolines 1 and 2 (Scheme 6). Whereas
with ethyl acetoacetate as shown in Scheme 5 can only
condense to form quinolines of type 10 via C→D, the ethyl
acetopyruvate has two carbonyls a and b as depicted in 13 that
result in regioisomeric products upon ring closure. The desired
quinoline 11 requires ring closure onto carbonyl b.
To that end, ethyl sodioacetopyruvate was prepared via Claisen
condensation of acetone with diethyl oxalate and sodium
ethoxide in ethanol [28]. Isatoic anhydride 9f was then added to
the solid enolate and both were dissolved in DMA and warmed
to 60 °C for 12 hours. Following the general work-up protocol
as described for Scheme 4, a light tan solid was isolated in
modest yield after trituration with methanol that was deter-
mined to be exclusively compound 12 by NMR. The formation
of either regioisomer 11 (via b) or 12 (via a) results from 6-exo-
trig cyclization of the common nucleophilic acyl substitution
intermediate 13. The 13C NMR data of the product has a singlet
at δ 199 ppm that shows a correlation by HMBC to the singlet
integrating to three protons in the 1H NMR at δ 2.52 ppm. That
same proton singlet in the HMBC only shows one other correla-
tion to a carbon singlet at δ 121.6 ppm. These methyl group
correlations can only be observed in compound 12 as the
Scheme 5: Mechanistic hypothesis for the cyclocondensation reaction.
HMBC experiment detects two and three-bond correlations. In
Scheme 6: Quinoline synthesis with ethyl acetylpyruvate.
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11, correlation of the methyl singlet to the ketone is 4JCH and in-process analysis (TLC and HPLC) indicated quantitative
would not be detected. The α-keto carbonyl group a in com- reduction, the isolated yields from the reductions were only
pound 11 would be expected to have a chemical shift more poor to modest despite utilizing standard workup conditions
upfield than δ 199.3 ppm. Therefore, the product was deter- with sodium potassium tartrate. Subsequent oxidation of the pri-
mined to unequivocally be the undesired quinoline 12.
mary alcohol to the aldehyde 15 was accomplished with the
pyridine sulfur trioxide complex in 52% yield over two-steps
We then turned to a functional group transformation of the ethyl [29].
ester at the 3-position to address the acetic acid sidechain prob-
lem (Scheme 7). First, the 4-hydroxy group in quinoline 10f The carbon atom at the acid oxidation state was installed by ad-
was substituted for chlorine with neat phosphorus oxychloride dition of trimethylsilyl cyanide to the aldehyde 15 in the pres-
to afford chloride 14 in 91% yield. The ethyl ester was then ence of lithium chloride in THF [30]. Initially, the trimethyl-
smoothly reduced with DIBAL to the benzyl alcohol. While the silyl cyanohydrin 16 was subjected to solvolysis in ethanol with
aqueous sulfuric acid. Unfortunately, those conditions resulted
in displacement of the 4-chloro substituent with ethanol giving
the 4-ethyl ether 17 in 35% yield. To circumvent this undesired
substitution at the 4-position, the cyanohydrin 16 was hydro-
lyzed by a two-step process. First, hydrogen chloride in ethanol
(3.3 molar) was used to produce the imidate 18 in quantitative
yield. The structure of 18 was verified by NMR to prove that
the 4-position had not suffered displacement by ethanol. Subse-
quent hydrolysis of 18 with dilute aqueous hydrochloric acid
afforded the desired ethyl ester 19 in 59% yield. Given the three
steps required to convert the aldehyde 15 into the desired
α-hydroxy acetic acid ethyl ester 19, we decided to pursue a
more direct one-carbon homologation procedure.
We envisioned a milder alternative to the acidic conditions re-
quired for cyanide hydrolysis that would provide the side chain
at the correct oxidation in one pot. To that end, we turned to
masked acyl cyanide (MAC) chemistry [31] in which the
reagent 20 acts as an acyl anion via umpolung reactivity [32].
With the aldehyde 15 in hand, homologation involving the addi-
tion of the MAC reagent 20 afforded the TBS protected
α-hydroxyacetic acid ethyl ester 21 in in 76% yield (Scheme 8).
Based on the purported mechanistic reasoning of Nemoto, addi-
tion of the methine anion of 20 to 15 proceeds to the intermedi-
ate alkoxide G that undergoes a [1,4]-shift of the silicon group
Scheme 7: Elaboration of the benzoic acid ethyl ester to the acetic
acid residue.
with concomitant ejection of cyanide anion to form acyl
cyanide H [33]. As the reaction is run in the presence of
Scheme 8: Umpolung addition of ethoxycarbonyl via a MAC strategy.
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Beilstein J. Org. Chem. 2018, 14, 2529–2536.
ethanol, nucleophilic acyl substitution of cyanide H for the transferred to a 250 mL Erlenmeyer flask equipped with cylin-
ethoxy group furnishes the ethyl ester 21 in one pot. We were drical stir bar and 50 mL of methanol was added. The slurry
therefore able to construct the desired benzene substituted was stirred for 10 minutes and then collected by vacuum filtra-
quinoline 21 in six steps from 2-amino-4-bromobenzoic acid in tion. The filter cake was dried under vacuum (0.1 mmHg at
31% overall yield.
25 °C) for 12 hours to afford 9b as a white powder (90% yield).
Physical characteristics of 9b: white powder with 95.4% purity
as determined by quantitative 1H NMR using maleic acid as the
Conclusion
In conclusion, an efficient route for the synthesis of substituted internal standard; mp > 270 °C; IR (solid) cm−1: 3170, 1751;
quinolines 10a–h has been demonstrated from commercially 1H NMR (DMSO-d6, 400 MHz) δ 11.86 (s, 1H, N-H), 7.98 (d,
available anthranilic acids AA (Scheme 4). This strategy J = 2.3 Hz, 1H, Ce-H), 7.88 (dd, J = 8.7, 2.3 Hz, 1H, Cd-H),
achieved the replacement of sodium hydride with sodium 7.19 (d, J = 8.7 Hz, 1H, Cf-H); 13C NMR (DMSO-d6,
hydroxide thereby obviating any special equipment requiring 100 MHz) δ 158.8 (s, Ca), 146.7 (s, Cb), 140.6 (s, Cc), 139.3
the capture or scrubbing of hydrogen gas evolved. The exten- (d, Cd), 130.5 (d, Ce), 117.6 (d, Cf), 114.5 (s, Cg), 112.4 (s,
sion of the 3-position ethyl ester into the α-tert-butoxy acetic Ch); HRMS (ESI): calcd for [C8H4BrNO3 + Na]+ 263.926677;
acid residue was also demonstrated via a cyanohydrin-hydroly- found: 263.926475; anal. calcd for C8H4BrNO3: C, 50.34; H,
sis route (10f→19) and an umpolung acyl addition strategy 3.90; found: C, 49.98; H, 3.80.
(10f→21). The development of a library of quinoline scaffolds
is currently underway within our lab utilizing this synthetic General procedure for quinoline synthesis
process [34,35].
Experimental
General procedure for isatoic anhydride
synthesis
Ethyl 6-bromo-4-hydroxy-2-methyl-3-carboxylate (10b). To
a 250 mL single-necked round bottom flask equipped with foot-
ball-shaped PTFE stir bar (16 mm × 37 mm) was added isatoic
anhydride 9b (10.85 g, 44.8 mmol, 1.0 equiv), ethyl aceto-
acetate (11.3 mL, 89.7 mmol, 2.0 equiv), and N,N-dimethylacet-
6-Bromo-2H-benzo[d][1,3]oxazine-2,4(1H)-dione (9b). A amide (75 mL, 0.6 molar) resulting in a clear yellow solution.
500 mL single neck round-bottomed flask equipped with a foot- To the reaction solution was then added solid sodium hydrox-
ball-shaped PTFE stirring bar (16 mm × 37 mm) was charged ide (1.79 g, 44.8 mmol, 1.0 equiv) that dissolved over time. The
with 2-amino-5-bromobenzoic acid (10.0 g, 46.3 mmol, reaction vessel was placed in a fitted metal heating mantle and
1.0 equiv) followed by the addition of tetrahydrofuran (230 mL, heated at 100 °C for 12 hours. The reaction solution was cooled
0.2 molar) and solid triphosgene (13.7 g, 46.3 mmol, 1.0 equiv) to room temperature (25 °C) and poured into a 500 mL beaker
resulting in a suspension. The reaction vessel was placed into a equipped with cylindrical PTFE stir bar (16 mm × 37 mm) con-
fitted metal heating mantle and the neck was equipped with a taining 250 mL of deionized water causing a beige solid to pre-
24/40 Liebig condenser. The suspension was stirred (500 rpm) cipitate out of solution. The solid was collected on a Büchner
and the heating mantle set to 70 °C. The suspension became funnel (7.6 cm diameter) with Whatman #1 filter paper (70 mm)
homogenous before a white solid precipitated out after about and air dried by pulling a vacuum through for 10 minutes. The
30 minutes at 70 °C. The heterogeneous reaction mixture was material was further dried in a vacuum oven (0.1 mmHg at
aged for 12 hours then cooled to room temperature (25 °C). The 25 °C) for 24 hours to afford 11.1g of 10b as a white powder
slurry was poured into a 600 mL beaker equipped with over- (80% yield). Physical and spectroscopic characteristics of 10b:
head mechanical stirrer (PTFE 75 mm paddle) containing white powder with 97.9% purity as determined by quantitative
250 mL of deionized water. With vigorous stirring, the mixture 1H NMR using maleic acid as the internal standard;
became homogenous followed by precipitation of a pale white mp 270–272 °C; IR (solid) cm−1 1705; 1H NMR (DMSO-d6,
solid. The solid was collected by vacuum filtration on a 400 MHz) δ 12.03 (s, 1H, O-H), 8.13 (d, J = 2.3 Hz, 1H, Cf-H),
Büchner funnel (7.6 cm diameter) with Whatman #1 filter paper 7.82 (dd, J = 8.8, 2.4 Hz, 1H, Ce-H), 7.51 (d, J = 8.8 Hz, 1H,
(70 mm) and air pulled through for 5 minutes. The material was Ch-H), 4.24 (q, J = 7.1 Hz, 2H, Ck-H), 2.39 (s, 3H, Cl-H), 1.27
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Beilstein J. Org. Chem. 2018, 14, 2529–2536.
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(t, J = 7.1 Hz, 1H, Cm-H); 13C NMR (DMSO-d6, 100 MHz)
δ 172.0 (s, Ca), 166.4 (s, Cb), 149.4 (s, Cc), 138.0 (s, Cd),
134.9 (d, Ce), 127.1 (d, Cf), 126.0 (s, Cg), 120.6 (d, Ch), 116.3
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Supporting Information
Supporting Information File 1
Experimental procedures and analytical data.
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-14-229-S1.pdf]
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[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-14-229-S2.pdf]
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JK thanks the National Institute of Allergy and Infectious
Disease for AI127282. Funding for the Bruker UltraShield Plus
400 MHz NMR and ThermoFinnigan LXQ ESI LC–MS used in
this research was provided by National Science Foundation
Major Research Instrumentation under Grant Numbers 0840390
and 0639208, respectively. NGJ, JDH, and EBC thank the USM
INTERFACE National Science Foundation National Research
Trainee under Grant Number 1449999. We thank the Univer-
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MGD is a 2015 and 2018 recipient of the Lucas Award for
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ORCID® iDs
Nicholas G. Jentsch - https://orcid.org/0000-0001-8264-9222
Jared D. Hume - https://orcid.org/0000-0002-0214-3190
Emily B. Crull - https://orcid.org/0000-0003-3839-7579
Samer M. Beauti - https://orcid.org/0000-0003-0844-7686
Amy H. Pham - https://orcid.org/0000-0002-0969-6679
Julie A. Pigza - https://orcid.org/0000-0002-1289-5679
Jacques J. Kessl - https://orcid.org/0000-0001-8103-6678
Matthew G. Donahue - https://orcid.org/0000-0002-2608-1529
14.Chattha, F. A.; Munawar, M. A.; Ashraf, M.; Nagra, S. A.;
Mehr-Un-Nisa; Fatima, I. J. Chil. Chem. Soc. 2012, 57, 1237–1239.
doi:10.4067/S0717-97072012000300008
15.Avetisyan, A. A.; Aleksanyana, I. L.; Pivazyan, A. A.
Russ. J. Org. Chem. 2004, 40, 889–891.
doi:10.1023/B:RUJO.0000044555.03402.9b
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Heterocyclic Synthesis in Advances in Heterocyclic Chemistry;
Academic Press, 1981; Vol. 28, pp 127–182.
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